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September/October 2011 Volume 2 ▼ Number 5 http://magazine.embs.org

A MAGAZINE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY

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THE WORLD’S NEWSSTAND®

Can a simple blood test detect cancer before it’s cancer?

Find the latest biotechnology research in IEEE Xplore Wherever you find people developing the most advanced biotechnology, chances are you’ll find them using the IEEE Xplore digital library. That’s because IEEE Xplore is filled with the latest research on everything from DNA sequencing and tissue engineering—to moving one step closer to predicting cancer with a simple blood test. When it comes to biotechnology, the research that matters is in IEEE Xplore. See for yourself. Read “Genomic Processing for Cancer Classification and Prediction,” only in IEEE Xplore.

Try IEEE Xplore free— visit www.ieee.org/detectingcancer

IEEE Xplore® Digital Library Information driving innovation

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SEPTEMBER/OCTOBER 2011 Volume 2 ▼ Number 5 http://magazine.embs.org

A MAGAZINE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY

FEATURES

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Studying BME in the United Kingdom

19

A View from the Outside In

by Nadya Anscombe pg.

28

by Leslie Mertz

25 28

Image-Guided Therapies by Dieter Haemmerich, Matthew R. Dreher, Dorin Panescu, and Heinz-Otto Peitgen

Thermal Tumor Ablation in Clinical Use by Chris Brace

39

MRI-Controlled Ultrasound Thermal Therapy by Robert Staruch, Rajiv Chopra, and Kullervo Hynynen

48

Planning of Image-Guided Interventions in the Liver by Andrea Schenk, Dieter Haemmerich, and Tobias Preusser

56

© BRAND X PICTURES

Contrast Echocardiography for Cardiac Radio-Frequency Ablation

COVER IMAGES: ©BRAND X PICTURES, PHOTODISC

by Dirar S. Khoury, Liyun Rao, and Dorin Panescu

COLUMNS & DEPARTMENTS 3 5 6 8 10

pg. 80

FROM THE EDITOR PRESIDENT’S MESSAGE GOLD STUDENT’S CORNER PERSPECTIVES ON GRADUATE LIFE

66 68 72 84 86

PATENTS SENIOR DESIGN RETROSPECTROSCOPE OPINION CALENDER

IMAGE COURTESY OF NATIONAL LIBRARY OF FRANCE

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EDITOR-IN-CHIEF Michael R. Neuman Michigan Technological University Houghton, Michigan, USA

DEPUTY EDITOR-IN-CHIEF Silvestro Micera Scuola Superiore Sant’Anna Pisa, Italy

ASSOCIATE EDITOR Cynthia Weber Michigan Technological University Houghton, Michigan, USA

EDITORIAL BOARD Shanbao Tong Shanghai Jiao Tong University Shanghai, China Stuart Meldrum Retired from Norfolk and Norwich Health Care NHS Trust Norwich, UK Semahat Demir National Science Foundation Washington, D.C., USA Samuel K. Moore IEEE Spectrum New York, New York, USA Yongmin Kim University of Washington Seattle, Washington, USA

Patricia J. Soterin Communications Michigan Technological University Houghton, Michigan, USA Ann Brady Director Program in Scientific and Technical Communication Michigan Technological University Houghton, Michigan, USA

CONTRIBUTING EDITORS A Look At

Jean-Louis Coatrieux University of Rennes France Book Reviews

Paul King Vanderbilt University Nashville, Tennessee, USA Emerging Technologies

Dorin Panescu St. Jude Medical St. Paul, Minnesota, USA Government Affairs

Luis Kun National Defense University Washington, D.C., USA International News

John G. Webster University of Wisconsin, Madison, Wisconsin, USA

Patents

Maurice M. Klee Fairfield, Connecticut, USA Point of View

Gail Baura Keck Graduate Institute Claremont, California, USA

IEEE PERIODICALS MAGAZINES DEPARTMENT MANAGING EDITOR Debby Nowicki

Retrospectroscope

SENIOR ART DIRECTOR

Max Valentinuzzi Universidad Nacional de Tucumán and Universidad de Buenos Aires Argentina

Janet Dudar

ASSISTANT ART DIRECTOR Gail A. Schnitzer

Senior Design

Jay R. Goldberg Marquette University Milwaukee, Wisconsin, USA

PRODUCTION COORDINATOR Theresa L. Smith

Student’s Corner

Renfei (Iris) Yan Pennsylvania State University, University Park, Pennsylvania, USA Student Activities

Lisa Lazareck City University London, UK GOLD

Matthias Reumann IBM Research Carlton, VIC, Australia

BUSINESS DEVELOPMENT MANAGER Susan Schneiderman +1 732 562 3946 [email protected] ____________ Fax: +1 732 981 1855

ADVERTISING PRODUCTION MANAGER Felicia Spagnoli

PRODUCTION DIRECTOR Peter M. Tuohy

EDITORIAL DIRECTOR Dawn Melley

STAFF DIRECTOR, PUBLISHING OPERATIONS Editorial Correspondence: Address to Michael R. Neuman, Department of Biomedical Engineering, Michigan Technical University, 1400 Townsend Dr. Houghton, MI 49931-1295, USA. Voice: +1 906 487 1949. E-mail: __________ [email protected]. Indexed in: Current Contents (Clinical Practice), Engineering Index (Bioengineering Abstracts), Inspec, Excerpta Medica, Index Medicus, MEDLINE, RECAL Information Services, and listed in Citation Index. All materials in this publication represent the views of the authors only and not those of the EMBS or IEEE.

MISSION STATEMENT The Engineering in Medicine and Biology Society of the IEEE advances the application of engineering sciences and technology to medicine and biology, promotes the profession, and provides global leadership for the benefit of its members and humanity by disseminating knowledge, setting standards, fostering professional development, and recognizing excellence.

Fran Zappulla

IEEE prohibits discrimination, harassment, and bullying. For more information, visit http://www.ieee.org/web/aboutus/whatis/ policies/p9-26.html. ________

IEEE Pulse (ISSN 2154-2287) (IPEUD6) is published bimonthly by The Institute of Electrical and Electronics Engineers, Inc., IEEE Headquarters: 3 Park Ave., 17th Floor, New York, NY 10016-5997. NY Telephone +1 212 419 7900. IEEE Service Center (for orders, subscriptions, address changes, Educational Activities, Region/Section/Student Services): 445 Hoes Lane, Piscataway, NJ 08854. NJ Telephone: +1 732 981 0060. Price/Publication Information: Individual copies: IEEE Members $20.00 (first copy only), nonmembers $88.00 per copy. Subscriptions: $5.00 per year (included in Society fee) for each member of the IEEE Engineering in Medicine and Biology Society. Nonmember subscription prices available on request. Copyright and Reprint Permissions: Abstracting is permitted with credit to the source. Libraries are permitted to photocopy beyond the limits of U.S. Copyright Law for private use of patrons: 1) those post-1977 articles that carry a code at the bottom of the first page, provided the per-copy fee indicated in the code is paid through the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA; 2) pre-1978 articles without fee. For all other copying, reprint, or republication information, write to: Copyrights and Permission Department, IEEE Publishing Services, 445 Hoes Lane, Piscataway, NJ 08854 USA. Copyright © 2011 by the Institute of Electrical and Electronics Engineers, Inc. All rights reserved. Printed in U.S.A. Periodicals postage paid at New York, NY and at additional mailing offices. Postmaster: Send address changes to IEEE Pulse, IEEE, 445 Hoes Lane, Piscataway, NJ 08854 USA. Canadian GST #125634188 PRINTED IN USA


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FROM THE EDITOR

Playing the Rating Game Michael R. Neuman

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t seems as though much of our activities these days are associated with some type of rating. Football teams are evaluated in an effort to predict their outcome at the end of the season. Recorded music is evaluated based on sales. Universities are rated as to the quality of their education and research. Scientific journals are rated by the score that is familiar to all of us: the impact factor. All of these rating scores and lists of organizations, events, and products from best to worst, or as we in academia referred to, by percentile score, are supposed to help us make choices. Which football team should we support, which song do we want to hear, which university should we or our children attend, or which journals should we send our manuscripts to? In many cases, these ratings are helpful, but in other situations, they may represent an effort to quantify the unquantifiable. Although there are many factors that can help us evaluate a football team and determine whether they will be World Cup champions, frequently the predictions of sports pundits are not fulfilled in practice. Similarly, the music that sells the most recordings or downloads may not turn out to be the best artistically but only the most popular; this music may not be what one prefers to listen to personally. Likewise, universities with the highest rating may not be the best for a particular area of study and may not be as outstanding when one takes into consideration location, cost, quality of instruction, or opportunities to move on for advanced study. Journals with high impact factors may contain frequently cited

Digital Object Identifier 10.1109/MPUL.2011.942595 Date of publication: 11 October 2011

papers, but these may not necessarily be the best journals in which to publish in a specific area. I make this argument because lately I’m hearing a lot about organizations concerned with how to improve their ratings. I think this is most notable in educational institutions and scientific publishing. Every university I have visited in recent years, including my own, wants to improve their rating. This seems to me to be a reasonable goal since increasing the rating means improving the quality of the activities at that university. Nevertheless, having a goal of just being better based on an improved rating score may miss the point. An institution ranked in the top 50 of academic institutions that wants to improve their status to be in the top 25 needs to realize that to do this another institution in the top 25 will need to be displaced. It may be difficult to find an institution willing to give up this position. Perhaps a better approach would be to choose some areas where the quality of the university’s work could be improved, allowing that institution to become more widely recognized for its excellence in that field whether it results in an improvement in rating or not. One could make a similar argument for scientific publishing. All of us in the field would like to see our publications show improvement in impact factor. I remember several years ago when I was interviewed for the editor-in-chief position for a biomedical engineering-related journal, I was asked what I would do to improve the impact factor of that journal. I told the panel of scientists interviewing me that that was an easy question; I would just publish something that included incorrect science. There was what

seemed to be an uncomfortably long period of silence following my answer, but then one of the panel members began to laugh, followed by everyone else. It was not my intention to publish a paper with incorrect science, but the way the impact factor is calculated is based on the number of citations a particular paper might have. This suggests that if you publish something that is wrong, several other authors will attempt to set the record straight and, in the process, cite the paper with incorrect science. Thus, we see that there can be a flaw in the measurement system. Not only that, but some publishers or universities can purposely exploit the measurement system to improve their scores for marketing purposes as opposed to really improving their quality. I receive e-mails from scientific journal publishers pointing out a new important paper that they have recently published and offering it as a free download. Initially I thought, “How nice. They are sharing their material with those of us who could not afford to subscribe to the journal.” Upon later reflection, I thought maybe they had more sinister intentions in this act of generosity. Perhaps, by making this paper more widely available, they are hoping that more people will read it and that it will receive more citations in the reader’s own work that will result in improving the journal’s impact factor. Currently, I’m getting too cynical about these ratings, but I am concerned that the rating scores are moving beyond their original intention. We need to have ways to describe the quality of things ranging from football teams to scientific journals. It is easy to base the quality of a sports team on the percentage of games they win, but who were they playing? Were these easy wins or were they overcoming major challenges? How predictive is the percentage of wins in the past on future competition success? Similarly, it is easy with today’s computational systems to be able to count the number of citations for a particular journal article and to use that as a measure of the journal’s impact. SEPTEMBER/OCTOBER 2011

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encouraged to publish in Indeed, the impact factor a top-tier journal may not will tell us how many of Our goals should get his or her report into the journal’s papers were always be to improve the hands of colleagues cited by other publicathe quality of what we who could best apprecitions, and this in itself is do, whether we are ate what was done. There an interesting measure; a football team or a might be a journal that but does it really indicate scientific publication. is not in the top tier that the overall impact that the is preferred and read by journal has on the scieneveryone working in the tific field? A paper may field of impedance tomography. Such a be so innovative and revolutionary that periodical would be more appropriate for it will change its scientific field, but this publishing these results than a top-tier change may not become evident for sevjournal. This publication would be more eral years and may not show up quickly likely to disseminate the information to in terms of impact factor. those who could fully appreciate it and Last week, I visited a major university recognize the quality of the institution and was told that the goal of the univerfrom which it came. Thus, setting specific sity was to ascend to the list of the 100 top rules to improve rating scores may, in universities worldwide. One of its ways fact, defeat the primary goal: to improve of doing this was to encourage its facthe quality of the institution. ulty to only publish in scientific journals I hope that you, the reader, can apthat were rated in the top quartile with preciate what I’m trying to say. Our goals regard to impact factor. This, again, is a should always be to improve the quality noble goal, but it also has flaws. A faculty of what we do, whether we are a footmember at this university who works in ball team or a scientific publication. We a specific area, for example, electrical imas engineers prefer to do this by trying to pedance tomographic imaging, by being

quantify measures that can then be rank ordered to give a percentile score because we are comfortable working with numbers. However, we must consider whether such numeric scores are appropriate for the problem. Although quantifying various factors may help to assess the quality of an organization, we may be adding unnecessary constraints that can be counterproductive and perhaps even oppose the original goal. I like to think of quality as being more difficult to assess. I remember the famous quote from the U.S. Supreme Court Justice Potter Stewart who, in writing on a case involving pornography, stated that although he couldn’t define it, “I know it when I see it.” We know outstanding football teams when we see them, outstanding songs when we hear them, and which universities and publications are the best in our particular fields whether we try to quantify them or not. Impact factors and rating scores may help us in this evaluation, but in my opinion, they should never be the ends themselves.

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PRESIDENT’S MESSAGE

in Biomedicine (ITAB)” and enrich EMBS’ STC portfolio by providing a high-quality meeting in the area of great importance to EMBS. The first meeting of this STC series will be held in Hong Kong/Shenzhen, 5–7 January 2012, focusing on the theme “Global Grand Challenge on Health Informatics.” It will provide a platform to have a systematic discussion of enabling technologies for the acquisition, storage, retrieval, devices and systems that optimize display, and use of information in the acquisition, transmission, prohealth and biomedicine, including cessing, storage, and retrieval of biohealth-care informatics applications medical and health information as such as clinical decision support. well as to report clinical studies on The organizing committee includes the novel application of health inDr. Nicolas Chbat (conference chair), formation systems. By strategically Dr. Mark Evans (program cochair), placing this meeting in Hong Kong/ and Dr. Seong K. Mun (program coShenzhen, the EMBS will also use chair), who are recognized experts the platform to organize in the field. For more various membership serinformation about the Our conferences vice activities, includmeeting, please visit have been greatly ing an editors’ forum the conference Web and a regional Chapter site: http://ama-ieee. successful, and I hope ______ chairs meeting, to betembs.org/. we can count on your ter serve our members ▼ EM BS International continued support. and the biomedical enConference on Biomedigineering community in cal and Health Inforthe region. The meeting is being ormatics: After significant discusganized under the leadership of Dr. sions by the conference committee Yuan-Ting Zhang, who is the editorwithin the last couple of years, the in-chief of IEEE Transactions on InforEMBS Administrative Committee mation Technology in Biomedicine. For (AdCom), upon the recommendamore information about the meeting, tion of the conference commitplease visit the conference Web site: tee, approved a motion during the http://bhi2012.embs.org/. spring AdCom meeting in San Diego, Conferences are the core activities 8–10 April 2011, to launch a new speof EMBS. We have enjoyed great succial topic conference (STC) titled “Incess of our conference activities thanks ternational Conferences on Biomedito the hard work of our dedicated volcal and Health Informatics.” This unteers and your enthusiastic participanew STC will build on the success tion. I hope that we can count on your and experience of a previous meetcontinued strong support of our confering held ten times with the title “Inence activities, and I look forward to ternational Conference on Informaseeing you at those meetings. tion Technology and Applications

More Exciting Conferences . . . Zhi-Pei Liang, EMBS President, 2011–2012 [email protected] ____________

T

he 33rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBS) has come to a successful end in Boston, and I’d like to use this column to bring your attention to two upcoming, exciting conferences sponsored by the EMBS. ▼ AMA-IEEE Medical Technology Conference: To better serve the biomedical community, especially the medical community and the medical technology industry, EMBS and the American Medical Association (AMA) have entered into a strategic partnership to offer a new medical technology conference. The First AMA-IEEE Medical Technology Conference was successfully held in Washington, DC, 21–23 March 2011, with the theme “Individualized Health Care.” The conference attracted about 150 participants from around the world. Building on this success, the Second AMA-IEEE Medical Technology Conference will be held in Boston, 16–18 October 2011. This conference will be devoted to health care IT, a technical area in which EMBS has considerable strengths. The conference will provide a unique platform to discuss resources, devices, and methods required to optimize Digital Object Identifier 10.1109/MPUL.2011.942596 Date of publication: 11 October 2011


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NEURO ENGINEERING

GOLD

some of the most significant and changing transitions in your life: you start your first serious job. You might marry and even have children. And yes, you are likely to move at least once to wherever your job will take you. Each of these transitions are challenging in their own right. That is what I was experiencing exactly a year ago. I had a transition period, organizing a move halfway from Germany to the United States, it around the world, finishing the old was not just me moving, but also my job, starting the new job, and having wife. A container and a shipping coma baby. All these activities can take a pany had to do the work. You actually lot of attention away from the work do feel homeless at times before your you are committed to, belongings arrive in the and they can also crenew place. So this time, ate stress in your private I thought I was more Wherever you go, life. But professionally, clever. The move from you will find someone you do not need to feel United States to Austrain EMBS who will lost. The great thing is lia required the help of offer his or her help. that the IEEE Engineera shipping company once ing in Medicine and Biagain. It is pretty sweet if ology Society (EMBS) your contract has an alis like a family. Everyone offered suplowance for it so that you need not pay. port after I made contact with the local If not, you will need US$15,000–20,000 people in Melbourne. No one can be as for a small container to ship by air. That useful as the people in the place where is an out-of-pocket expense that you you are moving to. Persons in our Soreally do not want to have. In my air ciety always know someone who can shipment, I carried some personal behelp, which makes the transition much longings such as some important toys I easier. Wherever you go, you will find used to have in my office and my favorsomeone in EMBS who will offer you ite coffee mug. It so happened that the his or her help. You will not be alone. shipment arrived before my arrival in While this might sound cheesy, it is a Melbourne. So on day one, I had the great comfort when you do actually pleasure of having my coffee from my move. You do not have to take advanown mug, and the transition seemed so tage of the help, but it is there if you much easier. need it. The IEEE thrives on offering While this story sounds funny, it is its Members a professional home. In important to feel at home during pemy experience, EMBS is truly a profesriods of transition. In the decade after sional home in the truest sense. your graduation, you will likely have

EMBS Is a Professional Home in Times of Transition Matthias Reumann

I

had moved to Melbourne, Australia, from New York about a year ago. It was during this transition that I realized that we graduates of the last decade (GOLDies) face the most transitions in our lives. My friends used to make fun of me that I had moved house and country about 12 times in maybe five years during my undergraduate degree. But that was not all too difficult. I just had to pack a suitcase and backpack and off I went. Now, a move is a more difficult operation. Three years ago when I moved


CALL FOR BOOK REVIEWS Have you read a good book lately? Are you willing to share your thoughts? IEEE Pulse encourages readers to join the conversation by writing reviews on recent publications in the field. For more information, please contact the Contributing Editor Paul King at _________ paul.h.king@ vanderbilt.edu. _________ Digital Object Identifier 10.1109/MPUL.2011.943072

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________________________

IEEE BioRob 2012 IEEE International Conference on Biomedical Robotics and Biomechatronics June 24-28, 2012 Roma, Italy Sponsored by IEEE Robotics and Automation Society & IEEE Engineering in Medicine and Biology Society

Call for Papers

GENERAL CHAIR Eugenio Guglielmelli Università Campus Bio-Medico di Roma, Italy

PROGRAM CO-CHAIRS Nicolas Garcia Aracil Universidad Miguel Hernandez, Spain

Hermano Igo Krebs Massachusetts Institute of Technology, USA

ADVISORY COMMITTEE George Bekey University of Southern California, USA

Alain Berthoz College de France, France

The fourth IEEE RAS/EMBS International Conference on Biomedical Robotics and Biomechatronics - BioRob 2012 - is a joint effort of the two IEEE Societies of Robotics and Automation - RAS - and Engineering in Medicine and Biology - EMBS. BioRob covers both theoretical and experimental challenges posed by the application of robotics and mechatronics in medicine and biology. The primary focus of Biorobotics is to analyze biological systems from a "biomechatronic" point of view, trying to understand the scientific and engineering principles underlying their extraordinary performance. Biorobotic systems can also be used as powerful experimental platforms for investigations in the biological domain, e.g. for basic research in neuroscience. This profound understanding of how biological systems work, behave and interact can be used for two main objectives: to guide the design and fabrication of novel, high performance bio-inspired machines and systems, for many different applications; and to develop novel nano, micro-, macro- devices that can act upon, substitute parts of, and assist human beings in prevention, diagnosis, surgery, prosthetics, rehabilitation and personal assistance. BioRob is a highly interdisciplinary conference that brings together scientists and engineers from different backgrounds to share and learn about research activities in this fast growing field. The IEEE RAS and EMBS share this vision and thus jointly sponsor this conference. The technical program of IEEE BioRob2012 will consist of invited talks, special sessions, posters, and paper presentations. Submitted papers must describe original work, in the form of modeling abstractions, algorithms, theoretical analysis, case studies, and experiments. Papers can cover areas of Biorobotics and Biomechatronics including:

Emilio Bizzi

• Technology for assisted surgery and diagnosis • Rehabilitation and assistive robotics • Micro/nano technologies in medicine and biology • Prosthetic devices • Wearable assistive and augmenting devices • Biological systems modeling

Massachusetts Institute of Technology, USA

Paolo Dario Scuola Superiore Sant'Anna, Italy

Blake Hannaford University of Washington, USA

Koji Ikuta Nagoya University, Japan

Rolf Johansson Lund University, Sweden

Oussama Khatib Stanford University, USA

Deirdre Meldrum Arizona State University, USA

Mamoru Mitsuishi The University of Tokyo, Japan

Yoshihiko Nakamura The University of Tokyo, Japan

Atsuo Takanishi

• • • •

Biologically inspired systems Biomechatronic and human-centred design Human-machine interaction Locomotion and manipulation in robots and biological systems • Neuro-robotics • Technology Assessment, Ethical and Social Implications of Biorobotics and Biomechatronics

Papers Submission: Author(s) should submit full papers electronically in double column IEEE compliant PDF format. All papers will be peer-reviewed. Accepted papers will have a choice for oral and/or poster presentations, and will be published in CD-ROM. Posters will be displayed throughout the conference and Poster Sessions will be scheduled for author/audience interaction. Six pages are allowed per paper, and detailed instructions for paper preparation and submission will be available on the conference web site: www.biorob2012.org

Waseda University, Japan

Venue: The venue for the conference is downtown Rome, one of the most beautiful cities in the world where art meets with history and progress. Rome is easily accessible from all over Johns Hopkins University, USA the world by two International airports (Leonardo da Vinci – Fiumicino and Ciampino), highspeed railway and highway. IMPORTANT DATES! January 15, 2012 March 31, 2012 April 30, 2012 Submission of full papers Paper acceptance notification Final paper submission Special sessions and workshop proposals

Russell Taylor


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STUDENT’S CORNER

How to Write a Research Grant Proposal Renfei (Iris) Yan

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riting a good research grant proposal is never an easy task. The first and most obvious thing to do is to read the advice offered by the funding agency. For this column, I will use the case of the National Institutes of Health (NIH) as an example and guide you through the writing of a research grant proposal. Before starting, there are several vital facts to bear in mind. ▼ Your proposal will not only be read by experts in your field but also by several judges who won’t be experts. You must write your proposal for their benefit also. ▼ Remember that reviewers see tens or hundreds of applications for support, so you have only a minute or less to grab your reader’s attention. ▼ What’s more important than innovation is that your results should have compelling significance. Writing a grant application is a major undertaking. Advice from experienced NIH staff to help you succeed is listed below.

What Do the Reviewers Want Most NIH grant applications are reviewed internally and by an external panel made up of experts in the field of the application. There are five criteria scores that are determined by the external reviewers: significance, investigators, innovation, approach, and environment. The principal reviewers of the application give a score for each of these criteria, and they and the entire review Digital Object Identifier 10.1109/MPUL.2011.942598 Date of publication: 11 October 2011

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Research Plan Development A top-quality research plan is the most important factor determining your application’s success in peer review. As with a scientific publication, developing your ideas is the key. Here are some general tips: ▼ Your application should be based on a strong hypothesis. ▼ Be sure your project has a coherent direction. ▼ Keep the sections of the plan well coordinated and clearly related to the focus. ▼ Don’t be overly ambitious— your plan should be based on a feasible timetable. ▼ Specific aims and experiments should relate directly to the hypothesis to be tested.

panel score the overall impact that the research will have on the biomedical field if it is successful. This all-inclusive score does not have to be an average of the five criteria scores, although there is usually some relationship to them. There are several components in a strong grant application. First, the subject must be creative, exciting, and worthy of funding. Then, the project must Budget be developed through a rigorous, wellThe five criteria scores and the overall defined experimental plan. Finally, you impact are based strictly on the science must make sure that the information and not the budget. Once the commitis presented in clear language and that tee has determined the scores, they will your application follows the rules and review the budget and advise the NIH if guidelines detailed in the grant applicathey think it is appropriate or needs retion kit. vision. Thus, the budget has no effect on Read through your case for support rethe overall impact score, but the commitpeatedly and ask whether the answers to tee’s comments on the budget may affect the questions below are clearly answered. the amount of funding that the applicant receives if her/his applica▼ How high are the intion is recommended for tellectual quality and funding. merit of the study? Writing a grant The reviewers try to ▼ What is its potential application is a major ensure that the grant is to impact? undertaking. be used in a cost-effective ▼ How novel is the promanner. If the proposal is posal? If not novel, to too expensive for the probable gain, you what extent does potential impact overmight want to cut the request for people/ come this lack? Is the research likely to equipment/travel to something more reaproduce new data and concepts or consonable. Or if it looks like your proposal firm the existing hypotheses? might be done by a Ph.D. student on a ▼ Is the hypothesis valid, and have you computer, then it may also be rejected. presented evidence supporting it? Research agencies will usually fund re▼ Are the aims logical? search that requires resources beyond the ▼ Are the procedures appropriate, adproposers’ current ability. equate, and feasible for the research? ▼ Are the investigators qualified? Have ▼ Reviewers evaluate a requested budthey shown competence, credentials, get to see if it is realistic and justiand experience? fied by the aims and methods of the project. Complete the budget section ▼ Are the facilities adequate and the after you have written your research environment conducive to the replan and have a good idea of costs. search?




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▼ Request only enough money to do

the work. Significant over- or underestimating suggests that you may not understand the scope of the proposed work. Avoid requesting expensive equipment unless you absolutely need it and justify it well. Don’t request funds for equipment already listed in the resources section unless you can provide an adequate explanation. Reviewers look for any discrepancies and will delete funds for equipment that should be available to you.

Common Problems With regard to the five review criteria, there are few common mistakes when writing the applications: ▼ Significance ■ not significant nor exciting or new research ■ lack of compelling rationale ■ incremental and low-impact research

▼ Specific Aims

▼ Environment

too ambitious, too much work proposed ■ unfocused aims, unclear goals ■ limited aims and uncertain future directions ▼ Experimental Approach ■ inappropriate level of experimental detail ■ feasibility of each aim not shown ■ little or no expertise with approach ■ not directly testing hypothesis ■ experiments not directed toward mechanisms ■ no discussion of alternative models or hypotheses ■ no discussion of potential pitfalls ▼ Investigator ■ no demonstration of expertise or publications in approaches ■ low productivity, few recent papers ■ no collaborators recruited or no letters from collaborators

inadequate institutional support. Finally, after sending out your proposal, make a call to the grant agency to make sure they received it. During the review period, if you have major new results or success, send a letter and let them know. Be patient, the review process can be quite time consuming.

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Renfei (Iris) Yan is currently studying at Pennsylvania State University.

References [1] National Institute of Neurological Disorder and Stroke, NIH. How to write a research project grant application. [Online]. Available: http://grants.nih.gov/grants/ about_grants.htm __________ [2] National Institute of Health. Grant process. [Online]. Available: http://grants. nih.gov/grants/about_grants.htm

Innovation doesn’t just happen. Read first-person accounts of IEEE members who were there.

IEEE Global History Network

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PERSPECTIVES ON GRADUATE LIFE

NEURO ENGINEERING

Summertime and the Research Is Easy Zen Liu

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ummertime in a research laboratory is a wonderful experience. The ebb and flow of research activity abides by no schedule, least of all an academic calendar, and yet there is a pervasive undertone of contentedness and ease in the summer that replaces the more frenetic forward tilt of the school year. For a student like me, fresh from his or her first year of graduate school, summer is a relief of coursework-free time practically begging to be overwhelmed with experiments and relevant literature. Anything seems possible. In fact, these may be the months during which Nobel prize-winning work is dreamed up and carried out. The summertime is a perfect opportunity to fully immerse oneself in the laboratory culture and organize or take part in social events. The bonds of camaraderie are solidified as laboratory members have more time to spend with each other, both during the workday and outside of it. With strengthened social and professional relationships, the atmosphere of scientific exchange is charged with new found energy. The laboratory is truly beginning to feel like home. A surprisingly pleasant symptom of summer is the inevitable influx of undergraduates on fellowship and high school volunteers into the laboratory. I myself fell in love with research because of the wonderful experiences I had as an undergraduate, working with some truly inspirational mentors who made me feel that I could be successful building a career in


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when it comes to standard procedures and techniques. Careful supervision is obviously necessary but is quite understandably intimidating at times and may be construed as distrust or criticism. I think back to my first few weeks in a research laboratory, and how fearfully I hung onto every word out of my mentor’s mouth, and I become immediately empathetic and a gentler teacher. innovation and discovery. So many of my All in all, it seems that successful colleagues today cite similar motivations mentorship and training requires a balfor becoming scientists as well, and for ance between firm guidance and relinthat reason, I have always admired the quishing control. Indeed, as much as apprenticeship and teaching traditions I may trust a student and for as many that are the foundation of times as I have seen that research. Now, for the first students execute a prototime, I am responsible for col perfectly, the controlThe summertime is a students that are inexperiling and exacting part perfect opportunity to enced and impressionable, of me finds it incredibly fully immerse oneself and I find myself restless difficult to walk away in the laboratory with excitement over the and officially pass off reculture and organize opportunity to imbue sponsibilities from my them with passion and the own projects to others. or take part in reckless enthusiasm that I At these moments, I try social events. have for my field. to take a step back and Mentoring and trainremember that someing a student is extremely challenging one had to take a chance on me too. I in more ways than I had expected. I remember all of the embarrassment and had originally thought that a straighthorror I felt after making a mistake, forward protocol with detailed explanasmall or large, irreversible or not. And I tions and a clear demonstration would remember how appreciative I was when be sufficient. Questions would be anmy mentors would brush it off, gently swered, and the students would be correct me, and ask me to start over. on their way to mastering yet another They trusted that I made mistakes betechnique. In actuality, however, the cause I was still learning and not because diversity of backgrounds and experiI was careless. ences from which visiting students have Learning curves in research laboratocome to us are a significant complicatries are steep, and honestly, it never ends. ing factor. To begin with, I have had to To this day, I am still being taught by othtailor my vocabulary and the depth to ers, making mistakes and apologizing for which I explain our methods and motimyself, and I am sure I will continue to vations to each individual student in an find myself in these situations for years effort to bring them all to the same level to come. That is what makes research so of understanding. This is not extraorfun and interactive and interesting, and dinarily difficult, but it takes time and that is why I love it. exposure to feel that they have fully absorbed what you are trying to impart Zen Liu is a first-year graduate student in to them and to be confident that they the Department of Biomedical Engineering at have developed an instinct and fluency Columbia University.




