Technology-Inspired Problem Solving

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Technology-Inspired Problem Solving

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Warren S. Grundfest, Eva Lai, Charles M. Peterson, and Karl E. Friedl

Abstract Large organizations develop layers and rules for members to operate within accepted processes and conventions whereas innovation tends to occur in a less constrained, less conventional, and less risk averse environment. This basic cultural difference creates a need for protected semi-autonomous centers that cultivate great ideas, providing freedom to explore new concepts and harbor the zealots to champion them past institutional barriers to change. The management objective at the Telemedicine and Advanced Technology Research Center (TATRC) is to advocate and accelerate technology development and ensure beneficial implementation in the shortest possible time. TATRC accomplishes this objective through integrating multidisciplinary teams that combine engineering technology and physical sciences with both basic and applied clinical biosciences to solve medical problems. This convergence in medical research complements Department of Defense (DoD) investments in long term basic research and large investments in high risk problem solving. TATRC successes in this “technology push to satisfy clinical need” began with radiograph digitization standards and has continued to spin out medical systems and program initiatives to new DoD core programs in rehabilitative medicine (e.g., regenerative medicine, advanced prosthetics, vision research, and integrative pain management), medical modeling and simulation, and current combat zone telemedicine applications. TATRC “technology scouts” look for transformational approaches across traditional boundaries and provide active assistance to build new capabilities and to successfully complete projects through commercialization and DoD implementation. Many near term problems can be addressed by mature technologies in medical robotics, synthetic biology, tissue engineering, nano- and biomaterials science, medical imaging, and neuroengineering. Everyday technologies such as smartphones can be immediately harnessed for better access to medical care, improved safety and efficiency in medicine, technology management and ultimately reduced medical costs. The end result of this culture of convergence can be transformational, calling for disruptive change in technology and capability as exemplified by telemedicine and m-Health, fostered through the unique TATRC research management model. Digital Object Identifier 10.1109/MCAS.2012.2205974 Date of publication: 22 August 2012

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U.S. Government work not protected by U.S. Copyright.

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I. Introduction n the 1990s, the U.S. Army had a problem with timely and efficient delivery of radiographic films between medical facilities in Bosnia. This clinical need was addressed by an Army officer trained in informatics, Fred Goeringer, and a small ad hoc team of academic and industry collaborators in the Medical Diagnostic Imaging Support (MDIS) project [1,2]. The key product was a standard approach to digitization that evolved into today’s international Digital Imaging and Communications in Medicine (DICOM) standards. The center that he started as the Medical Advanced Technology Materiel Office (MATMO) became the Telemedicine and Advanced Technology Research Center (TATRC). TATRC initially operated with a total annual budget of five million dollars, but soared to a high mark of $450M in fiscal year (FY) 2010, primarily in the form of Congressional Special Interest (CSI) funds that TATRC actively shaped to match investigator and institution capabilities with military medical needs. In FY2011 and FY2012, a moratorium on Congressional earmarks reduced this to $50M/year of potentially militarily relevant “national programs.” Many of these CSI programs have dual use applications with direct benefits to the nation, including the civilian medical community and military medicine. Furthermore, military medical science and technology has been tremendously enhanced by leveraging a disease focus such as diabetes (e.g., soldier physiological monitoring and weight management advances), Parkinson’s and Alzheimer’s diseases (e.g., neuroimaging technologies and early detection of neurological changes in soldiers), and pain management (e.g., integrative medicine concepts). Other sources of funding such as Small Business Innovative Research (SBIR), Small Business Technology Transfer (STTR), and some new Defense Health Program core military medicine research dollars are being actively managed through the existing nationwide TATRC network. Today, TATRC is an innovation center and a systems integration laboratory, focused on connecting researchers to each other, to funding opportunities, and to DoD relevant problem solving. The practices of TATRC and closely allied partners, such as the Center for Integration of Medicine and Innovation Technology (CIMIT) in Boston, MA have eluded clear articulation, but their special research niche has recently been characterized through the concept of convergence science [3]. Part of the difficulty in definition is due to the resistance of unconventional centers in large organizations to risk defining themselves too

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precisely and succumbing to bureaucratic policy-driven requirements-driven stovepipes themselves instead of problem-solving adhocracies (http://en.wikipedia.org/ wiki/Adhocracy). Potentially great research that has never been done before often does not satisfy a predetermined list of scoring criteria precisely because it has never been tried and the outcomes are not readily dictated in a contract or planned by committees. Providing precise definitions and criteria for how to run an adhocracy that nurtures great research is dangerous to their continued success. In 2006, Major General Eric Schoomaker, Commanding General for U.S. Army Medical Research and Materiel Command (USAMRMC), directed TATRC to identify the unique processes (the “secret sauce”) that made this center so successful in spinning out novel and important solutions for military medicine. He wanted to apply any useful generalizable practices to the conventional programs. Some of the “activist management” practices of TATRC have since been embraced in other programs and the TATRC network is now directly involved in management of specialized research portfolios for some of the conventional programs. At about the same time, the Wellcome Trust and CIMIT came together at the Harvard Business School to analyze the CIMIT model, hoping to define elements of an exportable medical research management model [4]. This paper summarizes some of the observations of what works, what doesn’t work, ingredients for building a successful technology innovation cell, and highlights some successful examples of medical innovations. II. Science Management Models A. “Convergence” Science and Technology Acceleration The merging of life sciences with the physical sciences, mathematics, and engineering has been billed as the “third revolution in medicine,” following molecular biology contributions in the 1970s and the human genome in the 1990s [1,3,4]. The key goal of this approach is to accelerate problem solving in medicine, often with a technology push that is matched to a clinical pull. These solutions can be disruptive to existing processes and infrastructure and they are likely to be termed “innovative” if they become accepted changes in efficiency

TATRC convergence and innovation efforts have been supported by the U.S. Congress through Special Congressional Appropriations. Currently, there is no programmed funding source for this effort.

