2011 Annual Report

Rochester Center for Biomedical Ultrasound

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2011Annual Report RCBU laboratories are advancing biomedical ultrasound across many topics in diagnostic imaging, ultrasound therapy, and fundamental acoustics. See inside for highlights of RCBU research in 2011.

Rochester Center for Biomedical Ultrasound Director: Diane Dalecki, PhD Associate Director: Deborah J. Rubens, MD Executive Committee: Diane Dalecki, PhD, Vikram S. Dogra, MD, Morton W. Miller, PhD, Kevin J. Parker, PhD, and Deborah J. Rubens, MD Provost: Ralph W. Kuncl, MD, PhD Senior Vice President and Robert L. and Mary L. Sproull Dean of the Faculty of Arts, Sciences, and Engineering: Peter Lennie, PhD Dean of the School of Medicine and Dentistry: Mark B. Taubman, MD Dean of the Hajim School of Engineering and Applied Sciences: Robert L. Clark, PhD Editor and Designer: Maria Randazzo Rochester Center for Biomedical Ultrasound, University of Rochester 311 Goergen Hall, PO Box 270168, Rochester, New York 14627 Phone: (585) 275-9542 n Email: [email protected] Web site: www.urmc.rochester.edu/rcbu © University of Rochester, 2012 2011 RCBU Annual Report

Rochester Center for Biomedical Ultrasound 2011 Annual Report

Table of Contents

2011 Research

Tissue Elasticity Conference Highlights

RCBU Awards

Innovation

RCBU Member Education

3 This year’s annual report The Imaging Sciences summarizes progress from RCBU Ultrasound Department laboratories across diverse continued its growth in exam topics in biomedical ultrasound and patient volumes in 2011, imaging and therapy. This year performing examinations marked the tenth anniversary on 24,800 patients. The of the International Tissue unit continued to expand Elasticity Conference. Over its clinical coverage; adding the years this conference has more sonographer positions to grown to become the premier manage the increased demand. conference for researchers in The University of Rochester the field of elasticity imaging. Medical Center was represented The RCBU continues to advance by sonographers and physicians new elastography techniques and included within this in education nationally and internationally. As faculty report are highlights of innovations by RCBU faculty and for the American Institute of Radiologic Pathology students in areas such as sonoelastography, crawling in Washington DC, Dr. Rubens continued to teach waves, intravascular ultrasound elasticity imaging, and courses on spleen, testis, scrotum, portal Doppler, and radiation force imaging techniques. testicular Doppler. Drs. Bhatt, Dogra, Rubens, Strang, On a more reflective note, this year the RCBU and Voci also participated as faculty at the Radiological and the broader ultrasound community lost one of its Society of North America (RSNA), the American Institute most important pioneers, Wesley Nyborg. Wes was a of Ultrasound in Medicine (AIUM), the Society of Charter Member of the RCBU. His seminal theoretical Gastrointestinal Radiologists (SGR), and the Society of and experimental work forms the foundation of our Uroradiology (SUR) Annual Meetings. Internationally, understanding of the biological effects of ultrasound. Drs. Rubens, Bhatt, Dogra, and Strang lectured at The The RCBU continues to play a prominent role Society for European Uroradiology in Dubrovnik, Croatia, in clinical and technological advances in the use of and Drs. Rubens and Strang lectured at the Israeli Society ultrasound for diagnostic imaging and therapy. Nonlinear for Ultrasound in Diagnostic Medicine in Haifa, Israel. imaging techniques, sonoelastography, and ultrasound Dr. Rubens also lectured at Cambridge University in contrast agents all have foundations from innovations England, and Dr. Dogra in Egypt and Turkey. within RCBU laboratories. This year a new patent Dr. Rubens continued her research with the BME in ultrasound imaging was issued to RCBU member Department in collaboration with General Electric Robert C. Waag. Collaborative projects between and Rensselaer Polytechnical Institute on the NIH RCBU clinicians, engineers, and scientists continue to funded grant, 3D Prostate Cancer Imaging Based on advance novel diagnostic and therapeutic applications of “Crawling Wave” Excitation, to create and assess a ultrasound. novel 3D imaging scanner applied to prostate cancer. This annual report details research from RCBU Investigations with elastography have expanded from members on many topics in biomedical ultrasound, the prostate to evaluation of thyroid cancer, with Dr. including elasticity imaging techniques, ultrasound Jonathon Walsh of ENT, and to assessment of hepatic technologies for tissue engineering, intravascular steatosis and fibrosis with Dr. Christopher Barry from ultrasound, ultrasound therapies, acoustic cavitation, and the liver transplant program. Dr. Barry with co-authors bioeffects. The RCBU also provides a rich environment Parker, Hah, Rubens, Mills, Mooney, and Ryan, had for education and training in biomedical ultrasound. their landmark paper, Shear Wave Dispersion Measures Educational advances, as well as special awards and Liver Steatosis, accepted this year for publication in achievements by RCBU members and students, are Ultrasound in Medicine and Biology. The Ultrasound summarized within this annual report. We welcome your Division is also co-investigator with Duke University, in comments on any of the enclosed reports. assessing DVT in oncology patients. Dr. Charles Francis, URMC faculty and Dr. Gary Lyman, Duke University, are Principal Investigators on the study. Dr. Mark Frampton, from Pulmonary Medicine, is conducting a clinical trial using ultrasound of the brachial artery to assess pulmonary response to environmental toxins. Clinical parameters for this trial will be assessed by the URMC ultrasound division.