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The End of the First Year Matthew C. Canver

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he sixth and final course of the first year of medical school was immunology, microbiology, and pathology (IMP). As mentioned in my previous column, this course began immediately after spring break in mid-March and ended the first week of June, spanning 11 weeks in total. The course was essentially three separate courses combined into one (the first half was dedicated to immunology and pathology while the second half was dedicated to microbiology). The immunology and pathology portion of the course covered major topics such as the important components and functions of the immune system, cancer, autoimmune disease, and inflammation. The microbiology portion of the course involved learning bacteriology, virology, and parasitology as well as pharmacology (including antibiotics and some antivirals). This course represented a paradigm shift in our medical education. This was the first time we learned about things going wrong. Previously, we had only learned about the normal function of the human body; however, during this course and throughout the entire second year of medical school, the emphasis is on what happens when things go wrong in the body (pathology/pathophysiology). About halfway through IMP (specifically after the first week of May 2011), the Harvard Medical School (HMS) Society Olympics started. As mentioned in an older column, before matriculation, the entire first year class is randomly sorted (exactly like in Harry Potter) into one of each of the following societies: Castle, Cannon, Holmes, and Peabody [and the Health Sciences and Technology (HST) students are all placed in the London Society]. An HMS tradition in the springtime of the first year is to have the Society Olympics as a fun event for both faculty and students. The Olympics consist of each of the five societies competing in various games Digital Object Identifier 10.1109/MPUL.2011.942600 Date of publication: 11 October 2011

to earn as many points as possible. The society that accumulates the most points is declared the winner and takes home the coveted prize, the Pink Flamingo, for an entire year until the next Olympics. The Society Olympics started on a Friday after classes had ended for the day. The main events for this year’s Olympics included: participation in a service hunger walk, a picture scavenger hunt contest, a societywide choreographed dance, a relay race, a limbo contest, an eating contest, a dodgeball tournament, a tug-of-war, and a waterballoon fight. Each of these events was assigned a point value (typically ten points for first place and scaled down by two points for each subsequent place). Faculty members were integrated into the Olympics day by serving as judges to determine the scoring for each of the events. At the end of all the events, the scores for each society were tabulated to determine the winner. In the end, the London Society (HST) took home the 2011 Pink Flamingo, while my society (Peabody) had a strong showing in second place. The games ended with a large food festival, which essentially meant a lot of pizza for all students and faculty. Overall, it was a fun event that allowed the first-year class to have a break from studying, an opportunity to play some games, and the ability to interact with many faculty members in a more informal setting. After the Society Olympics had passed and IMP ended, and before summer break could begin, there was still one week of class left, which was called integration week. The goal of integration week was to integrate all of the medicine and basic science we had learned this year by working in groups to analyze a patient case. This week was completely nongraded to keep the emphasis on integrating material and reviewing with your peers rather than it serving as a source of stress since the idea was not to attempt to cram a year’s worth of medical education into one week of studying. The class was divided into

groups of approximately nine students, and we received a few pages of the patient case each day, which provided more information and details about the case (i.e., information from the medical history, physical exam, laboratory values, and so on). Each group was expected to try to understand the mechanisms of the disease and to attempt to integrate all of the data/ information provided to try to understand what was going wrong with the patient. After a few days, the integration week ended with the entire class coming together in a fashion similar to how the year started in August. After a brief recap of the entire year, there was a classwide lunch that officially signaled the end of the first year of medical school. The full summer between the end of the first year and the start of the second year of medical school lasts for nine weeks (considerably shorter than the traditional undergraduate summer break). In spite of its short duration, this is an important summer because of the freedom you have to explore various medical specialties, try a health-care policy internship, and explore basic or social science research in a variety of areas. It’s also a special summer break because the summer vacation between the first and second year is always referred to as the last summer break of your life. While that is a somewhat disheartening thought, it is true that, after this summer break, we will always be working during the summer, which is seemingly a rite of passage into adulthood. Most students take a week off for vacation, travel, and/or visiting family, which leaves eight weeks to work on their respective summer projects. On an average, half of the class leaves Boston to work abroad or elsewhere in the United States, while the remaining half chooses to stay in Boston to work on summer projects. This summer I elected to stay in Boston to work in a cardiac-focused laboratory at the Massachusetts Institute of Technology, which focuses, among other things, on tissue engineering and vascular biology. In the next issue of IEEE Pulse, I will talk about the summertime as well as provide an overview of the second year of medical school including the United States Medical Licensing Exam Step I. Matthew C. Canver is a first-year medical student at HMS in Boston, Massachusetts. SEPTEMBER/OCTOBER 2011

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Studying BME in the United Kingdom By Nadya Anscombe

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n the United Kingdom, the field of engineering in biology and medicine is so new that universities cannot agree on what to call it or even where to teach it. Undergraduate students in the United Kingdom can register for degrees in bioengineering, biomedical engineering, medical engineering, clinical engineering, medical physics, or even rehabilitation engineering; and these could be taught in specialist institutions, mechanical and electronic engineering departments, medical schools and hospitals, or even by distance learning (see “Long-Distance Masters”). Before 2002, the term bioengineering did not even feature in the database of undergraduate courses held at the Higher Education Statistics Agency (HESA), but today, it is one of the fastest growing engineering disciplines with several universities offering undergraduate courses for the first time each year. While several universities have offered taught master’s courses in bioengineering and all its variants for some time, undergraduate courses in the subject are a relatively new concept in the United Kingdom and have resulted in every university designing its own course with its own curriculum and specialties. Undergraduate courses in bioengineering are often standard mechanical or electronic engineering courses, with additional biology- or medicine-related modules added in the final year. It is for this reason that statistics on the number of bioengineering graduates is difficult to find. According to HESA data, there has not been an increase in bioengineering graduates over the last six years. This is because they are often classified as mechanical engineering or physics graduates and not as bioengineering or medical physics graduates. This means that the discipline of bioengineering is not well known among prospective students or their parents, so persuading them to choose bioengineering as a degree is often the first challenge that needs to be overcome. Julia Shelton, director of taught courses in the School of Engineering and Materials Science (SEMS) at Queen Mary University in London (QMUL), says that attracting students is difficult because the subject is not taught in schools and students have often never considered combining engineering and medicine before. QMUL was one of the first universities in the United Kingdom to offer three- and four-year undergraduate degrees in medical engineering. Based at the SEMS, the medical engineering course has many aspects

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in common with other courses offered by the university, such as medical and dental materials. But rather than graduating as materials scientists, the medical engineering course is accredited by the Institution of Mechanical Engineers, and students graduate as engineers with a qualification that enable them to progress, with appropriate work experience, to full chartered engineering status. “We have to do a lot of outreach work in schools in order to persuade parents that medical engineering is a proper subject,” says Shelton. “We have seen a resurgence in mechanical engineering applications, which has helped, and we find that the subject also attracts a large number of female students who ordinarily would not consider engineering.” The QMUL medical engineering courses are different than many other bioengineering or biomedical engineering courses run at other universities because, rather than sending students off to other schools to attend medical or biology lectures, the students are taught by SEMS staff who are active in medical engineering research, with a wide range of interests. This enables QMUL to deliver a wide range of specialist modules and also to support a diverse number of projects. “We have redesigned our course many times and we are now confident that we have found the best way of teaching this subject,” said Shelton. “Some of our teaching is centered on problem-based learning. For example, we don’t teach anatomy as a separate subject. The students learn anatomy and physiology as part of their other modules, through addressing clinical medical engineering problems and their final-year design project, which is often carried out in partnership with either industry or hospitals” (see “Problems and Projects”). This collaboration with hospitals and industry can be a huge challenge to organize, but is ultimately very rewarding for the students. Ensuring that the students have no gaps in their knowledge of clinical topics, such as anatomy, is also a challenge with this type of course, but Shelton and her colleagues at QMUL believe that the students learn and retain physiology and anatomy information better when they have learned it in this way. In most other bioengineering courses across the country, medical subjects, © STOCKBYTE AND ED SIMPSON


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Long-Distance Masters The most innovative and unique taught master’s program available in the United Kingdom is an M.Sc. degree in medical physics from Open University, a university that has pioneered distance learning (Figure S1). While the bulk of students come from the United Kingdom, this M.Sc. is available globally because it is taught entirely through distance learning. “We have students from many different countries, including the Bahamas, Nigeria, and the Ukraine,” said Elizabeth Parvin, module team chair at Open University. “Many of our students have full-time careers, perhaps working in a hospital already, and want to further their career.” The students are provided with a study guide that leads them through a comprehensive set of resources. At the heart of the student’s study is a personalized Web site where students can access all the study materials as well as the university’s extensive electronic FIGURE S1 The Open University five-treatment plan on screen. library. Students are also given access to an imageprocessing package and a radiotherapy treatmentdifferent backgrounds, and while many of them might already work planning teaching package. Contact with a personal tutor is in a clinical environment, many will never have been in a maintained via electronic forums and e-mail. Assignments are radiotherapy department.” So Parvin and her colleagues went to a submitted electronically at regular intervals and returned to the large hospital and filmed inside the radiotherapy department to student with extensive comments as well as marks. explain to all the students what all the different pieces of equipment Students are expected to work between 12 and 15 hours per are called and how they work. Second, to teach radiotherapy, for week by researching assignments, attending lectures online, or example, students need to learn the basics of how to plan working with tutors online. The course consists of three modules: radiotherapy treatment, and for this they are given remote access to imaging in medicine, radiotherapy and its physics, and a project. a teaching package on radiotherapy treatment planning produced Those students wanting accreditation by the Institute of Engineering by Sheffield Hospital. Using this they can work out treatment plans and Physics in Medicine must do an extra module that includes for different regions of the body. Students on the imaging module topics such as statistics, health and safety, and anatomy, and the use an image processing package to learn how to get extra project they undertake must be a practical project. Students information from images. typically take around three years to complete their master’s degree. For the imaging and radiotherapy physics modules, the final Alternatively, it is possible to accelerate the program by working assessment involves the presentation of a poster and short review more intensively for more than two years or to spread it out over a (imaging module) and a 15-minute conference-style presentation longer period. (radiotherapy module). In both cases, these require the student to “Doing a master’s degree through Open University is hugely use electronic journals to research a subject beyond the core challenging for the students because most of them work full time material of the module and present it to a general medical physics while they are studying,” said Parvin. “But this also means that some audience. For students who can travel to Milton Keynes, where of them have expertise in areas that can be useful to the other Open University has its headquarters, these assessments are carried students, and they will help each other out by answering questions out at conference days and are often the one and only time students in forums that we have set up.” get to meet their tutors and each other in person. For students from Lectures take place online using a video conferencing package distant places, the assessment can be carried out via video or called Elluminate. The lecturer gives a PowerPoint presentation and telephone. students are able to “raise their hands” or “applaud.” Each student has “While teaching through distance learning can be extremely a headset with a microphone, so they can ask questions and interact. challenging, it is also very rewarding,” said Parvin. “Our students are “Teaching medical physics at Open University is challenging for highly motivated, very hard-working, and a delight to teach.” many reasons,” said Parvin. “First, the students come from many

such as anatomy, are taught as a separate subject. For example, at Newcastle University, which will have its first bioengineering graduates in 2013, anatomy is taught to mechanical engineers using a combination of innovative software, human joint models, bespoke teaching materials, and peer-to-peer learning (see “Teaching Anatomy to Engineers”). Tom Joyce, module leader, explains, “For the majority of the bioengineering students, this would be the 14 IEEE PULSE

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“We have to do a lot of outreach work in schools in order to persuade parents that medical engineering is a proper subject,” says Shelton.

first time they had been formally introduced to anatomy and the associated medical terminology. Research has shown that even medical students frequently encounter problems understanding certain dynamic aspects of functional anatomy, so for engineering students the subject can be particularly challenging.” To make learning anatomy interactive and fun for the student, Joyce applied for funding to buy dedicated anatomical software and also




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Problems and Projects At QMUL, students learn about the challenges of medical engineering through problem-based learning and industry-led projects (Figure S2). For example, take the case of Michael’s Knee (a professional footballer) who has hurt his knee. The students are given a complete case history and are told about the symptoms in detail. The students are then asked to gain information from the symptoms and suggest tests that could be used to allow accurate diagnosis of the clinical problem. Results from diagnostic tests and possible treatment options are discussed as well as rehabilitation regimes and the likelihood of the patient being able to return to professional sports. In this scenario, the patient presents classic symptoms of an acute rupture of the anterior cruciate ligament (ACL). By working through this scenario, the FIGURE S2 QMUL students in a tissue lab. students develop an understanding of the anatomy of the knee and the ACL and menisci in particular and understand how this injury can alter functions. They set out. Where a group is struggling, the facilitator should become also gain knowledge of diagnostic, treatment, and rehabilitation more proactive but in a manner that guides rather than informs. We options for patients suffering from a ruptured ACL and torn find that this is a very effective way of learning and also gives the meniscus. students skills, such as group work and report writing, which they The students are required to keep notebooks in which they will need in their careers.” record the information they have acquired and details of In the fourth year of the medical engineering degree, students experimental protocols and results. They work in groups to write work on a group design project, many of which are associated with about their findings that are presented in the form of a clinical an industrial sponsor. This is a major exercise that occupies 50% of report prepared for the chief medical officer of the player’s students’ time in the fourth year. “In the professional world, football team. engineers do not work in isolation, and therefore need to be good at “We ask the students to keep notebooks because not only does managing complex group design work,” said Knight. “Our group it document the progress of their learning, it is also something that design project offers students a challenging and realistic professionals are required to do so that an organization can assignment, helping them prepare for the real world in professional document intellectual property claims,” explains Martin Knight, engineering.” director of the Medical Engineering Degree Program at QMUL. In The examples of current and previous group design projects group sessions, the students are assisted by an academic facilitator include investigation of shock wave lithotripsy for unblocking an whose role is to guide the discussion in a manner that should allow encrusted urethral stent (sponsored by P&N Medical), the students to understand the problem and find appropriate development of an arthroscopic suturing tool for the repair of answers. “Just as in professional situations, the students appoint a shoulder tendons (sponsored by Atlantech), development of a chair to chair the meeting and a secretary who takes notes and bioreactor for cartilage tissue engineering (sponsored by Bose), distributes them to members of the group,” said Knight. “The and design of an improved ankle replacement implant facilitator is not there to provide answers, so may take an extremely (sponsored by DePuy). passive role when a group is working well and achieving the goals

in which degree courses are developed in U.K. some models of human joints. He also arranged universities. For example, until recently, Oxford a two-hour visit to the dissecting rooms of The IPEM does accredit University offered only a one-year taught masNewcastle University’s Medical School where an M.Sc. degree in ter’s program in biomedical engineering. Four students were given access to human hip and medical engineering, years ago, the Department of Engineering Sciknee joints. “The software was expensive, but but it currently ence realized that it had appointed enough facfeedback from the students has been very posdoes not accredit ulty with an interest in biomedical engineering, itive,” said Joyce. “Mechanical engineers like undergraduate and it started to offer the subject to its underto see things three-dimensional (3-D), and graduates. And in 2008, the university set up the software and joint models certainly help degrees. the Institute for Biomedical Engineering, where them grasp the subject quickly.” the research in this area is now consolidated. The bioengineering degree at Newcastle In the United Kingdom, Oxford is unique in the way it was developed because the School of Mechanical and Systems teaches engineering. All its students are taught the same core Engineering believed it to be an important and growing area subjects for the first two years, and then they have a choice of modern engineering and found it to have enough staff inof six options: mechanical, electronic, chemical, information, terested in teaching the subject. This is often the organic way SEPTEMBER/OCTOBER 2011

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Teaching Anatomy to Engineers At Newcastle University, the subject of bioengineering is taught as a module for more than two semesters to a combined group of fourth-year undergraduate students as well as postgraduate taught master’s students in the School of Mechanical and Systems Engineering. One part of this module involves the students writing an engineering critique of a commercially available design of a total joint replacement prosthesis. As such a critique needs to be founded on a full appreciation of the anatomy and function of the human joint that is being replaced; the challenge was how to facilitate student learning on the complex subject of anatomy [S1]. The module starts with a series of lectures on FIGURE S3 Students at Newcastle University learn through innovative total hip replacement and biotribology. These give software and models. appropriate background knowledge through a case study of the most common and successful type of joint replacement. After this, students are allocated an individual Scientific (Weston-super-Mare, United Kingdom) and organized project where they were asked to critique a specific design of a two-hour visit to the dissecting room of Newcastle University’s replacement joint and describe the anatomy of the relevant Medical School. Students first worked through the software natural joint. using bespoke training notes written by Joyce. He also wrote Each of these projects was intended for one of the less notes in relation to the human joint models and students commonly replaced human joints, specifically the shoulder, elbow, worked in self-selected groups to answer preset questions wrist, ankle, and various finger and toe joints. By gaining a full based on the models. understanding of the anatomy of human joints, Tom Joyce, module “I find that Web-based learning empowers the learner, enables leader, intended that his bioengineering students would individualized instruction and collaborative peer-to-peer learning, appreciate the inherent challenges of joint replacement and and transfers greater control to learners to decide when, how much, problems faced by clinicians who have to implant such devices. He and to what extent study and instruction takes place,” said Joyce. “It also explained students how artificial joint replacement can allows learners to progress at their own pace and provides the improve people’s lives and felt that the students want to learn facility for student-centered learning, making students responsible more about the subject. for their own learning.” To aid with this anatomical understanding, Joyce applied for a grant to buy dedicated anatomical software as well as models Reference of human joints and incorporated these into his teaching [S1] T. Joyce, “Non-traditional subjects taught to engineers: A case (Figure S3). The anatomical software chosen was Primal Pictures study of teaching anatomy,” in Proc. Conf. Paper Engineering Systemic edition (http://www.primalpictures.com/). Education, The Higher Education Academy Engineering Subject ___________________ He also bought static and dynamic models of human joints from 3B Centre, 2010 [Online].

This lack of consensus also means that students and their civil, or biomedical engineering. “Thirty years ago, we only potential employers are concerned whether they will gain sufhad three streams,” said Stephen Payne, course director for ficient knowledge of engineering to be effective the taught M.Sc. in bioengineering at Oxford engineers and can obtain enough knowledge of University’s Engineering Sciences Department. medical topics to feel that they are gaining the “Now we have six streams and medical engi“Ensuring that sufficient exposure to clinical expertise. In many neering is very popular.” students get a good ways, the first of these considerations will be anThe subjects taught under the banner of education in both swered if students complete a degree accredited biomedical engineering include physiology, engineering and by one of the various professional institutions signal processing, image processing, tissue medical aspects is a such as the Institution for Mechanical Engineers engineering, and drug delivery. This may and the Institution of Physics and Engineering be significantly different than what other major challenge,” says in Medicine (IPEM). An accredited degree will universities teach as part of a bioengineerSandra Shefelbine. require appropriate output standards in engiing degree because the subjects depend on neering knowledge and other numerate subjects. the specialties of the staff. “We play to our The IPEM does accredit an M.Sc. degree in medical engineerstrengths,” said Payne. “Biomedical engineering, or bioening, but it currently does not accredit undergraduate degrees. gineering, is such a new area that U.K. academia has not yet However, this seems to be changing, as a spokesperson for IPEM agreed on a core of subjects that should be taught. There is told PULSE magazine: “IPEM plans to play an increasingly imno standardization, but I would be interested to see if this portant part in the accreditation of undergraduate degrees in happens in the future.” 16 IEEE PULSE

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medical physics, bioengineering, medical engineering, and biomedical engineering in the future and is seeing an increased demand for this from universities in the United Kingdom and overseas.” “Ensuring that students get a good education in both engineering and medical aspects is a major challenge,” says Sandra Shefelbine, who teaches first-year mechanics and also orthopedic biomechanics to master’s students at the Imperial College in London ( Figure 1). At Imperial, undergraduate students study a range of traditional engineering as well as bioengineering modules from the start of their degree. Subjects in the first and second years include not only electrical engineering, mechanics, and mathematics but also mediFIGURE 1 Study of bioengineering at the Imperial College in London. cal sciences, cell biology, and wet laboratory skills. In their final year, the students cover a her lecture. “I find students are much more willing to answer range of topics focused specifically on bioengineering such truthfully using clickers, rather than a ‘hands-up’ voting system as imaging, modeling, biomechanics, synthetic biology, and where they are often persuaded by the majority,” she said. “The informatics. real-time feedback of student understanding was useful to me “The challenge is making sure that our students are masto gauge where I should spend more time on certain concepts. ters of something and not a ‘jack of all trades,’” says Shefelbine. Guessing the outcome of the experiment with a clicker system “Imperial is one of the few universities in the United Kingdom will encourage students to think conceptually about the physics that has a department of bioengineering and offers undergraduproblems.” ate and postgraduate degrees in the subject.” All the classes our While using wireless clickers has brought many benefits, it students take are taught in the department of bioengineering, has required Shefelbine to rethink how she delivers her lecso while we do teach the fundamentals such as mechanics, we tures and the amount of material she uses. “It is a different are able to make sure that the content is relevant to bioengineerway of lecturing, and it requires reorganization of the delivery ing,” says Shefelbine. For example, when talking about conserof the lecture,” she said. However, she does not use the clickers vation of energy, Shefelbine might look at how insects jump, when teaching master’s students as they tend or when looking at mechanics, she might look at to be in smaller groups. “Like our undergraduhow children with cerebral palsy walk. ate degrees, our master’s program has become Shefelbine enjoys teaching and was a recent To capture the increasingly popular,” says Shefelbine, who winner of the ExxonMobil Excellence in Teachimagination of is a U.S. citizen. “The number of students has ing award, which is awarded annually to innoundergraduate tripled in the last three years, and I am pleased vative educators in engineering. To capture the students and that the United Kingdom is finally catching up imagination of first-year undergraduate students with the United States where the number of and help them grasp fundamental concepts, she help them grasp bioengineering students is much higher and still uses large-scale physical demonstrations in the fundamental increasing.” lecture hall. Each demonstration illustrates a concepts, There are many differences between the different mechanics concept and has the capabilShefelbine uses United States and the United Kingdom in terms ity of projecting real-time measurements onto a large-scale physical of bioengineering education. The field is more screen for student participation. “The main cost demonstrations. mature in the United States, and the main differinvolved was the salary for a full-time mechanence is that in the United Kingdom, courses tend ics technician to help put together the demonto have an emphasis on mechanical engineerstrations and equipment required,” said Shefeling or sometimes electrical engineering. In the United States, bine. “Now the demos are shared by various departments and degree programs tend to have a strong commitment to biology are a great resource that helps the students make the connecand its related disciplines. tion between two-dimensional problems on paper (or computer Another unique feature about the United Kingdom is screen) and 3-D motion.” types of job opportunities available to graduates. Although Shefelbine is a fan of wireless clickers and uses them in all the United Kingdom has led many of the developments in the her lectures. For example, before a demonstration, students field of bioengineering, from the design of the first clinically were asked to vote anonymously on what they think will hapsuccessful hip replacement in the 1960s to the development pen. They can also be used to give instant feedback. In this of computer tomography and magnetic resonance imaging, manner, Shefelbine can assess if the students have understood SEPTEMBER/OCTOBER 2011

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there are certainly not enough jobs for all the graduates from the students study. From September 2011, all training provibioengineering degrees currently being run in the United sions, including the highly regarded IPEM training schemes, will be replaced by new arrangements for health-care scienKingdom. For example, none of the large scanner manufactists (corresponding approximately to the previous job title of turers have their manufacturing base in the United Kingdom, clinical scientists), health-care science practitioners (correso any graduate wanting to work in this industry will go to sponding approximately to the previous job title continental Europe or the United States. Howof clinical technologists), and support workers ever, according to a report by the Royal Acadat the assistant/associate practitioner level. emy of Engineering [1], the number of jobs in A large proportion Although IPEM has well-established training bioengineering in the United Kingdom should of bioengineering schemes for the professions in its sector, this is by increase in the next few years as small and meundergraduates in no means the case across the NHS workforce as a dium enterprises (SMEs) and start-ups look the United Kingdom whole. Also, while the IPEM scheme was highly for multidisciplinary people. The report states: are from overseas and regarded by the DH and produces high-quality “The large companies will continue to employ trainees, it was, according to the IPEM, “perspecialists, such as mechanical engineers or many of them will go ceived as lengthy and not financially justifiable electronic engineers who have graduated with back to their native in the long term.” limited biomedical knowledge. . . . however, a countries to work in While many in academia and industry agree growing number of SMEs need their employees the bioengineering that a change was needed, many are not happy to have a broad range of background knowlindustry. with how the changes have been carried out. edge for two different reasons. First, due to There are concerns about the speed at which their size, they are not able to employ a range of MSC is being implemented and inadequate disspecialists. Second, and more importantly, they tribution of universities offering B.Sc. and M.Sc. courses as are relying on turning novel ideas and concepts into devices part of MSC, requiring some students to travel long distances and implants. Hence, they need multidisciplinary people such to participate. as medical engineering graduates.” As this article went to print, an announcement was expectHowever, the report also points out that “Medical deed from the DH about which universities have been awarded vice, medical implant, and equipment manufacture is generthe contract to deliver the master’s courses that are part of the ally a small-scale, high-value-added industry; thus, the highly Scientist Training Program. The first intake of students will be trained graduates completing such degrees will be working in in September 2011, and there are expected to be about two or a type of manufacturing environment for which the United three universities offering an M.Sc. degree as part of the MSC Kingdom is very suitable. However, it should be noted that, at program. the moment, the U.K. manufacturing base in this area is low in In a statement issued in April 2011, the IPEM stated: “MSC spite of the appropriateness to the U.K. public limited company means radical change for IPEM, for our members and for the (plc) and the high U.K. research activity in the area of medical areas of health-care science for which we speak. It has also engineering.” been clear from the start that changes were going to take place This is perhaps one of the reasons that a significant numand that the status quo was not an option. IPEM Council and ber of graduates who have studied bioengineering in the United Trustees took the view that the institution should work with Kingdom end up working in finance and other industries unthe DH teams to make sure that the outcomes are in the best related to engineering. A large proportion of bioengineering interests of our professions, rather than simply opposing these undergraduates in the United Kingdom are from overseas and proposals.” many of them will go back to their native countries to work in It is hoped that with bodies, such as the IPEM, determined the bioengineering industry. to promote the area of bioengineering (and all its variants) Many bioengineering graduates want to work in the National and increasing job opportunities, more undergraduates will Health Service (NHS) of the United Kingdom, which is one of the be encouraged to study the subject in the future, irrespeclargest employers of scientists in the United Kingdom. However, tive of the degree’s official title or in which department it is the NHS’s graduate training scheme is currently undergoing a taught. complete restructuring called modernizing scientific careers (MSC). The initiative is being led by the Department of Health (DH), not by any of the professional organizations, such as the IPEM. It has Nadya Anscombe (www.nadya-anscombe.com) is a freelance been under development for several years, with the overall aim science and technology journalist living in the United Kingdom. of harmonizing training arrangements for the numerous small scientific and technical groups in the NHS and improving workReference force flexibility. [1] E. Tanner, “First degrees in medical engineering: A positive step This initiative involves devolving the training of scientists for engineering?”in United Kingdom Focus for Biomedical Engineering. and engineers to universities and changing the curricula that Royal Academy of Engineering, 2007.

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© BRAND X PICTURES

A View from the Outside In By Leslie Mertz

I

n today’s operating rooms, surgeons are more likely to be scrutinizing a computer screen than examining a patient’s opened chest or abdominal cavity. In just a few short years, imaging techniques such as computed tomography (CT), magnetic resonance (MR) tomography, and ultrasound have graduated from tools that help a doctor diagnose a health condition to tools that can actually guide therapy. Doctors are currently using these imaging techniques to navigate the brain during neurosurgery, to perform virtual colonoscopies, and to pinpoint the location and size of malignant tumors to help ensure their complete removal. This is just the beginning, according to experts in the field. Research is under way to expand the use of image-guided therapies so that surgeons can perform heart-valve replacements and other cardiovascular procedures without having to cut the

chest cavity. Additional studies are ongoing to use image-guided therapy for pancreatic and other cancers that are now difficult or nearly impossible to treat and for the development of new drug delivery systems that will transport chemotherapeutic agents to the target site, and only to the target site, thereby drastically reducing a patient’s drug dose and the associated side effects. “There’s a pretty wide range of therapies that can fall under the description of image-guided therapies, but the main idea is that you have some kind of medical imaging modality that is used during an intervention therapy,” said Dieter Haemmerich, Ph.D., associate professor of pediatrics at the Medical University of South Carolina. He described the main imaging technologies as follows: ▼ CT, which uses X-rays to obtain data that are constructed into cross-sectional or other images ▼ MR imaging (MRI), which uses a magnetic field and radio waves to produce images ▼ ultrasound imaging, which uses ultrasonic waves to create representations of internal body structures.

Image-Guided Therapies Quickly Becoming a Foundation of Medical Care


2154-2287/11/$26.00©2011 IEEE

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“Using these various technologies, sometimes in concert, image-guided therapy has begun to infiltrate many areas of medical care, with cancer and cardiovascular treatment being two of the major beneficiaries,” Haemmerich said.

Finding the Way

group are taking a different track. They’re dragging a tracked probe over an organ’s surface and using that as a reference for the computer image. He said, more work is necessary, noting that interdisciplinary efforts will drive a solution. “We need engineers who work with surgeons,” he said. “This is about design.”

The primary job of image-guided therapy is to provide a useful and detailed picture of the inside of the body. In cancer Especially Tough Cancers treatment, it means finding a tumor and determining its exact It was only a few years ago that a small group of researchers, boundaries. including Galloway, had what he called the “bizarre idea” of using image guidance in neurosurgery. “Today, it’s the standard of “I see image-guided therapy as being something where we care,” he remarked. “If you do an intracranial procedure today take tomograms— either a CT scan or an MR scan, maybe even a positron emission tomography (PET) scan— and match and you don’t use an image-guided surgery system, you have to show cause as to why you didn’t use one. It’s that to the physical space of the patient, and become a billion dollar a year business.” then show the surgeon where they are as they treat the patient,” said Robert L. Galloway, Jr., He thinks the same will be true of many Of the structures Ph.D., professor of biomedical engineering, medical procedures in the near future. “If you of interest to the think about minimally invasive surgery, what professor of surgery, professor of neurosursurgeon, the most you’re doing is going in and repairing or takgery, and director of the Center for Technolcritical are arteries ogy Guided Therapy at Vanderbilt University. ing something out, and at the same time, exand veins. posing as little healthy tissue to the therapeutic In other words, he explained, the tomograms process as possible,” Galloway said. “To do that are a series of stacked image slices that, when reconstructed on a computer, produce a threein anything is not simple. To do that in those places where the stakes are high— in the brain and also in abdimensional (3-D) image that the doctor uses as a map when dominal organs that are heavily vascularized— guidance really performing a procedure on the patient. “That lets them see matters.” where they are, for instance, relative to a tumor, and it also lets them see where they are relative to blood vessels that Liver cancer is a case in point. Although it is the second leading cancer killer worldwide, and despite the fact that surgery is they want to miss, because an awful lot of this is not only the most effective treatment, the vast majority of liver cancer pahitting the target, but missing things you don’t want to hit.” tients do not undergo surgery. A key part of that is registration, or how the image relates The reason is that liver surgery is very difficult. For one thing, to physical space. “Although the doctor may have a rotatable, rendered image on the computer screen, the screen itself is still liver tumors are often adjacent to major blood vessels. “In the United States, we’re particularly fond of our fatty foods, and me inherently two-dimensional (2-D),” he said. “So how do you in particular, so the chances of me getting colon cancer are highconvey 3-D information? Even if they had 3-D glasses, they are at best two-and-a-quarter-dimensional, because if I’m looking er,” Galloway said. “The problem is the metastatic disease that at you on a 2-D movie screen, I can’t see the back of your head comes along with it and infiltrates the liver. Because it’s bloodborne— that is, you’ve got tumor cells from your colon transportno matter what. I know where you are in the room, but I don’t ing via the vascular system— the tumors tend to grow near the know what’s on the back of your head, and I sure as heck don’t know what’s inside of your head, so I’m not seeing 3-D at all bigger blood vessels. So the surgeon is afraid to go in and cut something out near a major blood vessel, because they’re worthere. I have no problem imagining 3-D, but I just have trouble ried about cutting in that blood vessel and killing the person on visualizing it.” The single leading step in image-guided therapy is therethe table.” fore registration between image space and physical space, he On top of that, liver surgery is trickier than brain surgery, he said. Part of the issue is that the liver and other abdominal organs said. “We try to provide that information in such a way that slouch, shift, and otherwise change shape during surgery. “The the surgeon can construct the 3-D image in his or her head and determine the relative positions of the structures in the brain rests in a rigid skull, which helps. It does deform, but it doesn’t fold over on itself or anything like that,” he said. “When patient.” Of the structures of interest to the surgeon, he said, you move into abdominal organs, however, now you’re dealing the most critical are arteries and veins. “Surgeons are not really afraid of tissue; they’re terrified of blood vessels.” A mistaken with things that can deform, things that are much more free to move than the brain is, so you’ve got to bring a better level of cut of a major vessel can be fatal. That is an issue with tumor engineering sophistication to the problem in order to be able to surgery, because large numbers of blood vessels are typical of correct for those sorts of things.” fast-growing tumors. A number of researchers from around the world are apDespite the considerable challenges of registration between image space and physical space in abdominal organs, and the proximproaching the problem of registration, often using relatively ity of liver tumors to blood vessels, surgery is still the best possible fixed points in the patient’s own anatomy, such as certain forked option, and image guidance is the way to make it possible, he said blood vessels, or specified points on the surface of the body to (Figure 1). “We know that surgery is the best outcome. There’s correlate the image to the patient. Galloway and his research 20 IEEE PULSE

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FIGURE 1 A surgeon consults a display generated by the image-guided system developed at Vanderbilt University to perform liver surgery. Liver surgery is especially difficult for several reasons, including the number of blood vessels in the organ. Image guidance helps surgeons avoid the vessels. (Photo courtesy of Dr. Robert L. Galloway and Dr. William Chapman.)

wreck. Conversely, if you’ve got one-and-a-half kidneys or nothing else that even comes close, so if we can do that and make 1.7 kidneys, then you’ve got a little more reserve, and the that possible, make that safer, then we know that we’ve got a win.” quality of your life is going to be much better.” For those Kidney cancer presents its own obstacles. Conventional reasons, he said, partial nephrectomies may become more treatment for kidney cancer is to remove the entire affectcommon as image-guided procedures mature ed kidney, because a person can survive on (Figure 2). just one. “That’s just two major blood vessels and the ureter that you need to control, so Treatment for pancreatic cancer is on the Surgeons are not it’s pretty straightforward surgery,” he said. horizon, too— thanks to a new blood test that really afraid of The complication arises when the surgeon promises to detect the cancer much earlier than tissue; they’re opts to remove only the cancerous part of current tests. “Nobody asked before how you terrified of blood the organ. “Once you cut into a kidney, then could operate on a pancreas because by the time things get surgically much more complex, you figured out that somebody had pancreatic vessels. because you’ve got blood vessels and you’ve cancer, they were pretty much dead,” he said. He got a collecting system and you’ve got to get expects that image-guided surgery will become all that straightened out,” he explained. But it’s worth the the standard of care there, too. effort. “If you’re down to one kidney, you had better not In all three cases, he said, “The trick, of course, is getting ever become hypertensive and you’d better not be in a car surgeons who are trained in how to make certain decisions

(a)

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FIGURE 2 (a) The traditional laparoscopic view of the kidney when using the da Vinci Surgical System (Intuitive Surgical Inc., Sunnyvale, California). (Photo courtesy of Dr. Robert Galloway and Rowena Ong.) (b) Work done at Vanderbilt University adds image guidance to the system via the operating room image-oriented navigation (ORION) system and allows the surgeon to see structures beneath the surgical tool as they operate. SEPTEMBER/OCTOBER 2011

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“One advantage of MR-focused ultrasound is that you can measure temperature with MR thermometry, which is important when you use temperature as a way to determine whether you have effectively treated tissue. You can’t do that with ultrasound,” Kassell said. In addition, MR-focused ultrasound provides far better imaging capabilities, said Mark Hurwitz, M.D., director of regional program development for the department of radiation oncology at the Dana-Farber Brigham and Women’s Cancer Center at Harvard Medical School. “MR provides more information about the target as well as the tissue the focused ultrasound beam is passing through. We can find exactly where the nerves, vessels and organs are in terms of planning the treatment.” Once the procedure is complete, he said, he can also employ MR to ensure that the tumor was ablated and that healthy tisPutting on the Heat sue sustained no damage. Image-guided technologies are finding a place in heat-abHurwitz is currently studying how effectively MR-guided lation procedures that turn up the temperature on tumors ultrasound, as well as combined radiation and ablation, treats until their cells die. Haemmerich is conducting research bone metastasis and prostate cancer. He is also the principal inon the use of electric current to heat tissues, a procedure vestigator of a large phase III trial on bone metastasis. While he known as radio frequency (RF) ablation, which is already in can’t discuss the phase III results yet, he noted use clinically. “In this case, a catheter is run that earlier trials showed very good pain-reducthrough a small incision in the skin, and intion results with more than a third of patients reserted into the tumor using image guidance. A mistaken cut porting partial relief and another third reporting Then, the tumor and the surrounding tissue of a major vessel complete relief. are heated and destroyed by heat. The heat can be fatal. Besides the use of image-guided heat to enis used to directly kill the cancer.” It is not hance radio sensitivity and kill tumor cells, it is always 100% successful, he said. “One liminow part of several additional therapies, such as tation is still that sometimes you kill most of thermal ablation to destroy areas of the brain as a treatment for the tumor but not all of it, and then the tumor grows back. neuropathic pain and essential tremor and to destroy blood clots, This research is to try to get better heating devices to unihe said. formly kill the whole tumor.” Although heat ablation with current devices does not destroy the whole tumor all the time, it is still a beneficial procedure Straight to the Heart with excellent success rates particularly for smaller tumors of less Another huge area for image-guided therapy is in the carthan 3 cm in diameter. When paired with chemotherapy or radiovascular realm. A common procedure that uses imaging diation therapy, it can provide additional advantages. is the implantation of stents, small expandable tubes used “With chemotherapy, it’s often difficult to treat the center to open blocked blood vessels, said Haemmerich. “For that, regions of the tumor, because there’s not much blood flow in you need some kind of imaging to tell you where you are the center,” Haemmerich said, noting that the chemotherapeuand where you want to go. That’s how you place the stents tic drugs are carried through the bloodstream. “That means and then confirm that they are at the location you want that some cancer cells may still survive there. With the heatthem to be.” based methods, the lack of blood flow is no problem, and you One of the researchers who is pushing the envelope is Robcan kill the center of the tumor very easily. Afterward, the ert J. Lederman, M.D., senior investigator in the division of inchemotherapy is much more effective, because you have altramural research at the National Heart, Lung, and Blood Instiready destroyed a large part of the tumor, including the center tute (NHLBI). He is also director of cardiovascular intervention where the chemotherapy doesn’t reach.” at the National Institutes of Health (NIH) and heads its ImageNonlethal heat and radiation is also a winning combinaGuided Cardiovascular Intervention Fellowship Program. “I’ve tion, because the heat makes the tumor cells more susceptible been working now for a decade to do something that’s very difto radiation, said Neal Kassell, M.D., professor of neurosurficult, and that’s to use MRI instead of X-ray to guide catheter gery at the University of Virginia and chair of the Focused procedures.” The problem with X-ray, the current standard of Ultrasound Surgery Foundation. The foundation specializes in care, is that it provides only quick glimpses of the target area, MR-guided ultrasound. “The type of ultrasound that people he said. “When we work under X-ray, we can’t really see what are familiar with is for diagnosis, but there is a field of therawe’re doing except for a few moments when we occasionally peutic ultrasound that includes ultrasound-guided and MRinject contrast to fill up the blood space.” However, with MRI, guided ultrasound. Some indications are better treated with a doctor can not only continuously see the blood and the soft MR-guided, and some are adequately treated with ultrasoundtissue, but he or she can also see in real time how their own guided,” he said. medical devices are interacting with tissues. and how to do certain procedures, and get them to think a little bit outside of the box.” Functional engineering is also critical. “The absolute dumbest thing an engineer can do is walk up to a surgeon and tell them that what they are doing isn’t good enough, because where do we get off with that? So it has to be an engineer-and-surgeon team working on this, or else we’re going to create something really goofy, or we’re going to create something that is only marginally different,” he asserted. Overall, he said, “Sure, we all want the magic bullet. If you get cancer and can take a pill and the cancer would go away, wouldn’t that be wonderful? In the meantime, engineers can help make surgery both possible and less damaging.”