Warren S. Grundfest, Eva Lai, Charles M. Peterson, and Karl E. Friedl are with the Telemedicine and Advanced Technology Research Center (TATRC), U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, USA (e-mail: [email protected]).

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Part of the “secret sauce” in this medical convergence is bringing multidisciplinary experts together in an atypical teaming environment. The convergence approach also works in basic (discovery) research where technology solutions accelerate discovery opportunities. (e.g., substantially reduced costs in medical care, improved patient health outcomes and safety, enablement of individual self-care, etc.). There is no program to train convergence science. Success comes from combining the talents of individuals who are deep experts in their respective areas of specialized research. The Robert S. Langer lab at the Massachusetts Institute of Technology (MIT) in Boston, MA is a prototype model for convergence science in academia with high productivity. Dr. Langer has authored more than 1,100 research papers, has approximately 800 issued and pending patents worldwide that have been licensed or sublicensed to more than 220 companies, and has a hand in creating some 25 companies [7]. Many academic laboratories have engaged similar approaches and been highly productive. These labs are characterized by creative leadership, exceptional involvement and mentoring, freedom to explore and productivity in people and scientific endeavor. They tend to be time limited because they are so often centered on a single individual’s vision. Industry has produced several examples of uniquely creative cultures, but they are relatively rare. Notable examples in industry include Bell Labs, Xerox Palo Alto Research Center (PARC), and the “i-team” at Apple. Again key ingredients appear to include a visionary and inspired leader, time to create outside of the critical goals as well as a focus on design oriented production. Bell Labs and Xerox PARC were relatively long lived entities, but succumbed to an increasingly competitive “bottom line” oriented business culture and financial priorities. Part of the “secret sauce” in this medical convergence is bringing multidisciplinary experts together in an atypical teaming environment. In the CIMIT program, the scientists who do this are referred to as “site miners” [4]. These individuals are asked to contribute a portion of their time to identifying potential research collaborations and making the active introductions and further facilitation across disciplines, as necessary. Portfolio managers and subject matter experts at TATRC play a similar role and reach across a large network of investigators. Various convening functions such as twice monthly “product line reviews” (PLRs) and specialty meetings have been key to facilitating unexpected transdisciplinary collaborations. Centers that conduct convergence are now indoctrinating a new generation of 16

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researchers in this novel collaborative model of medical technology acceleration [4,7,8]. B. Basic Discovery Research Support to basic research is critical to the fueling of new discovery which provides the foundation for revolutionary advances in science. Unlike convergence projects, important advances in basic science are unpredictable. Army funding of basic research is a longterm investment (Strategic Research Objectives are 10 year initiatives) and peer-reviewed publications are the key metrics of progress. TATRC has relatively small involvement in basic research programs. One example is support to research on olfactory signals, emotion, and learning at the Monell Chemical Senses Center; another important investment is a program in virtual human technology at the Institute of Creative Technology, an Army Research Office University Affiliated Research Center (UARC). The convergence approach also works in basic (discovery) research where technology solutions accelerate discovery opportunities. One TATRC example is the introduction and support of two CSI funded investigators, one with quantum dot receptor labeling technology and the other with a need to be able to follow individual receptors in neural cells. This collaboration between Tania Vu and Paul Greengard led to the identification of new pathways for serotonergic receptor cellular recycling and contributes to better understanding of depression [9], as discussed in more detail below. Other recent technology-facilitated basic research studies supported by TATRC elucidated mechanisms for the special vulnerability of striatal dopaminergic neurons (using specialized two photon laser scanning microscopy) [10], importance of p11 protein as a marker of physiological changes in depression (utilizing bacterial artificial chromosome (BAC) transgenic mice) [11], the discovery of a gamma secretase activating protein that may be a key therapeutic target in Alzheimer’s disease [12], and applications of terahertz imaging technologies in wound treatment [13]. These may contribute to better protection and treatment of soldiers and Marines exposed to deployment hazards. Breakthrough findings are not predictable, but are increased by the number of investigators working on a problem and facilitated by new technologies and techniques that expand options for exploration. THIRD QUARTER 2012

SBIR and STTR funding has been a key TATRC mechanism promoting technology applications in medicine, especially in health IT and medical training and simulations applications. C. Big Science and Grand Challenges Organizations fostering transformative processes within established government bureaucracies are perhaps even more difficult to establish and sustain. Nevertheless, several prominent examples are characterized by big science investments such as the Manhattan Project, Conseil Européen pour la Recherche Nucléaire (CERN, European Council for Nuclear Research), and Defense Advanced Research Projects Agency (DARPA). DARPA is a model of revolutionary research that seeks high risk projects with potentially high payoff, providing large amounts of short term funding (e.g., 18 months of concerted Manhattan project-style effort). Building capable cross-disciplinary teams is a common feature of these projects. Some of the efforts initially stimulated through DARPA interest and support have produced technologies that were later harvested in TATRC convergence projects. For example, the microfluidics program at DARPA further advanced this technology development and permitted TATRC to support the only Food and Drug Administration (FDA) approved disposable blood typing card (ABORhCard) that can be used in austere environments [14,15]. This product was developed in less than five years to address a medical gap in rapid typing of blood for transfusion in the field. Other contributions are emerging from DARPA programs in augmented cognition (e.g., medical information displays) [16], trauma pod (e.g., robotic systems such as a multiaxis serpentine arm) [17], plasma physics in wound treatment (e.g., Leishmania treatment) [18], and detection and computational analysis of psychological signals (DCAPS) (e.g., virtual human technologies for medical training and simulation) [19]. D. DoD Acquisition Model Applied to Medical Research The traditional model in DoD medical research has been linear and evolutionary (Figure 1), even as other parts of DoD research and development have adopted new iterative processes to increase technological agility. The traditional model relies on development of major systems based largely on proven technologies that can produce evolutionary advances in capabilities; sequential milestone decisions that terminate or continue efforts based on preset thresholds for schedule, cost, and performance; and a relatively inflexible commitment to a THIRD QUARTER 2012

