Continuous Wave Terahertz Reflection Imaging of ... - Semantic Scholar

Continuous Wave Terahertz Reflection Imaging of Human Colorectal Tissue Pallavi Doradlaa,b, Karim Alavic, Cecil S. Josepha,b, Robert H. Gilesa,b a

Bio-Medical Terahertz Technology Center, University of Massachusetts Lowell, Lowell, MA;

b

Department of Physics and Applied Physics, University of Massachusetts Lowell, Lowell, MA;

c

Division of Colon and Rectal Surgery, University of Massachusetts Medical School, Worcester, MA.

ABSTRACT Continuous wave terahertz (THz) imaging has the potential to offer a safe, non-ionizing, and nondestructive medical imaging modality for delineating colorectal cancer. Fresh excisions of normal colon tissue were obtained from surgeries performed at the University of Massachusetts Medical School, Worcester. Reflection measurements of thick sections of colorectal tissues, mounted in an aluminum sample holder, were obtained for both fresh and formalin fixed tissues. The two-dimensional reflection images were acquired by using an optically pumped far-infrared molecular gas laser operating at 584 GHz with liquid Helium cooled silicon bolometer detector. Using polarizers in the experiment both co-polarized and cross-polarized remittance form the samples was collected. Analysis of the images showed the importance of understanding the effects of formalin fixation while determining reflectance level of tissue response. The resulting co- and cross-polarized images of both normal and formalin fixed tissues showed uniform terahertz response over the entire sample area. Initial measurements indicated a co-polarized reflectance of 16%, and a cross-polarized reflectance of 0.55% from fresh excisions of normal colonic tissues. Keywords: Continuous-wave terahertz imaging, colorectal cancer, Reflection imaging, formalin fixation, polarization

1. INTRODUCTION The terahertz (THz) frequency regime of the electromagnetic spectrum extends from 0.1 to 10 THz and lies between the microwave and infrared regions of the spectrum. The high sensitivity of THz radiation to water concentration, resulting from low energy interactions with the low frequency molecular motions, has expanded its applications into the areas of imaging and spectroscopy [1, 2]. Due to its non-ionizing property (unlike X-rays), THz technology has become increasingly important for biological applications [3]. Some frequencies in the THz can penetrate several millimeters of tissue to enable detection of the differences in water content and tissue density. According to recent investigations, it was shown that cancer cells absorb more water than normal cells [4-6]. As THz radiation is highly sensitive to water concentration, active THz imaging is an alternative and convenient way to ascertain the location of affected cells in the tissue. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in world [7] with more than 1.2 million people diagnosed each year. It is the fourth most common cancer in men after skin, prostate, and lung cancer and also the fourth most common cancer in women after skin, breast, and lung cancers [8]. Most colon studies showed the growth of CRC from polyps and adenomas. The staging of CRC and subsequent treatment of CRC is dependent upon current imaging technologies, such as CT scan, PET, MRI, and colonoscopy. The current standard of care for diagnosis and treatment of early CRC and pre-cancerous lesions is use of conventional colonoscopy which relies on visual inspection by the physician. During the colonoscopy, the decision to remove the mucosal growths (abnormal tissue) is based on the physician’s experience. As terahertz imaging offers intrinsic contrast between cancerous and normal tissue, a THz Terahertz, RF, Millimeter, and Submillimeter-Wave Technology and Applications VI, edited by Laurence P. Sadwick, Créidhe M. O'Sullivan, Proc. of SPIE Vol. 8624, 86240O · © 2013 SPIE · CCC code: 0277-786X/13/$18 doi: 10.1117/12.2004385 Proc. of SPIE Vol. 8624 86240O-1 Downloaded From: http://proceedings.spiedigitallibrary.org/ on 04/05/2013 Terms of Use: http://spiedl.org/terms