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ologists burn small sections of myocardium (heart muscle) He is especially interested in using real-time MRI to perform to treat cardiac rhythm disorders,” he said. This blocks the radiation-free heart catheterization in children. He is not alone electric current that drives the incorrect heart contraction and in his desire to reduce radiation exposure in children. A naresolves the arrhythmia. “When they do this procedure, howtional campaign, called Image Gently, notes that children are ever, they can’t see the target tissue. MRI would be attractive, more sensitive to imaging radiation than adults are and warns because it would allow physicians to interactively assess the that cumulative radiation exposure may have adverse effects target tissue while they work. They could watch it heat up. over time. They could confirm that they are destroying the desired short As MR-guided catheterization research progresses, some circuits while they work.” issues must be resolved, he noted. One of the most pressing is the design of the catheters themselves. Lederman explained that catheters, which were made for X-ray use, simply don’t Edging into Orthopedics show up on MRI. In addition, he said, “Long, conductive deBesides cancer and cardiovascular treatment, image-guidvices can heat up under MRI, and almost all catheters are ed therapies are becoming more prevalent in orthopedic long and conductive.” In answer, his and other laboratories surgeries, such as minimally invasive knee replacements. at the NHLBI are working on MRI-compatible The technology not only can provide the opcatheter prototypes, as well as imaging techerating physician with a preoperative view of niques tailored to guide treatments and not the affected joint but may also allow the opLarge numbers of just diagnoses. “These are very complex and erating physician to make adjustments durblood vessels are expensive undertakings that can be a little offing procedures so that joints can be aligned typical of fastputting to industry, so we’re using our governmore precisely. growing tumors. ment labs to jumpstart the process.” Health-care costs do come into play with As that work continues, Lederman is inimage-guided orthopedic procedures, howvolved in another big project: doing heartever, because many such procedures are alvalve replacements without cutting open the chest. “One reready very successful without image guidance, noted Galloally exciting line of work in our lab is to access the beating way. “There have been a lot of times when I’m approached by heart through the chest wall, but without surgery and withsomebody about image guidance, and I ask, ‘Will the inforout arresting the heart. Then we can put a large port directly mation provided by guidance help you?’ If they hesitate or into the ventricular cavity from the outside— without surgiif they answer, ‘Well yes, sometimes,’ then it’s probably not cal exposure— and put in a large prosthesis like a mitral valve worth doing,” he said. replacement. Those devices are gigantic! Or, we can put in a “You want to be a little bit aware of the cost of technology valve prosthesis for aorta. When we’re done, we could close in health care. If we can do something with image guidance, the hole remotely, without opening the chest.” and it means somebody goes home with 1.8 kidneys instead This work is in the developmental stages. “We’re proceeding of one, that’s a win. That’s a huge win. If you double the step-wise,” he said, noting that he has conducted some animal price of having a knee operation and only one in a hundred testing and has only recently started to perform simple MRI-guided heart catheterization procedures in humans. “One of my goals in life is to provide non-surgical alternatives.” Several trends in cardiovascular work are worth watching, he said. One is MRI generated and very detailed anatomical maps to the patient’s body. Such maps would allow medical professionals to perform faster catheterization procedures with less X-ray exposure to the patient. “We are working to replace ‘static’ roadmaps with dynamic roadmaps that morph dynamically to correct for cardiac and respiratory motion,” he said. “Another trend is 3-D ultrasound, whether through the chest wall, through a transesophageal probe (that is inserted through esophagus to view the heart), or using ultra-miniaturized imaging ultrasound probes that are put directly inside cardiac chambers,” he said. He also noted that some laboratories are pur- FIGURE 3 Image guidance is also used in drug delivery. Here, the ORION system developed at Vanderbilt helps guide drug delivery to the back of the eye. The suing real-time MRI for use in treating cardiac image in the lower right quadrant is a live endoscopic feed. (Photo courtesy of arrhythmia. “Currently, cardiac electrophysi- Dr. Robert Galloway and Dr. Louise Mawn.) SEPTEMBER/OCTOBER 2011

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is conducting research to make it possible. “These are 100to 200-nm spheres made of lipids. If we heat them above a Tissue Drug certain threshold, they release their contents, which are the (μg/g) Concentration 100 chemotherapy drugs. That way, we can locally heat tissue and 9 Hyperthermic locally deliver the chemotherapy.” The remaining, unheated Zone (40–50°C) 8 liposomes circulating in the body are eventually degraded by 90 the liver and kidney, and their contained drugs are never re7 leased into the bloodstream. 80 6 In his research, Haemmerich is conducting computer simulations to learn the temperatures needed and the du5 70 ration of heat needed to melt the liposomes and maximize the drugs delivered to the tumor. “This is not clinically 4 used yet, but there is a lot of interest currently in using 60 3 that method.” Kassell agreed. “Focal or targeted drug delivery is a huge 2 50 area,” he said. Research is also under way on another delivery vehicle, called microbubbles, which burst under ap1 1 cm plication of focused ultrasound. “They’re not temperature0 37 sensitive. They’re sensitive to the ultrasound pressure, which causes them to burst and release their payloads.” The FIGURE 4 Image guidance can also assist drug delivery. Chemoresult is the same: drugs are delivered only to the target therapy drugs can be encapsulated in liposomes, which are area, and systemic side effects are drastically reduced or spheres made of lipids. The tiny spheres, which range from eliminated. 100–200 nm in size, are heated to release their contents. By selectively heating certain areas of the body, the drugs are For liposomes, ablation of tumors and other uses, MRdelivered only at the site of a tumor. Heating is accomplished guided focused ultrasound is here to stay, Kassell said. “There via electric current in a procedure known as RF ablation. is the potential for focused ultrasound to revolutionize theraThe figure at the left shows tissue drug concentration if RF py to the same degree that MR scanning revolutionized diagablation is combined with liposomes and demonstrates the complementary effect of killing of the center regions of tunosis,” he said. “It could be the ultimate in minimally invasive mors by heat alone (more than 50 ºC), while depositing drugs surgery; a new way to deliver drugs, which means it could in the surrounding region for additional treatment effect. change drug therapy; and an alternative for much of radio(Image courtesy of Dieter Haemmerich.) therapy. In doing so, it could be used to treat a broad spectrum of serious medical disorders and thereby improve the lives of millions of people worldpeople need it, then you really don’t need us,” wide.” he commented. Although heat Image-guided procedures have already Studies are currently under way to deterablation with current nosed their way into medical care, added mine whether image guidance provides suffidevices does not Galloway. “Image-guided neurosurgery is ciently improved outcomes, such as less pain destroy the whole now the standard of care. I would put the and faster recovery, to warrant their costs. tumor all the time, number of such image-guided procedures it is still a beneficial that we’ve done just at Vanderbilt in the Zeroing in Drugs hundreds, if not the thousands, and other While it may not be an obvious connection, reprocedure. hospitals internationally and across the search into methods of drug delivery is also tapUnited States are also doing them.” Multiple ping imaging technology (Figures 3 and 4). hospitals are beginning clinical testing on image-guided When cancer patients receive chemotherapy today, drugs flood liver and kidney surgeries, and he said Vanderbilt hopes the entire body and the patients experience various side effects. to do the first glaucoma treatment using image-guided “You’re kind of hoping that enough goes into the tumor,” Haemtherapy next spring. merich said. “There’s currently a lot of research going on in terms “So the work goes forward,” he said. “We can never get of getting chemotherapy specifically into the tumor, and also getenough NIH funding to have the people in place to work on ting radiation more concentrated in the region where the tumor this, but it’s going forward.” is located. The idea is to get more into the tumor and to get less everywhere else in the body to reduce the side effects.” Leslie Mertz ([email protected]) One way to do this is by encapsulating the chemother____________ is a freelance science and medical writer and author as well as an educator. apy drugs in tiny spheres called liposomes, he said, and he Temperature (°C)

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Image-Guided Therapies By Dieter Haemmerich, Matthew R. Dreher, Dorin Panescu, and Heinz-Otto Peitgen

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he discovery of X-rays in the late 19th century marked the advent of medical imaging, and today, a wide array of medical imaging technologies [several of which provide three-dimensional (3-D) information] are clinically available. For many diseases, imaging has become an essential component for both initial diagnosis and continued monitoring of therapy. Advanced methods of image acquisition, processing, and visualization have facili-

tated novel applications of imaging; for example, the imaging of organ and tissue functions rather than anatomical imaging. The availability of real-time imaging [in part made possible by the advent of digital imaging methods such as computed tomography (CT), ultrasound imaging, and magnetic resonance imaging (MRI)] has allowed for the use of imaging during interventional procedures for intraprocedural guidance. More recently, realtime image guidance has enabled minimally

An Introduction

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ment cost, with some specific examples given invasive procedures that replace traditional below. surgery and may yield equivalent or better efComputational ficacy with the added benefit of shorter hospital image-processing stays and reduced morbidity. However, in the Image-Guided Cancer Interventions techniques are age of evidence-based medicine, the benefit of Traditional cancer therapies include surgical facilitating a these often expensive imaging modalities must removal of the tumor, radiation therapy, and transition from be demonstrated to truly benefit the patient to chemotherapy. While surgery can be considtraditional radiologic justify clinical use. ered a localized intervention, the latter two Computational i mage-processi ng techhave traditionally been systemic therapies, i.e., diagnosis toward one niques are also facilitating a transition from they affected tissues within the whole body, where computational traditional radiologic diagnosis based primarwith corresponding toxicities and side effects. image analysis plays a ily on human vision toward one where comMore recently, in cancer therapy, locoregional central role. putational image analysis plays a central role, therapies have become available to primarily with the human eye only providing assistance treat the desired target region with reduced during the diagnostic process. As every diagdamage to the body. nosis is subjective to the radiologist inspecting the medical ▼ Intensity-modulated radiation therapy spatially focuses the images, there is an inherent high variability in diagnoses. radiation exposure on the target volume (tumor) with reComputer-aided systems can potentially reduce this operaduced exposure to other body regions compared with contor-dependent variability and make image-based diagnostic ventional radiation therapy. techniques more reproducible. In addition, computational ▼ Chemoembolization infuses high concentrations of chemoimage-processing methods facilitate development of software therapeutic drugs directly into the tumor while also shutplatforms for planning of procedures, intraprocedural guidting down tumor blood supply. ance as well as monitoring of treatment results. ▼ Localized thermal therapies (tumor ablation) locally deIn many cases, image-guided therapies have clinical advanstroy targeted tissue volumes by heating or freezing. tages over standard techniques and may result in better proceAll these localized cancer therapies have, in common, dural outcomes as well as potential reduction in overall treatimaging as a central component of preprocedural planning,

SVC

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FIGURE 1 The EnSite image-guided ablation system provides a view of registered right and left atria details. The views are from the valve plane, looking into the atria. Details such as the location of the left and right atrial appendages (RAA, LAA) and of the right and left superior pulmonary veins (RSPV, LSPV) are shown. The image of a mapping catheter is shown in the coronary sinus (CS). A circular mapping catheter is positioned at the ostium of the RSPV. An ablation catheter is positioned in proximity to the circular mapping catheter. SVC: superior vena cava; IVC: inferior vena cava; TV: tricuspid valve; MV: mitral valve.

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intraprocedural guidance, and postprocedural Imaging has become the preferred guiding confirmation of treatment outcome. In additechnology for interventional cardiovascular In cancer therapy, tion, image guidance has had a considerable procedures as well. Optical coherence tomogralocoregional therapies impact on the more traditional field of surphy (OCT) or intravascular ultrasound (IVUS) have become gical procedures as well, where nowadays, are two of the commonly used techniques to imavailable to primarily preprocedural planning based on images is a age and measure coronary arteries before treattreat the desired prerequisite. ment. Presently, the typical treatment consists target region with While metastatic cancer disease requires of delivery of drug-eluting stents. Imaging helps some kind of systemic therapy for the forethe cardiologist in selecting the appropriate stent reduced damage to seeable future for effective cancer treatment, size and placing the stent at an optimal coronary the body. for cancers diagnosed sufficiently early (i.e., location. As an example, a recent OCT system that have not spread to other organs), localoffers the ability to characterize the coronary arized therapies considerably reduce toxicity tery wall tissue to determine the composition of and side effects, with often similar efficacy to conventional lesions. Similarly, another commercially available system can be treatments if patients are selected appropriately. Furtherused to trace the contour of coronary arteries for proper sizing more, these localized therapies may be used in tandem with of stents or angioplasty balloons. more traditional systemic therapies without compounding While image-guided technologies such as those discussed the toxicity due to the improved safety profile of locoregionabove have been in development for more than a decade, it al therapies. has been just in recent years that their performance improved to levels that showed significant clinical benefit to patients. The articles in this issue will present some of the image-guidImage-Guided Cardiovascular Interventions ed therapies available today, specifically localized therapies In the last few decades, significant efforts have been made for cancer and cardiovascular applications, including disto integrate imaging tools with cardiovascular therapeutic cussion of computer-aided treatment planning platforms for devices. To improve outcomes of electrophysiology prothese types of therapies. cedures, several companies now provide image-guided systems that can precisely target locations for cardiac interventional electrophysiological procedures. For example, Acknowledgments a recently introduced system can be used to integrate and The authors wish to acknowledge contributions and guidance register CT or MRI images with maps of cardiac electrical in assembling this article series on image-guided therapies by activity. Device tracking is particularly helpful when commembers of the IEEE Technical Committee on Therapeutic bining interventional procedures with image guidance, as Systems and Technologies. For more information on this techit allows locating the interventional device (e.g., catheter) nical committee, please refer to http://tc-therapeutic-systems. relative to images taken before or during a procedure. Variembs.org/ ous systems for tracking of cardiac interventional catheters are commercially available and typically use electromagnetDieter Haemmerich is with the Department of Pediatrics, Medical Uniically based methods (i.e., from measurements of electric/ versity of South Carolina and the Department of Bioengineering, Clemmagnetic fields within the body). An example is presented son University. Matthew R. Dreher ([email protected]) ____________ is with in Figure 1, where data on local electrical activation of the the Center for Interventional Oncology, Radiology and Imaging Sciences, heart is collected and visualized in a 3-D model of the heart NIH. Dorin Panescu ([email protected]) ________________ is with Newcarchamber. Other clinically available technologies allow overdio, Inc., Santa Clara, California. Heinz-Otto Peitgen (heinz-otto. _______ lay of anatomical structures from real-time intracardiac ul- __________________ [email protected]) is with the Institute for Medical Imtrasound images. age Computing, Fraunhofer MEVIS.


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By Chris Brace

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(depressed tissue temperatures). The temperature change is he field of image-guided interventional therapies is concentrated to a focal zone in and around the tumor. The rapidly growing, both in technical development and overall objective of thermal tumor ablation is quite similar clinical adoption. Such interventions are increasingly to that of surgery: remove the tumor and a 5–10-mm thick being used to treat many types of cancer [1]. Most canmargin of seemingly normal tissue. Surgical removal consists cerous tumors are now diagnosed with computed toof physical excision; during thermal ablation, the tissue is mography (CT), magnetic resonance imaging (MRI), killed in situ and then absorbed by the body over the course or ultrasound imaging. After diagnosis, surgical removal conof several months. Like surgery, thermal ablation can be pertinues to be the preferred treatment for most focal tumors. formed using an open, laparoscopic, or endoscopic approach; However, open surgery is however, it is most commonly applied using a percutaneous traumatic. It often requires or noninvasive approach (Figure 1). The choice of approach general anesthesia, several days of hospital recovery, often depends on the type of tumor, its anatomic location, and weeks of outpatient physician’s preference, as well as the underlying health of recovery and rehabilitation the patient. before the patient can reAlthough a surgical procedure is performed by visual sume normal daily funcinspection with histopathological assessment of the excised tions. For millions of cancer tumor and margins, percutaneous and noninvasive thermal patients every year, the medical risks of surgical tumor removal ablation is performed strictly with the aid of imaging. Apdo not outweigh the potential benefits conferred. plicator guidance into the target zone, treatIn addition, the significant financial cost of surgery ment monitoring and verification, and clinical has put pressure on the health-care system to find follow-up rely on effective imaging. Detailed Thermal ablation alternative treatments that are less expensive but discussion of imaging is beyond the scope of refers to the equally as effective. This is not a novel problem: a this article, but the influence of imaging on destruction of popular aphorism from Hippocrates can be transthe choice of thermal ablation or procedural tissue by extreme lated as “those diseases which medicines do not approach will be discussed as needed. More hyperthermia or cure, iron cures; those which iron cannot cure, information on imaging for interventional fire cures; and those which fire cannot cure, are therapies can be found in other articles in this hypothermia. to be reckoned wholly incurable.” Thermal tuissue of IEEE Pulse. mor ablation is an extension of this concept in modern form. Clinical Indications The most common anatomic site for thermal ablation is the liver. Primary cancers arising in the liver are the seventh leading Definition cause of cancer worldwide, accounting for more than 750,000 Thermal ablation refers to the destruction of tissue by extreme new cancer cases and 700,000 deaths each year [2]. The most hyperthermia (elevated tissue temperatures) or hypothermia significant risk factor for liver cancer is cirrhosis, usually associated with chronic infections of hepatitis B or C viruses, alcoDigital Object Identifier 10.1109/MPUL.2011.942603 Date of publication: 11 October 2011 holism, or long-term fatty liver disease [3]. The liver is also a

A Minimally Invasive Treatment Option for Cancers

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shown a long-term benefit against primary liver cancer. Therecommon site of metastatic tumors from different organs because fore, there is a strong need for effective alternaof the large blood flow and filtering function of tive treatments for tumors in the liver. the liver. In addition, benign hepatic tumors and The most common As clinical data begin to support its use cysts can become symptomatic enough to reagainst liver tumors, interest in thermal ablaquire intervention. Surgery or transplantation is anatomic site for tion is growing for the treatment of other canthe preferred treatment for hepatic tumors, but thermal ablation is cers. Thermal ablation has effectively replaced up to 80% of liver cancer patients are not eligible the liver. surgery as the treatment of choice for benign for surgery because of poor baseline health, risk osteoid osteomas, especially in pediatric paof excessive bleeding due to poor blood clotting, tients [5]. A large proportion of primary kidney tumors are or lack of sufficient liver function reserve [4]. Radiation is parnow being treated with thermal ablation, with many centers ticularly hard on normal liver cells, and chemotherapy has not SEPTEMBER/OCTOBER 2011

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(a)

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FIGURE 1 A percutaneous thermal ablation procedure. The tumor is identified, and the applicator is inserted using imaging guidance. An ablation zone is created to cover the entire tumor with margins and then verified using follow-up imaging. (a) Diagnosis. (b) Follow-up. (c) Preablation. (d) Postablation.

considering ablation as a possible first-line option [6]. Thermal ablation is also being investigated for inoperable pulmonary nodules and breast tumors, but the availability of traditional therapies in these organs has inhibited wider clinical adoption to date. There may also be a role for thermal ablation in the treatment of tumors in the neck, adrenal glands, and pancreas, as well as cystic tumors and endocrine tumors that can present a problem for traditional treatments. Clinical adoption in these areas will depend on long-term results in ongoing pilot studies.

Thermal ablation is a transient heat-transfer problem and is thus most commonly described using Penne’s formulation of the Fourier heat equation: rCp

'T 5 k=2T 1 Qh 1 Qm 1 Qp, 't

(1)

where r is the tissue density (kg/m3), Cp is the specific heat capacity (J/kg ? K), T is the temperature (K), t is the time (s), k is the thermal conductivity (W/m ? K), Qh is the heat flux of the ablation source, Q m is the metabolic heat flux, and Q p is the blood perfusion heat flux. In most Thermal Ablation Biophysics Either hot cases, metabolic heat generation is much slower As mentioned earlier, either hot (hyperther(hyperthermic) or than either the perfusion or source terms, so can mic) or cold (hypothermic) temperatures can cold (hypothermic) be ignored. There are other models that account produce cellular necrosis. Cells in the human temperatures can for microvascular blood flow and heat transfer body can withstand a wide variety of temproduce cellular differently, but because of the high temperatures peratures, and some cells are more thermonecrosis. and rapid heating rates associated with thermal tolerant than others. The probability of death ablation, the formulation above is most common. is related to the thermal history or thermal The presence of large or high–low blood vesdose of each particular cell [7], [8]. As a gensels in the target area creates a substantial source (or sink) of eral rule, complete necrosis occurs almost instantaneously thermal energy (Figure 2). Vessels smaller than about 3 mm at temperatures below 240 °C or in excess of 60 °C for most cell types [9]. Less extreme temperatures require longer extypically are not problematic, but larger vessels may buffer posure times, with temperatures between 5 and 41 °C proadjacent cells from the intended thermal damage [10], [11]. viding no long-term therapeutic benefit. As a result, large vessels have been linked to increased local 30 IEEE PULSE

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(a)

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FIGURE 2 Effect of vessels on the ablation zone. (a) A high-flow vessel indents the ablation zone from the expected circular crosssectional shape. (b) The presence of a large vessel near the tumor creates a high probability of local recurrence, (c) as observed in the three-month follow-up exam.

recurrence rates [12]. Therefore, the goal of thermal ablation systems is to overcome local perfusion or vascular heat sinks by more intense heating or cooling— i.e., to create a larger difference between Qh and Qp.

Hyperthermic Ablation Elevated temperatures affect cells in a variety of ways, but the primary means of cell death during thermal tumor ablation is acute coagulative necrosis. Temperatures up to 41 °C cause blood vessel dilation and increased blood perfusion and trigger a heat-shock response that aims to protect the cell from thermal injury and repair any damage incurred [9]. These temperatures have little long-term effect even when maintained for hours. Up to 46 °C, irreversible cell damage begins to occur. The heat-shock response is intensified, but exposures up to 10 min will lead to necrosis of a significant population of the cells. Those that recover may exhibit an increased tolerance to elevated temperatures. Temperatures of 46–52 °C reduce the time needed to achieve cell death and also begin to cause microvascular thrombosis, ischemia, and hypoxia. This cascade cuts off the cells’ nutrient supply and leads to delayed necrosis. Temperatures in excess of 60 °C cause rapid protein denaturation and melt the plasma membrane that allows the cells to survive. Further rises in temperature are associated with physical changes such as water vaporization, desiccation, and carbonization. These changes in physical properties do not enhance cell death directly but do influence the delivery of energy from the ablation device. In particular, water vaporization and tissue charring cause a precipitous drop in 1) tissue conductivity, which impedes radio-frequency (RF) power delivery; 2) complex permittivity, which alters microwave antenna performance and power delivery; 3) optical transmission, which irreversibly prohibits laser light penetration; and 4) ultrasound transmission. In each case, the therapeutic heating process itself alters future energy delivery. All systems must account for these changes to maximize efficacy.

Technologies Overview RF electrical current, microwave radiation, laser light, and ultrasound acoustic waves are the most common sources of clinical hyperthermic tumor ablation. With the exception of noninvasive high-intensity focused ultrasound (HIFU), these energies are applied using interstitial devices that are essentially needlelike in form. Clinical systems consist of two main systems: a source of either heating or cooling and a delivery system. For surgical or percutaneous approaches, the delivery system consists of an applicator that is inserted into the tumor and a method for coupling the applicator to the source (Figure 3). Since percutaneous

FIGURE 3 A microwave ablation system illustrates the main components of most ablation systems: a generator with some type of user interface or control, a power distribution system, and a delivery device that is applied directly to the tumor. (Image courtesy of NeuWave Medical, Inc.) SEPTEMBER/OCTOBER 2011

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During RF ablation, electrical current is applied directly to the thermal ablation procedures are performed by radiologists actarget zone; however, at least two electrodes are required to customed to image-guided biopsy, most ablation devices have a complete an electrical circuit through the body. The typical apneedlelike form similar to biopsy devices. Percutaneous ablation proach is to insert one electrode into the body (interstitial elecdevices are less than 2.5 mm in diameter to reduce complications trode) with a second electrode fixed to the skin surface (disassociated with larger, more traumatic devices [13]. persive electrode or grounding pad). Since only one electrode When possible, solitary tumors are treated using a single is applied to the tumor, this setup is referred to as unipolar. applicator. However, depending on the size, shape, and locaBipolar operation implies that current oscillates tion of the tumor, such an approach is neither between two interstitial electrodes applied to always feasible nor optimal. MRI can be used to the tumor (Figure 4). Historically, tumors too large to be treated with a single applicator placement required multiple Modern RF ablation systems are capable of precisely measure overlapping ablations to cover the tumor volume generating up to 250-W power output or about temperature and completely [14]. This procedure is fraught with 2.3 A of current in a typical 50-W tissue load. thermal dose. challenges, including visualization of the residual The RF generator operates primarily as a volttumor after each subsequent treatment on imagage source, so the average power delivered can ing and the potential for complications or tumor seeding due be calculated from Ohm’s law: P 5 V2 /Z, where Z is the imto applicator repositioning. Multiple devices can also be used in pedance of the circuit, which is determined by the surface concert to exploit synergistic interactions between the growing area of the electrode–tissue boundary and the types of tissue ablation zones [15]–[17]. Recent studies have proven the beninvolved in the current path. For example, liver is relatively efits of using multiple applicators simultaneously: larger ablation conductive because of its high water and ion content, so crezones, improved confluence and homogeneity of temperatures ates a low-impedance electrical current path. Conversely, aerin the ablation zone, and more rapid placement of each applicaated lung and fat have lower water and ion contents, so are astor due to clear imaging visibility and the ability to use previous sociated with much higher electrical impedance. This makes applicators as a guide for subsequent placements [18]–[20]. The RF ablation challenging in lung since even electrically condrawback to this approach is that placing multiple devices inductive tumors are surrounded by lung parenchyma. In addicreases procedural trauma and financial expense. tion, tissue heated to ablative temperatures, especially those near 100 °C, experience rapid dehydration as water is boiled to water vapor. This sudden decrease in tissue water content Radio Frequency Ablation leads to a spike in the circuit impedance and a corresponding RF ablation evolved from electrocautery in the 1990s and has drop in applied power. Therefore, the ablative heating process become the most widely used ablation modality worldwide.

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FIGURE 4 (a) Unipolar and (b) bipolar RF ablation in a simulated abdomen. Electrical current oscillates between one or more electrodes applied directly to the tumor. Heat generation is proportional to current density, which is greatest near the interstitial electrodes but can cause skin burns near improperly placed surface electrodes. 32 IEEE PULSE

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trode to condense. The resulting increase in tissue conductivity allows greater RF power to be applied during the next heating cycle. Since thermal conduction through the tissue is much slower than RF heating itself, turning the power off does not detract ablation zone growth. In fact, the combina2 2 tion of electrode cooling and pulsed power creates larger ablasE J 5 , Qh 5 J # E 5 (2) tion zones than either solution alone [22]. 2s 2 Another solution to increase RF ablation zone size is to spatially distribute the power throughout the tumor volume, where J is the current density (A/m), E is the electric field ineither by using multiple needle electrodes or electrodes with tensity (V/m), and s is the electrical conductivity (S/m). This deployable tines (Figure 5) [23]–[25]. The former solution relationship illustrates the fact that RF heating is proportional to the square of current density. requires insertion and guidance of up to three electrodes. RF electrodes are designed to create zones The electrodes may be operated in parallel, as of high current density that are large enough to a bipolar array, or by sequential switching to cover the tumor plus an ablative margin. Early improve heating uniformity within the target Most cancerous electrodes consisted of simple bare wires, but zone. The latter requires the placement of only tumors are diagnosed heating with this design was easily subverted one device, with the umbrella or star-shaped with computed by water vaporization and tissue dehydration. array of deployed tines providing the necestomography, MRI, or A work-around is to cool in the interior of the sary distribution of electrical current. These ultrasound imaging. electrode itself to reduce temperatures at the deployable electrodes are larger in diameter electrode–tissue interface [21]. This solution than cooled electrodes (2.4-mm versus 1.5-mm works best when combined with power pulsdiameter), and the tines can be difficult to ading. That is, when the circuit impedance begins to spike, RF vance into many tumors. Both multiple-electrode and deploypower is suspended for several seconds to allow the tissue able techniques have been shown to increase the size of RF temperatures to equilibrate and water vapor around the elecablations. itself is a limitation for RF ablation. The mechanism of heating in RF ablation is oscillation of ions primarily in the extracellular fluid space, leading to Joule or resistive heat generation. The heating term from (1) is:

(a)

(b)

(c)

(d)

FIGURE 5 RF ablation electrodes in common clinical use: (a) unipolar water-cooled single and (b) cluster and deployable arrays with (c) star and (d) umbrella shapes. (Reprinted with permission from [1].) SEPTEMBER/OCTOBER 2011

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cables to the applicator antenna [30]. The antenna can be furIt is also possible to augment the electrical conductivity of the ther subdivided into handle, shaft, and radiating sections. The surrounding tissue medium by infusing an ionic fluid such as radiating section has received the most attention in the literasaline. This technique can be beneficial to cool the tissue around ture, with dozens of designs having been described [31], [32]. the electrode and counteract the low conductivity of dehydrated All antenna designs aim to achieve the same two goals: 1) efor charred tissue [26]. This is particularly useful during bipolar ficient radiation into the surrounding tissue to maximize energy RF ablation, since the electrode–tissue interface and current path delivery and 2) control of the radiation pattern to produce the is relatively small compared with unipolar ablation with disperdesired ablation zone geometry. In many cases, a spherical heatsive electrodes. Saline infusion is not widely used, however, being geometry is desirable to match the shape of most tumors cause the distribution of saline can be unpredictable and inhotargeted by thermal ablation, but more elongated shapes can mogenous. Some reports have shown that the saline can migrate be advantageous when using arrays of interstitial antennas or in the body cavity and causes severe heating distant from the when treating tumors surgically. intended treatment zone [27]. One of the early difficulties with microwave ablation was the Overall, RF ablation has found the greatest utility in treatinability to control heating along the proximal portion of the ing small tumors (up to 3-cm diameter) in the liver and kidney antenna, resulting in teardrop-shaped ablation zones. Similarly, as well as benign bone tumors. The use of deployable devices the small-diameter coaxial cables that comprise the antenna can or multiple-electrode systems has increased the efficacy of RF overheat and fail when delivering high microablation for medium tumors (up to 5-cm diamewave powers (. ,30 W). Overheating cables ter) and improved RF energy delivery in the lung. lead to excessive temperatures along the antenHowever, RF ablation still suffers from the probIn many ways, na shaft and potentially dangerous complications lem of relatively slow heat generation. A possible microwave ablation such as fistulas. Larger cables (>3-mm diameter) solution is to use higher generator powers (up may be the natural that handle high powers without overheating to 1,000 W), but such a system has not yet been evolution of RF are not suited for percutaneous application. One clinically deployed [28], [29]. Even with higher ablation. solution to this problem is to limit the power and powers, RF is limited by the reliance on electritime applied by the antenna. Early clinical studcal current conduction. High-impedance tissues, ies that used this technique were able to mitigate including the RF ablation zone itself, preclude efcomplications, but with predictable limitations on ablation size fective RF ablation when the applied power is limited. Therefore, and efficacy for common tumors. A more recent solution is to investigations have lately been focused on alternatives to RF for cool the antenna using either water or cryogenic gas expansion. thermal tumor ablation. With effective cooling, it is now possible to deliver more than 200 W of power through antennas 1.5 mm in diameter. As a Microwave Ablation result, microwaves can produce large ablation zones (above 4 Microwave tissue heating has been explored in many forms cm in diameter) in relatively short amounts of time (10 min or since the 1970s, primarily for externally applied low-temperless) (Figure 6). ature hyperthermia. The widespread utilization of microwaves for thermal tumor ablation is more recent. As with RF ablation, In many ways, microwave ablation may be the natural evomicrowave energy is delivered into the tumor using a needlelution of RF ablation. Since electromagnetic wave propagation like applicator. However, microwaves radiate from an interstitial is not limited by desiccated tissue, water vapor, or low-water antenna. Since radiation occurs by virtue of the antenna geomcontent tissues, microwave ablation may be a more effective etry, no ground pads are required, and the drawbacks associated modality for tumors in the lung, bone, or cystic lesions. Microwith electrical current conduction are minimized. In particular, waves also seem able to create larger ablation zones in less time microwave energy will propagate through all types of tissue, inthan RF, making them attractive for those procedures for which cluding water vapor and dehydrated or desiccated tissue inside RF ablation has become more conventional (liver, kidney, and of ablation zones. Heat is generated primarily by electromagbenign tumors of the bone). Health-care economics and longnetic interaction with polar molecules such as water. Similar to term clinical data will determine how many centers switch. RF ablation, the heat generation term from (1) is

Laser Ablation sE2 Qh 5 2 where s is now the effective conductivity, which accounts for effective and displacement currents. It is important to remember that while low-conductivity tissues will generate less heat than a higher conductivity tissue under the same applied field, energy will propagate through those tissues with less attenuation; propagation and attenuation are inversely related. The microwave power source may be either based on solidstate or vacuum devices, and power is distributed via coaxial 34 IEEE PULSE

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Lasers have a long and varied history in the medical field and are more commonly associated with eye, skin, vascular, and dental applications than do oncology. However, laser tumor ablation has evolved over the last two decades to become a viable treatment option for many of the same tumors as RF or microwave ablation [16], [33]. Laser light interacts with various tissue components depending on the light wavelength, but most ablation systems target the 800–1,100-nm range to capitalize on deeper energy penetration. Laser light is very energetic and generates heat rapidly near the applicator. Attenuation can be equally rapid; however,




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FIGURE 6 Microwave ablation created using 140 W at 2.45 GHz for 10 min. The (a) 4.5 3 6.0 cm ablation zone was produced by a 1.5-mm diameter, gas-cooled triaxial antenna in in vivo porcine liver. The same system was used to ablate the 3.2 3 3.4 cm primary liver tumor shown (b) before and (c) after treatment.