4 The Rochester Center for Biomedical Ultrasound (RCBU) was created at the University of Rochester to unite professionals in engineering, medical, and applied science communities at the University of Rochester, Rochester General Hospital, and the Rochester Institute of Technology. Since its founding in 1986, the RCBU has grown over the years to nearly 100 members, with several visiting scientists from locations around the country.

The Center provides a unique collaborative environment where researchers can join together to investigate the use of very high frequency sound waves in medical diagnoses and therapy.

The Center’s mission encompasses research, education, and innovation.

Research Innovation

• RCBU laboratories are advancing the use of • The RCBU maintains a long history of leadership ultrasound in diagnosis and discovering new and innovation in biomedical ultrasound. therapeutic applications of ultrasound in medicine and biology. • RCBU innovations have produced steady progress in new imaging modalities and therapeutic • The Center fosters collaborative research between applications of ultrasound. laboratories and investigators with expertise in engineering, clinical medicine, and the basic • RCBU members hold numerous patents in sciences. ultrasound and imaging. The UR is a leader in technology revenue income among all higher • The RCBU provides an ideal forum to exchange education institutions in the nation. information through formal Center meetings and monthly newsletters. About the University of Rochester • Interactions of RCBU members with industry, governmental organizations, and foundations The University of Rochester (www.rochester.edu) is encourage mutually beneficial research programs. one of the nation’s leading private research universities. Located in Rochester, New York, the University’s environment gives students exceptional Education opportunities for interdisciplinary study and close • RCBU laboratories provide a rich environment collaboration with faculty. Its College of Arts, Sciences, for graduate training in biomedical ultrasound. and Engineering is complemented by the Hajim School Students have access to state-of-the-art research of Engineering and Applied Sciences, the Eastman facilities to engage in leading-edge research in School of Music, Simon School of Business, Warner ultrasound. School of Education, Laboratory for Laser Energetics, • The UR offers graduate-level courses in and Schools of Medicine and Nursing. biomedical ultrasound and closely related fields.

• RCBU laboratories offer opportunities for post- doctoral research in ultrasound and collaborations with other areas of biomedical imaging.

• Throughout its history, the RCBU has offered short courses in specialized topics in ultrasound that attract national and international experts.

5 2011 RESEARCH

Research laboratories of RCBU members are advancing the use of ultrasound for diagnosis and therapy. The pages that follow highlight research accomplishments in 2011. Selected publications and presentations of this year can be found on pages 27-29.