product as originally envisioned months to years before the final result. This development model may be better suited to military materiel, for which it was created, than to medical research and technology. In recent years, the DoD has modified research acquisition policies based on lessons learned in how to increase agility and innovation (Figure 2). Joint capabilities requirements (“deliberate needs”) drive “deliberate solutions” through a centralized solutions process and multi-year budgeting. However, a parallel path is now recognized for a rapid, responsive, and flexible program that provides agile solutions to emergent needs within the budget year. This involves a tolerance for diversified and decentralized solutions processes, including a small, non-traditional business “on-ramp.” The new path allows for successful initiatives to transition into the deliberate process. This alternate process is described as a transformation engine and innovation enabler. TATRC has filled this unique niche for military medical research innovation using numerous sources of special funding such as SBIR, JCTD, and CWP (Figure 2). SBIR and STTR funding has been a key TATRC mechanism promoting technology applications in medicine, especially in health IT and medical training and simulations applications. A TATRC-supported Coalition Warfare Program is developing and testing smartphone applications for medical humanitarian assistance such as just-in-time and refresher medical training, medical language translation, and medical logistic supply tracking with twenty-two partner nations [20]. A joint U.S. Department of Veterans Affairs (VA) and DoD program (the Joint Incentive Fund program) has been used to support an implementation test of an automated hand washing reminder system to reduce hospital borne infections at Boston VA Medical Center and the U.S. Army Institute of Surgical Research, testing a product that came out of the CIMIT Accelerator Program. A Joint Concept Technology Demonstration (JCTD) project on precision air resupply and casualty evacuation (“Best JCTD,” 2010) was used to evaluate proposed solutions to efficiently capture point of injury medical data and populate the electronic health record ahead of the patient evacuation. This is now being further tested in other relevant and realistic field exercises such as Network Integration Exercises (NIE) to demonstrate the concept of use for patient monitors that could be used by the medic for casualty monitoring, telementoring, and data acquisition. IEEE CIRCUITS AND SYSTEMS MAGAZINE

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Figure 1. Department of Defense (DoD) acquisition, technology, and logistics life cycle management framework. Every step of technology development is finely orchestrated in a process designed to evolve existing systems and ensure advanced planning for fielding and sustainment of the new solutions. [Source: Defense Acquisition University (http://akss. dau.mil) and http://spacese.spacegrant.org/uploads/Project%20Life%20Cycle/DAU_wallChart.pdf.]

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Acquisition On Ramp—Test to Procure Tech Refresh Service, SOCOM Nominated Test to Procure Congressionally Directed—DOD Lab Tech Push

Defense Acquisition Challenge Foreign Comparative Testing Tech Transition Initiative

Figure 2. Agile technology transfer process in DoD programs. This approach acknowledges the importance of various technology accelerators and allows for integration of solutions from these special programs into the linear R&D process model at various levels of maturity [technical readiness levels (TRL), operation and maintenance (O&M), Defense Advanced Research Projects Agency (DARPA), Defense Threat Reduction Agency (DTRA), coalition warrior interoperability demonstration (CWID), combatant command (COCOM), advanced concept technology demonstrations (ACTD), joint capability technology demonstrations (JCTD), special operations command (SOCOM), joint forces command (JFCOM), joint experimentation (JE), joint integration and interoperability (JI&I), joint systems integration command (JSIC), quick reactions special projects (QRSP), rapid reaction fund (RRF), combating terrorism technology task force (CTTTF), and improvised explosive device (IED)].

Additional funding from TATRC will address practical challenges about communications security; size, weight, and durability of the devices; and complexity of the data, all of which can be parsed to solvable issues involving smartphones with security systems, computational tools, and graphic representations. No new discovery is required to solve the problem of telemedical support to the medics at point of injury; the focus is on testing best available technical solutions and determining how to integrate this into existing systems. TATRC is experienced in management of Congressionally directed medical research programs and many of these have turned into key products entered into the formal DoD acquisition process. Two current examples include a system for reducing blood pathogens that is expected to greatly expand the worldwide supply of blood for transfusion and to increase safety from infection [21]; and development and testing of s-ketamine THIRD QUARTER 2012

enantiomer with the potential of more than doubling the analgesic and anesthetic potency of ketamine, allowing a reduction in pain medication and reduced side effects. Other projects have led to commercialized medical products that are suited to DoD procurement such as a new field portable x-ray system [22,23] and new lower limb prostheses that support normal walking and running [24–26]. Other innovation projects have been funded by TATRC that addressed newly identified problems from theater such as a now FDA approved blood warmer that provides active thermal resuscitation during evacuation of hypothermic patients with severe hemorrhage [27]. These are success stories that each began in the face of significant bureaucratic opposition and research policy barriers. Nevertheless, each effort involves a design oriented approach to solving an important military medical problem. Due to the universality of medical issues, many have or will transition to the civilian sector. IEEE CIRCUITS AND SYSTEMS MAGAZINE

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Innovation can be an extraordinarily simple application that revolutionizes access to medical care and efficiency in the military healthcare system—mCare is an example of this (www.tatrc.org/mCare). III. Examples of Transformational Outcomes A. Telemedicine and Mobile Health Innovation can be an extraordinarily simple application that revolutionizes access to medical care and efficiency in the military healthcare system—mCare is an example of this (www.tatrc.org/mCare). Soldiers recovering from injuries are connected to their case workers through their personal cell phones. This is a disruptive concept because it changes current processes and policies about person-to-person contact, requires new approaches to

Figure 3. CPT Dan Luckett is one of about 40 soldiers currently serving in combat zones with state-of-the-art prostheses. As a double amputee (part of a foot and a lower leg amputation caused by a roadside bomb), CPT Luckett leads his soldiers on patrol in Afghanistan and is an early beneficiary of medical technology developments to restore function to seriously wounded soldiers. This return to duty capability was not possible a decade ago. (Source: Associated Press Photo, Todd Pitman.)