the zone of active heating is approximately 1 cm from the Ultrasound Ablation applicator. Even more importantly, as with RF ablation, dehyUltrasound energy can be delivered using interstitial devicdrated and especially charred tissue increases light attenuation es or external transducers. Interstitial devices are similar to and inhibits energy delivery [34]. Therefore, laser ablation systhose of other ablation modalities in that they take a needletems employ power control and applicator cooling to prevent like form; however, the applicator typically contains an array charring. There are several laser applicator variants described of transducers whose wave amplitude and phase can be indiin the literature, but most systems use a diffusing tip to more vidually controlled [37], [38]. This permits more control over isotropically distribute light around the applicator tip [35]. Dethe heating pattern— axially and longitudinally— than can spite these technical advances, laser ablations from a single apcurrently be achieved with other interstitial devices. Howplicator are typically not larger than 2 cm in diameter. Larger ever, these devices have not yet been made widely available tumors must be treated with multiple applicators, with some in the marketplace, so clinical data are currently lacking. series reporting an average of more than four applicators per Perhaps, the most attractive feature of ultrasound is the treatment [16]. ability to ablate tissue noninvasively. HIFU relies on conDespite this potential drawback, laser ablation applicators verging ultrasound beams from an external source to prohave an additional feature that makes them increasingly interduce a focal zone of ultrasound heating [39]. The heating esting: MRI compatibility. The applicators are fabricated from zone is typically about the size of a grain of cooked rice and glass optical fibers, allowing them to be used safely in MRI without creating substantial imaging defects. An MRI is 30 °C important because it can be used to precisely measure temperature and thermal ΔT dose [36]. Therefore, laser ablation can be performed in conjunction with MRI thermometry to accurately treat 5 °C tumors in difficult locations such as the brain and prostate with good confidence about the treatment zone and lack of thermal damage to critical adjacent nervous tissues (Figure 7). Therefore, while laser ablation has only been used by a few centers worldwide to date, its clinical utilization may advance in large FIGURE 7 An MRI-guided laser ablation in the brain. The diffusing laser fiber (upper right) is placed academic centers that have transcranially into the tumor using MRI guidance. MR thermometry provides feedback about ablainterventional MRI or MRI tion growth in near real time, allowing accurate control over the treatment zone to avoid peripheral tissue damage. (Images courtesy of Jason Stafford. Reprinted with permission from [33].) thermometry available. SEPTEMBER/OCTOBER 2011

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to cell death. For this reason, most cryoablation procedures incorporate at a succession of freeze–thaw cycles to maxirapeutic Transduc mize cell death [41]. er The Modern cryoablation eqImaging uipment uses common reTransducer frigeration techniques. Most systems continue to use the Joule–Thomson effect with argon as the refrigerant. (a) As the argon gas expands in the tip of the cryoprobe, Undamaged Tissue it creates a negative heat in Front of Focus source that cools the adjacent tissue to approximately Tumor HIFU Beam 2160 °C. The rest of the abFocus lation zone grows by thermal Target Organ conduction, with the lethal isotherm lying 4–10 mm inAblated Tumor Volume (Lesions) side of the edge of the visible ice ball (Figure 9). Joule– (b) Thomson systems have been used now for decades to great FIGURE 8 HIFU involves the overlapping of several small focal zones to create a complete treatment. cancers of the liver, lung, (a) An external transducer is coupled to the skin surface to efficiently apply energy with a convergkidney, prostate, breast, and ing beam form. (b) When the beam converges, the energy density rapidly increases, leading to small focal zones of thermal damage in the target zone. (Reprinted with permission from [39].) bone, but the ablation zone produced by a given cryoprobe is inversely proportional to its surface area (diameter). can be produced in several seconds. An entire treatment is In addition, small-diameter cryoprobes produce a weaker heat accomplished by overlapping hundreds of these focal zones sink than larger probes because of the smaller to cover the tumor volume beginning with pressure drop and limitations on gas flow. Althe distal aspect (Figure 8). HIFU proceternative refrigeration techniques include gases dures can take hours to complete and require Laser light is very held near the critical point. At this point, many precise control over the treatment zone over energetic and materials (such as nitrogen) have a markedly that time. Therefore, HIFU has been applied generates heat rapidly increased heat capacity that creates a greater primarily in areas that are easily accessible near the applicator. heat sink. Since the material is at the critical and without substantial motion from breathpoint, it has the viscosity of a gas and is easier ing, such as benign fibroids in the uterus and to move through small-diameter cryoprobes. breast and benign prostate hyperplasia. As the However, controlling the gas at the critical point can be techtechnology of generating and controlling HIFU improves, nically challenging, so systems with this technology are not applications in more difficult locations such as the brain or yet widely available. abdomen may become clinically feasible. The main advantages to cryoablation over other thermal ablation modalities are increased visibility on imaging due to Hypothermic Effects ice-ball formation, reliance only on thermal diffusion (rather Cryoablation aims to capitalize on all of the detrimental effects than energy interaction to produce heat), and less damage to many have encountered during cryopreservation [40]. Ice crystal the tissue architecture. The freezing process leaves the collaformation, cell membrane rupture, and osmotic imbalances are gen structures largely intact, potentially allowing faster and the primary mechanisms for cell death. Cooling near the cryomore complete tissue healing [42]. Yet, cryoablation is not inablation source (usually a cryoprobe) is rapid enough to cause dicated for some types of cancer. Cryoablation does not provide intracellular ice formation, which mechanically expands the cell a cautery effect, so the rapid introduction of cellular contents membrane beyond repair and almost always kills the cell. Tisinto the bloodstream after thawing can lead to a dangerous resues more peripheral to the cryoprobe cool slower. Extracellular sponse known as cryoshock [43]. A similar effect can be noted ice formation leads to an increase in ion concentration in the with neuroendocrine tumors. For this reason, cryoablation is remaining extracellular fluid, which causes cellular dehydration not typically used to treat tumors in patients with cirrhosis or as the cell tries to create equilibrium. Continued ice formation poor clotting factors. In addition, while the ice ball is easily viscreates mechanical stress on the shrunken cell. When the tisible, the lethal zone inside that ice ball is not clear on imaging. sue thaws, the osmotic imbalance is typically amplified and leads 36 IEEE PULSE

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Ice Ball Argon Input

Vacuum Vacuum Expansion Chamber (a)

(b)

FIGURE 9 Cryoablation using a Joule–Thomson argon probe. (a) Argon expansion near the probe tip creates (b) an ice ball that is easily visible on CT. The lethal isotherm of approximately −40 °C lies several millimeters inside the ice-ball surface. (Reprinted with permission from [1].)

Finally, gas tanks needed to store the cryogen are not always widely available, and their size can make cryoablation systems more cumbersome than hyperthermic ablation systems. Nevertheless, cryoablation has a prominent role in the thermal ablation armamentarium.

Conclusions Image-guided thermal tumor ablation continues to make inroads as a viable treatment option for many focal cancers. Ablation methods based on both heat and cold can be used, and there is no single optimal treatment for all clinical presentations. RF ablation has been the dominant energy for hyperthermic ablation to date but may be supplanted by microwave ablation in the coming years. Laser ablation offers MRI compatibility for precise thermal monitoring, while HIFU offers external energy delivery along with MRI compatibility. Cryoablation is used for many of the same tumors and is more visible that hyperthermic ablations on CT and ultrasound but may not be suitable for some cancers because of a lack of coagulation. Despite several years’ worth of clinical experience, most ablation systems are in a first or perhaps second generation of development. As technologies for energy delivering continue to improve, expect to hear more about thermal tumor ablation. Chris Brace ([email protected]) __________ is with the University of Wisconsin, Madison.

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MRI-Controlled Ultrasound Thermal Therapy By Robert Staruch, Rajiv Chopra, and Kullervo Hynynen

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dvances in medical imaging have enabled the development of new minimally and completely noninvasive therapies that produce a desired biological effect in a target, such as a tumor, with minimal damage to the surrounding tissue. One means of noninvasively achieving bioeffects in tissue is the use of ultrasound to generate heat. Thermal ablation uses temperatures greater than 50 °C, where cellular and tissue structural proteins denature in seconds, losing their shape in the process of thermal coagulation, resulting in an irreversible loss of cell structure and function. Mild hyperthermia uses lower temperatures (40–43 °C) maintained for longer durations (minutes to hours), resulting in temporary changes that enhance

Technology and Delivery Strategies

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Tumor

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FIGURE 1 Strategies for heating tumors using externally focused therapeutic ultrasound transducers. Spherically curved transducers (a) must be geometrically focused and mechanically steered to heat multiple millimeter-sized focal spots while the focus of phased-array transducers (b) can be electronically focused and steered. Both scenarios require a clear acoustic path from the skin to the focus to achieve high energy deposition and temperature elevation at the focus and prevent unintended heating in intervening tissue. (c) Complex tissue interfaces and undesired hot spots.

ble temperature elevation between the transducer and the focus. and localize the effects of other therapies. Increased blood flow Pulsed exposures of a few milliseconds in length produce presin response to heat makes tumors more sensitive to radiation by sure elevations that can be used with ultrasound increasing their oxygenation; it also brings more contrast agents to enhance blood vessel permeanticancer drugs to tumors. Additionally, mild ability without increasing temperature. Conheating causes widening of gaps between the One means of tinuous-wave exposures of 1–10 s can increase cells lining tumor vessels, allowing more drug to noninvasively temperatures to greater than 55 °C for thermal leave the vessels and reach tumor cells. ablation (irreversible thermal damage of tissue). Specialized ultrasound transducers can be achieving bioeffects Longer continuous-wave exposures of several used to generate focal regions of heating nonin tissue is the use minutes at lower power can be used to achieve invasively, without inserting anything into of ultrasound to mild heating in the hyperthermia regime (40– the body or affecting the tissue outside the generate heat. 43 °C), subject to the smoothing effect of thermal target region. Ultrasound thermal therapy can conduction and the cooling effect of blood flow. be used with magnetic resonance (MR) imClinically relevant targets such as tumors are aging (MRI) guidance and MRI temperature commonly much larger than the millimeter-sized ultrasound fofeedback to automatically control temperature distributions cus (Figure 1). Larger regions can be heated either by mechaniduring heating, producing accurate thermal lesions, or maincally repositioning a single element transducer or electronically taining optimal conditions to enhance drug delivery. steering the focus generated by tens or hundreds of small, independently driven transducer elements in a phased array [1]. MRI-Guided Focused Ultrasound: However, the temperatures achieved at the focus are dependent Principles and Development not only on the ultrasound frequency and applied power but also on unknown, spatially and temporally varying blood flow Ultrasound and ultrasound absorption in tissue. Complex tissue interfaces Ultrasound is a pressure wave that propagates within a medium can affect the position of the ultrasound focus, and undesired inducing particle vibrations at frequencies of 20 kHz to 20 MHz hot spots can occur if there is bone or air in the beam path. and causing a variety of biological effects. These include the generation of heat, mechanical displacement, and the creation and manipulation of gas bubbles (cavitation). As the ultrasound travMRI Guidance and Thermometry els through tissue, it is attenuated through absorption, and the Imaging guidance is vital in treatment planning for noninvasive energy of the induced particle vibrations is converted to heat. thermal therapy and is also useful in the posttreatment assessBy generating ultrasound with spherically focused piezoceramic ment of tissue changes caused by thermal damage. MR has extransducers, a focal point on the order of the ultrasound wavecellent anatomic resolution and high sensitivity for both tumor length (1.5 mm at 1 MHz in water) can be obtained. Increased depiction and thermal damage assessment, allowing for accurate energy deposition at the focus enables the heating of millimetertreatment planning and verification. MR is also the only clinisized targets several centimeters beneath the skin, with negligically accepted method to noninvasively quantify temperature 40 IEEE PULSE

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background phase images spanning the entire range of poschanges deep within tissue. MR thermometry can be used to sible displacements is collected, and the correct reference for identify the location of the ultrasound focus during low-power each subsequent image is selected during treatment [7]. The exposures [2] as well as to monitor temperatures in the target phase-difference technique is also sensitive to slow variations and normal tissues during treatment [3]. This temporal and spain the main magnetic field, which can be measured and cortial temperature information allows us to nonivasively estimate rected in image regions where the temperature is known to be the delivered time–temperature history, or thermal dose, and is constant. Finally, because the technique measures a relative the most important feature of MRI for guiding thermal therapy. temperature change, it requires accurate temMost tissue properties that can be measured perature information when the background using MRI vary with temperature, including images are acquired. Despite these limitations, proton resonance frequency (PRF), T1 relaxation Imaging guidance phase-difference MR thermometry has been time, proton density, and diffusion. For thermal is vital in treatment essential to the clinical translation of noninvatherapy, the phase-difference PRF shift techplanning for sive ultrasound thermal therapy. nique [4] has several advantages over the other noninvasive thermal techniques and is by far the most commonly used. The physical basis for the PRF technique Commercial Development therapy and is is the miniscule change in local magnetic field Integration of ultrasound heating technolalso useful in the around water protons as they are heated while in ogy into the MRI environment was an early posttreatment the MRI, caused by the weakening of hydrogen technical challenge. The strong magnetic assessment of tissue bonds with increase in temperature. The resofields required ultrasound transducers to be changes caused by nance frequency of a water proton is proportional rebuilt using MRI-compatible materials, with thermal damage. to the magnetic field it experiences, and during the remaining ferromagnetic objects such as the echo time between MR signal excitation and impedance matching networks being kept at measurement, the small frequency change rea safe distance away from the magnet bore. sults in an accumulated phase offset proportional to the change Traditional electromagnetic motors are commonly replaced in temperature. These offsets are captured in MR phase images, by piezoceramic actuators and optical encoders, but hywhich are typically ignored but accompany the more familiar draulic and lead-screw designs are also used. MR scanner magnitude image in all gradient-echo MRI acquisitions. These rooms are electrically shielded, and all signals driving the images also include phase variations arising from static sources transducer and positioning system must be filtered and of field distortion, which arise every time an object is placed in connected into the room’s Faraday cage through a groundthe bore. By subtracting phase images acquired before and dured radio frequency penetration panel. Finally, customized ing (or after) heating, the relative temperature changes can be imaging coils are often used to improve image SNR for acisolated with [4]: curate thermometry. Through partnership with GE Medical Systems, a robust ref22f1 search system was developed in the early 1990s and used in a . (1) DT 5 # feasibility study to treat patients with breast fibroadenomas [8]. g TE # a # B0 The system consisted of a single element transducer housed in a water bath with the positioning system. The patient would lie This relationship between temperature change 1 DT 2 and prone on top of the device while a series of 10-s sonications sepaphase difference 1 f22f1 2 depends only on the main magnetrated by 1-min cooling intervals were delivered in an overlapping ic field strength (B0, often 1.5 or 3.0 T), the prescribed echo raster pattern to achieve complete thermal coagulation of a tartime (TE, typically 5–30 ms), the gyromagnetic constant ( get region prescribed on anatomical T2-weighted MR images. In g = 42.58 MHz/T), and the PRF shift coefficient (a = 0.01 this initial clinical study, the investigators demonstrated that MR ppm/°C). The PRF shift coefficient is a constant for a wide temperature measurements could be used for treatment targetrange of temperatures (0–100 °C) across all nonadipose tising and monitoring and that prescribed targets could be noninvasues even after coagulation [5]. Phase images can be rapidly sively ablated using MR-guided focused ultrasound. acquired (typically 0.1–5 s) through the use of fast gradientCurrently, a variety of sophisticated phased-array clinical sysecho pulse sequences, while maintaining sufficient signal-totems are either clinically approved or under investigational use noise ratio (SNR) for temperature measurement uncertainty for the following applications: uterine fibroids [9], bone metasless than 1 °C. tases [10], breast cancer [11], brain tumors [12], and functional The biggest challenge with the phase subtraction techneurosurgery in the brain [13]. For uterine fibroids, more than nique is motion. Object motion in the image plane causes 6,000 patients have now been treated in more than 50 centers misregistration of the image subtraction, while motion outworldwide. side the image plane can cause artifactual changes in the These vendor systems are highly optimized for their spebackground phase that mask the temperature signal. There cific clinical applications but somewhat restrictive for research are some promising solutions: the self-referenced method investigations in small animals, which require more flexibili[6] estimates the background phase from the current image ty, higher spatial resolution, and higher throughput. To bridge and thus isn’t affected by sudden displacements between imthe gap between home-built experiment setups and clinical ages. For periodic displacements, a series of rapidly acquired SEPTEMBER/OCTOBER 2011

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FIGURE 2 A commercially available MRI-compatible system designed to enable focused ultrasound research in small animals. (a) RF electronics. (b) MRI-compatible positioning system. (c) MRI-compatible transducers. (d) Independent of vendor and field strength. (Images courtesy of Dr. Adam Waspe.)

[15]. These variations, caused mainly by tissue interfaces and vendor-specific systems, commercial-grade vendor-indepenvariations in energy absorption, are perhaps unimportant in dent systems are being developed for use in small animals thermal ablation as long as a certain threshold is reached, but [14], with a goal of lowering the technology barrier to investimild hyperthermia applications require a much finer degree of gate applications of focused ultrasound. Based on a laboratory control. In an MRI-controlled approach, temperature measuresystem developed for research, the FUS Instruments RK100 ments are made rapidly and used as input to a feedback control small animal system consists of an MRI-compatible computeralgorithm that automatically updates exposure parameters durcontrolled three-axis positioner as well as calibrated focused ing treatment to track the prescribed target temultrasound transducers and driving electronics peratures, achieving and maintaining a desired (Figure 2). It uses nonmagnetic piezoceramic spatial and temporal heating pattern. motors, includes appropriate signal filters and To bridge the gap What is fast enough to be real time? The electrical isolation, and has been tested at 1.5 between home-built thermometry requirements for closed-loop and 3 T on all of the major MRI system vendors. experiment setups feedback control depend on the type of treatand clinical vendorment and tradeoffs that can be made. In pointMRI-Controlled Ultrasound Thermal by-point ablation, large temperature increases Therapy: From MRI Guidance to Control specific systems, in small focal regions over short durations reFigure 3 illustrates the differences between MRIcommercial-grade quire high spatial and temporal resolution, but guided and MRI-controlled ultrasound thermal vendor-independent the requirement for temperature resolution is therapy. In a typical MR-guided treatment, anasystems are being relaxed, as it is primarily important that damtomical MR images are used in treatment plandeveloped for use in age occurs. For volumetric ablation where a ning to prescribe a target region and temperasmall animals. large region is rapidly heated to high temperature or thermal dose. Energy is deposited with tures all at once, temporal resolution is impora predefined power, spatial deposition pattern, tant, but the spatial resolution requirement is and duration, and the resulting temperature elrelaxed. For mild heating to enhance chemo- or radiotherapy, evation is measured with MRI, verifying treatment outcome by temperatures are gradually increased and maintained over a thermal dose or other indicators of thermal damage. In a series long duration with the conduction effects spreading the heat of uterine fibroid treatments, temperature elevations for a given over time. In this case, temporal and spatial resolution are applied power were seen to vary by 10–20 °C, between both less important, but precise temperature control is required, different patients and individual sonications for one patient 42 IEEE PULSE

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FIGURE 3 An MRI-controlled ultrasound thermal therapy. Target regions, temperatures, and treatment duration are prescribed based on anatomical MR images in treatment planning. During treatment, energy deposition is affected by spatial and temporal variations in blood flow and ultrasound absorption. MR thermometry allows temperature monitoring during heating. This time–temperature history provides a measure of treatment success, in addition to posttreatment imaging, which can identify tissue changes indicative of thermal damage. In an MRI-controlled approach, target temperatures measured by MR thermometry are used to automatically adjust exposure parameters during treatment to compensate for variations in heating efficiency.

from Chrit Moonen’s laboratory in Bordeaux, France [18]. In their approach, every time a temperature image is acquired (less than 1 s), the energy to be deposited at each point of a targeted three-dimensional tissue volume is prescribed Binary Control of Uterine Fibroid Ablation using a customized version of the traditional proportionalThe simplest method to control treatment is determining integral-derivative feedback control algorithm that accounts when to turn power on or off. This binary control technique specifically for the spread of heat by thermal conduction. has been applied clinically in the ablation of uterine fibroids The proportional term corrects for the instanwith the Philips Sonalleve MR-HIFU systaneous error between the measured and tartem [16], [17]. Instead of applying a series of get temperatures. The derivative term acts to short, millimeter-sized ablations interleaved The phase-difference increase power when the target temperature with cooling delays, their approach is to elecPRF shift technique is changing, and the integral term uses the tronically steer a focal point along concentric has several sum of past temperature errors to gradually circles to efficiently heat centimeter-sized advantages over the adjust the applied power. An additional term regions. During treatment, temperatures are other techniques and adds energy to replace heat dissipated by thermeasured in planes across and along the beam mal conduction, and the prescribed power is path, and the controller switches from smaller is by far the most scaled by a constant that adjusts for variations to larger circular trajectories when the avercommonly used. in heating efficiency. This prescribed ideal enage temperature in the boundary voxels of the ergy deposition for the current time step is dicurrent circle reach a threshold temperature vided into a physically realizable series of short sonications of 57 °C, treating targets up to 16 mm in diameter. This simat discrete locations, using a model of the beam’s acoustic ple approach robustly controls target border temperatures field to account for beam overlap and optimally deliver enand achieves precise, reproducible lesions with a clinical ergy between MRI temperature measurements. Targeting a MRI-controlled focused ultrasound system. 12-mm diameter spherical volume in an in vivo rabbit thigh using a 256-element phased-array transducer, temperature Proportional-Integral-Derivative Control elevations of 10 °C were achieved and maintained for sevof Thermal Ablation eral minutes, with maximum overshoots of about 3 °C in Several research groups have developed more sophisticated the center of the target volume [18]. This important work control algorithms, with impressive in vivo results coming as fluctuations of 1–2 °C can cause dramatic changes in biological effect.


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FIGURE 4 (a) An MRI-controlled focused ultrasound hyperthermia setup showing a rabbit lying on its side in an MRI above a degassed water bath containing a single-element focused ultrasound transducer. During continuous sonication, the transducer is rapidly repositioned to heat a 10-mm diameter circular target region. (b) A screenshot of the treatment control software developed for MRIcontrolled focused ultrasound hyperthermia, displaying temperature image and horizontal temperature profile (right) and time–temperature history (bottom left) achieved by adjusting ultrasound output power based on MR temperature measurements.

and temperature images, and applies a simple proportionalintegral control algorithm to determine the output powers to be delivered by the transducer. A screenshot is shown in Figure 4(b). Temperature measurements in selected pixels Mild Hyperthermia for Localized Drug Release along the scan path are used to temporally adjust the applied Similar control strategies can be applied to achieve proacoustic power every 5 s when a new image is acquired, and longed, mild heating to enhance or trigger other therapies spatial control is achieved by switching the power eight times without direct tissue damage. In our research, MRI-conper second based on the location of the focus. trolled focused ultrasound generates mild hyperthermia to Figure 5(a) shows a snapshot of the temperaachieve localized drug release from temperture distribution achieved while heating a 10ature-sensitive, drug-carrying nanoparticles mm diameter target region to temperatures of called liposomes [19]. Traditional 43 °C during intravenous liposome infusion. The In feasibility experiments, a commercial electromagnetic time–temperature curve in Figure 5(b) shows formulation of thermosensitive liposomal that the temperature in the target region was doxorubicin was infused intravenously in motors are maintained for 20 min, with the temperatures in healthy rabbits during MRI-controlled heating commonly replaced the surrounding unheated regions staying below of 10 mm diameter regions in the thigh muscle by piezoceramic 37 °C, demonstrating the localization of heating to a temperature of 43 °C for 20 min, using the actuators and optical to the 5-mm radius target region. Drug concensetup shown in Figure 4(a). Liposomes in the encoders. trations measured in excised tissue samples by vasculature remain intact but rapidly release the fluorescence intensity of the released chemotheir chemotherapeutic payload when passing therapeutic agent doxorubicin showed a 16-fold through vessels of the heated region, allowing increase in drug deposited in heated muscle versus unheated the free drug to leave the vasculature and accumulate in the muscle in the contralateral thigh. This work provided evidence targeted tissue [20]. Uniform heating of a 10-mm diameter that MRI-controlled focused ultrasound hyperthermia can be target region using a 1-mm diameter focus was achieved by used with temperature-sensitive drug carriers to achieve imagemechanically scanning a single-element focused ultrasound guided localized drug release [19]. transducer along the periphery of the target region at 1 r/s using a computer-controlled three-axis positioning system [14] during continuous sonication and MRI. Raw MR data was imTransurethral Thermal Therapy mediately transferred to a control computer, where customA major limitation for noninvasive, externally focused ultraized software developed in MATLAB reconstructs anatomical sound thermal therapy is that it requires a clear acoustic path represents the first example of three-dimensional temperature control in vivo using externally focused ultrasound.

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FIGURE 5 An MRI-controlled focused ultrasound hyperthermia for thermally mediated drug delivery. (a) Temperatures greater than 39 °C overlaid on corresponding magnitude images acquired in the plane indicated in Figure 4(a) at one time point during the 20-min plateau period. (b) Temperatures in the indicated control pixels are used to adjust applied power, maintaining uniform temperature distributions near the desired temperature of 43 °C in the 10-mm diameter target region, with minimal heating of surrounding tissue, as shown in the time–temperature history.

sibility study was performed in men who were scheduled for from the skin to the target. For some targets inaccessible to radical prostatectomy immediately after a conservative ulnoninvasive externally focused transducers due to bone, air, trasound thermal therapy treatment with an arbitrary target or complex soft tissue interfaces along the beam path, miniboundary defined safely within the prostate boundary. These mally invasive intracavitary devices have been developed. promising early results suggest that MRI-controlled transOver the past ten years, members of our group have been urethral ultrasound thermal therapy is feasible and safe in developing a transurethral system for minimally invasive, humans [21]. MRI-controlled ultrasound thermal therapy of prostate cancer [21]. Their MR-compatible transurethral ultrasound devices consist of a linear array of four Future Directions and Applications to nine planar ultrasound transducers with each of MRI-Controlled Focused Ultrasound Object motion in the element producing a directional, collimated ulThe examples shown here demonstrate the benimage plane causes trasound beam [Figure 6(a) and (b)]. The device efit of applying feedback control to MRI-guided can be detected on anatomical MR images for ultrasound thermal therapy: improved reliabilmisregistration treatment planning, and for spatial control of ity (and hence safety) of thermal ablation, and of the image heating, the device is rotated by an MR-compatprecise control of mild hyperthermia for optisubtraction, while ible positioning system. During treatment, MR mal enhancement of radio- or chemotherapy. motion outside the temperature images are continuously acquired Several important challenges and opportunities image plane can for each element, and the device rotation rate exist: two issues that have attracted attention recause artifactual as well as the transducer element frequency cently are the treatment of moving organs and and power are adjusted to achieve a desired advanced control of drug delivery. changes in the temperature threshold at the intersection of As mentioned earlier, MR thermometry is background phase the ultrasound beam and the prescribed target sensitive to motion, preventing treatment of tarthat mask the boundary, taking less than 30 min to coagulate gets in the abdomen such as tumors of the liver, temperature signal. a large prostate. kidney, and pancreas. In a promising approach Figure 6(c) shows the maximum temperato correct for periodic respiratory motion [29], ture elevations measured during MRI-cona series of pretreatment background phase imtrolled ultrasound thermal therapy for a canine prostate, ages are acquired to sample the entire range of motion. During demonstrating a good agreement between the target boundtreatment, images are registered to a common reference posiary in white and the 55 °C isotherm in red, which in other tion and an appropriate background phase image is selected to experiments was also shown to match the histologically veriisolate temperature changes, producing seemingly stationary fied coagulated region [22]. In this case, the target region temperature images. However, being able to image the moving was defined to be smaller than the prostate boundary shown target is only half the problem; the heat deposition has to track in black. Based on successful simulation [23], [24], gel [25], the target too. Generally, this is done by modeling the periodic [26], and in vivo [27], [28] results, a clinical safety and feamotion to predict the target’s future location and prescribing a SEPTEMBER/OCTOBER 2011

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FIGURE 6 (a) Transurethral applicator developed for minimally invasive MRI-controlled ultrasound thermal therapy for prostate cancer. (b) A closeup showing an array of planar transducer elements that deliver collimated ultrasound beams into the prostate during continuous sonication, device rotation, and MR thermometry. (c) Maximum temperature distribution achieved during MRI-controlled thermal therapy of a canine prostate, acquired in a transverse plane to the cylindrical device. The 55 °C isotherm (red), used as a threshold to ensure thermal damage, corresponds well with the target boundary (white), which in this case was defined within the prostate boundary (black). The white cross indicates the device location. (Images courtesy of Dr. W. Apoutou N’Djin.)

spatial deposition pattern to match it by rapidly switching the location of a phased-array transducer’s focus with a watchful eye for system latency. Advanced delivery approaches like this will eventually allow for noninvasive ultrasound ablation or hyperthermia in abdominal organs. In the current MRI-controlled approaches, temperature measurements are typically used as the only input for feedback control, prospectively selecting a time–temperature history to be delivered. When hyperthermia is used to achieve drug delivery, a new approach using thermosensitive liposomes that release both drugs and MR contrast agents upon heating has been proposed to control treatment based on the quantity of drug delivered in a targeted region [30]. In this approach, MR temperature measurements are used by a standard feedback control algorithm to maintain optimal conditions for triggered release, while contrastenhanced images acquired either simultaneously or periodically allow the clinicians (or, in the future, a control algorithm) to monitor drug deposition, adjusting the prescribed spatial temperature distribution to achieve a desired spatial drug distribution. 46 IEEE PULSE

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Focused ultrasound provides a means of noninvasively heating targets deep within the body to either high temperatures for direct thermal damage or mild temperatures to enhance the effects of radiation or chemotherapy. MRI guidance enables accurate target definition and treatment assessment, with MR thermometry allowing localization of the focus and temperature monitoring during treatment. This noninvasive approach has provided uterine fibroid pain relief for thousands of patients worldwide. However, for a given ultrasound power and duration, temperature elevations vary considerably. Online feedback control of treatment parameters based on MR temperature measurements made during heating dramatically increases the reproducibility of thermal exposures for more predictable lesions or to maintain optimal conditions for enhanced drug delivery. Early clinical results suggest the feasibility of MRIcontrolled therapies for targets such as uterine fibroids and prostate cancer, while ongoing research aims to enable the treatment of tumors in moving organs and provide accurate control of heat-triggered drug delivery.

Acknowledgments The authors thank Apoutou N’Djin and Adam Waspe for generously providing figures for this manuscript as well as Aaron Boyes, Mathieu Burtnyk and Charles Mougenot for many useful discussions. We also thank members of the Focused Ultrasound Laboratory at Sunnybrook Health Sciences Centre for technical assistance with the drug delivery experiments, especially Alexandra Garces, Shawna Rideout, Melissa Togtema, and Anthony Chau. Robert Staruch ([email protected]), _______________ Rajiv Chopra, and Kullervo Hynynen are with the Centre for Research in Image-Guided Therapeutics, Sunnybrook Health Sciences Centre in Toronto, Canada, and the Department of Medical Biophysics, University of Toronto, Canada.

References [1] D. R. Daum and K. Hynynen, “Thermal dose optimization via temporal switching in ultrasound surgery,” IEEE Trans. Ultrason. Ferroelect. Freq. Contr., vol. 45, no. 1, pp. 208–215, 1998. [2] A. H. Chung, K. Hynynen, V. Colucci, K. Oshio, H. E. Cline, and F. A. Jolesz, “Optimization of spoiled gradient-echo phase imaging for in vivo localization of a focused ultrasound beam,” Magn. Reson. Med., vol. 36, pp. 745–752, Nov. 1996. [3] H. E. Cline, J. F. Schenck, R. D. Watkins, K. Hynynen, and F. A. Jolesz, “Magnetic resonance-guided thermal surgery,” Magn. Reson. Med., vol. 30, no. 1, pp. 98–106, 1993. [4] Y. Ishihara, A. Calderon, H. Watanabe, K. Okamoto, Y. Suzuki, K. Kuroda, and Y. Suzuki, “A precise and fast temperature mapping using water proton chemical shift,” Magn. Reson. Med., vol. 34, pp. 814–823, Dec.1995. [5] R. D. Peters, R. S. Hinks, and R. M. Henkelman, “Ex vivo tissuetype independence in proton-resonance frequency shift MR thermometry,” Magn. Reson. Med., vol. 40, pp. 454–459, Sept. 1998.




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[6] V. Rieke, K. K. Vigen, G. Sommer, B. L. Daniel, J. M. Pauly, and K. Butts, “Referenceless PRF shift thermometry,” Magn. Reson. Med., vol. 51, pp. 1223–1231, June 2004.

[19] R. Staruch, R. Chopra, and K. Hynynen, “Localised drug release using MRI-controlled focused ultrasound hyperthermia,” Int. J. Hyperthermia, vol. 27, no. 2, pp. 156–171, 2011.

[7] S. Roujol, M. Ries, B. Quesson, C. Moonen, and B. D. de Senneville, “Real-time MR-thermometry and dosimetry for interventional guidance on abdominal organs,” Magn. Reson. Med., vol. 63, no. 4, pp. 1080–1087, 2010.

[20]D. Needham and M. W. Dewhirst, “The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors,” Adv. Drug Deliv. Rev., vol. 53, pp. 285–305, Dec. 31, 2001.

[8] K. Hynynen, O. Pomeroy, D. N. Smith, P. E. Huber, N. J. McDannold, J. Kettenbach, J. Baum, S. Singer, and F. A. Jolesz, “MR imaging-guided focused ultrasound surgery of fibroadenomas in the breast: A feasibility study,” Radiology, vol. 219, no. 1, pp. 176–185, 2001.

[21]R. Chopra, M. Burtnyk, W. A. N’Djin, and M. Bronskill, “MRIcontrolled transurethral ultrasound therapy for localised prostate cancer,” Int. J. Hyperthermia, vol. 26, no. 8, pp. 804–821, 2010.

[9] C. M. C. Tempany, E. A. Stewart, N. McDannold, B. J. Quade, F. A. Jolesz, and K. Hynynen, “MR imaging-guided focused ultrasound surgery of uterine leiomyomas: A feasibility study,” Radiology, vol. 226, no. 3, pp. 897–905, 2003. [10] D. Gianfelice, C. Gupta, W. Kucharczyk, P. Bret, D. Havill, and M. Clemons, “Palliative treatment of painful bone metastases with MR imaging-guided focused ultrasound,” Radiology, vol. 249, no. 1, pp. 355–363, 2008. [11] H. Furusawa, K. Namba, H. Nakahara, C. Tanaka, Y. Yasuda, E. Hirabara, M. Imahariyama, and K. Komaki, “The evolving nonsurgical ablation of breast cancer: MR guided focused ultrasound (MRgFUS),” Breast Cancer, vol. 14, no. 1, pp. 55–58, 2007. [12]N. McDannold, G. T. Clement, P. Black, F. Jolesz, and K. Hynynen, “Transcranial magnetic resonance imaging-guided focused ultrasound surgery of brain tumors: Initial findings in 3 patients,” Neurosurgery, vol. 66, no. 2, pp. 323–332, 2010. [13] E. Martin, D. Jeanmonod, A. Morel, E. Zadicario, and B. Werner, “High-intensity focused ultrasound for noninvasive functional neurosurgery,” Ann. Neurol., vol. 66, no. 6, pp. 858–861, 2009. [14] R. Chopra, L. Curiel, R. Staruch, L. Morrison, and K. Hynynen, “An MRI-compatible system for focused ultrasound experiments in small animal models,” Med. Phys., vol. 36, no. 5, pp. 1867–1874, 2009. [15] N. McDannold, C. M. Tempany, F. M. Fennessy, M. J. So, F. J. Rybicki, E. A. Stewart, F. A. Jolesz, and K. Hynynen, “Uterine leiomyomas: MR imaging-based thermometry and thermal dosimetry during focused ultrasound thermal ablation,” Radiology, vol. 240, pp. 263–272, July 2006. [16] M. O. Kohler, C. Mougenot, B. Quesson, J. Enholm, B. Le Bail, C. Laurent, C. T. Moonen, and G. J. Ehnholm, “Volumetric HIFU ablation under 3D guidance of rapid MRI thermometry,” Med. Phys., vol. 36, pp. 3521–3535, Aug. 2009. [17] J. K. Enholm, M. O. Kohler, B. Quesson, C. Mougenot, C. T. Moonen, and S. D. Sokka, “Improved volumetric MR-HIFU ablation by robust binary feedback control,” IEEE Trans. Biomed. Eng., vol. 57, pp. 103–113, Jan. 2010. [18] C. Mougenot, B. Quesson, B. D. de Senneville, P. L. de Oliveira, S. Sprinkhuizen, J. Palussiere, N. Grenier, and C. T. Moonen, “Three-dimensional spatial and temporal temperature control with MR thermometry-guided focused ultrasound (MRgHIFU),” Magn. Reson. Med., vol. 61, pp. 603–614, Mar. 2009.