endoscope can be used as a potential tool in the examination and detection of cancerous or pre-cancerous regions of a biological (colorectal) tissue. In addition, the recent development of low-loss hollow flexible THz waveguides [9] provides a clear path for in vivo transmission of the THz radiation complementing the endoscopic design. The potential of THz endoscopic imaging for colorectal studies was encouraged by the positive results obtained from the terahertz imaging of skin [10, 11], breast [12], liver [13], and other biological materials. As water is a polar molecule, it is highly absorbing in the THz region and thus a likely source of imaging contrast. Nevertheless, THz imaging studies of dehydrated samples (Paraffin embedded) showed the evidence of contrast between normal and cancerous colon tissues [14]. These studies suggest the possibility of other factors for contrast such as increase in lymphatic systems, vasculature, and other molecular/structural changes of diseased, in comparison to normal tissue [15].

2. BACKGROUND Based on the nature of the source, THz imaging systems can be classified into pulsed and continuous-wave (CW). THz pulsed imaging (TPI) systems use a sequence of wide-bandwidth, low-power, electromagnetic pulses generated from either an ultra-fast TI:sapphire or similar pulsed lasers. On the other hand, CW systems use very narrow bandwidth essentially single frequency, high power (several millwatts) radiation sources. The ultra-fast pulsed lasers are relatively complex and expensive. The optical power of TPI systems is limited, so large arrays of sources and detectors cannot be easily constructed; and the need to sample the pulse in the time domain using some form of mechanical delay line means systems are relatively slow. However inexpensive compact CW laser systems can provide high resolution, spectral selectivity, superior SNR values, narrow line width, and versatility. Most medical research in terahertz imaging thus far has been focused on terahertz pulsed imaging due to their higher depth of fields, as well as the lack of commercially available CW terahertz sources. TPI has already been used to identify colorectal cancer in ex vivo studies. A study based on THz pulsed imaging of human colonic tissues showed a contrast between dysplastic and healthy tissue, based on the increased absorption and refractive index of the diseased tissue. The tissue staining studies identified an accession in lymphatic systems and vasculature of the diseased tissue compared to normal. These studies indicate the importance in physical differences between the tissue pathologies in determining the underlying contrast mechanisms in THz imaging [15]. Another study that distinguishes normal and cancerous regions in the sample when fixed in formalin or embedded in paraffin, confirms the possibility of additional contrast-contributing factors other than water [14]. Transmission time-domain spectroscopy shows contrast between normal and cancerous regions of colon tissue in the frequency range 0.5 – 1.5 THz with the greatest difference at 0.6 – 0.8 THz, and rectum tissue in the frequency range 0.5 – 3.0 THz with the maximal difference in refractive index at 0.6 THz and absorption coefficient in 0.5 - 2.5 THz range [16]. However, the source mechanism for the contrast in TPI images of colorectal cancer is not yet clearly understood. Also, their do not seem to be any resonances in this region, which is expected as the THz response of water is the dominant mechanism. Thus, a continuous-wave imaging system operating in between 0.6 – 0.8 THz should be able to detect contrast between normal and cancerous tissue. This will facilitate the delineation of cancerous and normal regions of a colorectal tissue with the clear understanding of contrast mechanisms.

3. EXPERIMENTAL SETUP The terahertz reflection imaging system at 584 GHz consists of a CO2 optically pumped far-infrared (FIR) gas laser. The output power of these CO2 lasers is in the range of 100 – 150 Watts. Pumping different transitions of the gas in the FIR cell can be achieved by tuning the output frequency of the CO2 laser. The combination of the right gas in the FIR cell and correct frequency of the CO2 laser provides the ability to lase different frequencies in the terahertz region. The required 584 GHz (513 µm) vertically polarized transition in Formic acid (HCOOH) was obtained by pumping the 9.23R28 transition of CO2 laser. A dielectric waveguide was placed at the output of the FIR laser to attenuate the higher order modes and obtain a Gaussian output mode [17]. The measured output power before and after the dielectric tube were 33 mW, and 10.23 mW respectively. Since the 2.15 mm diameter beam emerging from the FIR laser expands