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documenting the patient contact in the medical record, and produces challenges to data security. In its initial and simplest application, mCare is demonstrating a large impact on efficiency with reductions in missed appointments, user satisfaction, and improved information dissemination. This “Army’s Greatest Invention for 2010” worked through issues of patient privacy, military internet security, open architecture software development that could work on major cell phone carriers, and defense business certification processes to gain approval for the use of this “everyday technology” in medical care. mCare can now be rapidly expanded to test other applications such as better management of pain and depression in response to patient reports of symptoms. Next steps beyond this involve current research efforts with virtual humans for the smartphone-soldier interface, physiological sensing to detect neuropsychological status changes, and significant artificial intelligence and computational models for meaningful virtual human interactions such as in the SimCoach effort at the Institute of Creative Technologies [19]. B. Rehabilitation and “Reset”— Soldiers Can Be Repaired and Retained Improvements in body armor protection have decreased rates of soldiers who are killed in action and shifted the pattern of injuries to a higher proportion of survivable limb losses. In the recent conflicts in Iraq and Afghanistan, more than 1000 soldiers and Marines have sustained limb loss, with the majority of these injuries involving lower extremities. Bioengineering technologies supported through special congressional appropriations at TATRC for the past decade have greatly improved prosthetic technologies to return functionality, even to the point of permitting soldiers to return to combat zones with lower limb prosthetic feet and legs (Figure 3). New powered knees and foot-ankle prosthetics permit more natural biomechanical gaits, and new hardened systems can better withstand harsh field conditions. Applications of derivative exoskeleton technologies will contribute to human performance augmentation systems for future warfighters. Next steps include efforts on proprioceptive feedback on position and “feel” of the artificial limbs [28,29], osseointegration of the prosthetic devices, and neuroengineered neural control. Advances in transplants are producing even greater restoration of function, with very recent THIRD QUARTER 2012

TATRC funded breakthroughs in understanding of how to reduce the problem of tissue rejection and reduce the need for immunosuppressive drug therapy [30,31]. Ultimately, regenerative medicine technologies will rebuild and repair biological organs [32]. C. Computational Biology Applications There is a massive need for computational models in the DoD for prediction of health risks, real time decision support tools for commanders and for medical personnel, and for biosurveillance. Unfortunately, the complexity and effort required to produce valid and useful models is generally underestimated, with an assumption that there is always useful behind the scenes “artificial intelligence” ensuring safety of new systems, performance predictions from a new physiological monitor, clinical assessments from high tech medical devices, and continuous coverage of global medical biosurveillance. A major convergence effort at TATRC has been developed and led by Dr. Jaques Reifman to bring mathematics and computer science skills to these military medical problems. A key challenge has been to convince other researchers that this expertise can provide revolutionary paradigm-shifting advances to military medical needs and is not simply an afterthought related to the statistical analysis of data. The team has developed a family of high performance computing tools for biological defense research [33–35], new models and methods in physiological modeling including fatigue and performance [36] and predictions of impending thermal casualties [37], and real time casualty evacuation physiological monitoring [38]. Systems biology computational strategies have been developed to address pressing questions about traumatic brain injury and post- traumatic stress disorder (PTSD) pathogenesis. Other computational tools are being developed for: 1) in silico whole organism test systems such as M. tuberculosis for new efficient drug testing [39]; 2) a systems approach to coagulopathies in trauma [40]; and 3) blood glucose predictions and algorithms for automated insulin delivery systems important in shock and postsurgical patients [41]. Previous and continuing efforts by Dr. James Stuhmiller (Jaycor, Inc. San Diego, CA) have developed a very important family of predictive models for developers of new military systems to ensure protection of human operators. These models include prediction of health and performance risks associated with blast overpressure of new high powered weapons systems [42,43], survivability in burning vehicles and aircraft [44], evaluation criteria for new lighter weight body armor systems [45], and improved helmet design to withstand forces acting on the head. THIRD QUARTER 2012

These convergent modeling efforts by Dr. Reifman and Dr. Stuhmiller have advanced the analysis of years of discovery research data, substantially reduced the need for animal tests, and improved current protection of soldiers [46]. Other TATRC efforts, as previously mentioned, involve very challenging research to develop the substantial artificial intelligence to drive believable human-avatar interactions, especially for the DARPA led DCAPS program (http://www.darpa.mil/Our_Work/I2O/ Programs/Detection_and_Computational_Analysis_of_ Psychological_Signals_(DCAPS).aspx). IV. Examples of TATRC-Sponsored Nanotechnology and Biomaterials Convergence Research The following examples highlight projects that TATRC has managed in the Nanotechnology and Biomaterials Portfolio. These projects illustrate the spectrum of activities within one single TATRC portfolio and exemplify the many ways in which TATRC works with investigators to focus their research, build collaborations, and identify stakeholders within the DoD. Some projects require greater management and input from TATRC managers, while others require less attention as they are shaped during the proposal approval process. In some instances, ongoing review activities promote collaboration outside the investigator’s usual contacts which may lead to novel interdisciplinary research. Improved management of hemorrhagic shock has been a major goal of military medicine for hundreds of years. Recently, technology developed in the laboratory of Dr. Robert Langer at MIT has been applied to improve the delivery of oxygen through the blood stream using artificially created oxygen-carrying cell-like particles. These particles have a synthetic membrane which contains a novel oxygen carrying compound, which in turn provides this oxygen to the cells (Figure 4). If successful, this might dramatically improve

Figure 4. Particle structure for an oxygen gas-filled nanoparticle [47].