[22]A. Boyes, K. Tang, M. Yaffe, L. Sugar, R. Chopra, and M. Bronskill, “Prostate tissue analysis immediately following magnetic resonance imaging guided transurethral ultrasound thermal therapy,” J. Urol., vol. 178, pp. 1080–1085, Sept. 2007. [23]M. Burtnyk, R. Chopra, and M. J. Bronskill, “Quantitative analysis of 3-D conformal MRI-guided transurethral ultrasound therapy of the prostate: Theoretical simulations,” Int. J. Hyperthermia, vol. 25, no. 2, pp. 116–131, 2009. [24]M. Burtnyk, R. Chopra, and M. Bronskill, “Simulation study on the heating of the surrounding anatomy during transurethral ultrasound prostate therapy: A 3D theoretical analysis of patient safety,” Med. Phys., vol. 37, no. 6, pp. 2862–2875, 2010. [25]K. Tang, V. Choy, R. Chopra, and M. J. Bronskill, “Conformal thermal therapy using planar ultrasound transducers and adaptive closed-loop MR temperature control: Demonstration in gel phantoms and ex vivo tissues,” Phys. Med. Biol., vol. 52, pp. 2905– 2919, May 21, 2007. [26]M. Burtnyk, W. A. N’Djin, I. Kobelevskiy, M. Bronskill, and R. Chopra, “3D conformal MRI-controlled transurethral ultrasound prostate therapy: Validation of numerical simulations and demonstration in tissue-mimicking gel phantoms,” Phys. Med. Biol., vol. 55, no. 22, pp. 6817–6839, 2010. [27]R. Chopra, N. Baker, V. Choy, A. Boyes, K. Tang, D. Bradwell, and M. J. Bronskill, “MRI-compatible transurethral ultrasound system for the treatment of localized prostate cancer using rotational control,” Med. Phys., vol. 35, pp. 1346–1357, Apr. 2008. [28]R. Chopra, K. Tang, M. Burtnyk, A. Boyes, L. Sugar, S. Appu, L. Klotz, and M. Bronskill, “Analysis of the spatial and temporal accuracy of heating in the prostate gland using transurethral ultrasound therapy and active MR temperature feedback,” Phys. Med. Biol., vol. 54, no. 9, pp. 2615–2633, 2009. [29]B. D. de Senneville, C. Mougenot, and C. T. Moonen, “Real-time adaptive methods for treatment of mobile organs by MRI-controlled high-intensity focused ultrasound,” Magn. Reson. Med., vol. 57, pp. 319–330, Feb. 2007. [30]A. H. Negussie, P. S. Yarmolenko, A. Partanen, A. Ranjan, G. Jacobs, D. Woods, H. Bryant, D. Thomasson, M. W. Dewhirst, B. J. Wood, and M. R. Dreher, “Formulation and characterisation of magnetic resonance imageable thermally sensitive liposomes for use with magnetic resonance-guided high intensity focused ultrasound,” Int. J. Hyperthermia, vol. 27, no. 2, pp. 140–155, 2011.


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By Andrea Schenk, Dieter Haemmerich, and Tobias Preusser

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igital three-dimensional (3-D) imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound imaging, have permitted the development of computer-aided systems for patient-specific treatment planning. Generally in such a system, after image processing of digital image data sets, patient-specific models are developed and can then be employed for planning of the procedure and/or guidance during the procedure. The type of computational model employed varies depending on the specific application but can include geometrical, mechanical (e.g., deformation), and functional models (e.g., blood flow and cardiac electrical activity) as well as tissue interaction (e.g., with radiation, heat, and drugs), among others. Today, computational modeling has found its way into clinical use for treatment planning in a number of image-guided interventions, for example: ▼ surgical procedures, e.g., neuro and liver surgery ▼ training for laparoscopy procedures ▼ dental applications, e.g., implants ▼ bone fractures and implants ▼ intensity-modulated radiation therapy (IMRT), where high-energy radiation is focused on cancerous tumors. Computational treatment planning is particularly useful for either complex new procedures (e.g., IMRT) or complex cases of procedures that have traditionally been used without computational modeling assistance. In the latter, computer-aided platforms may allow treatment of patients who would otherwise have not been candidates for the therapy due to the complexity of the cases as well as provide more consistent treatment results. In the following, we demonstrate the use of computational modeling for treatment planning of interventional procedures on the example of two clinically used therapies for liver cancer, which are used for both primary tumors (i.e., cancer originating in the liver) as well as metastatic tumors.

Use of Computer-Aided Treatment Systems


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Liver Cancer Surgery

of months until the liver volume is similar to Computational before surgery. The treatment options for liver cancer have There are several risks during surgical resecbeen limited compared to other cancer types modeling has found tion of tumors, with the most severe risk being since chemotherapy and radiation therapy its way into clinical liver failure. Two major risk factors include insufused in other cancers are typically not curative use for treatment ficient volume of the remnant liver after surgery due to biological reasons. Surgery historically planning in a number as well as deficient health of the remaining liver has been established as the gold standard, and of image-guided tissue. The latter can result from preexisting liver in recent years, additional localized therapies interventions. diseases, such as steatosis (fatty liver degenera(e.g., thermal tumor ablation, described in tion) or fibrosis/cirrhosis (liver tissue scarring), as more detail later) have been clinically adapted well as reduced blood flow, hampered by the refor liver cancer cases where surgery is not possection. In case of a healthy liver, a future remnant liver volume sible. During liver surgery the part of the liver containing the of 25–30% of the functional tumor-free volume before surgery tumor is surgically removed (i.e., surgical resection) via differis sufficient. This remnant volume has to be higher for diseased ent methods that transect liver tissue while limiting bleeding. organs and the exact amount of minimum volume necessary is This can be done during open surgery or by a laparoscopic difficult to predict in these cases. procedure through small access holes in the patient’s skin and To minimize the chance of tumor recurrence (i.e., cancer with specialized surgical tools. Owing to the high regenerative regrowth after surgery), a margin of healthy tissue surroundpower of the liver, liver tissue grows back within a couple ing the tumor (safety margin) has to be removed during resection, typically a rim of 10–15 mm. This safety margin is a critical marker for the success of the surgery, as often there are cancer microsatellites present in the rim surrounding the tumor. For example, if the surgeon cuts into the cancerous tissue or cancer cells are found on the resection surface in pathology, the probability of a recurrent tumor exceeds 90%. Therefore, the resection should be performed by transsecting tissue (e.g., cutting) at a certain distance from the tumor(s). The goal of saving as much healthy liver tissue as possible is conflicting with the aim of a large safety margin around the tumor, especially in the context of keeping the resection procedure simple. To simplify the surgical procedure, 1) the surface area of the resection plane is minimized, 2) access to the tumor is as simple as possible (note that the liver is fixed in the abdomen by several lines of connective tissue), and 3) the number of surgical cuts is minimized (particularly for multiple tumor cases). A typical strategy while considering these criteria without (a) any patient-specific modeling is followed during a standard liver resection procedure. A standard resection is based on an artificial subdivision of the liver into so-called segments, sectors (usually contain 2–3 segments), and lobes (right and left part of the liver) according to blood supply (Figure 1). A tumor would then be removed together with the segments, sectors, or lobe it is located in. Without support by dedicated software, the division of the liver is roughly estimated via the stack of two-dimensional (2D) radiological images [Figure 1(a)], taking into account the locations of the main branches of portal and hepatic veins (note that liver is, contrary to other organs, primarily supplied by venous blood). The two competing goals of obtaining a sufficient safety margin around the tumor while saving sufficient volume of (b) functional liver tissue, together with the complexity of the liver vasculature, motivated the development of a patient-specific, FIGURE 1 Patient-specific model of liver anatomy. (a) From CT computer-assisted planning platform. This system is particularly images, all relevant structures are identified. (b) A 3-D visualizauseful for liver surgery in difficult cases with multiple tumors tion shows the tumors (yellow) in relation to the portal venous and/or diseased organs, where achieving sufficient remaining system (turquoise), hepatic veins (dark blue), and hepatic artery healthy liver volume is challenging. (red), with transparent liver surface. 50 IEEE PULSE

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Patient-Specific Modeling of Liver Anatomy and Perfusion

margin, and vessel structures within these regions (tumor + margin) are identified. Based on the potentially truncated vascular branches as a consequence of the resection, the tissue depending on (i.e., being supplied or drained by) these vessels is computed (Figure 3). As a result, an assessment of different safety margin extents around the tumor as well as of the hemodynamically safe volume of the future remnant liver can be performed. The second step in supporting the surgical treatment decision is by interactive evaluation of different resection strategies in the patient’s liver model (i.e., performing virtual surgical resections). The resection plane (i.e., plane through which tissue transsection would occur during the procedure) is user defined as follows: The user draws an initial cutting line on the surface of the liver, from which a 3-D

The treatment options for liver cancer have been limited compared to other cancer types since chemotherapy and radiation therapy used in other cancers are typically not curative.

Basis for a decision about whether resection is possible and on the specific resection plan is the individual liver anatomy of a patient extracted from contrast-enhanced medical imaging data (typically, CT or MRI data). During contrast-enhanced image acquisition, contrast media is injected as bolus into the blood stream and flows first through the liver arteries, then through the portal vein system, and finally leaves the organ via the hepatic vein system. At different time points, 3-D image data sets are acquired, showing one or two of these vascular structures (depending on which vessel system the contrast agent is located in at the time of imaging). A registration (spatial matching) of the different imaging data sets will thus be the first step for image analysis, guaranteeing for the correct alignment and visualization of all relevant structures after combining the different image data sets in a virtual 3-D model of the patient’s organ (Figure 1). Besides the assessment of the vascular anatomy and variations thereof, knowledge about the functional subdivision of the liver regions based on blood supply can support the surgical decision. For patient-specific planning of liver surgery, a software assistant was developed (HepaVision, Institute for Medical Image Computing and Visualization, Fraunhofer MEVIS) that is described later. This software platform comprises all necessary image processing steps: ▼ identification (segmentation) of vascular structures based on contrast imaging [1] (see Figure 1) ▼ extraction of the organ boundaries [2] ▼ identification (segmentation) of tumor region based on type and imaging modality [3] ▼ spatial matching of image data sets obtained at different time points (registration) ▼ division of liver into territories based on blood supply, via algorithmic computation based on distance evaluation from closest vessels of the portal venous liver blood supply [1] (Figure 2). The subsequent automatic computation of volumes of tumors, (tumor-free) liver, and territories (based on blood supply) allows for an evaluation of surgical resection strategies based on patient-specific anatomy (i.e., treatment plans).

(a)

Simulation of Surgery and Risk Analysis In cases of multiple or large tumors or in diseased organs with a requirement of larger remnant liver volume, a simulation of different resection strategies and patientspecific risk analyses, based on the computational models discussed previously, are used to support the decision on the specific procedure according to the following analysis steps. In the first step, the distances between tumors and surrounding vascular structures are calculated. For each tumor and for varying extents of safety margin as desired by the surgeon, the tumor volume is virtually enlarged by this

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FIGURE 2 Modeling of liver segments. (a) After the identification of portal venous subbranches, (b) the individual anatomical subdivision of the liver based on the portal venous blood supply is computed. It shows the relative position of the tumors and can be used for initial planning of the surgical procedure. Segments are defined such that each individual segment can potentially be surgically removed without affecting blood supply to any other segments. SEPTEMBER/OCTOBER 2011

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plane transsecting the liver is computed. This Liver Tumor Ablation plane can then locally be deformed by the user Today, surgical resection of primary cancer and During an RFA to adapt to the individual patient anatomy, e.g., solitary metastases is the gold standard for tumor procedure, an treatment in the liver. However, out of more than to avoid important vessels (Figure 4). Subseapplicator containing 5 million cases of liver cancer per year, worldwide quently, truncated vascular branches and shape electrodes is inserted only 15–30% are suitable for surgical resection. and volume of the removed tissue as well as of into the tumor and In patients who are not eligible for surgical resecremnant tissue with identification of perfused connected to an tion due to the number and location of the tuand nonperfused areas is estimated. The assessmors or their general condition, local treatment ment of the volume of the remnant tissue with electric generator. adequate blood supply and potentially impaired forms such as radio-frequency ablation (RFA) have become increasingly clinically used. RFA is liver tissue (i.e., without blood supply) togetha therapy that locally destroys tissue by heating it to above 50 ºC, er with adjustment of the tumor safety margin allows for a where tissue (both tumor and normal) is destroyed due to therpatient-specific risk assessment and comparison of different mally induced coagulation of cellular proteins. The first promisresection strategies. ing investigations on thermal ablation of tumors have been perThe described software platform has so far been used for formed in the 1990s, and RFA has since become a widely used treatment planning in over 5,000 patients around the world, and approach for the treatment of primary cancer and metastasis in a clinical study found that the use of this software has resulted in the liver, and other organs such as lung and bone. During an change of the treatment originally proposed by the surgeon (i.e., RFA procedure, an applicator containing electrodes is inserted without the software) in 33% of the cases [4]. into the tumor and connected to an electric generator, which causes the local flow of an alternating electric current through the tissue. Since the tissue has resistance to the electric current, heat develops leading to thermal destruction of the cells in the vicinity of the probe. Alternative thermal ablation approaches consider the heating of tumor cells by laser irradiation or microwaves, but clinically, heating via RFA has so far been the most widely used approach. For successful treatment of the cancer patient, the evolving heat must destroy all tumor cells to ensure that there is no tumor regrowth from surviving cancer cells (recurrence). However, full thermal tumor destruction can be difficult to achieve as the blood flow in medium- and large-sized blood vessels in the vicinity of the RF applicator will remove heat, thus preventing cells close to these vessels to reach adequate temperatures for destruction. (a) Since RFA is a minimally invasive technique, it is difficult to monitor the amount of tumor destruction during the treatment, and intraprocedural monitoring options in the daily clinical routine are limited. Attempts to monitor the heat development by MRI or ultrasound are still rarely used or in the preclinical development phase. Clinical studies show that RFA is a very promising technique for tumor treatment, and recent clinical studies have found efficacy rates comparable to surgical resection in certain patient populations [10], [11]. Clearly, if RFA could be performed in all tumors with efficacy similar to surgical resection, it would be a true alternative, because it is much less traumatic for the patient with lower morbidity and considerably less expense. However, particularly for RFA of large tumors, clinical studies found high recurrence rates up to 60% [9]. In addition to tumor size, proximity to large vasculature is (b) associated with tumor recurrence due to blood flow mediated cooling described previously. FIGURE 3 Risk analysis with multiple metastases. Subbranches of the portal vein would be affected during surgery, depending on the safety margin. For support of surgical planning decision, varying safety margins are color coded: 5 mm (red), 10 mm (yellow), or 15 mm (green). (a) Based on the vascular analysis, (b) the risk territories are computed for the portal vein and the different safety margins. 52 IEEE PULSE

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Software Assistance for RFA The above expositions motivated the development of computer assistance for the planning and assessment of RFA. The goal was to develop software that allows predicting the outcome of RFA




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model after identification of tumor and vessels). and interactively planning the optimal placement Moreover, for the planning of the placement of of the RF applicator. Furthermore, the software Today, surgical the applicator, it is important to determine vital platform facilitates evaluation of the treatment resection of primary structures in the vicinity of the organ, which quality, i.e., whether the volume of destroyed cancer and solitary must not be damaged (e.g., heart and colon). tissue covers the tumor with a sufficient safety metastases is the gold The main goal of the planning of RFA is to margin (similar to tumor resection described prestandard for tumor find the best placement of the applicator such viously, a margin of normal tissue surrounding treatment in the liver. that the tumor and a sufficient safety margin the tumor needs to be destroyed during RFA to around it is destroyed, while taking into account reduce risks of tumor recurrence). structures that must not be penetrated by the As RFA is often a percutaneous procedure applicator (large blood vessels, diaphragm, and intestines) and (i.e., performed through a small incision in the skin), medical that cannot be transversed (ribs and spine). A linear access path imaging with MRI, CT, or ultrasound receives an important role must be found from the surface of the body of the patient to the throughout the whole process from diagnosis, through treatment tumor so that the mentioned constraints are fulfilled. Besides planning, guidance during treatment, and for follow-up. Durthese safety constraints, practicability criteria also need to be ing the planning stage, preinterventional image data is used to taken into account: small liver capsule penetration angles, small determine the size and location of the tumor in relation to the penetration depth, small angulation of the path to the transverblood vessels (i.e., generation of patient-specific geometric 3-D sal plane, position and posture of the radiologist for performing the penetration, and so on. Taking into account these criteria and constraints makes RFA planning a constrained multicriteria optimization problem. Similar to the surgical treatment planning platform described previously, a software assistant for RFA planning was developed at Fraunhofer MEVIS. The software assistant considers multiple cylindrical projections of the relevant criteria along paths starting from a selected target point inside the tumor to all points on the patient’s skin. Together with adequate weighing functions, these criteria can be combined to a multicriteria map, the extreme values of which yield access paths of particular good quality. In this initial approach, only a very rough estimation of the volume of coagulated (thermally destroyed) tissue is considered by giving preference to paths, which are parallel to the tumor’s main axis. (a)

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FIGURE 4 Two potential resection plans in the 3-D model of the patient’s liver showing portal vein (turquoise) and hepatic artery vessel systems (red). (a) A single resection plane for simultaneous removal of all tumors (red tissue volume is removed) results in a small remnant liver (shown in transparent) of 30% of the original volume. (b) Performing the procedure by two small (local) resections will leave a remnant volume of 75% but with reduced safety margin for one of the tumors to only 2 mm (right).

FIGURE 5 The simulated thermal tissue destruction for a configuration with three electrodes is shown. In this case, the lesion (blue, only partly visible) is very close to vascular structures. It is clearly visible how the volume of thermally destroyed tissue (red) is compromised by the cooling blood flow (yellow). The lungs, which lie directly above the liver, are shown in transparent blue. (Reprinted from [12] with permission.) SEPTEMBER/OCTOBER 2011

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Mathematical Modeling and Computer Simulation of RFA

sue, as well as cooling by blood flow and perfusion. Finally, with the Arrhenius equation we estimate the volume of destroyed tissue based on the temporal evolution of the tissue temperature. To obtain an accurate estimate of the extent of the coagulated The equations of the mathematical models take into account a volume, a simulation of the biophysical processes must be pervariety of tissue characteristics such as the electric and thermal formed for the given individual data of the patient under treatconductivity and perfusion. Since these tissue properties depend ment. We need to consider three basic biophysical processes: on the temperature, the equations of the model are nonlinearly First, the delivery of energy to the tissue via the alternating coupled [5]. electric current; second, the generation of heat, its diffusion, For the patient-specific prediction of the volume of thermal and the cooling through blood flow and perfusion; and third, tissue coagulation, this system of equations needs to be solved the denaturation of proteins in the tissue cells by the heat. These with the help of numerical computations on the computer biophysical processes are described by mathematical models considering patient-specific geometry. Using special model consisting of partial differential equations, integral equations, simplifications and with additional acceleration via implemenand algebraic equations. An electrostatic equation describes the tation on graphics processors, an interactive and patient-specifelectric potential in the tissue depending on the settings of the ic prediction of the thermal ablation is achieved [6]. Figure 5 electric generator. The bioheat-transfer equation models the tisshows the result of a simulation of the thermal tumor destrucsue heating by the electric current, diffusion of heat in the tistion during RFA. In this figure, the cooling effects of the blood flow and potential remainder of the tumor close to the vessel become clearly visible. In Figure 6, a screenshot of the software assistant for interventional radiology (SAFIR) system developed by Fraunhofer MEVIS is shown [7]. The user interface of SAFIR is designed such that it fits optimally into the clinical workflow from therapy planning to therapy assessment. In contrast to the software assistance for surgical resection described previously, the RFA assistant does not require a complete image analysis of the full 3-D data set. Only local information in the vicinity of the tumor is needed, which can be obtained through one-click segmentaFIGURE 6 A screenshot of the SAFIR Software Assistant of Frauntions of the tumor and blood vessels. The volume visualization hofer MEVIS. The graphical user interface shows the classical shown in Figure 6 displays the local vascular structures in the two-dimensional and 3-D viewers on the left as well as a series of input tabs on the right. liver, lungs (above the liver), and RF applicator as well as the estimation of the thermally ablated tissue. The user can move the applicator interactively Ultrasound Image and thereby explore the risk of therapy failure and unintendPatient Model Intraoperative Data ed damage to sensitive nearby with Resection Plan (Ultrasound, Tracking Positions) tissues for various placements of the applicator. In summary, the image processing, modeling, simulation, and optimization of RFA discussed here provide information about the treatment, which is beyond Matching of the visual inspection of the Ultrasound and patient-specific image data Planning by the attending radiologist. Model Navigation System It allows for the interactive exploration of the complex interplay among the heat emerging from the electric FIGURE 7 Integration of components for navigated surgery. The navigation system (CAScination current, cooling influence of AG and University of Bern, Switzerland) tracks the position of instruments and the ultrasound the blood flow, and therapy transducer in the operating room. The virtual liver model including the resection plan is matched constraints posed by other to the ultrasound images based on landmarks and vascular structures. The combination allows for anatomical structures. Setreal-time visualization of instruments in the liver model and more accurate implementation of the treatment plan. tings can be identified in 54 IEEE PULSE

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advance, in which the cooling blood flow or other anatomical structures may pose a limiting factor for therapy success. Thus, we expect that the use of SAFIR will lead to an enhanced quality of the treatment in particular for configurations with large tumors or tumors in the vicinity of large blood vessels. Currently, clinical partners are evaluating the SAFIR prototype.

Future Perspectives Patient-specific liver models can potentially be used for planning of other interventions in addition to surgery and ablation as presented here, e.g., dosimetry planning for radiation therapies and local delivery of chemotherapy. In the context of liver surgery as well as tumor ablation described previously, the logically next step is the transfer of planning results into the operation room (see Figure 7). Commercially available navigation systems are able to track the position of surgical instruments and imaging devices (e.g., ultrasound transducers) during the intervention and align the real organ with the virtual model [8]. Research projects in surgical navigation focus on the precise matching of the organ, computation of organ movements (e.g., by breathing or surgeon’s interaction), and workflow in the operating room. In contrast to established navigation procedures in brain surgery, highly deformable organs such as the liver pose a particular challenge for navigated surgery. The combination of computer-aided simulation with patientspecific imaging data allows optimization of a treatment plan based on the specific case, while combination of tracking and intraprocedural imaging simplifies the procedure and ensures accurate implementation of the plan. Particularly for complex interventional procedures, further advances in the technologies presented here in the near future will likely facilitate the integration of computer-aided modeling as an instrumental part of planning of image-guided procedures as well as for intraprocedural guidance.

Acknowledgments The authors thank K.J. Oldhafer from the Asklepios Hospital Hamburg-Barmbek, Y. Wang from the Eastern Hepatobiliary Surgery Hospital in Shanghai, as well as A. Mahnken from the University Clinic Aachen, Germany, for providing the clinical data sets shown in the figures. They also acknowledge the research team and collaborators of Fraunhofer MEVIS, who have contributed to the results shown here. In particular, they acknowledge C. Rieder, D. Ojdanic, C. Hansen, S. Zidowitz, M. Hindennach, and T. Kröger for their support and for providing the images shown in Figures 5–7. Andrea Schenk ([email protected]) ______________________ is with the Fraunhofer Institute for Medical Image Computing MEVIS, Bremen, Germany, Dieter Haemmerich is with the Department of Pediatrics, Medical University of South Carolina, and the Department of Bioengineering, Clemson University, South Carolina, and Tobias Preusser is with the Fraunhofer Institute for Medical Image Computing MEVIS, Bremen, Germany, and School of Engineering and Science, Jacobs University Bremen, Bremen, Germany.

References [1] D. Selle and H.-O. Peitgen, “Analysis of the morphology and structure of vessel systems using skeletonization,” in Proc. SPIE, 2001, vol. 4321, pp. 271–281. [2] A. Schenk, G. Prause, and H.-O. Peitgen, “Efficient semiautomatic segmentation of 3D objects in medical images,” in Proc. MICCAI (LNCS 1935). Berlin: Springer-Verlag, 2000, pp. 186–195. [3] J. H. Moltz, L. Bornemann, J. M. Kuhnigk, V. Dicken, E. Peitgen, S. Meier, H. Bolte, M. Fabel, H. C. Bauknecht, M. Hittinger, A. Kießling, M. Püsken, and H.-O. Peitgen, “Advanced segmentation techniques for lung nodules, liver metastases, and enlarged lymph nodes in CT scans,” IEEE J. Select. Topics Signal Processing, vol. 3, no. 1, pp. 122–134, 2009. [4] H. Lang, A. Radtke, M. Hindennach, T. Schroeder, N. R. Frühauf, M. Malago, H. Bourquain, H.-O. Peitgen, K. J. Oldhafer, and C. E. Broelsch, “Impact of virtual tumor resection and computer-assisted risk analysis on operation planning and intraoperative strategy in major hepatic resection,” Arch. Surg., vol. 140, no. 7, pp. 629–638, 2005. [5] T. Kröger, I. Altrogge, T. Preusser, P. L. Pereira, D. Schmidt, A. Weihusen, H.-O. Peitgen, “Numerical simulation of radio frequency ablation with state dependent material parameters in three space dimensions,” in Proc. MICCAI (LNCS 4191). Berlin: SpringerVerlag, 2006, pp. 380–388. [6] T. Kröger, T. Pätz, I. Altrogge, A. Schenk, K. S. Lehmann, B. B. Frericks, J.-P. Ritz, H.-O. Peitgen, and T. Preusser, “Fast estimation of the vascular cooling in RFA based on numerical simulation,” Open Biomed. Eng. J., vol. 4, pp. 16–26, Feb. 4, 2010. [7] C. Rieder, M. Schwier, A. Weihusen, S. Zidowitz, and H.-O. Peitgen. “Visualization of risk structures for interactive planning of image guided radiofrequency ablation of liver tumors,” in Proc. SPIE Medical Imaging: Visualization, Image-Guided Procedures, and Modeling, 2009, pp. 726134.1–726134.9. [8] M. Peterhans, A. vom Berg, B. Dagin, D. Interbitzin, C. Baur, D. Candinas, and S. Weber, “A navigation system for open liver surgery: design, workflow and first clinical applications,” Int. J. Med. Robotics Comput. Assist. Surg., vol. 7, no. 1, pp. 7–16, 2011. [9] Y. S. Kim, H. Rhim, O. K. Cho, B. H. Koh, and Kim Y, “Intrahepatic recurrence after percutaneous radiofrequency ablation of hepatocellular car-cinoma: Analysis of the pattern and risk factors,” Eur. J. Radiol., vol. 59, no. 3, pp. 432–441, 2006. [10] T. Livraghi, F. Meloni, M. Di Stasi, E. Rolle, L. Solbiati, C. Tinelli, and S. Rossi, “Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice?,” Hepatology, vol. 47, pp. 82–89, Jan. 2008. [11] A. R. Gillams and W. R. Lees, “Five-year survival in 309 patients with colorectal liver metastases treated with radiofrequency ablation,” Eur. Radiol., vol. 19, pp. 1206–1213, May 2009. [12] T. Preusser and H.-O. Peitgen, “Patient-specific planning for radio-frequency ablation of tumors in the presence of uncertainty,” IT Technol., vol. 52, no. 5, pp. 265–271, 2010.

Further Reading S. Vaezy and V. Zderic, Eds., Image-Guided Therapy Systems, 2009.


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Contrast Echocardiography for Cardiac Radio-Frequency Ablation By Dirar S. Khoury, Liyun Rao, and Dorin Panescu

T

he contraction of the heart is carefully orchestrated spatially and temporally by a specialized network of electrical pathways along which the electrical activity spreads. Abnormalities in these conduction pathways or localized aberrations of electrical activity of cardiac cells (myocytes) can result in irregular heart beats (cardiac arrhythmia). Usually, cardiac arrhythmia is associated with a particular chamber of the heart, e.g., ventricular tachycardia describes an arrhythmia with rapid contraction of the ventricles. Traditionally, drugs have been the treatment of choice for the vast majority of cardiac arrhythmias. In the last couple of decades, an image-guided form of localized treatment named cardiac catheter ablation has found wide clinical acceptance. During this treatment, a catheter is introduced through the vascular system into the heart and placed in contact with the cardiac tissue to be treated. Typically, fluoroscopy (i.e., X-ray imaging combined with intermittent infusion of contrast agent to visualize heart and vascular structures) is used as imaging modality to guide the procedure. Local electrical activity is recorded by several catheters placed in various locations of the heart to identify the location where the arrhythmia originates (so-called electrophysiological mapping). After the target site has been identified, a small tissue volume at the target site is destroyed by either heating or freezing (Figure 1). Often, heat-based methods where heat is generated by electric current in the radio-frequency (RF) range are used (RF ablation). Acute success is confirmed in the electrophysiology laboratory where the procedure is performed by terminating the arrhythmia and inability to reinitiate it. Advanced methods for mapping the electrical activity within the heart in three-dimensional (3-D) form, which are particularly helpful for complex arrhythmias, have been developed and implemented in the clinics within the last few decades. Companies, such as St. Jude Medical and Johnson and Johnson, now provide image-guided systems that can precisely target locations for

Image-Guided RF Ablation


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by adding real-time intracardiac echocardiography (ICE) detail. These technologies bring tremendous benefits to patients, as they facilitate accurate delivery of therapy.

Thermal Ablation Lesion Geometry and Microscopic Appearance The lesions generated during cardiac catheter ablation procedures are typically ellipsoidal in shape with the maximum diameter below the endocardial surface (see Figure 2). Examination of stained tissue samples under a microscope reveals different regions within the thermal ablation lesion, resulting from the specific local temperature profile achieved around the electrode: 1) central necrosis zone characterized by loss of nuclei and granulation, 2) zone of tissue hymolysis and capillary injury, and 3) a sharp ring of inflammatory cell infiltration. The peripheral rim has normal myocardium as well as preserved microcirculation and, except for the inflammatory cells, is indistinguishable from the normal myocardium. Therefore, the tissue region that is permanently destroyed does not include this peripheral rim (i.e., only zones 1 and 2).

Imaging of Ablation Lesions © MASTERSERIES

Advancing the benefits of catheter ablation is contingent on developing techniques that 1) identify RF ablation. Ensite, from St. Jude Medical, can be Contrast microbubbles the mechanism and location of the arrhythmia used to integrate and register computed tomograwith respect to underlying cardiac anatomy phy (CT) or magnetic resonance imaging (MRI) enhance the and 2) elucidate the effects of ablation therapy images with maps of cardiac electrical activity backscattered (i.e., intraprocedural monitoring). Currently, [1]. Navigation features, such as Ensite NavX, ultrasound signal. the treating physician (i.e., electrophysiologist) help physicians guide RF catheters within imagedoes not have any feedback of how large the debased anatomic context. Carto XP EP navigation stroyed tissue region is and where exactly this system, from Johnson and Johnson, also provides created thermal lesion is located. This is particularly important CT or MRI image registration [2]. Using electromagnetic sensors for treatment of ventricular tachyarrhythmias, where due to incorporated into RF catheters, the Carto system displays the limitations in mapping techniques and difficulties in quantify3-D location of the catheter tip onto the registered images. The ing the effects of therapy, success of catheter ablation has been CartoSound module provides another layer of image integration SEPTEMBER/OCTOBER 2011

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Reference Patch Electrode on the Dorsal Side Handle

RF Generator Catheter Body

Ablation Electrode

FIGURE 1 Schematics cardiac catheter ablation. A cardiac RF catheter is inserted through a leg vein and steered to the target site inside the heart. A reference patch electrode (i.e., a ground pad) is placed on the patient’s back. The small black region around the RF electrode at the catheter tip depicts the ablation zone. (Reproduced with permission from Panescu et al. [20].)

limited [4]. Inadequacy in determining the effects of ablation and failure to prevent arrhythmia recurrence are often due to 1) limitations in electrocardiographic criteria, 2) difficulty in determining lesion intramural depth, and 3) possible involvement of intramural or epicardial regions in arrhythmias. Treatment of atrial fibrillation (AFIB), which is characterized by quivering of the atria rather than controlled contraction, is also increasingly performed by cardiac catheter ablation. This is technically a difficult procedure, as several linear lesions have to be created, with particular importance of transmurality (i.e., lesions have to extend from endo to epicardial side). The procedure is typically lengthy (many hours), and efficacy is limited (approximately 60%) mainly due to the difficulty of reliably producing transmural lesions. An imaging technology that can visualize thermal lesions may thus provide clinically relevant information to potentially shorten treatment time and increase success rates for AFIB treatment.

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FIGURE 2 (a) A cross section of a lesion that was subsequently sectioned and stained with H&E. The panel shows the regions from which microscopic pictures were taken: (b) a central region consisting of severe necrosis with loss of nuclei and cellular granulation that decreased in severity with the increasing distance from the endocardial site of ablation, (c) a grossly dark and sharp ring that was characterized by minimal tissue or vessel disruption but with an intense inflammatory response, and (d) a region outside the area of injury showing normal tissue architecture and no granulation or inflammation. (Reproduced with permission from [3].) 58 IEEE PULSE

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ablation procedures. Feasibility of this approach Several imaging technologies could potenis described in detail in this article. ICE, where an tially provide information on location, size, and The lesions generated ultrasound transducer is placed within the cardimensions of the induced thermal lesion. MR during cardiac diac chamber, has been useful in other specific imaging with appropriate parameters allows imcatheter ablation cardiac imaging applications, e.g., for imaging aging of ablation lesions without any contrast procedures are endocardial structures [9], [10], guiding RF abagent but is practically not feasible for cardiac typically ellipsoidal lation [11], and describing tissue characteristics ablation procedures. Equipment used for cardiac in shape with the at ablation sites [12]. We in previous studies decatheter ablation is usually not MR compatible, scribed the feasibility of noncontact, electrical– and the high cost of MR imaging time would maximum diameter anatomical, and catheter imaging by integrating result in considerable higher costs of the procebelow the endocardial in a single system 1) a multielectrode catheter dure. CT may allow imaging of the thermal lesurface. probe for electrical imaging and 2) an ICE cathsion when combined with use of a contrast agent. eter for endocardial anatomical imaging [17]. InLimitations of CT for this particular application tegration of single-beat noncontact mapping with include limited availability for interventional EP ICE provided detailed, 3-D electrical–anatomical images of the procedures, no real-time imaging capabilities with current techendocardium. nology, and radiation exposure. Further, it is not clear whether the spatial resolution would be adequate to resolve the thermal lesions required resolution in the sub-mm range. The low cost of Microbubble Contrast Echocardiography ultrasound imaging, combined with the ability to visualize imContrast agents containing gas-filled, encapsulated microbubbles ages in real time, makes ultrasound imaging an attractive choice with properties similar to those of red blood cells are clinically for the purpose of intraprocedural monitoring of cardiac catheter available and can be introduced into the blood stream to serve as

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FIGURE 3 An ICE image obtained (a) in the LV at baseline, (b) at the baseline with contrast infusion, and (c) after RF energy application in lateral LV. A 4-mm tip ablation catheter was placed in the lateral LV. (d) A contrast-enhanced ICE image after RF energy application. A focal lesion is clearly depicted at the site of ablation. (e) An endocardial surface view of the lesion in (d); dashed line indicates the cut plane. (f) A cross-sectional view of the ablation lesion. The arrowheads in (e) indicate the viewing direction. (Reproduced with permission from [3].) SEPTEMBER/OCTOBER 2011

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catheter was inserted through the arterial vessel network into a coronary vessel. The microbubbles were typically in the diameter range of 2.0–4.5 mm and consisted of a suspension of Albumin microbubbles, which were infused either as bolus or continuous injection for visualization of vasculature during echocardiography.