Crawling wave sonoelastography of benign to be formed without using a focused aperture. and malignant thyroid nodules Briefly, this method uses multifrequency J.M. Walsh, Brady Mills, BS, Deborah Rubens, (< 2 kHz) shear wave propagation perpendicular MD, Kevin J. Parker, PhD, Liwei An, PhD, to the direction of ultrasound propagation to Morton Miller, PhD, Zaegoo Hah, PhD apply a variety of deformations to the target to The purpose of this study was to determine if be imaged. These deformations shift the phase Crawling Wave (CrW) Elastography, a novel of the received ultrasound echo. By proper sonoelastography technique, can be utilized to demodulation of the phase shift of the ultrasound provide quantitative measurements of thyroid signal, the lateral position of the echo source may tissue shear velocity (a measure of tissue stiffness) be determined. The axial (range) component of and distinguish between benign and malignant position is determined through time of flight as thyroid nodules. Fresh thyroid specimens (N in conventional ultrasound. In SWIPE imaging, = 21) with 44 regions of interest were imaged lateral resolution is determined by the range over a 9-month period at a single institution. of shear wave frequencies used to interrogate CrW sonoelastography was performed and the target, rather than the focal properties of shear velocity (SV) estimations with contrast to the aperture. Lateral focusing provided by an noise ratios (CNR) were calculated. Histologic extended aperture serves to determine the diagnosis was correlated with SV and CNR illuminated region of the tissue. values. The SV and CNR of Papillary Thyroid Our previous experimental results Carcinoma (PTC) (N = 11, CNR = 4.04, SV = demonstrated the ability of SWIPE to achieve 2.39 m/s) was significantly higher than benign lateral resolution independent of aperture nodules (N = 22, CNR = -0.988, SV = 1.90 m/s) focusing. However, the point spread function (for CNR pp = 0.003, [95% CI 0.199 - 0.801]). (PSF) showed higher sidelobe levels than CNR values have a sensitivity and specificity of anticipated. The increased sidelobe levels were 100% and 90.9%, respectively, for differentiating found to be due to deviations from a linear PTC from benign nodules. Additionally, SV dependence of target motion phase on shear has a sensitivity and specificity of 81.8% and wave frequency. 68.2%, respectively. Insufficient samples were The model developed assumes the presence obtained for SV and CNR comparison of other of a plane, z-polarized, +x-going harmonic histologic types. In conclusion, crawling wave shear wave, which is conveniently described sonoelastography can provide quantitative analytically. Unfortunately, waves generated by estimations of shear velocity (SV) depicting the finite sources are more complex to describe, and elastic properties of thyroid nodules. The SV do not lend themselves to compact analytical with CNR can differentiate between benign expressions. A further complication exists when thyroid nodules and papillary thyroid carcinoma. the excitation is at the surface of the elastic However, prospective in-vivo studies are body. Surface or Rayleigh waves are generated needed to verify the accuracy and utility of CrW in addition to shear waves. The speed of the elastography. Rayleigh wave is ~0.96 that of the shear wave in an incompressible medium, and its Shear Wave Induced Phase Encoding (SWIPE) amplitude is dominant near the surface, falling Stephen McAleavey, PhD exponentially with depth into the medium. The We have recently demonstrated a technique, interaction of Rayleigh and shear waves, and their Shear Wave Induced Phase Encoding (SWIPE), that varying relative amplitude at a given excitation allows B-scan-like images of tissue echogenicity frequency, result in a non-linear dependence on 6 the phase of the displacement in response to a plane source. Future work will investigate the use harmonic excitation as a function of frequency. of acoustic radiation force to realize this shear This non-linear dependence violates the wave source. V. D ISCUSSION assumptions made in the SWIPE model, resulting &'('"'## &'('"'## " " in distortion of the image. Comparison of simulations and experimental results with To better understand the effects of source surface sources geometry on SWIPE image quality, finite-element $% $% The non-linear dependence of phase on frequency and !!" !!" simulation was used to calculate the total wave the resulting distortion of the SWIPE PSFs associated with !! " ! !! " ! motion due to the application of surface and ## ## surface excitation of shear (and surface) waves seen in sub-surface forces in a 2D axi-symmetric model. &'(')'## &'(')'## the ﬁnite element simulations displays a good qualitative Two sinusoidal driving forces were simulated: " " matches to previous experimental observations [2]. Because a surface load applied over a 5 mm diameter the deviation from linear phase response is spatially depen- region centered atop the cylinder, modeling $% $% dent, elimination of this distortion is not straightforward. !" !" the displacement applied in our experimental ! ! The use of internal excitation, which allows shear waves apparatus by an electromagnetic shaker, and an !! " ! !! " ! to be generated while avoiding the creation of surface waves, internal, Gaussian distributed load, designed to ## ## yields a much more linear phase response and nearly ideal mimic the forcing that would be applied by an &'('!'## &'('!'## point spread function. The forcing function described is acoustic radiation force source. " " The phase of the z component of similar to what could be achieved with the acoustic radi- displacement in response to the two sources $% $% ation force of a weakly focused low-frequency ultrasound !" !" was calculated for a source frequency of 0.1-1 ! ! transducer. !! " ! !! " ! Taken together these results suggest that further develop- kHz. The lateral component of the point spread ## ## ment of SWIPE is best suited to applications where acoustic function (PSF) was calculated from the measured &'('*"'## &'('*"'## phase response, with Hamming windowing used " " radiation force or other means can be employed to generate to avoid sidelobes due to the otherwise abrupt shear waves sufﬁciently distant from any boundaries to avoid truncation of the k-space data. The excess width