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combat casualty care, drastically improving oxygen delivery, reducing the need for transfusions during operations, and extending the blood supply. TATRC’s role has been to provide subject matter expertise to the investigators and provide administrative support required to obtain the necessary Army animal and human subjects protocol approvals. This project is in its early stages of development and TATRC is working with the research team to identify potential military and civilian collaborators. Improved management of eye trauma has been a long term goal of the military. Recently Dr. Buddy Ratner, at the University of Washington, developed a novel porous biomaterial that enhances wound healing and controls the influx of white blood cells. Preliminary studies demonstrated that the use of the materials dramatically reduced the inflammatory phase of tissue healing (http:// depts.washington.edu/bioe/people/core/ratner.html). TATRC identified this project as one with the potential of high significance and has linked it to innovation funding. Dr. Ratner’s efforts have identified a key facet in the

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(b) Figure 5. Comparison of titanium nitrite surface coatings using (a) unfiltered arc versus (b) filtered arc large area filtered arc deposition (LAFAD) technology. The filtered arc process used in the research permits particle-free coating deposition. (Images courtesy of Dr. John Wallace, American Eagle Instruments.)

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control of the healing response. While there are multiple applications of this technology, there is an urgent military need for improved eye bandages, and this project directly addresses that need. TATRC assists its investigators in identifying the critical path to commercialization. Innovative Micro Technology (IMT) in Santa Barbara, CA, received congressional support for the development of microelectromechanical systems (MEMS) based cell sorting technology using a combination of microfluidics and optical technologies (http://www.imtmems.com/). This complex system required integration of expertise from multiple disciplines over a six year development process. The initial proposal identified a large potential opportunity that carried significant risk due to the advanced nature of the technological development required for success. TATRC provided both subject matter expertise and management guidance. In order to successfully translate the concept into a practical device, IMT combined expertise in microfluidics, optics, MEMS fabrication, and cell biology to produce a novel, high speed, MEMS based cell sorter. This technology has now been commercialized for the agricultural and medical markets. The team at American Eagle Instruments in Missoula, MT, developed a novel process that significantly reduces friction and improves the wear characteristics of metal surfaces (Figure 5). The team demonstrated the ability to fabricate complex multi-layer nanostructured coatings on a variety of metal surfaces. Initial efforts focused on biomedical applications of these coatings, including improved orthopedic implants and surgical tools, and demonstrated greater longevity. The coatings improved implant resistance to wear and had lower particle formation, leading to greater longevity of these implants [48–50]. This technology may also find wider application in the military as it reduces the friction of metal-on-metal surfaces and improves wear characteristics, thus increasing longevity and efficiency of weapons platforms and motorized equipment. Through “activist management,” TATRC facilitated a project that developed quantum dot (QD) imaging for tracking serotonin receptors (e.g., 5-HT1B) and neurotrophic typrosine kinase receptors (e.g., BDNF-TrkB) [51–52]. Dr. Tania Vu, at the Oregon Health and Science University was introduced to Dr. Paul Greengard, at the Rockefeller University, and this led to significant and productive collaborations [9]. Using the QD nanotechnology developed in this project, Dr. Vu and her team were able to measure the surface expression and the mobility of these receptors on neuronal membrane surfaces to study the modulation of the receptors by p11, a candidate protein strongly implicated in depression signaling THIRD QUARTER 2012

(Figure 6). Measurements from these refined quantum dot probes compare favorably to those from classical techniques (e.g., biotinylation, radio labeling, green fluorescent protein (GFP), and immunohistochemistry) used to determine receptor surface expression by antidepressants. This group demonstrated that QD probes can be used to track discrete movement of protein receptors on the neuronal surface. This research is highly relevant to the military as many returning soldiers suffer from PTSD and depression. Antidepressants are used widely to treat PTSD; however, these treatments are only partially effective, therapeutic responses are delayed, and the drugs can have debilitating side effects. The QD technology provided insight into cellular mechanisms that regulate the surface expression of neural receptors at the molecular level. These receptors play a key role in the molecular modulation of affect, which may help explain the molecular basis of depression. Another research effort utilizes nanofabrication techniques for tissue engineering to develop an artificial wearable bioartificial kidney (WEBAK) that will be compact, inexpensive, self-monitoring and readily deployable for clinical application. In order to develop a nanofabricated kidney, the team learned to integrate renal epithelial cells onto artificial membranes, creating devices that can be used for acute and chronic renal dialysis [53,54]. These devices form an intermediate step in the development of a true artificial kidney and provide a novel technology platform to explore the application of this technology for treating human diseases. The team integrated biomaterial and scaffold technology with micro-pumps and transducers. A robust cell source was established, employing a process by which adult renal progenitor cells are expanded to yield adequate cell numbers sufficient to meet anticipated clinical needs for renal cell therapy in acute and chronic applications. This enhanced propagation process was used to generate the cells required for the Bioartificial Renal Epithelial Cell System unit that is integrated into the circuit of the WEBAK [55] (Figure 7). The Center for Advanced Bioengineering for Soldier Survivability (CABSS) at the Georgia Institute of Technology has utilized a “Triple Helix” approach in common with models promoted by TATRC and other students of innovation, such as Dr. Etkowitz [56], in bringing together academic, industry, and government collaborators to advance research and translate bench findings to bedside medicine. Through this approach, concepts and ideas are conceived, developed, and refined through discussions with military scientists, clinicians, and program managers to understand the military medical problems and constraints. These steps are followed by discussions with industry experts to strategize market opportunity THIRD QUARTER 2012

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Figure 6. Fluorescent nanoparticle quantum dots are used to image single groups of serotonin receptors and distinguish their location on cell membranes (blue arrow) and inside the cell (white arrow). (Image courtesy of Dr. Tania Vu.)