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rapidly as it propagates in n air, an opticcal system wass designed to focus the raddiation onto thhe sample, achhieving a h cooled ssilicon bolomeeter detector manufactured byy IRLabs resolution off 0.68 mm. Thee detector used was a liquid helium which had a noise equivaleent power (NE EP) of 1.13 x 10-13 W/Hz1/2, rresponsivity off 2.75 x 105 V//W, response ttime of 5 n of 200. The crystalline quarrtz (Garnet pow wered) window w on the bolom meter rejected w wavelengths beelow 100 ms, and gain µm. n Figure 1, a beam b waist of 22.36 mm was measured exitting from the ddielectric Thee optical layoutt is depicted in waveguide. This T beam exp panded in freee space beforee being collim mated by a 24”” focal length TPX lens andd passed through a wiire grid polarizzer. Then, the beam passed through t 50-50 Mylar beam ssplitter, and fiinally focused onto the imaging plan ne using a sho ort focal length h off-axis paraabolic (OAP 11) mirror (Lasser beam path was shown w with pink arrows). Thee full width at half max (FWHM) was meaasured to be 0.668 mm at the sample plane. The componennt of the incident radiaation that was reflected by th he beam splitterr was dumped into a THz abssorber (Anechooic). 3.5 " FL Focusing opti

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Thee signal remitteed from the saample was rediirected and foccused into the detector, usingg OAP 2 afterr passing through OAP P 1, the beam splitter, and an a analyzing wire w grid polarrizer (beam paath was shownn with gold arrrows). In order to detect either co- or cross-polaarized light, th he signal remiitted from the sample will be passed thrrough an he reflection arm m (shown as rred dotted line in Figure 1). A An automated two-axis analyzing wiire grid polarizzer sitting in th stage was used to raster scan the tissue holder h (as discu ussed in Sectioon 4) in the im maging plane w with a resolutioon of 0.1 mm and dweell time of 150 0 ms per poin nt. The laser beam was opticcally modulateed using a choopper. The moodulating frequency (8 83 Hz) served as the referen nce for a lock--in amplifier. T The system’s signal to noisee ratio using a lock-in amplifier was 65 dB. The in nset of Figure 1 shows the terrahertz reflectaance image of a metal plate, ccontaining 0.2 mm and meter holes (sep parated by 10 mm), m scanned using u the descrribed system. 0.5 mm diam

4. 4 SAMPLE PREPAR RATION Fressh thick excesss colorectal specimens weere imaged wiithin 2 hours after standarrd surgical proocedures performed att University off Massachusettts Memorial Hospital H under an Institutionaal Review Boaard approved pprotocol. For this stud dy, the two setss of normal co olon samples were w imaged frresh, and fixedd with formalinn. The thickness of the colon specim mens obtained was approxim mately 1 cm, with w the lateraal dimensions between 8 annd 15 mm. Thhe colon specimens were w transported d to the Univerrsity of Massaachusetts Loweell in saline, to prevent dehyddration, withinn 45 min. Then the en-face specimen sections were imaged within n 2 hours. ging, the colon tissue specimeens were mounnted in an alum minum two-piece sample holdder (with For terahertz imag s in Figurre 2. The tissuee specimens weere placed behhind the 1 mm tthick z-cut quaartz slide 3” x 1” frontt opening), as shown of the samplle holder. The colorectal tisssue specimens were coveredd with wet gauuze, soaked in pH balanced ((pH 7.4)