(b)

ICE is performed via small, specialized ultrasound transducers that are part of intraFIGURE 4 An MCE image acquired during (a) contrast infusion in the circumflex coronary artery and (b) microbubble infusion in the left anterior descending coronary artery. The ablation lesion vascular catheters. Since the is clearly depicted in the posterior LV (a) that could not be seen in (b). (Reproduced with permistransducer is in direct consion from [3].) tact with the myocardium, localized sub-mm resolution is possible during real-time imaging— something that curultrasonic intravascular tracers. Contrast microbubbles enhance rently none of the other imaging modalities are capable of. the backscattered ultrasound signal. Consequently, in myocarThe ICE catheter described here contained a distal imaging dial contrast echocardiography, microbubbles have been used window and a rotatable imaging core with a distal transducer during ultrasound imaging to improve the detection of endocarthat emitted and received ultrasound energy. dial borders and more importantly to assess tissue Two-dimensional (2-D) imaging is achieved by microvascular perfusion [5]–[8]. Marchlinski et attaching a motor drive unit that enabled autoal. [13] were the first to use echocardiographic ICE is performed via matic and continuous rotation of the transductechniques to document lesion formation during small, specialized er at a fixed speed. The motor drive unit is in ablation and demonstrate its value in quantifyultrasound turn connected to an imaging console (model ing lesion depth. Using contrast-enhanced epitransducers that are ClearView) to acquire echocardiographic imcardial echocardiography, the finding of diminpart of intravascular ages of the left ventricle (LV). ished myocardial blood flow within acute focal While ICE typically only generates 2-D imRF lesions was later demonstrated by Nath et al. catheters. ages, controlled movement of the ultrasound [14]. Since the microbubbles flow in the coronary transducer while recording images in multiple microcirculation, microbubble contrast echocaradjacent planes allows the generation of 3-D image data sets. diography (MCE) was previously used in animals and humans to Here, the tip of the sheath was advanced to the LV apex and determine the extent of myocardial infarction [6], [7]. shaft was positioned along the LV major axis. The combination The goal of the methods presented below was to introduce of the ICE catheter and motor drive unit was fitted to a pullback efficient and clinically applicable means to describe the effects device that enabled automatic and accurate withdrawal of the of ablation immediately after delivery of therapy. Since RF ablaICE catheter inside the sheath. ICE imaging is then performed tion results in coagulation of tissue and vasculature, blood flow within the sheath to minimize catheter motion artifacts duris abolished within the thermal coagulation region (thermal leing pullback. The pullback device was connected to a computsion). Microbubbles, which are only present within the vasculaer-based data acquisition and control system (model Compact ture (i.e., not within the ablated tissue), may therefore be used 3-D IVUS). The computer system 1) externally controlled the for monitoring the thermal lesion created during RF ablation. pullback device, 2) acquired continuous ICE images at multiple We assumed that microbubble-rich blood flow in the corolevels along the LV major axis in 1-mm increments, and 3) renary microcirculation enhance the backscatter of intracardiac constructed the LV 3-D geometry by stacking multiple ECG- and ultrasound signals reflected by the normal myocardium, and respiration-gated ICE slices using specialized software (model blood-deficient ablation lesions could subsequently be distinfour-dimensional IVUS Scan Software). guished from the neighboring normal myocardium. Thereby, thermal lesions induced by RF ablation can be differentiated from normal myocardium and quantified by MCE. Image-Guided Lesion Assessment We demonstrate the potential advantages of intracardiac To compare the performance of the described imaging system contrast echocardiography for guidance method for cardiac ablaunder different conditions, both focal (i.e., small and localized) tion procedures. To administer the microbubble contrast agent, a thermal lesions were created, as well as linear lesions (i.e., 60 IEEE PULSE

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FIGURE 5 (a) An ICE image obtained after ablation in lateral LV. Charring caused by RF energy application is depicted as increased echogenicity in the image. (b) Contrast-enhanced ICE image of the same lesion in (a). The actual diameter and intramural depth of the lesion are revealed beyond the charring. (c) A cross section of the corresponding lesion showing endocardial charring.

prolonged). By variation of the time for which RF ablation was spots did not exist in the contrast-enhanced ICE images obperformed, thermal lesions of varying sizes can be generated. tained at the baseline. Importantly, the ablation lesions are To image focal lesions, the ICE catheter was placed at the well delineated from the surrounding normal myocardium level of the ablation tip electrode. Standard and contrast-enthat remained well opacified with microbubbles. As typically hanced 2-D ICE images were initially acquired at the baseobserved in cardiac catheter ablation, the focal lesions were line. After ablation, standard and contrast-enhanced 2-D ICE ellipsoidal in shape with the maximum diameter below the endocardial surface. These ablation spots were clearly delineated images at the original level of the electrode–tissue interface for an average of 10 s after initiation of ablawere acquired immediately after creating the tion, before the appearance of concentrated lesion as well as 30 min later. For imaging of intracavitary microbubbles that precluded aslinear lesions, 3-D echocardiography was iniThermal lesions sessment of the echocardiographic images. The tially performed at baseline, and about 30 min induced by RF microbubbles were completely washed out of after ablation, the electrode-catheter was rethe cavity in about 4 min. moved and 3-D ICE was performed with conablation can be tinuous infusion of Optison. The location where infusion of the microbubdifferentiated from ble contrast agent takes place is of primary impornormal myocardium tance. Microbubble infusion in the left anterior In Vivo Validation and quantified by descending artery resulted mainly in opacificaFor validation of ICE as an accurate method for MCE. tion of the anterior–lateral LV region, whereas intraprocedural feedback of induced thermal infusion in the circumflex artery mainly opacilesions, the thermal lesion can be accurately fied the posterior–lateral LV region. Figure 4(a) quantified by direct inspection after extraction of the heart tissue. Two methods commonly used are gross depicts a posterior–basal lesion that was enhanced by contrast examination as well as histological examination where thin microbubble infusion in the circumflex artery. As shown in Figtissue sections are made, stained by hematoxylin and eosin ure 4(b), the same lesion could not be depicted when the con(H&E), and then examined under a microscope (Figure 2). To trast microbubbles were infused in the left anterior descending artery, which mainly resulted in opacification of the anterior LV. demonstrate the feasibility of the described imaging approach, If excessive heat is generated during cardiac ablation, tisstudies were performed in a canine animal model, where thersue charring and coagulum formation can occur. The imagmal lesions were created in the LV by clinically used ablation ing appearance in these cases showed increased echogenicity catheters. Compared with the standard ICE images [Figure in the ICE image that was evident at the site of ablation after 3(a)], intracoronary infusion of Optison contrast microbubRF energy delivery [Figure 5(a)]. Even though the increased bles at baseline (before ablation) resulted in immediate myocardial opacification [Figure 3(b)]. Note that contrast agent echogenicity was indicative of the site of ablation, the ICE image alone could not delineate the intramural depth of the is required to visualize the thermal lesion, and standard ICE actual lesion. However, intracoronary infusion of contrast alone [Figure 3(c)] cannot delineate either the diameter or microbubbles clearly revealed the extent of the underlying intramural depth of the focal lesion. Following intracoronary lesion beyond charring, as shown in Figure 5(b), and was microbubble infusion, thermal lesions are clearly distinguishconfirmed by examining the actual lesion that is shown in able at the ablation electrode locations as well-defined dark Figure 5(c). spots that lacked contrast enhancement [Figure 3(d)]; these SEPTEMBER/OCTOBER 2011

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9 8 7 6 5 4 y = 1.10 + 0.87 × x r = 0.90, n = 12, P < 0.001

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FIGURE 6 Linear regression relationship between (a) focal lesion maximum depth determined by MCE immediately after ablation (t = 0 min) and the maximum depth determined from pathological examination and (c) focal lesion maximum diameter determined by MCE immediately after ablation (t = 0 min) and the maximum diameter determined from pathological examination. (b) Same as in (a) and (c) but at t = 30 min. (d) The focal lesion maximum diameter determined by MCE immediately after ablation (t = 0 min) and the maximum diameter determined from pathological examination. (Reproduced with permission from [3].)

Base

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Notable for translation of the presented results toward application in humans, a 9-F 9-MHz ICE catheter, similar to the one employed in the present study, was previously used in humans in guiding RF ablation in the LV [18] whereby ICE identified anatomical landmarks, electrode–endocardial contact, and ablation electrode movement. Imaging the human LV with a phased array system operating at a lower ultrasound frequency [19] may allow deeper sound wave penetration inside the myocardium that ensures more distinct contrast echocardiographs and may obviate the need for multiple arterial access by perhaps imaging from the right side of the heart.

Epicardium

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Geometry of Focal Lesions Comparison of thermal lesion dimensions from extracted tissue samples (Figure 2) to dimensions measured by MCE, both in depth and diameter, confirms accuracy of this imaging approach (Figure 6). This is particularly notable due to the small dimensions of these lesions and demonstrates the advantage of the high spatial resolution of this approach. Lesion depth from these studies was in the range of 5.5 mm, with diameter of around 10 mm; accuracy of dimensions determined by imaging was thus in sub-mm range (approximately 0.2 mm), which likely would not be feasible with other imaging modalities such as MRI or CT.

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FIGURE 7 (a) A 3-D MCE reconstruction of the LV depicting a lesion created by an 8-mm tip electrode-catheter. (b) The corresponding longitudinal-sectional view of the ablation lesion. (Reproduced with permission from [3].) 62 IEEE PULSE

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(i.e., extending throughout the myocardium from endo- to epicardium) is here of primary importance, and imaging guidance may provide relevant information for improving the currently limited success rate for AFIB treatment. In addition, linear lesions have been applied in the atrium to manage atrial flutter [15] and ventricle to manage ventricular tachycardia [4]. Figure 7 illustrates a lesion created by an 8-mm tip electrode catheter and confirms that the lesion was successfully reconstructed by 3-D MCE as compared to that of pathology. A radiographic image of a loop ablation catheter inside the LV is depicted in Figure 8(a), and the corresponding geometry reconstructed by 3-D echocardiography is shown in Figure 8(b). A lesion was created in the posterior LV by two adjacent electrodes on the loop catheter and was successfully reconstructed by 3-D MCE [Figure 8(c)] as compared to that of pathology [Figure 8(d)].

Summary


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FIGURE 8 (a) A radiograph depicting a 14-electrode ablation catheter in the LV, an ICE catheter inside a sheath in the LV, and a lumen catheter in the circumflex coronary artery. A 3-D (b) ICE reconstruction of the LV interior depicting the ablation catheter and anatomical features such as LV septum and posterior papillary muscle and (c) MCE reconstruction of the LV depicting a linear lesion created by two adjacent electrodes in the posterior region. (d) The corresponding longitudinal-sectional view of the ablation lesion.

We presented a first application of 2-D contrast-enhanced containing the lesion (Figure 4). Issues related ICE in localizing RF ablation lesions and, more to patient safety, following this approach, have importantly, accurately and reproducibly quantiTreatment of AFIB, to be considered, particularly the inherent risk fying their extent and depth within the myocarwhich is characterized associated with multiple arterial access and indium in the intact beating heart. Furthermore, by quivering of tracoronary infusion (In this study, no ECG the study extended this application and presentthe atria rather changes were observed acutely during or followed, for the first time, a novel method based on than controlled ing microbubble infusion.). Focal dimensions contrast-enhanced 3-D ICE to describe details contraction, is determined by MCE were highly reproducible of contiguous linear lesions. By delineating the for more than 30-min duration after RF energy capillary microcirculation, MCE was capable of also increasingly delivery. The present study also demonstrated identifying those necrotic areas with high acperformed by cardiac the feasibility of 3-D MCE in reconstructing lincuracy. We utilized the penetrating nature of catheter ablation. ear lesions. ICE, its tomographic perspective, and its ability Clinical application of the demonstrated to directly image the endocardium to provide imaging modality for image-guided cardiac unique images of ablation lesions. In this mancatheter ablation may thus provide currently missing informaner, contrast-enhanced ICE provided immediate feedback on tion on location, size, and dimensions of the induced thermal the nature of ablation lesions and furnished a true anatomical lesions. Such imaging guidance currently missing in clinical endpoint for ablation. However, it is of importance to locally inprocedures may increase success rates and potentially reduce fuse contrast microbubbles into the coronary microcirculation SEPTEMBER/OCTOBER 2011

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treatment times for this clinically widely used interventional procedure.

Acknowledgment Equipment support was provided by EP Technologies/Boston Scientific, San Jose, California. Dirar S. Khoury ([email protected]), __________ Liyun Rao ([email protected]), ________ and Dorin Panescu ([email protected]) ______________ are with the Methodist Hospital Research Institute, Houston, Texas. Dorin Panescu is also with NewCardio, Inc., Santa Clara, California.

References [1] EnSite™ System [Online]. Available: ______________ http://www.sjmprofessional.com/Products/US/Mapping-and-Visualization/ ___________________________________ EnSite-System.aspx ____________ [2] CARTO® XP EP System [Online]. Available: http://www. biosensewebster.com/products/navigation/cartoxp.aspx [3] D. S. Khoury, L. Rao, C. Ding, H. Sun, K. A. Youker, D. Panescu, and S. F. Nagueh, “Localizing and quantifying ablation lesions in the left ventricle by myocardial contrast echocardiography,” J. Cardiovasc. Electrophysiol., vol. 15, no. 9, pp. 1088–1090, 2004. [4] W. G. Stevenson and P. L. Friedman, “Catheter ablation of ventricular tachycardia,” in Cardiac Electrophysiology: From Cell to Bedside, D. P. Zipes and J. Jalife, Eds., 3rd ed. Philadelphia, PA: W. B. Saunders, 2000, pp. 1049–1056. [5] P. A. Friedman, D. L. Packer, and S. C. Hammill, “Catheter ablation of mitral isthmus ventricular tachycardia using electroanatomically guided linear lesions,” J. Cardiovasc. Electrophysiol., vol. 11, no. 4, pp. 466–471, 2000. [6] A. J. Kemper, T. Force, L. Perkins, M. Gilfoil, and A. F. Parisi, “In vivo prediction of the transmural extent of experimental acute myocardial infarction using contrast echocardiography,” J Amer. Coll. Cardiol., vol. 8, no. 1, pp. 143–149, 1986. [7] S. Kaul, W. Glasheen, T. D. Ruddy, N. G. Pandian, A. E. Weyman, and R. D. Okada, “The importance of defining left ventricular area at risk in vivo during acute myocardial infarction: An experimental evaluation with myocardial contrast two-dimensional echocardiography,” Circulation, vol. 75, no. 6, pp. 1249–1260, 1987. [8] S. F. Nagueh, N. M. Lakkis, Z. X. He, K. J. Middleton, D. Killip, W. A. Zoghbi, M. A. Quiñones, R. Roberts, M. S. Verani, N. S. Kleiman, and W. H. Spencer III, “Role of myocardial contrast echocardiography during nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy,” J Amer. Coll. Cardiol., vol. 32, no. 1, pp. 225–229, 1998. [9] J. F. Ren, D. Schwartzman, D. J. Callans, S. E. Brode, C. D. Gottlib, and F. E. Marchlinski, “Intracardiac echocardiography (9 MHz) in humans: Methods, imaging views and clinical utility,” Ultrasound Med. Biol., vol. 25, no. 7, pp. 1077–1086, 1999. [10] P. A. Friedman, D. Luria, A. M. Fenton, T. M. Munger, A. Jahangir, W. K. Shen, R. F. Rea, M. S. Stanton, S. C. Hammill, and D. L. Packer, “Global right atrial mapping of human atrial flutter: The presence of posteromedial (sinus venosa region) functional

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block and double potentials. A study in biplane fluoroscopy and intracardiac echocardiography,” Circulation, vol. 101, no. 13, pp. 1568–1577, 2000. [11] F. X. Roithinger, P. R. Steiner, Y. Goseki, K. S. Liese, D. B. Scholtz, A. Sippensgroenewegen, P. Ursell, and M. D. Lesh, “Low-power radiofrequency application and intracardiac echocardiography for creation of continuous left atrial linear lesions,” J. Cardiovasc. Electrophysiol., vol. 10, no. 5, pp. 680–691, 1999. [12] J. F. Ren, D. J. Callans, D. Schwartzman, J. J. Michele, and F. E. Marchlinski, “Changes in local wall thickness correlate with pathologic lesion size following radiofrequency catheter ablation: An intracardiac echocardiographic imaging study,” Echocardiography, vol. 18, no. 6, pp. 503–507, 2001. [13] F. E. Marchlinski, R. Falcone, R. V. Iozzo, N. Reichek, J. A. Vassallo, and S. B. Eysmann, “Experimental myocardial cryoinjury: Local electromechanical changes, arrhythmogenicity and methods for determining depth of injury,” PACE, vol. 10, no. 4, pt. 1, pp. 886–901, 1987. [14] S. Nath, J. A. Redick, J. G. Whayne, and D. E. Haines, “Ultrastructural observations in the myocardium beyond the region of acute coagulation necrosis following radiofrequency catheter ablation,” J Cardiovasc. Electrophysiol., vol. 5, no. 10, pp. 838–845, 1994. [15] M. D. Lesh, “Catheter ablation of atrial flutter and tachycardia,” in Cardiac Electrophysiology: From Cell to Bedside, D. P. Zipes and J. Jalife, Eds., 3rd ed. Philadeplphia, PA: W. B. Saunders, 2000, pp. 1009–1027. [16] P. Jais , D. C. Shah, M. Hocini, T. Yamane, M. Haissaguerre, and J. Clementy, “Radiofrequency catheter ablation for atrial fibrillation,” J. Cardiovasc. Electrophysiol., vol. 11, no. 7, pp. 758–761, 2000. [17] L. Rao, R. He, C. Ding, and D. S. Khoury, “Novel noncontact catheter system for endocardial electrical and anatomical imaging,” Ann. Biomed. Eng., vol. 32, no. 4, pp. 573–584, 2004. [18] F. Lamberti, L. Calo, C. Pandozi, A. Castro, M. L. Loricchio, A. Boggi, S. Toscano, R. Ricci, F. Drago, and M. Santini, “Radiofrequency catheter ablation of idiopathic left ventricular outflow tract tachycardia: Utility of intracardiac echocardiography,” J. Cardiovasc. Electrophysiol., vol. 12, no. 5, pp. 529–535, 2001. [19] J. F. Ren, F. E. Marchlinski, D. J. Callans, and H. C. Herrmann, “Clinical use of AcuNav diagnostic ultrasound catheter imaging during left heart radiofrequency ablation and transcatheter closure procedures,” Amer. Soc. Echocardiogr., vol. 15, no. 10, pt. 2, pp. 1301–1308, 2002. [20] D. Panescu, et al., “Three-dimensional finite element analysis of current density and temperature distributions during radiofrequency ablation,” IEEE Trans. Biomed. Eng., vol. 42, no. 9, pp. 879–890, Sept. 1995.

Further Reading D. J. Wilber, D. L. Packer, and W. G. Stevenson, Catheter Ablation of Cardiac Arrhythmias: Basic Concepts and Clinical Applications. Malden, MA: Blackwell Publishing, 2007.




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10th IEEE EMBS

INTERNATIONAL SUMMER SCHOOL ON BIOMEDICAL IMAGING Berder Island, France, 22-30 June, 2012

Christian ROUX and Jean-Louis COATRIEUX, Chairs The spirit of this Summer School is inspired by the most prestigious school ever founded in France, Saint Flour, the influence of which has spread to generations of researchers in Mathematics. Since its establishment in Brittany in 1994, this school has become a worldwide reference. It is resolutely international (participants from more than twenty countries have participated to the previous editions) and accessible to young scientists. It is an open yet privileged place for exchanges and discussions of major on-going work. Informal and warm, at a location where the sea and the land combine in a time varying relation, this school brings together, every two years for ten days, the world great teachers and researchers in Biomedical Imaging. Lectures, seminars, and discussions are organized at the highest level, but with the freedom of spirit that is the tradition of Brittany. The school objective is to contribute without any exclusion to advances in a rapidly evolving field, and to foster participation in the adventure of research. It provides up-to-date, state-of-art knowledge on emerging areas and addresses important issues dealing with complex, multivariate systems, going from basic to applied research. Audience: The Summer School is open to graduate students (M.S., PhD), post doctoral scientists, radiologists, biologists, researchers and engineers in industry.

Candidature submission open from November, 2011 to February 15, 2012

PRELIMINARY PROGRAM SIMON CHERRY, University of California Davis, USA

RUSS TAYLOR, Johns Hopkins University, USA -

MICHAEL UNSER, Ecole Polytechnique Férérale de Lausanne, Switzerland SIMON ARRIDGE, University College London, UK KOJI IKUTA, University of Tokyo, Japan GUEST AND PANEL LECTURES To be announced

JUNIOR LECTURE To be selected after a Call for papers among the former students participants in the Summer School

FOR INFORMATION, CONTACT Valérie BURDIN - Inserm, CS 83818, F- 29238 Brest, France E-mail : Valerie.Burdin@telecom [email protected] ___________________________ http://ieeess.enst-bretagne.fr Fax: +33 229.00.10.98 Web : http://ieeess.enst

Candidature submission open from Nov., 2011 to Feb. 15, 2012 Digital Object Identifier 10.1109/MPUL.2011.942956


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NEURO ENGINEERING

PATENTS

Hummingbirds, Orioles, and Butterflies Maurice M. Klee

I

s there a limit on the prior art a patent examiner can cite in rejecting a patent application, or is everything that is early enough fair game? That was the question before the Court of Appeals for the Federal Circuit (CAFC) in the recent case of In re Klein. Klein was in the niche business of nectar feeders for hummingbirds, orioles, and butterflies. Unlike typical bird feeders, the food in nectar feeders is a sugar-water mixture intended to mimic the animal’s natural food sources. As it turns out, different animals eat different types of nectar. Hence, the sugar–water mixture for hummingbirds needs to be one part sugar to four parts water, whereas the ratio for orioles is 1:6, and for butterflies is 1:9. Klein noted that customers, including repeat customers, often needed reminding of the ratios. Also, experts had expressed concern that sugar-rich nectar solutions could be harmful to birds. Accordingly, Klein set about to develop what he called a convenience nectar mixing and storage device that would solve these problems. His device was beautifully simple. It used just two parts: a container and a divider that could be slid into one of three sets of grooves to form two compartments, one for sugar and the other for water. The first set of grooves was marked for hummingbirds and gave a 1:4 sugarto-water ratio; the second set was for orioles and gave a 1:6 ratio; and the third set was for butterflies and gave a 1:9 ratio. After the compartments were filled, the Digital Object Identifier 10.1109/MPUL.2011.942607 Date of publication: 11 October 2011

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divider was slid out and used to mix the sugar with the water. To avoid the problem of a lost divider, Klein designed his container so that it would accept the divider as a cover. Having put a lot of thought into his device, Klein decided to file for a patent. Not surprisingly, the patent examiner did not find any prior art relating to nectarmixing devices. Using Klein’s application as the starting point, he collected three prior art patents showing containers having removable/adjustable dividers and two prior art patents showing containers for liquids having two fixed-size compartments. Based on this collection, the examiner concluded that Klein’s invention was not patentable because it was obvious. A lesser man might have quit at this point, but Klein persevered, first within the patent office by appealing to the Board of Patent Appeals and Interferences and, when the board agreed with the examiner, to the CAFC. The CAFC judges began their analysis by summarizing the well-established rule that only analogous prior art can be cited against a patent claim. Analogous prior art falls into two categories: 1) art from the inventor’s field of endeavor regardless of the problem the art addresses and 2) art from any field of endeavor provided that the art is reasonably pertinent to the particular problem with which the inventor is involved. None of the prior art cited by the examiner qualified for the first category, so the question became whether the cited references were reasonably pertinent to the problem Klein had worked on.

During the patent office proceedings, the board had defined Klein’s problem as making a nectar feeder with a moveable divider to prepare different ratios of sugar and water for different animals. Before the CAFC, the government attorney representing the patent office tried to broaden the problem to be a compartment separation problem, but the CAFC would have none of that game playing and used the board’s description of the problem to determine if any of the cited prior art was reasonably pertinent. With the board’s narrow definition, the CAFC easily concluded that the patent office had been wrong in rejecting Klein’s claims because none of the references the examiner had found qualified as analogous art. Klein’s victory is an example of the old adage that it does not pay to be greedy. Klein crafted his claims to cover just what he had invented. Indeed, the claims specially refer to hummingbirds, orioles, or butterflies. If he had gone broader and tried to cover his device in the abstract, both his field of endeavor and the range of reasonably pertinent prior art would have grown commensurately. But at the end of the day, Klein’s interest was in nectar-mixing devices, and, by limiting his claims to just that, he ended up as a winner. A copy of the full text of the In re Klein decision can be obtained from the CAFC’s Web site at http://www.fedcir.gov. Maurice M. Klee received his B.S. degree in physics from the University of Illinois, his Ph.D. degree in biomedical engineering from Case Western Reserve University, and his J.D. degree from George Washington University. He is a former assistant professor at the College of Engineering at Michigan State University and a former staff fellow at the National Institutes of Health. He practices patent, trademark, and copyright law in Fairfield, Connecticut. He is a member of Phi Beta Kappa and Order of the Coif.




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IEEE EMBC 2012 August 28 - September 1, 2012 Hilton San Diego Bayfront Hotel San Diego, CA, USA

“Engineering Innovation in Global Health” Conference Keynote Speakers:

William R. Brody, MD, PhD President, Salk Institute

Eric J. Topol, MD Vice-Chairman, West Wireless Health Institute

Rebecca Bergman Vice-President, CRDM Medtronic, Inc.

Proposals for organized sessions and submissions are invited in the following themes: • • • • • • • • • •

Biomedical Signal Processing Biomedical Imaging & Image Processing Bioinstrumentation: Sensors, Micro, Nano and Wearable Technologies Bioinformatics, Computational Biology; Systems Biology, Modeling Methodologies Cardiovascular & Respiratory Systems Engineering Neural Engineering, Neuromuscular Systems & Rehabilitation Engineering Molecular and Cellular Biomechanics, Tissue Engineering, Biomaterials Bio-Robotics , Surgical Planning and Biomechanics Therapeutic & Diagnostic Systems, Devices and Technologies, Clinical Engineering Health Care Information Systems, Telemedicine

Key Dates: October 1, 2011 January 15, 2012 February 1, 2012 March 15, 2012

Proposal Submission Open Proposal Submission Deadline Paper Submission Open Paper Submission Deadline

For more details, visit the EMBC’12 website: http://embc2012.embs.org/

Conference Chair: Michael Khoo,, University y of Southern California;; Program g Co-Chairs: Gert Cauwenberghs, g , University of California, San Diego; James Weiland, University of Southern California; International Program Chair: Shu Chien, University of California, San Diego; Tutorials & Workshops Chair: Atam Dhawan



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NEURO ENGINEERING

SENIOR DESIGN

Managing Student Expectations of the Real World Jay R. Goldberg

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s senior capstone design instructors, our job is to help prepare our students for careers in biomedical engineering. Since the majority of them will someday work for a medical device company, our focus on design is particularly important and relevant. Capstone design courses and biomedical engineering curricula help students develop technical, interpersonal, and communication skills and provide them with the broad knowledge base they will need for successful careers as biomedical engineers. Additionally, accreditation requires programs to meet several learning criteria to ensure that the students will be prepared for careers in biomedical engineering after graduation. There are many mechanisms in place that prepare our students to solve openended problems, think critically, and work well in teams. However, there are fewer mechanisms in place to let students know what to expect in their first job, what their early careers might be like, and how they are expected to behave and function in an organization. Students with cooperative, summer job, or internship experiences with medical device companies gain insight into how a business is run; how companies function to design, develop, and introduce new products; and how decisions are made within a company. They also learn what will be expected from them and what they can expect from their future employers. At Marquette University, in 2011, more than 60% of undergraduate biomedical engineering students particiDigital Object Identifier 10.1109/MPUL.2011.942608 Date of publication: 11 October 2011

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pated in the cooperative and internship program, where they worked for medical device companies. These experiences provide students with a preview of how it will be to work in an industry and help them develop reasonable expectations of their first job. When I began my career in the medical device industry in 1980, there were things that I did not learn as an undergraduate or graduate student that I would have liked to have known before starting my career. These are things that are typically learned on the job and may be a rude awakening to new engineers with certain expectations. Students without cooperative or internship experience should be aware of a few of these realities of industry before they begin their careers.

Project Assignments In many companies, engineers do not get to choose the projects they work on. This can be a rude awakening to many new engineers. Project assignments are typically based on market needs defined by marketing and sales departments, available engineering resources, and the qualifications of available resources. New engineers may find themselves working on projects that they may not be as interested in as they are in others and need to understand that engineering resources are assigned to projects that are expected to be the most profitable and generate the highest return on investment. New engineers may need to prove themselves and demonstrate their project management and design skills before they are assigned to more desirable, higher-profile projects.

Types of Projects Not all projects to which engineers are assigned will involve exciting, novel, stateof-the-art technologies. This can be disappointing to new graduates who expect to work on the newest, coolest technologies immediately after starting a new job. They must realize that only 10% of new product introductions are new-to-theworld products. Companies manage their project portfolios similar to a personal portfolio of investments. They will maintain a diversified mix of high-risk/highreturn and low-risk/low-return investments to keep a balance. Engineers can expect to work on a similar mix of projects including new-to-the-world products, line extensions (new size or color), product enhancements (new features), cost reductions, product repositionings, and other types of projects. In some companies, new engineers may not work on the higher risk/higher return new-to-theworld products until they prove they can handle to lower risk and less-complicated line extensions and cost reductions.

Skills for Career Advancement Students should understand that successful careers in engineering require not just technical skills but excellent interpersonal, communication, and team skills. In many companies, an engineer’s project management skills and his/her ability to get products out the door is the key to early career advancement. Effective project managers not only understand how to create and use a project schedule, manage tradeoffs between scope, schedule, and resources, and manage risk but they must also be proficient at negotiating with and motivating team members and support staff and communicating with team members and upper management. Advancement into and through the management ranks is aided more by an engineer’s interpersonal, administrative, and planning skills and less by his/her technical skills. As an engineer advances up the management ladder, technical skills become less important. Many engineers




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HONG KONG, SHENZHEN 5 7 JAN, 2012

IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI 2012)

Call for Papers Building on the success of the EMBS International Conference on Information Technology and Applications in Biomedicine (ITAB), EMBS has launched a new Special Topic Conference titled IEEE-EMBS International Conferences on Biomedical and Health Informatics (BHI), starting from this year. The inaugural meeting, BHI2012, will be held in Hong Kong and Shenzhen, China, January 5-7, 2012. To be held in conjunction with the 8th International Symposium on Medical Devices and Biosensors and the 7th International Symposium on Biomedical and Health Engineering, the BHI 2012 will be devoted to an inter-disciplinary research area intersecting engineering, information technology and computer science with biology, medicine and health. The conference is to examine enabling technologies of devices and systems that optimize the acquisition, transmission, processing, storage, retrieval (P-STAR) of biomedical and health information as well as to report clinical studies on the novel application of health information systems. The goal of the proposed joint event is to bring together academicians, clinicians, industrial representatives, government and private research agencies and funders to facilitate a dialogue on addressing the theme Global Grand Challenge on Health Informatics .

Features: Special IEEE-EMBS Editors-insponsored by IEEE Engineering in Medicine and Biology Society (EMBS) Special Academician & Fellow Forum sponsored by the Key Lab for Health Informatics of Chinese Academy of Sciences (HICAS) Special Forum on Imaging Informatics Special Challenge on Accepted papers will be included in IEEE Xplore Extended version of selected papers may be considered for publication in the IEEE Trans. on Information Technology in Biomedicine (SCI, EI, Scopus)

The conference covers a broad spectrum of themes including but not limited to the following topics: I) P-STAR of Biomedical and Health Information

Wearable and implantable devices Body sensor/area networks (BSN /BAN) Diagnostic and therapeutic systems Internet and web solutions for health care delivery Multi-scale modeling and information fusion; Ambient assisted living, smart homes; Electronic health records, interoperability and connectivity Context-aware retrieval p-health, m-health, u-health, e-health systems Organized and sponsored by:

Important Dates: Paper Submission Deadline: 14 Oct 2011 Notification of Acceptance: 11 Nov 2011 Early Registration: 2 Dec 2011 Pre-conference Workshop: 5 Jan 2012 (in Hong Kong) Conference Dates: 6-7 Jan 2012 (in Shenzhen)

II) Biologically Inspired Informatics

Virtual reality in medicine and surgery Bio-inspired robotics and biomimics Brain-computer interfacing and human computer interfacing III) Informatics in Biological Systems

Neuroinformatics Genomics and proteomics Bioinformatics, computational biology IV) Medical Imaging Informatics

Realtime imaging Multimodal imaging Molecular imaging V) Health Informatics Applications

Cardiovascular informatics Applications in the early diagnosis and treatment of cancers Technically co-sponsored by:

IEEE-Engineering in Medicine and Biology Society (EMBS) Key Lab for Health Informatics of Chinese Academy of Sciences (HICAS) CAS-SIAT Institute of Biomedical and Health Engineering (IBHE)

The Chinese University of Hong Kong Supported by: IEEE-EMBS Hong Kong Chapter

Contact Us: Ms. Laura J. Wolf, [email protected] Tel: + 1 732-981-3433

Ms. Julie Yang, [email protected] Tel: +86 755 8639-2249

Mr. Y. P. Liang, [email protected] Tel: +852 2609-8285

Conference Website: http://bhi2012.embs.org


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Winners of BMEidea The winners of this year’s BMEidea national student design competition were announced during the Medical Design Excellence Awards industry awards ceremony in New York in June. BMEidea is in its seventh year and is open to university teams from National Collegiate Inventors and Innovators Alliance (NCIIA) member institutions across the United States. The competition sponsors include NCIIA, National Science Foundation, Boston Scientific, Medical Device and Diagnostic Industry Magazine, and the Industrial Designers Society of America (IDSA). The winning entries ▼ solve a pressing clinical problem ▼ meet technical, economic, legal, and regulatory requirements ▼ feature a novel and practical design ▼ demonstrate potential for commercialization. First Place (US$10,000) “Magneto: Magnetic Induction Internal Bleed Detector,” University of Michigan, Ann Arbor: The Magneto internal bleeding monitor is a portable, noninvasive, autonomous, and costeffective device for detecting internal bleeding complications after catheterization procedures through the femoral artery. Second Place (US$2,500) “Oculeve,” Stanford University: Oculeve is a novel therapy that treats severe dry eyes more effectively and less expensively than do current treatments. It works by inserting a microstimulator at the size of a grain of rice into the lacrimal tear duct by using a needle introducer (similar to a Botox injection). The bead painlessly delivers an electrical current that restores natural tears. Third Place (US$1,000) “OSMOSE,” Medtric Biotech, Purdue University: OSMOSE is a line of antimicrobial dressings for the prevention and treatment of infected wounds. OSMOSE relies on a physical mechanism for eliminating bacteria. It is effective against a wide array of bacteria (including antibiotic resistant strains), promotes healing, and is a low-cost solution in a high-priced field. Digital Object Identifier 10.1109/MPUL.2011.942755

fail to realize that the job of a manager is very different than that of an engineer, and good engineers do not always make good managers.