and regulatory requirements in bringing forth a potential product. In addition, CABSS applies a convergence science research model in its product development in which the team includes basic life scientists, engineers, and clinicians. Through this combination of approaches, the team created a novel cell encapsulation and delivery device, where adipose-derived stem cells encapsulated in microbeads can survive for more than three weeks to release factors that promote wound healing. The microbead fabrication method prevents alginate calcification and a hyaluronic acid delivery vehicle was developed to ensure that the beads did not aggregate during percutaneous injection. The result is a novel cell delivery system that enables large number of cells to be injected into the wound site in a controlled manner, avoiding cell apoptosis due to poor diffusion of nutrients, and using the cells as living biological factories for production of continuous, controlled release of wound healing factors [57–59]. Currently, this technology is being developed to

Figure 7. Cell distribution, after two weeks in culture, on the nanomembrane used in the artificial kidney (fluorescent DAPI cell staining). (Image courtesy of Dr. David Humes.)

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Too much visibility or interest in the early stages of a project often jeopardizes the innovative nature of the effort.

Figure 8. The last flight of the space shuttle (STS-135) carried a cell culture bioreactor specially designed for the conditions in space. (Source: NASA.)

address cartilage regeneration strategies for chondral defects and has been licensed for product and commercialization development. V. What Works—Characteristics of a Technology Innovator A. Semi-Autonomy and Decentralized Efforts Revolutionary advances are usually disruptive to existing processes, making early stage efforts unlikely to be

Table 1. Steps to promote innovation. • Provide continuous small funding opportunities for early and rapid concept evaluation • Use a single level of review involving consensus among experts focused on identifying new good ideas and killing off only bad ideas • Phase support to the research starting with seed money for a first phase, with intentions to continue or transition to other funding based on progress • Build capability in new areas of inquiry through active facilitation of new and novel collaborations by thoughtful managers and technical experts • Provide active assistance in hurdling research and technology development processes to investigators and teams with good ideas • Place greatest peer review focus on results and progress after the research begins using an activist management strategy of assistance and linkages

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supported in the planned programs. Impending DoD budgetary reductions will predictably reduce even the exploratory investments by program managers that could lead to an important breakthrough, ensuring only incremental improvements to current systems. Semiautonomous “skunk works” are a common fixture in large organizations that want to test and promote novel concepts outside of the planned research program and culture. TATRC performs these special functions and supports a culture of innovation within the Headquarters, U.S. Army Medical Research and Materiel Command and reports directly to the Deputy Commander. TATRC has managed and shaped research initiatives with funding from Army medical technology demonstration funds, Congressional Special Interest funding, and SBIR and STTR programs. The Center also experiments with technology integration, particularly in health information technologies, telemedicine, and mobile health. A recently acquired function leverages the TATRC subject matter expert network to provide technical management of Defense Health Program planned research programs. Too much visibility or interest in the early stages of a project often jeopardizes the innovative nature of the effort. Mainstream “helpers” often take over the effort and promptly make it conform to current conventions in an area for which they feel they have assigned responsibility. A military culture with a history of “need to know” responsibility and timely handoffs can be helpful in this regard. B. Activist Management with a Problem Solving Focus The primary purpose of DoD medical research funding is to solve important problems. This design-oriented approach differs from the focus of programs that are responsible for supporting the scientific infrastructure of the country through investigator-initiated grants. It is also different from a culture of managers who support processes rather than direct and actively manage the indepth technical aspects of their programs by suggesting technical strategies, building partnerships, and facilitating dialogue with military end users. There is nothing subtle in the difference between program management that follows a rigid process of grant solicitation and investigator-initiated proposals, and a program that seeks out and nurtures new science and technology capabilities that might solve an important problem (Table 1). THIRD QUARTER 2012

The activist management approach requires far more effort throughout the duration of the project, but it is also more likely to result in solutions tailored to the military medical problems. Process-driven management is more likely to produce a collection of independent investigator-initiated projects distributed across key topics, instead of funding projects that build on previous advances or provide different, but related, slices of a particular problem area to promote novel solutions to areas of clinical need. The “management by keyword” approach produces more Brownian motion in an increasingly circumscribed StokesEinstein radius than directed and nurtured problem solving. This difference in risk tolerance modified by potential outcome value has been a recognized problem in the National Institute of Health (NIH) study section process where transformational science does not thrive and the focus is on relatively safe or incremental investments that may not significantly advance the healthcare of the nation. C. Connectors and Zealots Competent people with technical depth are essential to making connections in convergence science management and to conducting agile program management. Ideally, program managers are nationally recognized experts who can effectively shape and guide a portfolio of research because they know the field and can interact and provide thoughtful guidance to funded investigators. TATRC cultivates new initiatives by convening groups and connecting individuals [e.g., 61–68]. TATRC has traditionally obtained core management staff as part-time Interagency Personnel Agreement (IPA) from universities around the country. Nationally recognized scientists and clinicians who continue in their professional activities with one foot in the laboratory are best positioned to evaluate the feasibility of a new idea. TATRC is composed of individuals who are passionate about the opportunities to promote innovation and help solve important problems for the military and civilian populations. The personnel search thus incorporates a look for that spark of passion and altruism. The actual implementation of disruptive solutions into DoD use requires a special resilience and persistence, best described as zealotry. Exemplars of TATRC zealots are long-standing members of the TATRC Team Drs. Ron Poropatich (telemedicine) [60], Gary Gilbert (robotics and field medical technologies) [61], and Jaques Reifman (computational biology) [61]. Each has gained success for one or more research initiatives through a decade or more of sustained effort. Thus the TATRC culture has room for those who can contribute THIRD QUARTER 2012