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saline, to preevent tissue deehydration durring the experiimental study. During the m mounting proceess, both the ffront and back pieces of o sample hold der were gently y pressed onto the t tissue, to avvoid air gaps bbetween colon tissue and quaartz slide. Finally to en nsure the securrity of tissue specimen s posittion, the wholee assembly (quuartz slide, tisssue specimen, and wet gauze) was th hen placed in the t sample hold der and gently tightened withh four screws. Thee most common nly used fixative to preserve the biologicall samples for rroutine histopaathological diaggnosis is formalin. The resulting form malin fixed sam mples after hisstology processs are often useeful for retrospeective studies. In order n THz imaging g of colorectal samples, the ttissue specimenns were fixed with 3% to study the affect of formaalin fixation in neutral-buffeered formalin solution. s Beforre fixing the tissue t with forrmalin, the TH Hz response froom all the fresh colon sections weree obtained usin ng co- and crosss-polarized reflection imaginng. The volum me of formalin aapplied to eachh sample was at least 10 1 times the in nitial sample vo olume. The sam mple was then left to soak in the fixative in a sealed contaainer and refrigerated at a a constant temperature t (4 4º C). During imaging, i gentlle pressure waas applied to thhe sample to eensure it made good contact c with qu uartz as it becomes more diffficult due to tthe increment in the rigidityy of a fixed saample. In order to mon nitor the changees caused by th he formalin, eaach sample wass measured afteer being fixed for 24 h, 48 h ((2 days), and 120 h (5 days).

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Figu ure 2. Schematicc of sample moun nting for reflectiion measuremennts a) 2-piece aluuminum holder, bb) tissue placed beh hind the 1 mm th hick z-cut quartzz slide, c) colon tissue covered w with a gauze soak aked in pH 7.4 baalanced saline so olution, d) closin ng the assembly with w holder’s second piece, e) tiissue specimen m mounted in the sample holder.

5. POLARIZ ZATION IM MAGING Witth a time dom main terahertz spectroscopic system one ccan reject thee specular refllections from air-glass interface, an nd obtain the terahertz response of the glass-sample g innterface alonee, by using tim me gating tecchniques. However, forr continuous-w wave systems th he polarized light imaging teechnique, sugggested by C. S. Joseph and cooworkers [11], has beeen used to av void the unwaanted reflection ns. Usually, thhe co-polarizeed terahertz reesponse of thee sample includes Fressnel reflections from the air-quartz and qu uartz-sample innterfaces. In contrast, the cross-polarized tterahertz response effeectively rejectss the specular reflections, r as the t Fresnel com mponent is co--polarized withh the incident radiation. Thus cross-p polarized terah hertz imaging effectively e sam mples the tissuue volume. In imaging hum man nonmelanooma skin cancer, the cross-polarized c d THz responsee from the sam mple identifiedd the correct loocation of canccerous region bbased on image contraast between heealthy and disseased tissue [11]. This show ws the ability of cross-polaarized THz im maging in delineating th he normal and cancerous regiion of a biolog gical tissue.

6. RESUL LTS & ANA ALYSIS Thee co- and crosss-polarized refflection THz im mages were obbtained by colllecting the siggnal remitted ffrom the tissue specim men sitting on the raster scan nned XY-stagee and by placiing the approppriate analyzinng polarizer griid in the reflection arm m before the Si S detector. Th he THz imagess obtained from m reflection im maging were tthen processedd using a TM LabView program p that sy ynchronized th he sample posittion in the imaaging plane witth the return siignal obtained from the lock-in ampllifier. The co- and cross-polaarized images were w then calibbrated against the full-scale return from a flat gold

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front-surfacee mirror to deteermine the refl flectance. The image i was plootted in logarithhmic space annd the off sampple areas were removeed in post proceessing with thee reflected THzz signal quantiffied pixel by piixel using the rreflectance forrmula; 100% where R is th he terahertz refflectance valuee in percent (% %), Ime is the m measured reflecctance intensityy from the sam mple, and IFull is the fulll-scale return or o the measured intensity of the t incident be am reflected frrom a gold fronnt-surface flat mirror. Thee co- and cross--polarized terah hertz reflection n images of freesh (Figure 3 aa,b), and formaalin fixed (Figuure 3 c,d) colorectal saamples are show wn in Figure 3 with corresponding digital photographs. Figure 3a shoows the THz im mages of fresh colorecctal sample I. Both B the co- and a cross-polarrized terahertzz images did not show any ccontrast over thhe entire sample surfaace. The co-pollarized reflectaance image, plo otted in logarithhmic dB scale, shows a refleection of -7.5 – -8.5 dB and the crosss-polarized im mage shows a scale s of -21.5 – -22.5 dB. Thhe correspondiing reflectancee values obtainned were 16.50 ± 0.25% % and 0.68 ± 0.034%. 0 (a)