$% $% surface wave generation. The simulation results make clear of the PSF at the -6 dB and -30 dB levels was !!" !!" that the previously observed distortion is due (in addition to computed on the same mesh. !! " ! !! " ! any phase nonlinearities of the electromagnetic shaker) to the The effect of non-linear phase dependence ## ## mechanical response of the elastic target itself, rather than is readily apparent in the simulated PSFs, shown &'(')"'## &'(')"'## any data acquisition issue. in Figure 1. At all points except directly under " " the excitation source, the PSFs resulting from VI. CONCLUSIONS surface excition are significantly wider than $% $% !!" !!" The effects of two contrasting shear wave sources on the ideal response. In contrast, the more nearly SWIPE imaging resolution was evaluated. The use of a sur- linear phase response associated with the internal !! " ! !! " ! ## ## face source was found to present a strongly non-linear phase source results in near-ideal PSFs. The non-linear response. This was associated with the presence of both shear dependence of phase on frequency and the Figure 1. Lateral point spread funtion profiles. The PSFs associated with the surface source are on the left, the internal and surface waves, and resulted in signiﬁcant distortion of the resulting distortion of the SWIPE PSFs associated Fig. 3. Lateral point spread function proﬁles at the same locations used in with surface excitation of shear and surface waves source on the right. The dahsed lines indicate the PSF for the point-spread-function associated with SWIPE imaging. This Figureshear 2. wave The PSFsfrequency associated used. with the surface source are on the left, the seen in the finite element simulations shows good internal source on the right. The dashed lines indicate the ideal PSF for the result is consistent with prior experimental observations of qualitative agreement to previous experimental shear wave frequency range used. PSF distortion not predicted by the simple plane shear wave observations. Investigating the impact of spatial priors model of SWIPE. The use of an internal source was found Source 1, 6 dB Source 1, 30 dB These results suggest that further on the performance! of model-based! IVUS 1.25 to very closely approximate the PSF quality expected for an 0 0 development of SWIPE is best suited to elastography ideal plane source. Future work will investigate the use of applications where acoustic radiation force or Michael Richards, PhD, Marvin Doyley, PhD acoustic radiation force to realize this shear wave source. 2 2 1.2