and be supported as part of an ad hoc time limited team and those who can be supported for the “longer haul.” D. One Level of Review and Speed of Action Good project ideas should be advanced quickly and not require 1–2 years of process including development of funding announcements, extended scientific and programmatic reviews, and additional levels of approval to arrive at funding recommendations. A frequent and simple process should move decisions on good ideas quickly. This ad hoc capability is a key feature of accelerating technology solutions to practice in other successful labs and programs [4,7,8]. TATRC has weekly Proposal Review Board (PRB) meetings to evaluate pre-proposals and full proposals throughout the year. These reviews are conducted by consensus and involve participation of many of the TATRC and other military medical subject matter experts (SMEs) as well as representatives from other program management offices. This board of experienced research managers avoids the type of reviewer criticisms that effectively quench innovation such as: ■ Customer has not expressed a need for this (i.e., Henry Ford’s observation that his customers would have asked for faster horses) ■ There is no military requirement (i.e., a formal DoD acquisition process to specify desired systems) ■ “Could be hugely important, but this has never been tried before—so it should not be funded” ■ “Overly ambitious investigator” or “new to the field” ■ “Not in the pre-established research plan” ■ “Insufficient data to demonstrate feasibility.” E. Some Funding Required Modest funds must be available to endorse outstanding proposals that match competent people with relevant technology and recognized clinical needs. Often a relatively small amount of funding makes the difference for success of collaboration between two groups with funded grants, but no support for related collaborations to address a good idea. The typical range of TATRC innovation funding is $50-300 K and these modest grant amounts appear to fall in the “sweet spot” for convergent research that can result in high clinical impact (John Collins, CIMIT, unpublished results) (Table 2). Previous TATRC success stories have been based on a variety of modestly funded collaborations. Linking investigators that each had a TATRC CSI grant has been a primary use of remaining management funds. Linking successful CSI and SBIR grantees to Army or Navy advanced development funding such as TATRC casualty evacuation (CASEVAC) robotics and unmanned aerial vehicle (UAV) projects has been important to advancing military implementation [70]. A modest amount of supplemental funding to IEEE CIRCUITS AND SYSTEMS MAGAZINE

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The activist management approach requires far more effort throughout the duration of the project, but it is also more likely to result in solutions tailored to the military medical problems. The actual implementation of disruptive solutions into DoD use requires a special resilience and persistence, best described as zealotry.

Table 2. TATRC convergence funding criteria. Inclusion Criteria: • Includes engineering or physical sciences as major components of a life sciences project • Addresses a potentially important “big” idea • Links to a problem of military importance Exclusion Criteria: • Duplicates other appropriate funding opportunities • Does not articulate a coherent technical plan • Idea that is neither innovative nor scientific (the “empty square” of Pasteur’s quadrant) Other: • Does not necessarily require preliminary data • Risk of failure is justified by potential benefit • $300K is an approximate limit for an initial grant

Tissue Genesis, Inc in Honolulu, HI permitted continuation of studies onboard the final space shuttle flight space transportation system (STS-135) with adipose derived stem cells to understand key factors in wound healing. The unique environment of space is known to accelerate tissue breakdown similar to the cascade of events seen in injury and disease. A sophisticated bioreactor technology for cell studies in space developed over the duration of many previous space missions was incorporated into this study. The Space Tissue Loss program is a DoD payload integrated and flown under the direction of DoD’s Space Test Program (http://www.nasa.gov/mission_pages/station/research /experiments/STL-Regeneration.html). The availability of a small amount of rapidly provided funding is critical to many important exploratory projects which would otherwise be missed opportunities. F. Bureaucratic Readiness Level (BRL) Innovative advances in military medicine require special assistance in planning for their militarily-specific applications and integration; this is another essential aspect of TATRC assistance to extramural performers. Regardless of the maturity of a technology (Technology Readiness Level, TRL), integration to military use is unlikely if there is a low Bureaucratic Readiness Level. Combat and materiel developers must be forewarned of impending solutions to military problems. 26

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Operational Needs Statements (ONS), requirements statements, are critical first steps that may have to be rapidly produced in response to the emergence of a new or disruptive technology. Concepts of Operation must be developed with specific planning for how a new system or procedure will be procured, distributed, maintained, as well as how its use will be incorporated into training and doctrine. Additionally, FDA approvals for drugs and medical devices, Defense Business Certification for Information Technology Systems, and Validation, Verification, and Accreditation of models are examples of higher levels of BRL that must be achieved before military implementation. In an effort to better integrate emerging technologies into military medical research and applications, TATRC also assists with the management of projects that are deemed of high value from the core funded Joint Program Committees, which provide strategic guidance and oversight. VI. Conclusions Over the years, TATRC has developed the research infrastructure and subject matter expertise to manage convergent medical research programs based on realistic assessment of these technologies and an understanding of the clinical need for them. Each of these programs required integration across multiple research disciplines that do not usually interact with each other. TATRC’s role in facilitating the growth of these programs should not be underestimated. Active collaboration with principle investigators and facilitation of collaborations is an essential element of TATRC programs. The programs are successful in part due to the quality and dedication of the investigators, and in part due to the ongoing oversight of TATRC staff. The oversight and collaborations that result from TATRC management significantly enhance the opportunities for successful conduct of these research programs. TATRC’s input keeps programs focused on military medical needs while promoting commercialization. Every large organization needs similarly protected innovation hub incubators. VII. Acknowledgments The assertions and opinions in this paper are the personal views of the authors and should not be THIRD QUARTER 2012