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Figure 3. Digital photograph, co-, and crross-polarized teerahertz reflectioon images of hum man a) fresh h colon sample I, I b) fresh colon sample II, c) 48 hr formalin fixeed colon sample I, mple II. d) 120 hr formalin fixed sam

Thee co- and crosss-polarized imaages obtained from fresh collorectal samplee II also lie in the -8 dB andd -22 dB signal rangess respectively, with the correesponding 15.7 76 ± 0.27%, an and 0.54 ± 0.0228% reflectancce values, as sshown in Figure 3b. Again, A both pollarization imag ges of sample II did not shoow any contrasst over the sam mple except thee yellow dotted line visible v on the to op left corner in i each image.. As expected the effect has been observedd in the THz im mages of both fresh an nd formalin fix xed sample II, due d to the appearance of sidee and back surrfaces of coloreectal tissue in the front view, as sho own in the dig gital photograp phs of Figure 3b and 3d. T This was causeed by the nonn-uniform thickkness of colorectal tisssue, and the gentle pressure applied on thee tissue againstt quartz slide dduring the mouunting process to avoid air gaps.

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In order to understand the effects of formalin fixation on the THz properties of biological samples, the colon tissues were fixed with 3% neutral buffered formalin solution and stored in refrigerator at 4º C. Once the THz images of fresh tissues were obtained they were fixed with formalin, and imaged after 24 hr, 48 hr, and 120 hrs. Figure 3c & 3d shows the digital photograph, co-, and cross-polarized terahertz reflection images of 2-days fixed colorectal sample I, and 5-days fixed colorectal sample II. The co- and cross-polarized terahertz images of 48 hr formalin fixed sample I showed a constant terahertz response throughout the entire surface, identical to the fresh sample I. Also the 5-day formalin fixed tissue II did not show any contrast over the sample, except the yellow dotted line resulted from the nonuniformity of the tissue thickness, similar to the fresh colon tissue II. The reflectance values of 15.32 ± 0.299%, 0.54 ± 0.018% were obtained from formalin fixed colorectal sample I and 15.27 ± 0.24%, 0.52 ± 0.016% from colorectal sample II. The abatement in the reflectance values of formalin fixed samples, as compared with the fresh tissues, resulted from the change in refractive index of fixed tissue due to the replacement of water content by the formalin solution [18]. The reflectance values obtained from the formalin fixed samples after 24 hr were noticeably smaller when compared with fresh tissues, however there is a significant reduction in the reflectance after 48 hr as shown in Figure 3c. The reflected THz response values were reduced with formalin fixation. This is expected as the water content in the tissue that has refractive index of 2.4 at 0.6 THz will be replaced by formalin solution which has lower refractive index of 2 at 600 GHz. Despite this, the reflectance values of polarized THz images collected from the formalin fixed colonic samples were consistent after 48 hr up to 120 hr. The refractive index of human colonic tissue is 1.5 at 584 GHz, when measured by a pulsed terahertz system [16]. Therefore, the lower reflectance values obtained for fixed tissues were potentially resulted from the reduced internal refractive index of the colon tissue. Also, it was noticed that the terahertz response obtained from a formalin fixed colorectal tissue sample changes during the first 48 hours. Once the water content in the tissue was entirely replaced by formalin the THz response attained was consistent.

7. CONCLUSION Continuous-wave terahertz imaging has been used to study the terahertz response of human colonic tissues. Both the co- and cross-polarized THz images were obtained using a reflection based 584 GHz system. The THz imagery of fresh, 48 hr (2-day) formalin fixed, and 120 hr (5-day) fixed normal colon samples preserved at 4º C were studied. Neither of the co and cross polarized THz images of fresh colon samples show any contrast over the sample, as expected. Reflectance values of ~ 16% and ~ 0.55% were obtained from the co- and cross-polarized reflection images of normal human colonic samples. Finally, the effects of formalin fixation on the terahertz properties of colorectal specimens were investigated.

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