Importance of the Customer and Meeting Customer Needs Engineers working in industry must understand that successful businesses create products that meet customer needs. Innovation involves meeting needs in a new and better way. Design validation involves proving that they made the right product (one that meets customer needs). The design process focuses on the customer, and engineers should always keep this in mind.

Identifying New Product Opportunities Most companies maintain a pipeline of potential new projects from which to choose when deciding which new proj70 IEEE PULSE

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ects to fund. Sometimes the pipeline is empty, and engineering personnel work with marketing, sales, and other personnel to identify new product opportunities. Many new engineers feel that this is a marketing function, but, in my opinion, these needs-finding activities represent the initial phase of the design process and thus are within the domain of engineering design. Front-loaded (frontend) design places a heavy emphasis on properly identifying the needs and problems to be solved as well as thoroughly identifying customer needs. I feel that this is the most important phase of the design process. If not done well, companies will either develop new products that solve nonexistent problems or inadequately solve real problems. Owing to time constraints, many senior capstone design courses do not provide students with the opportunity to identify problems on which to base their capstone de-

sign projects. I feel that design curricula should include needs-finding opportunities to prepare students for these activities in the industry.

Working on Truly Multidisciplinary Teams Most capstone design students learn to work on multidisciplinary teams. Often these teams consist of engineering students of the same discipline. Some teams include students from other engineering or technical disciplines. Other teams may include business and other nontechnical students. Team members are usually close in age, share similar goals, and have similar levels of education. In industry, engineers will work on truly multidisciplinary teams with many nontechnical team members of various ages and nationalities, in different stages of life and with different goals and priorities. Their team members will have different educational backgrounds, levels of education, and work experience; and different cultural and religious backgrounds, political views, perspectives, and opinions. Therefore, their team members will look at problems differently. New engineers must learn to value different approaches to problem solving and work with and respect the diversity of these multidisciplinary teams. They will need to respect what each team member contributes to the project and understand that different ways of viewing a problem can increase the number of potential solutions. People with industrial experience should think about the things that they wished someone had warned them about or made them aware of. If you are a faculty member, I urge you to share your industry insights and perspectives with your students to better prepare them for their first industry experience. Based on my personal experience, I feel that if they have reasonable expectations, their early career experiences may be more positive. If you have some insights or other realities not listed here that you would like to share with students, please share them with me at ______________ [email protected]. For details regarding the Biomedical Engineering Innovation, Design, and Entrepreneurship Award (BMEidea) national student design competition, see “Winners of BMEidea.”




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Hawaii 1-7 December 2012

First Announcement Hawaii December 1-7, 2012 Save the date!!!! Various biomedical grand challenges facing our society and the world can be addressed in part or in whole by interfacing biology and medicine with micro- and nanoscale technologies. The potential impact of these technologies on the early diagnosis, therapeutics, and management of disease is very high. To address this challenge, IEEE EMBS is sponsoring the first Conference on Micro- and Nanoengineering in Medicine to foster interaction between scientists, engineers and medical researchers in the context of real-world medical needs and issues. The Conference will promote vigorous and open dialogue towards the development of cutting edge technologies for faster, more quantitative, and less expensive biomedical solutions using advances in micro and nanotechnology.

Conference Chairs: Professor Rashid Bashir, University of Illinois, Urbana-Champaign Professor Ali Khademhosseini, Harvard University Professor Michelle Khine, University of California, Irvine

Contact info: Ms. Laura J. Wolf,

Rashid Bashir

Ali Khademhosseini

[email protected] _________

[email protected], ____________

[email protected] ________________

Michelle Khine [email protected] __________



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NEURO ENGINEERING

RETROSPECTROSCOPE

Laplace’s Law Its Mathematical Foundation By Max E. Valentinuzzi and Alberto J. Kohen

Soap bubbles, rubber balloons, and distended bellies have been seen and experienced by men over centuries giving them the idea of tension and eventually the feeling of blowing out, until someone found a physicomathematical explanation to close the loop from practical to theoretical knowledge and so making a few guys happy, which does not mean at all that the inflated sensation will not show up again and that cattle in the country will not be treated with a stab in the tummy by a would-be-veterinary-doctor to relieve bloat (see “Bloat”).

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a Mécanique Céleste by P.S. Laplace was published for many years during 1790–1825 [1]. It consists of five volumes with a rather confusing organization, the first part with five books and the second part with 11. In turn, each book is constituted by chapters: e.g., Book 1: eight chapters; Book 2: eight chapters; Book 3: seven chapters; Book 4: five chapters; Book 5: three chapters; all the latter in the first part. Thereafter and already within the second part, Book 6: 18 chapters; Book 7: six chapters and a first supplement; Book 8: 18 chapters; Book 9: three chapters; Book 10: nine chapters and a second supplement. The fifth volume contains Books 11–16 with four, three, seven, three, two, and seven chapters, respectively. In addition, there is a third supplement and a final note. The subjects dealt with are regarding the movement of celestial bodies and their intervening forces. Somewhat unexpectedly, the supplement to Book 10 Digital Object Identifier 10.1109/MPUL.2011.942609 Date of publication: 11 October 2011

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deals with the theory of capillary action (pp. 349–499), and we say unexpectedly because the subject does not show any relationship whatsoever with the overall content. Moreover, Book 10 refers to several aspects of the world system—Sur Different Points Relatives au Système du Monde (in French meaning, About Different Aspects Relative to the World System), as for example, astronomical and terrestrial refractions or bodies falling from great altitudes or about planetary and satellite masses. Why was it included in that place? It obviously remains an open question.

Let us briefly refresh what a capillary tube is: it has a bore so small that it would only admit a hair (Latin, capilla). When such a tube of glass, opened at both ends, is placed vertically with its lower end immersed in water, the latter rises in the tube to a level higher than the water outside. The forces concerned are those acting between the neighboring parts of the same substance and are called forces of cohesion. Those that act between portions of matter of different kinds are called forces of adhesion. These forces only show up when the distance becomes exceedingly small. It has been determined that the greatest distance at which their effect is appreciated lies around 20,000th part of a millimeter. The subject is complex and has been a matter of scientific concern for a long time, recognizing several contributions, among which, perhaps, Leonardo da Vinci (1452–1519) must be considered as its discoverer [2]. The latter reference offers an excellent and detailed account.

Bloat

Laplace’ s Contribution (1806–1807)

The stomach of ruminant animals produces gas as a natural by-product of digestive fermentation. The animals continually belch, about once every minute, to get rid of the gas. Whenever anything interferes with this release of gas or if fermentation is too rapid, gas becomes trapped in the rumen causing a condition known as bloat. It can be a life-threatening condition if left untreated [17]. Eligio Perucca’s old textbook of physics must be mentioned [18]. In its chapter devoted to surface tension phenomena, the capillary effect is extensively developed, including a good derivation of Laplace’s Law (called by this name); however, the final equation is given in the form of (2), which is not fully correct for it considers the same surface tension over the two principal arcs of the principal radii, as well explained herein and in the previous note [3].

The subject content of the second supplement mentioned earlier, published in 1806–1807, is the following: Sur l’èquation fondamentale de l’action capillaire About the fundamental equation of capillary action Nouvelle manière de considerer l’action capillaire New way of considering capillary action De l’attraction et de la repulsion apparent des petits corps qui nagent à la surface des fluids Apparent attraction and repulsion of small bodies floating on the surface of a fluid Sur l’adhésion des disques à la surface des fluids Adhesion of discs to the surface of fluids De la figure d’une large goutte de mercure et de la depression de ce




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fluide dans un tube de verre d’un grand diamètre Shape of a large mercury drop and depression of this fluid within a glass tube of large diameter Considérations générales General considerations. In his first paragraph on p. 419, Laplace establishes the objective of the supplement as follows: to perfect the theory of the capillary phenomena that I have already done [our underlining], to extend its applications, to confirm it by new comparisons of these results with experiments and, by presenting the capillary action from a new point of view, to place more in evidence the identity of the attractive forces whose action depend on those that produce affinity. Observe (underlined in the paragraph earlier) that he had studied capillarity before; however, no clear reference is given. The text is extremely difficult to follow and is written in an obscure style. On p. 421, Laplace mentions Book 1, where Chapter 4 deals with the equilibrium of fluids. Equations are not clear either with poorly defined symbols. After a long mathematical and intricate development, second supplement (p. 428), the following equation is reached. 1 1 1 gD 1 h 1 z 2 5 a bHa 1 b, 2 R Rr

(1)

where he defines g as gravity (la pesanteur, in French), D is the fluid density, and (h 1 z) represents the height of the point above the surface level (why did he split it in two terms?) for the lefthand side of the equation. For the righthand side, H is obscurely presented in p. 423 as a positive quantity decreasing very rapidly (in French, une quantité dêcroissant avec une extreme rapidité). To complicate things further, H is also defined as a function of ƒ, the latter standing for the distance between a solid differential element and point O (we assume it is the point located above the surface level), where an osculating tangential force is exerted. We repeat that these definitions must be extracted from

different parts in the text. Equation (1) g D 1 h 1 z 2 5 P, (3) is the closest form we found in the celes1 1 1 1 1 tial mechanics resembling what is now a bHa 1 b 5 T c 1 d , (4) 2 R Rr R R called Laplace’s law. 1 2 On p. 432 of this supplement, in what Le Marquis titled “New Way of which dimensionally should be compatConsidering Capillary Action,” the first ible if they are to express the same quanparagraph says: tities or magnitudes, i.e., the dimensions La manière dont nous avons envisagé in (3) are length 3 mass/time2 or force/ jusqu’a present les phénomenes capillength2, obviously describing pressure. laires est fondée sur le consideration In (2), while the radii R 5 R1 and R9 5 de la surface du fluide renfermé dans R 2, the only possibility left over is surun espace capillaire, et sur les condiface tension T 5 (1/2)H, measured in tions de l’equilibre de ce fluide dans dynes/cm or, more generally, force per un canal infiniment étroit, aboutisunit length. Thus, in the end, (4) is exsant par une de ses extrémités à cette pressed in units of pressure too. surface et par l’autre extrémités à la surface du niveau du fluide indéfini Are There Antecedents dans lequel le parois de l’espace capilto Laplace’ s Contribution? laire sont plongées. Yes, there are— all focused on the capilThe way in which we have so lary effect and none ending in the mathfar envisaged capillary phenomematical formulation referred to above, ena is by considering the fluid either as (1) or (2). Let us review what surface as confined within a capthey were. illary space under conditions of 1) Looking back in time, we found a equilibrium of such fluid within communication made to the Royal a channel extremely narrow, atSociety of London by a physician, tached on one exJames Jurin, who at least treme to this surface 70–80 years before Laand on the other to place carried out studies In many respects, the undefined fluid on capillarity [4]. HowLaplace’s results are surface level where ever, no mathematical reidentical with those the capillary walls are lationship is offered. Sevof Young’s results, immersed. eral experiments were but his methods of Obviously, it is not at performed, and the only all a clear piece, especialcomment to be rescued arriving at them are ly if no adequate figure appears in p. 743, where purely mathematical. accompanies it to better the author recognizes explain how the overall that “the force of cohesystem was thought. Our conclusion sion or attraction opposes the descent forces us to state that Pierre Simon, in a of the water [within the capillary].” quite wavy and meandrous mathematiEvidently, he somehow had the concal fashion, came out with a physical cept of surface tension while clearly relationship that requires adaptation to seeing the influence of the diameter the nowadays accepted form. Thus, let of the small tubes employed. The us compare (1) with (2) introduced in article refers to several figures, and our first note [3], coincidentally also unfortunately, the version we could identified here as (2), and we should download from the Web does not recall, it is not quite correct because it have them, hence making it difficult considers the same tension T over the to follow the descriptions. We mentwo principal radii, tion this article as an early antecedent for the capillary effect knowledge development, loosely related to the 1 1 P 5 Tc 1 d. (2) law we are herein concerned about. R1 R2 The Encyclopedia Britannica goes into other capillarity details that do not By equating both left-hand and rightbelong to this note [2]. hand sides, we obtain SEPTEMBER/OCTOBER 2011

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sions of large drops of mercury and 2) However, there is still another comlarge bubbles of air in liquids under munication to the Royal Society, certain conditions [2]. slightly before Laplace’s second supAs far as we could determine, a first plement, by a physician, Thomas partial conclusion from a historical viewYoung, in December 1804, dealing point would be that Laplace, based on with the cohesion of fluids and, as a the capillary effect, was indeed the first consequence, within the same capilto obtain an equation resembling what is larity subject area, well developing now called Laplace’s law. the concept of surface We stress the word resemtension [2], [5]. In bles, because his maniits 22 pages, Laplace Gauss pointed out fested equation needs the is not mentioned, the importance of manipulations shown and no mathematics the angle of contact above to find an analogy is found (recall that between the two to the current statement the celestial mechanof the law. ics was already gointeracting surfaces. A second partial coning on, and one may clusion is that three reask if by any chance searchers [mentioned in 1), 2), and 3) both researchers were or had been above] chronologically encompass Lain touch). Once more, we deem it place in their respective concerns with only as a mere antecedent. In many the capillary phenomenon: Jurin (derespects, Laplace’s results are idencades earlier), Young (almost simultatical with those of Young’s results, neously), and Gauss (about two decades but his methods of arriving at them after). However, none of them reached are purely mathematical. Laplace or overtly printed in their reports the investigated the force acting on the equation we are familiar with, but Gauss fluid contained in an infinitely slenseems to have been the first to mention der canal, normal to the surface of Laplace. the fluid, arising from the attraction Before proceeding with the more reof the parts of the fluid outside the cent and easier to follow physicomathcanal. ematical derivations of Laplace’s law, 3) After Laplace, and in a way to be it is pertinent to make a few general considered as his immediate concomments: no doubt, the capillary eftinuator in capillarity studies, Gauss fect had attracted for a long time the (1829–1830) clearly stands out attention of the scientific community, [6]. He manifestly recognizes Le say since Leonardo’s times (15th cenMarquis as his antecessor in this retury until now, a good 500 years). spect and, perhaps, can even been Think it over, a very small tube that, credited with indirectly naming the when one of its extremes is vertically law. The mathematical formulation dipped in a fluid (such as water or othdoes not appear clear enough and er), literally sucks it up until it reaches is rather cryptic, using a notation a given equilibrium height! No active not currently in use. However, it is pump to account for the effect made deemed a big step in the treatment it look like magic. Besides, depending of the subject [2]. The principle he on the type of fluid, the fluid border adopted is that of virtual velocities, touching the tube wall could slightly gradually transformed later on into go up or down forming the so-called the principle of the conservation concave or convex meniscus (i.e., with of energy. Gauss pointed out the positive or negative curvature), as the importance of the angle of contact typical cases are of water and mercury. between the two interacting surYet today, Laplace’s law in physiology faces; thus, he supplied the principal usually refers without exception to defect in Laplace’s work. Besides, cavities of a given wall thickness under Gauss mentioned the advantages the action of a pressure from within. of the method of Segner and Gay Indeed, they look like two fully differLussac, afterward carried out by ent areas. Quincke, of measuring the dimen74 IEEE PULSE

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Woods’ Contribution (1892) Robert H. Woods was a throat surgeon at the Richmond Hospital and demonstrator of anatomy at Trinity College, Dublin, Ireland. He seems to be the first to have applied Laplace’s law in hollow organs (heart and urinary bladder), as we could find no other publication between Gauss’ article in 1829–1830 and Woods’ article in 1892 [7]. (Read before the Royal Academy of Medicine, in Ireland, on 15 January 1892.) Hence, there would be a rather long paucity of more than 60 years, and such a fact attracts our curious attention. The equation he used is (2), which we underline, is not correct, because it assumes the tension T to be equal at both curvature radii. This author neither provides any demonstration nor does he mention Laplace or any of the previous capillary predecessors.

Karl de Snoo’ s Contribution (1936) Another long period went by, from 1892 until 1936 (44 years), when de Snoo, in The Netherlands, came up with a clinical paper within the field of obstetrics, once more applying the law to a hollow organ— the uterus, during the dilatation period when in labor— as Wood did before in the heart and urinary bladder. He offered an ingenious simple geometrical and, almost correct demonstration but without mentioning Laplace and only recognizing the help of a mathematician Barrau in a footnote and without giving his full name. However, the final formula lacks generality, for it apparently looks restricted to the case of a thin sphere [8]. Thus, his derivation is incomplete and not fully clear (as we will see below). Relatively close in time, Valentinuzzi, Sr., [9], [10], while working in his medical doctor dissertation, repeated that demonstration expanding its application to cavities of any shape, but still considering a single value for tension and without taking into account the wall thickness. Since apparently de Snoo’s article was produced as an independent development, he called it Barrau–de Snoo’s law. This is why, perhaps, the law should be renamed Laplace–Barrau–de Snoo’s law. The same mathematical derivation can be found in the textbook by




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Valentinuzzi, Understanding the Human Machine [11]. Let us update and discuss it too. The law was rephrased by Valentinuzzi, Sr., [10] as follows: tension on any given point of the uterine wall is equal to the product of the intrauterine pressure and the curvature radius of the uterus at that point, or T = P 3 R. These articles are difficult to find and, besides, are written in languages other than English and published in obscure journals with little or no impact. The surface of a balloon of any shape, with pressure in it, can always be broken down into a number of elementary caps, as many as necessary. They would look like parachutes when quietly falling down to Earth. Let us take a section of an osculating circumference in one of these elements, coincident with one of the characterizing radii [Fig ure 1(b)], as already stated in the preceding note on Laplace [3]. From now on, everything in this demonstration is considered on the plane of the circle defined by such circumference. The pressure inside acts on the chord (AB) subtending the arc of radius R1 or R 2 (depending on which of the two planes we are considering); thus, the arc between points A and B is under the tension. T 5 P. chord 1 AB 2 ,

or (EOB), because their sides are perpendicular to each other. Solving (6) for T and replacing D by 2HP based on the action–reaction mechanical principle, the force that counterbalances the one which originated in the inner pressure, P(2H), yields

T 5 D / 2 sin a 5 P H / sin a,

(7)

but inspection of Figure 1 easily shows that sin a 5 H/R, which after substitution in (7), ends up in T 5 PR,

(8)

which describes in the plane the statement given above. For the sake of historical documentation and also to better discuss it, let us transcribe de Snoo’s own words Hieraus ergiebt ist, daß die Spannung in der Wand eines Ballons dem innerem Druck und dem Radius proportional ist. From here it comes out that tension on the surface of a bal-

(5)

loon is proportional to the inner pressure and the radius. The latter is equivalent to the statement given earlier by Valentinuzzi, Sr. [10]. However, de Snoo’s derivation is incomplete and not fully clear, as he stays within a single plane. Let us reproduce his words immediately after the sentence given above: Es wird nun durchaus verständlich, warum bei unserem Experiment die beiden Ballons ungleich gespannt sein konnten, obwohl der Innendruck P derselbe war. It is thus now understood why in our experiment both balloons showed different surface tensions, even though the internal pressure P was the same. Obviously, he was assuming spheres of equivalent different radii leading to different surface tensions under the same inner pressure: T = PR. The uterus, because of its pearlike shape, is often modeled by two spheres, the bigger above the smaller.

Tension, on any given point of the uterine wall, is equal to the product of the intrauterine pressure and the curvature radius of the uterus at that point.

T = F/d E

where P is in dynes/cm2 and (AB) is in cm, clearly saying that we are indeed getting units of tension, or dynes/cm, as defined in Figure 1(a). Besides, the chord AB is divided in two halves H, or in other words, chord (AB) 5 2H, so that the tension can be rewritten as T 5 P(2H). This tension is counterbalanced by an opposing tension D, divided in two equal components tangent to points A and B, respectively, and which can be graphically obtained by projecting, first, the two Ts along their directions until they intersect at point E, and second, by application of the parallelogram rule [Figure 1(c)]. Thus, Segment 1 EG 2 5 D/2 5 T sin a, (6) where a is the angle (ETG) = angle (EAB), because their sides are parallel, and is also equal to angle (EOA)

T

d

T

(a) Definition of Angle (ETG) ETG) = Surface Angle (EAB) EAB) = Tension Angle (AOP) AOP) =

G D B

F P R2

R1 (b)

Cap element showing its two principal radii and the force over the surface unit length. Pressure is applied from underneath.

A

O (c) The arc AB represents one of the two principal arcs on the lower left.

FIGURE 1 de Snoo’s derivation planes. (a) Surface tension definition. (b) The two principal radii over the curved distended surface. (c) Arc AB subtending its chord represents any of the two principal curves [see (b)]. Force D counterbalances force P(2H) sustained by the pressure inside. H = segment A (or B) to where P is applied; thus, AB = 2H, while OA = OB is one of the principal radii and sin a = sin(angle AOP) = H/OA = H/R. Modified and redrawn after [8]–[11]. SEPTEMBER/OCTOBER 2011

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in a cardiology journal for the first time. Hence, de Snoo indirectly admits a (To call the attention of the bibliophilic thin-walled sphere but does not proreader: The initial page of Wood’s paper ceed further in the derivation to a is 362, not 302, as it appears in Burton’s volumetric nonspherical hollow body. list of references.) He clearly states that Besides, the thickness of the organ is “Laplace’s Theorem [or not even mentioned. law or formula, these To overcome the difare the names given in ficulty and complete the Burton credited, the current literature] derivation, we take up reproduced, and applies to a membrane the suggestion made by discussed Woods’ separating two spaces of Valentinuzzi, Sr., many article and includes any shape, that has tenyears ago [10], i.e., for several interesting sion in it,” and the two one principal plane conprincipal radii are also taining the principal numerical well defined as “the maxradius R1, we have T1 = speculations imum and the minimum PR1, and for the other, regarding cardiac radii of curvature that perpendicular to the formechanics. we would find if we tried mer, and following exactall possible pairs of arc,” ly the same rationale as and he refers to explordeveloped earlier, we can ing around the whole 360° centered on obtain T 2 = PR 2. Solving each for P and the intersection shown in Figure 1(b), adding them up leads to where the distending force is applied. Burton credited, reproduced, and disP 5 1 1/ 2 2 1 T1 / R1 1 1 T2 / R2 2 , (9) cussed Woods’ article [7] and includes several interesting numerical speculabecause the pressure, by Pascal’s law of tions regarding cardiac mechanics. It is hydrostatics, has to be the same within an excellent contribution, but there is the cavity. The latter equation describes no mathematical background justifying the equilibrium of forces from within the law. and the forces of tension, besides and except for the constant (1/2), it coincides with (2). Stephen P. Timoshenko (1959) If now the concept of wall stress is Stephen P. Timoshenko’s original name introduced in a hollow organ with wall was Stepan Prokopovych Tymoshenko thickness, h, as defined in our previous (1878–1972), a native of Ukrania. He note [3], we get back to the pressureis reputed as the father of modern meequivalent radius product as being prochanical engineering with many semiportional to the wall stress–wall thicknal works, among which a classic textness product, PR 5 k (Ws h), where the book was favored for many years by many teachers and students [13]. In numerical value of the proportionality Chapter 14, titled “Deformation of Shells constant should be determined for each Without Bending,” its paragraph §105 particular case and, eventually, may be (p. 433) deals with shells in the form equal to one. It has to be underlined that of a surface of revolution and loaded de Snoo did not introduce in his article symmetrically with respect to their axis the second perpendicular plane to get (such as tanks or domes). A surface of (9); the latter is an added step that exrevolution is obtained by rotation of a tends the result to a volume. However, if plane curve about an axis lying in the one wants to be more rigorous, it would plane of the curve. The curve is called be necessary to introduce the differential the meridian and its plane is a meridian concept and integrate thereafter to obplane. Two adjacent meridians and two tain the equation. parallel circles cut out an element shell (this is a small parachute-like shape as Alan C. Burton (1957) we called it before). The position of a The heart is perhaps the organ mostly meridian is defined by an angle u, meataken as an application target from the sured from some arbitrary reference meviewpoint of our law, and Burton deridian plane. The position of a parallel voted a full article to it [12], published 76 IEEE PULSE

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circle (say, a decrement below an initial horizontal cross section) is defined by another angle w, made by the normal straight line to the surface with the axis of rotation. The meridian plane and the plane perpendicular to the meridian are the planes of principal curvature at a point of a surface of revolution, and they contain both principal radii of curvature. Besides, it is assumed that there are no shearing forces acting on the sides of the surface element. The magnitudes of the normal forces acting on the sides are the tensions Nw and Nu. The initial setting given by this highly respected and traditional author is beautiful and promising; however, as reading proceeds, everything becomes quite unclear and confusing, at least to the authors of this note. Nonetheless, the final equation is similar to (9). Actually, Timoshenko writes (using his own notation), Nw / r1 1 Nu / r2 5 2Z,

(10)

where Z is defined as the z axis component of the external load intensity (not defined in his text), which must be equivalent to the pressure in our discussion. Laplace is not mentioned. An interesting feature, perhaps a mere happenstance, calls our attention: his Figure 214 (p. 435) looks similar to de Snoo’s figure (Figure 1). No other comment appears appropriate, for this derivation was disappointing and very much ill defined; we leave the subject in the hands of more specialized readers.

Landau and Lifschitz (1959) These researchers presented a derivation of Laplace’s law based on modern physics concepts (as Timoshenko probably did before them) and within the area of surface phenomena; their approach was rather general and, in a sense, mathematically superseded previous developments [14]. Lev Davidovich Landau (1908–1968) was native to the old Soviet Union, with outstanding contributions in several areas of theoretical physics. He received the 1962 Nobel Prize for his development of a mathematical theory of superfluidity. A close collaborator, Evgeny Mikhailovich Lifschitz (1915–1985), was another physicist well known in




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general relativity. Both coauthored Fluid Mechanics (Course of Theoretical Physics), an ambitious series of textbooks that continues to be widely used. In volume 6, chapter 7, surface phenomena are addressed. Its first part (carrying the number 61) deals with Laplace’s formula, and so it is titled. Herein, what these authors developed is paraphrased, somewhat reduced and modified to improve its didactics. The mathematics is given here in more detail. Let us consider the phenomena that occur near the thin surface dividing two continuous media (separated by a narrow boundary layer). If the surface is curved, pressures near it in the two media are different, say p1 and p2. To determine the pressure difference (the surface pressure, the terminology that belongs to Landau and Lifschitz, in our opinion not a fortunate one because it tends to confuse), both media must be in thermodynamic equilibrium. Let the surface of separation undergo an infinitesimal displacement dz. At each point of that small shift, a normal straight line n is drawn toward any surface element df. Between the two surfaces, a volume dz.df is determined (colored cube in Figure 2), and above and below Media 1 and 2 there are pressures p1 and p2. The work requested to bring about that small volume change is

# 3 1 p2 2 p1 2 dz df , which is dimensionally consistent. However, there is also a change df in the surface area (because of the minute expansion or contraction, depending on the sign of displacement), meaning that another work component a.df must be added, where a is called the surface tension coefficient. Thus, the total work is dW 5 3 1 p2 2 p1 2 dz # df 1 a # df. (11) The condition of thermodynamic equilibrium is met when dW 5 0, i.e., the forces originating in superficial tension balance out the forces generated by the inside–outside pressure difference. The element lengths, dl1 and dl2, regarded

n

DUS

df D

p2 in Medium 2

C

A

B

ULS

δζ

R1 and R2

FIGURE 2 Landau—A parachute-like piece of curved surface characterized by its two principal radii. (ULS: undisplaced lower surface; DUS: displaced upper surface). Lightly colored cube element with upper and lower lid areas df = dl1.dl2, the latter two being its sides; n: normal straight line to any surface element df. R1 and R2: principal radii of curvature. The plane determined by R2AB is perpendicular to the plane defined by R1CD, and both fully identify each surface element df. The infinitesimal shift is dz, from the lower to the upper position. Remember that the thickness dz of the shift is infinitesimal, meaning that the bluish portion of the figure represents a fine film separating the Media 1 and 2, with above and below pressures p1 and p2, respectively. Modified and redrawn after [14].

as elements of the two circumferences with radii R1 and R2, respectively, are incremented during the expansion (or contraction) by (dz/R1)dl1 and (dz/R2) dl2; in other words, each longitudinal rectangular component changes proportionally to the relative radial change. In mathematical terms, the surface element df, after the displacement, becomes df 5 3 dl1 1 1 dz/R1 2 dl1 4 3 dl2 1 1 dz/R2 2 dl2 4

5 dl1 dl2 1 dl1 1 dz/R2 2 dl2

df > dl1dl2 3 1 1 dz/R2 1 dz/R1 4

df > dl1dl2 1 dl1dl2dz 3 1/R2 1 1/R1 4

df > df 1 df dz 3 1/R2 1 1/R1 4 .

1 1 dz/R1 2 dl1dl2

1 1 dz/R1 2 dl1 1 dz/R2 2 dl2

(13)

The bold-faced term in (13) is precisely the very small area change over the surface because of displacement. Hence, Landau and Lifschitz [14] said that it is seen that the total change in area at the separating film over the parachutelike piece must be precisely obtained by integration of that very small area change or

df 5 3 dza

1 1 1 bdf . R1 R2

(14)

or df 5 dl1dl2 3 1 1 dz / R2 1 dz / R1 1 dz2 / R2R1 4 .

(12)

In the latter part of (12), it is easily seen that the last term is a second-order differential that can be neglected so that we may rewrite it as

Substituting (14) in (11) under the equilibrium condition already mentioned earlier, dW 5 0, we obtain 3 1 p1 2 p2 2 dz. df 2 a3 dza


1 1 1 b R1 R2

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p1 2 p2 5 a

which can be rearranged as 3 dz e 1 p1 2 p2 2 2 aa

1 1 1 b f df 5 0, R1 R2 (16)

and the latter must hold for every infinitesimal displacement of the surface, i.e., for any dz; hence, the portion in braces must be identical to zero, i.e., 1 p1 2 p2 2 2 ~ a

1 1 1 b 5 0, (17) R1 R2

a1 a2 1 b, R1 R2

(18a)

so making it consistent with the previous considerations presented in this note and the previous one by Valentinuzzi and Kohen [3]. On the other hand, the derivation is general and based on good physical principles. Capillarity does not appear, and the thickness of the limiting membrane is not considered for it is assumed to be extremely thin.

leading to p1 2 p2 5 aa

Vsevolod I. Feodosiev (1972)

1 1 1 b, R1 R2

(18)

This well-reputed Russian has authored a textbook often used in Argentina by civil engineering students in a Spanish translawhich, no doubt, is our well-known Martion [15]. In its section §65 (pp. 311–312), quis de Laplace’s equation. In it, a, the surtitled “Determination of Tensions in Symface tension coefficient (as called by these metric Cupolas,” memauthors) evidently takes brane theory is used. The the place of surface tension following statement is T, and it appears as equal Landau and Lifschitz found: in both perpendicular dipresented a Cuanto menor es el esrections, which we know derivation of Laplace’s pesor de la bóveda, tanis not correct. In this relaw based on modern to más exacta sera la ley spect, the derivation shows physics concepts. que supone que las tena weak point. To take care siones son constantes en of it, the procedure should el espesor de la bóveda y consider each plane sepatanto más exactos serán los resultarately in a fashion similar to de Snoo’s prodos de la Teoría de Membrana. cedure to obtain

The smaller the cupola thickness, the closer the exactness of the law that assumes constant tension in the cupola thickness and the better the membrane theory results. Let us consider a symmetric cupola of thickness h from which an element dl1. dl2 is studied (Figure 3); in it, R1 and R2 represent the two principal radii, respectively. Over each tiny lateral faces of the element, there act parietal or wall stresses, Ws1 and Ws2, respectively, say in dynes/cm2. The resulting forces tending to pull the element in the two perpendicular directions are Ws2hdl2 and Ws1hdl1; besides, applied perpendicularly to the element due to the pressure coming from within, there is the force p.dl1dl2. Projecting all these forces over the normal straight line traversing the element and considering that the cosines of small angles practically coincide with the angles in radians, if the system is in equilibrium, the stress forces should counterbalance the pressure forces, i.e., p.dl1.dl2 5 Ws1.h.dl2.du 2 Ws2.h.dl1.df. (19) Now, let us recall that du = dl1/R1 and dw 5 dl2/R2, which, when replaced in (19), produce p 5 ha

Ws2hdl2 R2

dϕ dθ

Ws1hdl1

dl2

dl1 pdl1dl2

R1

h

Ws1 Ws2 1 b. R1 R2

(20)

The latter becomes (2) if one recalls that Wsi 5 Ti /h, where the subindex i stands for either one or two. We must admit that, so far, this has been the easiest, most direct, correct, and more general derivation of the law. However, Laplace is not acknowledged, making us conclude that apparently no author did a complete job, i.e., reaching physicomathematically to a full correct equation and, at the same time, clearly recognizing previous contributions. Well . . . human perfection does not exist.

Federico Armesto (2009)

FIGURE 3 Feodosiev—Shell in a symmetric cupola of thickness h from which an element dl1.dl2 is studied. R1 and R2 represent the two principal radii. Over each tiny lateral faces of the element, there act wall stresses, Ws1 and Ws2, respectively, in dynes/cm2. The resulting forces tending to pull the element in the two perpendicular directions are Ws2hdl2 and Ws1hdl1; besides, applied perpendicularly to the element due to the pressure coming from within, there is the force p.dl1dl2. 78 IEEE PULSE

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In 2009, we (the authors of this note) organized a small seminar at the Institute of Biomedical Engineering of the University of Buenos Aires with the idea of discussing this old, ubiquitous, and slithering law. A few young electrical engineering students showed up, but only




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one— Federico Armesto— became interested and one day gave us what, with his explicit permission, here is translated and reproduced (including some changes to make it more readable). Somehow, it also relates to de Snoo’s initial setting, as some repetitions are unavoidable for the sake of clarity. Based on what was said earlier, a volumetric body of any shape encompassing a cavity, when undergoing internal and external pressures, can be decomposed in semispherical shells defined by two main radii (Figure 4). It is assumed with a wall of negligible thickness. The pressure difference between the external and internal medium is called P while T stands for surface tension, the latter in units of force over length. Arc segments undergo the action of forces because of the pressure difference being counterbalanced by tangential superficial tensions; this takes place in any direction around the 360° of the center of the shell (Figure 4, point E). In space, the pressure is exerted in the upward direction, exactly at the intersection of the two principal radii Rx and Ry, which, as said before, characterize the shell [see Figure 5(a)]. Each tangential force projects to the vertical z axis. Since pressure is force per unit area, we would get force per unit length by calculating its flux as a linear integral along line AB. Up to here, everything is practically a repetition of de Snoo’s demonstration. In three dimensions, the force F in equilibrium with D will be the flux of pressure P crossing the rectangle formed by Hx and Hy, after differential approximation of the shell (or skullcap), i.e.,

1 3 2Tx sin ~x dly,

(22)

P.dxdy 5 F 5 Ty 1 dy/Ry 2 dx

(23)

Tx Ty 1 . Rx Ry

(24)

1 Tx 1 dx/Rx 2 dy 5 D

dy

or P5 F 5 2 Tysin ~ y3 dlx 1 2 Txsin ~ x3 dly dx

dy

5 2 Tysin ~ y dx 1 2 Txsin ~ x dy,

This last demonstration appears simple and rigorous, only needing the introduction of the wall thickness, as done earlier.

where Tx and ax and Ty and ay correspond to Conclusions the tensions and angles The objectives set for The stomach of on the x and y axes, rethis note have been acruminant animals spectively. However, the complished, i.e., collectproduces gas as a pressure P is constant all ing all of the available natural by-product over, and hence, it can be mathematical derivations of digestive taken out of the integral, of Laplace’s law and dewhile Tx and Ty remain termining its historical fermentation. origins. The first one, diconstant within the limrectly obtained from conits of the shell, meaning sidering a hollow container, as a balloon, that they too can be sifted out. As it was and without taking into account the wall done in the bidimensional demonstrathickness, is due to Karl de Snoo, aption, sines are replaced by each correparently with the help of Barrau, and sponding H/R. The area dA 5 dx.dy, and founded on purely geometrical considermoreover, H x and Hy in their differential ations. Feodosiev came up with a correct, form, can be replaced by dx/2 and dy/2, simple, and more general derivation, while the integrals, under these condistarting with a rigid (or highly inelastic) tions, can also be deleted. Thus, (22) structure as a cupola and including the becomes

Z Axis

E α

T

T

Ry Tx dY

Tx

D P A

α

B α

T

H

Ty T

Rx

dX

R

(a)

O

F 5 33 PdA 5 D

(21)

H

(or decomposed in two linear integrals), F is obtained by linear integration over one axis with the tension on the opposite axis. It must be taken into account that the integral results in either dx or dy because sines are constant within them, so that, recalling de Snoo’s geometrical equations (Figure 4), we can write, F 5 3 2Ty sin ~y dlx dx

FIGURE 4 One of the principal planes, as shown in Figure 5. Force D: obtained after the added projections on the axis of tensions T, i.e., D = 2Tsin(a). Pressure P is constant along segment AB = 2H. Its associated force F = P(2H). Forces D and F must balance each other to keep equilibrium: D = F = 2Tsin(a) = P(2H). Angle a (a, in the drawing) is equal to angles EAB, AEO, and EOA. Besides, sin a = H/R, which, when replaced in the expression above, produces Tsin a = TH/R = HP, from which T = PR. In space, there is another plane perpendicular to the surface of this page. Notice that the central z axis is the same (see Figure 5).