construed as official views or policies of the U.S. Army or the Department of Defense. We thank the many individuals in the extended TATRC network who have contributed to the development of the concepts articulated in this paper. Warren S. Grundfest is the former Chair of Biomedical Engineering at UCLA where he holds appointments as Professor of Bioengineering, Electrical Engineering and Surgery. He is currently the Co-Chair of the AIMBE Advocacy Committee and served previously as the Chair of AIMBE’s Council of Societies. He serves as the Senior West Coast Clinical Advisor and Portfolio Manager for Nanomedicine and Biomaterials for TATRC (the Telemedicine and Advanced Technology Research Center of the U.S. Army), and also serves as a member of the FDA Science Advisory Board on the Subcommittee for CDRH. He serves as a Panel Member for several NIH Study Sections and DoD review committees. He is one of the nation’s foremost experts on imageguided therapies and medical device development. His research interests include minimally invasive surgery, biophotonics, optical diagnostics, medical robotics, and advanced medical imaging technologies. Dr. Grundfest is past President of IMBISPS, a Fellow of the American College of Surgeons, the AIMBE, and SPIE. He holds 15 patents, has 3 more pending, and has authored 200+ papers and 46 book chapters. He has been involved with multiple corporate and venture technology development programs. Eva Lai obtained her B.S. in Chemical Engineering with minors in Biomedical Engineering and Chemistry from the University of Rochester in New York, followed by initiating new research in exploring and developing mathematical relationships between non-viral gene therapy delivery systems and transfection efficiency based on first principles in biophysics and mass action law to optimize delivery at the Johns Hopkins University, earning a Ph.D. in Chemical Engineering in the process. She worked at the Headquarters for the National Aeronautics and Space Administration (NASA) as a Senior Scientist (2001–2005) developing national and international research programs with investments worth over billion dollars for multiple research offices and directorates, including the Office of Biological and Physical Research, the Office of Space Flight, and the Exploration Systems Mission Directorate, and coordinating with interTHIRD QUARTER 2012

national space agencies. These programs included the Biomedical Research and Countermeasures, Human Health and Performance, Cellular and Macromolecular Biotechnology, Advanced Human Support Technology, Human and Robotic Technology, Fluid Physics, and Space Radiation. Dr. Lai returned to academia as a research faculty in the Whiting School of Engineering at the Johns Hopkins University in 2005 to pursue research in biomaterials, nanotechnology, tissue engineering, and neuroprosthetics. Since 2006, she has been on detail to the Telemedicine and Advanced Technology Research Center (TATRC) at the US Army Medical Research and Materiel Command (USAMRMC), first to support the Chief Scientist as a Deputy (2006–2008), then to lead the Mobile Health Computing Group (2007–2008), and later to manage several research portfolios including Biomonitoring Technologies, Regenerative Medicine, and Discoveries and Enabling Bioengineering Technologies. Charles M. Peterson received a B.A. from Carleton College, his M.D. from Columbia College of Physicians and Surgeons, and an M.B.A. from the University of California. While at Columbia he was the recipient of an International Fellowship from the School of International and Public Affairs as well as a Smith Kline and French Fellowship for study and work in Bolivia. He trained in Internal Medicine serving as Chief Medical Resident at Harlem Hospital and Rockefeller University Hospital. He was on the faculty of Rockefeller for 11 years continuing basic and clinical research begun at that institution during his medical training. Dr. Peterson was Director of Research/Medical Director and ultimately CEO of the Sansum Medical Research Institute in Santa Barbara and Director of the Division of Blood Diseases and Resources of the National Heart, Lung, and Blood Institute prior to joining TATRC in 2008. Scientific highlights include developing orphan drugs for sickle cell disease and thalassemia, documenting that hemoglobin A1c could be used as a measure of longer term “control” in diabetes mellitus, the observation that patient self monitored glucose values along with HBA1c values could be used as two independent means of quantifying “control,” documentation that improved glucose levels improve outcome of pregnancy in women with diabetes and reverse several pathologies associated with the disease, discovery of an assay that could be used to document levels of alcohol consumption over time, and the first use of atomic force microscopy to visualize cells. He holds 15 U.S. patents, has sponsored 7 Investigational New Drug applications IEEE CIRCUITS AND SYSTEMS MAGAZINE

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to the FDA, and was founder and President of the Diabetes Self Care Program. He has published over 400 peer reviewed primary articles, chapters, editorials, reviews and 21 books and monographs. His latest award was in May 2010 when he was the recipient of the Columbia University College of Physicians and Surgeons Gold Medal Award for Medical Research. Karl E. Friedl earned his B.A. (Zoology), M.A. (Zoology), and Ph.D. (Physiology) from the University of California at Santa Barbara, completing his research training in the University’s Institute of Environmental Stress. He is an ROTC Distinguished Military Graduate and entered the Army in 1983 as a Captain in the Medical Service Corps. As a research physiologist, he completed studies on human metabolic limits at Madigan Army Medical Center and the U.S. Army Research Institute of Environmental Medicine. As Director for the Military Operational Medicine (MOM) research program, COL Friedl established a coordinated plan of biomedical research on protection and enhancement of the Soldier. Between 1996 and 2003, he also chaired the Tri-Service Joint Technical Coordinating Group (JTCG-5) for MOM, expanding inter-Service cooperation and collaborative projects with other agencies such as the VA, NIH, NASA, and USDA. He directed major initiatives such as the Defense Women’s Health Research Program, DoD Gulf War Illnesses, Bone Health and Military Medical Readiness, and Neurotoxin Exposure Treatment (Parkinson’s) research programs. In 2003, COL Friedl assumed command of the U.S. Army Research Institute of Environmental Medicine and in 2006 was assigned as Director, Telemedicine and Advanced Technology Research Center. His current areas of focus are applications of metabolism and neurobiology technologies, metrics of research success, and strategies to accelerate research translation to practice. He has published over 100 papers. His awards include the Society of Armed Forces Medical Laboratory Scientists (SAFMLS) Outstanding R&D Scientist Award, Legion of Merit with oakleaf cluster, Order of Military Medical Merit, and the Surgeon General’s “A” professional designator.

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