Tx

Tx

Hx

dY Hy Ty dX (b)

FIGURE 5 (a) and (b): Looking at the curved piece in three dimensions—the rectangle Hx – Hy can be defined as a differential approximation of the curved surface. A flux F due to P would perpendicularly cross such rectangular area, from below upward on the z axis. Tensions Tx and Ty are shown on both perpendicular planes. SEPTEMBER/OCTOBER 2011

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ieee.org ) and Alberto J. Kohen ([email protected]) ______________ are with the Instituto de Ingeniería Biomédica, University of Buenos Aires, Argentina.

References

FIGURE 6 Front page of the Celestial Mechanics as part of the complete works. Downloaded from _______ http://gallica.bnf.fr/html/fr/editorial/conditions________________________ dutilisation-des-contenus-de___________________ gallica?ArianeWireIndex=true. ___________________ (Image courtesy of National Library of France.)

FIGURE 8 Laplace’s portrait as it appears in his complete works. Downloaded from _____________________ http://gallica.bnf.fr/html/fr/editorial/conditions-dutilisation-des-conte________________________ nus-de-gallica?ArianeWireIndex=true. _______________________ (Image courtesy of National Library of France.)

FIGURE 7 Front page of the Complete Works of Laplace as published in 1878. The Celestial Mechanics is in one of these volumes. Downloaded from http://gallica.bnf.fr/html/fr/editorial/ conditions-dutilisation-des-contenus________________________ de-gallica?ArianeWireIndex=true. (Im_____________________ age courtesy of National Library of France.) 80 IEEE PULSE

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wall thickness. Historically, there was no doubt that Le Marquis was the first to come out with it, although on the basis of the surface phenomena found in the capillary effect. As a consequence and to be fair, shouldn’t it be called Laplace– Barrau–de Snoo’s law? Finally, Armesto, a young student, produced a clever and excellent approach. We must admit and underline that the reduction of any hollow cavity to a sphere after calculating an equivalent radius (as carried out in many physiology textbooks) leads to good conceptual results and is useful in the understanding of pathologies (Figures 6–8). There is still another relatively recent contribution by Gregersen et al. [16], who— based on Laplace’s law— obtained a method to determine the longitudinal and c i rc u m ferent ia l membra ne st ress components of the intestine under balloon distension. They made several theoretical considerations (but not a demonstration of the law) followed by experimental validation. We merely mention it as a complement for the interested reader. Max E. Valentinuzzi (maxvalentinuzzi@ ____________ arnet.com.ar or _____________ maxvalentinuzzi@

[1] P. S. Laplace. (1790–1825). Mécanique Celeste (5 vols., 3 suppls., and a final note). Paris: Bibliothèque Nationale de France [Online]. Available: ____ http:// gallica.bnf.fr/. _______ Œuvres Complètes de Laplace (Laplace’s Complete Works). Paris: Gauthier-Villars-Imprimeur-Libraire, 1878 [which includes the celestial mechanics, also to be found at the Bibliothèque Nationale]. [2] Online Encyclopedia (as appearing in vol. V05, p. 258, 1911 edition of the Encyclopedia Britannica) [Online]. Available: http://encyclopedia.jrank.org/CAL_ ___________________ CAR/CAPILLARY_ACTION.html _________________ [3] M. E. Valentinuzzi and A. J. Kohen, “Laplace’s law: What is about, where it comes from and how is often applied in physiology,” IEEE Pulse, vol. 2, no. 4, pp. 74–81, 2011. [4] J. Jurin, “An account of some experiments shown before the Royal Society, with an enquiry into the cause of the ascent and suspension of water in capillary tubes,” Philos. Trans. pp. 739– 747, 1718 and p. 1083, 1719. [Online]. Available: http://en.wikipedia.org/ w i k i / You ng%E 2% 8 0 %93L aplace _ ______________________ equation _____ [5] T. Young. (1805). An essay on the cohesion of fluids. Philos. Trans. [Online]. 95, pp. 65–87. Available: http://catalogue. bnf.fr/ark:/12148/cb37571969b _________________ [6] C. F. Gauss, Principia Generalia Theoriae Figurae Fluidorum in statu Aequilibrii. Göttingen, 1829–1830, pp. 287–291 (Transl.: General Theoretical Principles of the Form of Fluid in Equilibrium, in Latin). [7] R. H. Woods, “A few applications of a physical theorem to membrane in the human body in a state of tension,” J. Anat. Physiol., vol. 26, pt. 3, pp. 362– 370, 1892. [8] K. de Snoo, “Die Bedeutung des Spannungsgesetzes für die Periode der Eröffnungsperiode (Ausdehnung),” Zentralblatt für Gynäkologie, no. 37, pp. 2162– 2169, Sept. 1936 (Transl.: “Meaning of the tension law during the mechanism of the dilatation period,” in German).




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CALL FOR NOMINATIONS Submission Deadline: 15 January 2012

Nominations are being sought for the IEEE Engineering in Medicine and Biology Society Technical Achievement Awards for 2012. Each award recipient will receive a plaque/certificate, an honorarium, and reimbursement in travel expenses associated with attending the EMBS Awards Presentation at the 34th Annual International Conference of the Society. The 2012 conference will be held in San Diego, CA, USA, 28 August – 1 September 2012 (http://embc2012.embs.org).

THE EMBS TECHNICAL ACHIEVEMENT AWARD Honorarium $1,500 USD/Travel Reimbursement up to $1,500 USD For outstanding achievements, contributions, or innovations in any area of bioengineering by an individual or group of individuals. Up to five awards will be selected each year. Qualifications for the award include, but are not limited to, new technologies or significant extensions of existing technologies, research results that extend domain knowledge, and design of new hardware or software having a significant impact in any area of bioengineering.

Examples of eligible Bioengineering Technologies (additional areas will also be considered) • • • •

Biosignal Processing Bioinstrumentation Bionanotechnology Cardiovascular and Respiratory Systems Engineering • Biomaterials • Biomechanics • Medical Device Design and Development

• • • •

Biomedical Imaging Biomicrotechnology Computational and Systems Biology Molecular, Cellular and Tissue Engineering • Biorobotics • Therapeutic and Diagnostic Systems • Health Care Information Systems

Nomination Procedure The required nomination packet consists of a two-page nomination form (see www.embs.org homepage), a current CV and letters from three references along with their address, telephone, facsimile number and e-mail address. It is the responsibility of the nominator to contact the references and solicit letters of endorsement. The complete nomination packet must be emailed to [email protected] and received no later than 15 January 2012 for the nominee to be considered for 2012. It is very desirable for nominations to be submitted well before the deadline. For questions, please contact the EMB Executive Office ([email protected]) Digital Object Identifier 10.1109/MPUL.2011.942963


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[9] M. Valentinuzzi, Sr., “Sobre algunas nociones de física del útero gravido: presión, tensión, tono, contracción y trabajo,” Boletín de la Sociedad de Obstetricia y Ginecología de Buenos Aires, vol. 18, no. 3, pp. 83–124, June 1939 (Transl.: “About some physics notions of the gravid uterus: Pressure, tension, tone, contraction and work,” Bull. Buenos Aires Soc. Obstet. Gynecol., in Spanish). [10] M. Valentinuzzi, Sr., “Contribución al estudio físico de la contracción uterine,” Doctoral dissertation, Med. Sch., Univ. Buenos Aires, Argentina, 1950 (Transl.: “Contribution to the physics of the uterine contraction,” in Spanish). [11] M. E. Valentinuzzi, Understanding the Human Machine: An Introduction to Bio-

engineering. Singapore: World Scientific, 2004. [12] A. C. Burton, “The importance of the shape and size of the heart,” Amer. Heart J., vol. 54, no. 6, pp. 801–810, 1957. [13] S. P. Timoshenko, Theory of Plates and Shells, 2nd ed. New York: McGraw-Hill, 1959. [14] L. D. Landau and E. M. Lifschitz, Fluid Mechanics (Course of Theoretical Physics, vol. 6), 1st ed. Oxford, New York: Pergamon, 1959 (reprinted 1975), p. xii, 536. (Transl. from Russian to English: J. B. Sykes and W. H. Reid, 2nd ed. Oxford: Pergamon, 1987). We used the Spanish edition. [15] V. I. Feodosiev, Materials’ Resistance (in Spanish, Resistencia of Materiales). Buenos

Aires: Editorial MIR, 1972. (Transl. from Russian and originally published in Moscow.) [16] H. Gregersen, G. S. Kassab, and Y. C. Fung, “Determination of membrane tension during balloon distension of intestine,” Mol. Cellular Biol., vol. 1, no. 3, pp. 191–199, 2004. [17] D. Hamito. (2009, Aug.). Bloat in sheep and goats: Causes, prevention and treatment. Ethiopia Sheep and Goat Productivity Improvement Program (ESGPIP), Tech. Bull. No. 31 [Online]. Available: http://www.esgpip.org; http://www. esgpip.net/PDF/Technical%20bulle______________________ tin%20No.31.pdf _________

YO U K N O W YO U R S T U D E N T S N E E D I E E E I N F O R M AT I O N . N O W T H E Y C A N H AV E I T . A N D Y O U C A N A F F O R D I T . IEEE RECOGNIZES THE SPECIAL NEEDS OF SMALLER COLLEGES,

and wants students to have access to the information that will put them on the path to career success. Now, smaller colleges can subscribe to the same IEEE collections that large universities receive, but at a lower price, based on your full-time enrollment and degree programs. Find out more–visit www.ieee.org/learning

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Nominations are being sought for the following IEEE Engineering in Medicine and Biology Society Awards for 2012. Each award recipient will receive a plaque/certificate, an honorarium, and reimbursement in travel expenses associated with attending the EMBS Awards Presentation at the 34th Annual International Conference of the Society. The 2012 conference will be held in San Diego, California, USA, 28 August – 1 September 2012 (http://embc2012.embs.org).

OUTSTANDING CHAPTER AWARD Honorarium $1000 USD/Travel Reimbursement of up to $1,000 USD For achievement in member development and delivering services to members of an EMBS Chapter during the previous calendar year. A single EMBS Chapter will be selected based on activities, community outreach and promotion of EMBS. BEST NEW CHAPTER AWARD Honorarium $500 USD/Travel Reimbursement of up to $1,000 For outstanding activities performed by a new EMBS Chapter within the first 12 months of Chapter formation. A single EMBS Chapter will be selected based on activities, community outreach and promotion of EMBS. OUTSTANDING PERFORMANCE AWARD for an EMBS Student Branch Chapter or Club Honorarium $500 USD/Travel Reimbursement up to $1,000 USD For achievement in demonstrating outstanding performance in promoting student interest and involvement in Biomedical Engineering during the previous calendar year. A single EMBS Student Branch Chapter or Club will be selected based on activities demonstrating initiative, innovation, and creativity; areas of progress and improvement; significant impact in biomedical engineering education; and contributions to the profession. BEST NEW STUDENT BRANCH CHAPTER or CLUB AWARD Honorarium $300 USD/Travel Reimbursement of up to $1,000 For outstanding activities performed by a new EMBS Student Club or Chapter within the first 12 months of formation. A single EMBS Student Branch Chapter or Club will be selected based on activities demonstrating initiative, innovation, and creativity; areas of progress and improvement; significant impact in biomedical engineering education; and contributions to the profession. Nomination Procedure The required nomination packet consists of a one-page nomination form and supporting documentation as outlined in the nomination form (see www.embs.org homepage). The complete nomination packet must be emailed to [email protected] and received no later than 15 January 2012.

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OPINION

Dollars Are Not an Output Arthur T. Johnson

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hat has happened to academic bioengineers? Faculty productivity used to be measured as a combination of teaching skills, professional service, and research output, but the system has been perverted by an inordinate emphasis on the number and amounts of outside money brought in. Previously, it wasn’t the total direct and indirect costs that were of importance but the source of the funds and whether the grant was from a prestigious or competitive agency. At that time, we could afford to spend some time developing and improving our classes because, although we were never given as much credit for teaching as we thought we should get, there was a chance that someone on the tenure committee thought that teaching was important for a neophyte faculty member to do well. Then, serving as committee members, officers, or program chairs for our professional societies was looked upon very strongly by our peers and superiors. It now seems that dollars snagged is the figure of merit not only for individual faculty members but also for whole universities. Our president and provost, when giving speeches bragging up our university, first declare the amounts of money brought in this year, decade, or period of time. Often, they don’t even get to a second declaration. There is competition among research universities, and the winner is the one with the most bucks. Gone, it seems, are the days when presidents bragged about fundamental research breakthroughs, grand technological advances, books written, students educated, peer-reviewed articles written,


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new pedagogic paradigms developed, unusual services performed, or mentoring successfully accomplished. It is now clear that the way to the top is through dollars ensnared. This change in emphasis has given academia a new view of itself. It now justifies its lofty efforts as generators of wealth. It used to be the paragon of knowledge. Our students are now looked upon as future wealthy alumni who can bequeath fortunes to the university. It used to be that we were educating them to serve humanity. President Dwight D. Eisenhower once warned that scientists could become prisoners of government funding, with contracts becoming a virtual substitute for intellectual curiosity. That day has arrived. The research work that gets done is the work that the government is willing to pay for. Anything without associated governmental dollars is ignored. At least, it seems that way. This had profound effects on our profession and those newly entering academia. The effect on the profession is the tendency to drive research toward reductionism, where fundamental research is given priority over applied research. This has turned engineering research toward scientific research and made the two often indistinguishable. For an applicant to fill a new faculty position, it has now become commonplace that postdoctoral experiences are necessary, and the more the better. It used to be unusual for a Ph.D. engineer to have postdoctoral experiences while joining as a faculty. The reason for the change is as follows: Ph.D. candidates used to be the ones determining the topics and methods used in their doctoral

researches. Advisors were there to guide and suggest, but the major decisions were made by the Ph.D. candidate himself or herself. There was a learning process involved in this, and the student developed mature judgment that allowed him or her to be qualified to develop a new research program immediately after the dissertation was completed. Nowadays, Ph.D. candidates are hired as supertechnicians to carry out the work promised on the grants for which they were recruited. They have little to say about the broad aspects of their research and, as such, are not given the opportunity to develop the skills needed to initiate new research projects. They can only develop these skills as postdocs. Course grade inflation has been occurring in the extreme since dollars snagged have become so important in the tenure process. There is a simple explanation for this. An assistant professor cannot take a lot of time away from proposal writing to spend with his or her courses. Students expect education, but they are satisfied by good grades. So, it is a lot simpler to give a lot of high grades than to answer students who complain about either the course or grade that they got. All of this is because time must be spent snagging dollars. If we turn our attention to the proposal writing process itself, how many of us can expect our proposals to be funded upon the first submission? None. Thus, a lot of time in writing proposals is spent revising past submissions to satisfy the comments of reviewers who may or may not have given quality reviews. There is not much creativity or inspiration involved in revising a proposal, and this turns into drudge work. Talk about the dulling of the faculty mind. There is no easy solution to this problem. Perhaps, we ought to begin to expect that faculties publish articles and educate students if they are lucky enough to receive outside funds.




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CLASSIFIED EMPLOYMENT To conform to the Age Discrimination in Employment Act, and to discourage age discrimination, IEEE may reject any advertisement containing any of these phrases, or similar ones: “recent college grad,” “1–4 years maximum experience,” “up to 5 years experience,” or “10 years maximum experience.” IEEE reserves the right to append to any advertisement, without specific notices to the advertiser, “Experience ranges are suggested minimum requirements, not maximums.” IEEE assumes that, since advertisers have been notified of this policy in advance, they agree that any experience requirements, whether stated as ranges or otherwise, will be construed by the reader as minimum requirements only. While IEEE does not ban the use of the term “entry level” its use is discouraged since, to some, it connotes an age rather than experience designation.

Department Chair, Biomedical Engineering The Department of Biomedical Engineering at New Jersey Institute of Technology (NJIT) invites applications for the position of Chair. The department, housed within the Newark College of Engineering, offers degrees from the baccalaureate to the doctorate and currently has ten tenured and tenure-track faculty, six teaching and research faculty, additional affiliated faculty from other departments and neighboring institutions, over 200 undergraduates, and 200 graduate students. The undergraduate degree is fully accredited by ABET. The department provides an excellent scholarly environment with research programs in the areas of neural engineering, cell and tissue engineering, rehabilitation engineering, biomechanics, and biomaterials. Collaborative research and core facilities within our University Heights community include the University of Medicine and Dentistry of New Jersey - NJ Medical School, Neurological Institute of NJ, Molecular and Behavioral Neuroscience at Rutgers–Newark, NJ Center for Biomaterials, Kessler Rehabilitation Institute and the Public Health Research Institute (PHRI). Candidates must have an earned doctorate in biomedical engineering or a related field. The successful candidate will have a sound vision of the future of biomedical engineering and the ability to lead and advance a student-centered and research-oriented department. He or she will have a demonstrated ability to work well with others, the ability to foster an atmosphere of collegiality in an environment of shared governance, and an established record of excellence in biomedical engineering research, education, and service sufficient to merit appointment as a tenured professor in the university. The successful candidate will be currently engaged in research and will be planning to continue as an active researcher. The new chair is expected to start in the summer or fall of 2012. Consideration of applicants will begin on December 1, 2011. Applications should include a letter, current curriculum vitae, and the names and addresses (including e-mail addresses) of at least five references. The application should also include a vision statement for research and education in biomedical engineering and the candidate’s preliminary vision for the department. Please visit https://njit.jobs ______ and search using posting #0600717 to apply. Inquiries can also [email protected]. be addressed to Treena Arinzeh, PhD, Chair of the Search Committee, ________ The search will continue until a successful applicant is appointed. AA/EOE NEW JERSEY INSTITUTE OF TECHNOLOGY

To place an ad in the IEEE PULSE Employment Opportunities section, call: Susan E. Schneiderman Business Development Manager +1 732 562 3946

UNIVERSITY HEIGHTS, NEWARK, NJ 07102-1982

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Faculty Positions Available ;OL *VSSLNL VM 5L^ 1LYZL` H OPNOS` ZLSLJ[P]L WYPTHYPS` \UKLYNYHK\H[L PUZ[P [\[PVU PU]P[LZ HWWSPJH[PVUZ MVY H [LU\YL [YHJR HZZPZ[HU[ VY HZZVJPH[L WYVMLZZVY ZOPW PU IPVTLKPJHS LUNPULLYPUN (WWSP JHU[Z T\Z[ OH]L H 7O+ PU IPVTLKPJHS LUNPULLYPUNVYYLSH[LKÄLSKH[[OL[PTLVM HWWVPU[TLU[ :WLJPÄJ YLZWVUZPIPSP[PLZ ^PSS PUJS\KL! [LHJOPUN JV\YZLZ PU Z`Z [LTZWO`ZPVSVNÌPVTLKPJHSZPNUHSZHUK Z`Z[LTZ HUK TH` PUJS\KL WO`ZPVSVNPJHS ZPNUHS WYVJLZZPUN HUK IPVPUZ[Y\TLU[H [PVU" HUK LZ[HISPZOPUN H YLZLHYJO WYV NYHT [OH[ PUJS\KLZ \UKLYNYHK\H[L Z[\ KLU[Z7YLMLYYLKX\HSPÄJH[PVUZPUJS\KLH IHJRNYV\UK PU J\YYPJ\S\TSHI KL]LSVW TLU[ WYLTLK HK]PZPUN HUK PUK\Z[YPHS L_WLYPLUJL ;*51 PZ [OL YLJPWPLU[ VM HU 5:- (+ =(5*, NYHU[ ^VYRPUN [V Z\WWVY[ [OL JHYLLYZ VM ^VTLU MHJ\S[` PU :;,4 KPZ JPWSPULZ I` KL]LSVWPUN Z`Z[LTPJ HW WYVHJOLZ[VPUJYLHZL[OLYLWYLZLU[H[PVU HUKHK]HUJLTLU[VM^VTLU ;VHWWS`ZLUKHSL[[LYVMHWWSPJH[PVUJ] Z[H[LTLU[ VM [LHJOPUN HUK YLZLHYJO PU [LYLZ[Z[YHUZJYPW[ZHUKUHTLZVM[OYLL YLMLYLUJLZ [V! )4, :LHYJO *VTTP[[LL *OHPY ]PH LTHPS _____________ LUNPULLYPUN'[JUQLK\ 9L]PL^VMHWWSPJH[PVUZ^PSSILNPU6J[V ILYHUK^PSSYLTHPUVWLU\U[PS [OLWVZP[PVUPZÄSSLK ;OL*VSSLNLVM5L^1LYZL`PZHU(MÄYTH [P]L(J[PVU,X\HS6WWVY[\UP[`,TWSV`LY

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The Department of Biomedical Engineering at the University of Minnesota-Twin Cities Campus invites applications and nominations for full-time tenure-track or tenured positions. Rank will depend upon the qualifications and experience of the candidate. Candidates in all areas of bio/biomedical engineering are encouraged to apply. Areas of interest include but are not limited to: cellular bioengineering, neural and cardiovascular engineering, cancer and immunity applications, biomedical imaging, and next-generation medical devices. Candidates must have a doctorate degree in biomedical engineering or a related field of science or engineering at the time of the appointment and outstanding academic and research records. The successful candidate is expected to develop a robust externally funded research program, initiate interdisciplinary and collaborative research, and engage in scholarly publication. She/he must have a strong commitment to excellence in teaching undergraduate and graduate students, especially advising Ph.D. students. Excellent opportunities exist in the department for interaction with medical school faculty located in the adjacent Academic Health Center and with the numerous medical device companies around the Twin Cities. Information about the department can be at http://www.umn.edu/bme. Applications for these positions must be completed online via _________________ https://employment.umn.edu (Requisition #173467/173468). Please upload a letter of interest, curriculum vitae (including a list of publications), research plan, and statement of teaching interests, and complete contact information for three references. The research plan (3-5 pages) **must include specific plans for at least one initial research project** as well as indicate the broad scope of research interests. Review of applications will begin November 1, 2011 with an application deadline of February 28, 2012. Questions regarding the search may be directed to __________ [email protected]. The University of Minnesota is an equal opportunity educator and employer.



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CALENDAR

SHANGHAI, CHINA

BEIJING, CHINA

SANTA CLARA, CALIFORNIA

Third Annual International Conference on Computational and Systems Biology (ICCSB2011)

International Conference on Body Area Networks

2012 IEEE Topical Conference on Biomedical Wireless Technologies, Networks, and Sensing Systems (BioWireleSS)

14–16 OCTOBER 2011

Contact: Dongqing Wei Phone: 86 21 342 04573 Web: http://iccsb.sjtu.edu.cn/ E-mail: [email protected] __________

7–10 NOVEMBER 2011 Contact: Foad Dabiri Phone: +1 310 367 8078 E-mail: __________ [email protected] Web: www.bodynets.org/

BANDUNG, WEST JAVA, INDONESIA SHANGHAI, CHINA Fourth International Congress on Image and Signal Processing (CISP 2011) and 4th International Conference on BioMedical Engineering and Informatics (BMEI 2011)

15–17 OCTOBER 2011

Contact: Lipo Wang Phone: +65 6790 6372 Fax: +65 6793 3318 Web: http://www.ntu.edu.sg/home/elpwang E-mail: ___________ [email protected]

BOSTON, MASSACHUSETTS AMA-IEEE Medical Technology Conference: Health Care IT

16–18 OCTOBER 2011

Contact: Dana Bernstein EMBC Executive Office Phone: +1 732 981 3451 Fax: +1 732 465 6435 Web: http://ama-ieee.embs.org/ E-mail: ___________ [email protected]

HANGZHOU, CHINA Yangtze River International Conference on the Applications of Medical Imaging Physics and the 6th National Annual Meeting of Medical Imaging Physics

22–23 OCTOBER 2011

Contact: Jiquan Liu Phone: +86 1 358 889 9165 Fax: +86 571 879 5196 Web: http://https://www.icmip.zju.edu.cn E-mail: ____________ [email protected]

SUZHOU JIANGSU, CHINA International Symposium on Bioelectronics and Bioinformatics (ISBB2011)

3–5 NOVEMBER 2011

Contact: Lijun Xiao Phone: +86 512 695 88025 Fax: +86 512 695 88099 Web: http://isbb2011.wmah.org E-mail: _________ [email protected]


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Second International Conference on Instrumentation, Communications, Information Technology, and Biomedical Engineering (ICICI-BME)

8–9 NOVEMBER 2011

Contact: Mitra Djamal Phone: +62 22 2500834 Fax: +62 22 2506452 Web: http://icici-bme.itb.ac.id E-mail: _________ [email protected]

WALTHAM, MASSACHUSETTS 2011 IEEE International Conference in Technologies for Homeland Security (HST\’ 11)

15–19 JANUARY 2012

Contact: Rizwan Bashirullah Phone: +352 392 0622 Fax: +352 392 8381 Web: http://www.radiowirelessweek.org/ biowireless/ ______ E-mail: __________ [email protected]

INNSBRUCK, AUSTRIA 9th IASTED International Conference on Biomedical Engineering (Biomed 2012)

15–17 FEBRUARY 2012

Contact: Karen Lee Phone: +403 288 1195 Fax: +403 247 6851 Web: http://www.iasted.org/conferences/ cfp-764.html _______ E-mail: __________ [email protected]

15–17 NOVEMBER 2011

Contact: R. Alongi Phone: +781 245 5405 Fax: +781 245 5406 Web: http://www.ieee.hst.org E-mail: _________ [email protected]

MAGALA, SPAIN Fourth ICST International Conference on eHealth

BETHESDA MARRIOTT, MARYLAND Grand Challenges in Biomedical Imaging

29 FEBRUARY–2 MARCH 2012 Contact: Dana Lynn Bernstein Phone: +1 732 981 3451 Web: http://gcbme2011.embs.org/ E-mail: ___________ [email protected]

21–23 NOVEMBER 2011

Contact: Martin Szomszor Phone: +44 2070403294 Web: http://www.electronic-health.org/ E-mail: ________________ [email protected]

HONG KONG, SHENZHEN IEEE-EMBS International Conference on Biomedical and Health Informatics

5–7 JANUARY 2012

Contact: Y.P. Liang Phone: +852 2609 8285 Web: http://bhi2012.embs.org E-mail: _____________ [email protected]

BALTIMORE, MARYLAND 2012 International Conference on Imaging and Signal Processing in Health Care and Technology

14–16 MAY 2012

Contact: Karen Lee Phone: +1 403 288 1195 Fax: +1 403 247 6851 Web: http://www.iasted.org/conferences/ cfp-771.html _______ E-mail: __________ [email protected]

BRITTANY, FRANCE MANAUS, BRAZIL 2012 ISSNIP Biosignals and Biorobotics Conference: Biosignals and Robotics for Better and Safer Living (BRC)

8–10 JANUARY 2012

Contact: Dinesh K. Kumar Phone: +61 3 9925 1954 Web: http://www.brc2012.org E-mail: [email protected] __________

IEEE EMBS International Summer School on Biomedical Imaging

22–30 JUNE 2012

Contact: Christian Roux Phone: +33 29 801 8107 Fax: +33 29 801 8124 Web: http://ieeess.enst-bretagne.fr/ E-mail: ____________________ [email protected]




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Nominations are being sought for the following IEEE Engineering in Medicine and Biology Society Awards for 2012. Each award recipient will receive a plaque/certificate, an honorarium, and reimbursement in travel expenses associated with attending the EMBS Awards Presentation at the 34th Annual International Conference of the Society. The 2012 conference will be held in San Diego, CA, USA, 28 August – 1 September 2012 (http://embc2012.embs.org).

THE EMBS ACADEMIC CAREER ACHIEVEMENT AWARD Honorarium $2,500 USD/Travel Reimbursement up to $1,500 USD For outstanding contribution and achievement in the field of Biomedical Engineering as an educator, researcher, developer, or administrator who has had a distinguished career of twenty years or more in the field of biomedical engineering. Accomplishments may be technological or theoretical and need not have proceeded the award date by any specific period of time. Individual must be a current member of EMBS. THE EMBS PROFESSIONAL CAREER ACHIEVEMENT AWARD Honorarium $2,500 USD/Travel Reimbursement up to $1,500 USD For outstanding contribution advancing Biomedical Engineering and its professional practices as a practicing biomedical engineer working in industry, government or other applied areas related to biomedical engineering. Accomplishments include, but are not limited to, technological advances, improvements in processes, or development of new products or procedures, and need not have preceded the award date by any specified period of time. Individual must be a current member of EMBS. THE EMBS EARLY CAREER ACHIEVEMENT AWARD Honorarium $1,000 USD/Travel Reimbursement up to $1,500 USD For significant contributions to the field of biomedical engineering as evidenced by innovative research design, product development, patents, and/or publications made by an individual who is within 10 years of completing their highest degree at the time of the nomination and is a current member of EMBS. THE EMBS DISTINGUISHED SERVICE AWARD Honorarium $1,000 USD/Travel Reimbursement up to $1,500 USD For outstanding service and contributions to the Engineering in Medicine and Biology Society. Accomplishments should be related to direct Society service and need not have preceded the award date by any specific period of time and individual must be a current member of EMBS. Nomination Procedure The required nomination packet consists of a two-page nomination form (see www.embs.org homepage), a current CV and letters from three references along with their address, telephone, facsimile number and email address. It is the responsibility of the nominator to contact the references and solicit letters of endorsement. The complete nomination packet must be emailed to [email protected] and received no later than 15 January 2012 for the nominee to be considered for 2012. It is very desirable for nominations to be submitted well before the deadline. For questions, please contact the EMB Executive Office ([email protected]) Digital Object Identifier 10.1109/MPUL.2011.942962


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NEURO ENGINEERING

ADVERTISING & SALES

James A. Vick Staff Director, Advertising +1 212 419 7767; Fax: +1 212 419 7589 [email protected] __________

The Advertisers Index contained in this issue is compiled as a service to our readers and advertisers: the publisher is not liable for errors or omissions although every effort is made to ensure its accuracy. Be sure to let our advertisers know you found them through IEEE Pulse.

Marion Delaney Advertising Sales Director +1 415 863 4717 Fax + 1 415 863 4717 [email protected] ___________ Susan E. Schneiderman Business Development Manager +1 732 562 3946; Fax: +1 732 981 1855 [email protected] __________

Biopac Systems, Inc., CVR 4 www.biopac.com +1 805 685 0066 IEEE Marketing Department, CVR 2 www.ieee.org/detectingcancer

PRODUCT ADVERTISING

MidAtlantic Lisa Rinaldo Phone: 732-772-0160 Fax: 732-772-0164 [email protected] __________ NY, NJ, PA, DE, MD, DC, KY, WV

IEEE MTT-S, page4 www.mtt.org/education.html RECRUITMENT The College of NJ, page 85 University of Minnesota, page 85 NJIT–New Jersey Institute of Technology, page 85

New England/South Central/ Eastern Canada Jody Estabrook Phone: 774-283-4528 Fax: 774-283-4527 [email protected] __________ ME, VT, NH, MA, RI, CT, AR, LA, OK, TX Canada: Quebec, Nova Scotia, Newfoundland, Prince Edward Island, New Brunswick Southeast Thomas Flynn Phone: 770-645-2944 Fax: 770-993-4423 [email protected] __________ VA, NC, SC, GA, FL, AL, MS, TN

Midwest/Central Canada Dave Jones Phone: 708-442-5633 Fax: 708-442-7620 [email protected] __________ IL, IA, KS, MN, MO, NE, ND, SD, WI, OH Canada: Manitoba, Saskatchewan, Alberta Midwest/Ontario, Canada Will Hamilton Phone: 269-381-2156 Fax: 269-381-2556 [email protected] ___________ IN, MI. Canada: Ontario West Coast/Mountain States/ Western Canada Marshall Rubin Phone: 818-888-2407 Fax: 818-888-4907 __________ [email protected] AZ, CO, HI, NM, NV, UT, AK, ID, MT, WY, OR, WA, CA Canada: British Columbia Europe/Africa/Middle East Heleen Vodegel Phone: +44 –1875-825-700 Fax: +44 –1875-825-701 [email protected] __________ Europe, Africa, Middle East Asia/Far East/Pacific Rim Susan Schneiderman Phone: +1 732-562-3946 Fax: +1 732-981-1855 __________ [email protected] Asia, Far East, Pacific Rim, Australia, New Zealand

New England/ Eastern Canada Liza Reich Phone: +1 212 419 7578 Fax: 212-419-7589 [email protected] ________ ME, VT, NH, MA, RI Canada: Quebec, Nova Scotia, Newfoundland, Prince Edward Island, New Brunswick Southeast Cathy Flynn Phone: 770-645-2944 Fax: 770-993-4423 [email protected] __________ VA, NC, SC, GA, FL, AL, MS, TN Midwest/South Central/ Central Canada Darcy Giovingo Phone: 847-498-4520 Fax: 847-498-5911 [email protected] __________ AR, IL, IN, IA, KS, LA, MI, MN, MO, NE, ND, SD, OH, OK, TX, WI Canada: Ontario, Manitoba, Saskatchewan, Alberta West Coast/Southwest/ Mountain States/Asia Tim Matteson Phone: 310-836-4064 Fax: 310-836-4067 [email protected] ___________ AZ, CO, HI, NV, NM, UT, CA, AK, ID, MT, WY, OR, WA Canada: British Columbia

RECRUITMENT ADVERTISING

MidAtlantic Lisa Rinaldo Phone: 732-772-0160 Fax: 732-772-0164 [email protected] __________ NY, NJ, CT, PA, DE, MD, DC, KY, WV

Europe/Africa/ Middle East Heleen Vodegel Phone: +44 –1875-825-700 Fax: +44 –1875-825-701 [email protected] __________ Europe, Africa, Middle East


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