other means can be employed to generate shear cm cm Recent work by RCBU members Mike Richards waves sufficiently distant from boundaries to ACKNOWLEDGEMENT and Marvin4 Doyley developed methods4 that avoid surface wave generation. The simulation provide pre-requisite information for computing 1.15 REFERENCES results make clear that the previously observed 0 2 4 0 2 4 circumferentialcm stress in modulus elastogramscm [1] S. McAleavey, Ultrasonic Backscatter Imaging by Shear-Wave- distortion is due in large part to the mechanical Source 2, !6 dB Source 2, !30 dB Induced Echo Phase Encoding of Target Locations, IEEE Trans recovered from vascular tissue. This information 1.1 response of the elastic target. The use of an 3 3 Ultrason Ferroelec Freq Control, vol. 58, no. 1, pp. 102-111, Jan 2011 could help cardiologists detect life-threatening [2] V. Kakkad, S. McAleavey, Wave Induced Phase Encoding Imaging internal source was found to very closely 4 plaques and predict their propensity4 to rupture. with Enhanced Resolution, in Proc. 2011 IEEE Int. Ultrasonics Sym- approximate the PSF quality expected for an ideal 5 5 cm 1.05 cm posium, Orlando, in press 6 6 7 [3] R.J. Zemp, C.K. Abbey, M.F. Insana, Linear System Models for 7 7 Ultrasonic Imaging: Application to SIgnal Statistics of Imaging, IEEE Trans Ultrason Ferroelec Freq Control, vol 50, no 6, pp. 642-654, 0 2 4 0 2 4 1 cm cm 2003 [4] K.F. Graff, Wave Motion in Elastic Solids. Belfast: Ohio State Uni- versity Press, 1975, ch. 6. Fig. 4. Maps of the width of the simulated point-spread-function relative to the ideal as a function of position for the surface source (top row) and internal source (bottom row). The grayscale depicts the simulated width as a multiple of the ideal, with black indicating ideal response and white indicating a width 25% or more greater than the idea. The left hand column indicates the result at the -6 dB level; -30 dB is at right. The modulus recovery process is an ill-posed tested to estimate the structural and biological problem; therefore, additional information properties in engineered tissues, such as cell is needed to provide useful elastograms. In concentration, spatial organization of cells, cell this work, prior geometrical information was proliferation, and cell migration. In addition, used to impose hard or soft constraints on the the mechanical properties of engineered tissues reconstruction process. Simulation and phantom can be estimated by the acoustic radiation force- studies were conducted to evaluate and compare based techniques such as Spatially Modulated modulus elastograms computed with soft and Ultrasound Radiation Force (SMURF) imaging. hard constraints versus those computed without High frequency ultrasound is used to attempt any prior information. The results revealed that to improve the spatial resolution of quantitative the contrast-to-noise ratio of modulus elastograms parametric images and stiffness maps that are achieved using the soft prior and hard prior representative of engineered tissue properties. In reconstruction methods exceeded those computed recent work, analyses of the frequency-dependent without any prior information. Also, the soft prior backscatter coefficient are used to detect relative and hard prior reconstruction methods could differences in the concentration of fibronectin-null tolerate up to 8% measurement noise, and the mouse embryonic fibroblasts in 3-D agarose-based performance of soft and hard prior modulus tissue constructs. The successful completion of elastograms degraded when incomplete spatial this project will provide researchers and clinicians priors were employed. This work demonstrates with ultrasound-based imaging and quantitative that including spatial priors in the reconstruction techniques for nondestructive assessment of process should improve the performance of engineered tissues. model-based elastography, and the soft prior approach should enhance the robustness of the reconstruction process to errors in the geometrical information. High frequency ultrasound characterization of engineered tissues Karla Mercado, MS, Maria Helguera, PhD, Stephen McAleavey, PhD, Denise C. Hocking, PhD, Diane Dalecki, PhD Advances in the fabrication of engineered tissues require quantitative techniques to characterize the tissues’ structural, biological, and mechanical BME graduate students Nicholas Berry (left) and Karla properties. Histology and direct mechanical tests Mercado (right) are current standard techniques to assess the Estimating axial and lateral strain using a properties of engineered tissues; however, these synthetic aperture elastographic imaging techniques are often destructive and lack the ability for monitoring dynamic changes in tissue system properties over time. The overarching goal of Sangamithra Korukonda, MS, Marvin Doyley, PhD this collaborative project among RCBU members Model-based elastography is an emerging is to develop novel, high frequency ultrasound technique with clinical applications in imaging technologies for nondestructive characterization vascular tissues, guiding minimally invasive of the structural, biological, and mechanical therapies and diagnosing breast and prostate properties of three-dimensional engineered tissues. cancers. Its usage is limited because ultrasound This project focuses on developing quantitative can measure only the axial component of ultrasound and elastographic techniques to assess displacement with high precision. The goal of tissue properties during fabrication and post- recent work in the laboratory of Professor Marvin implantation, in order to facilitate the fabrication Doyley was to assess the effect of lateral sampling of fully-functional engineered tissues. Quantitative frequency, lateral beam-width and the number ultrasound techniques, including analyses of the of active transmission elements on the quality of backscatter spectrum and echo statistics, are being axial and lateral strain elastograms. Elastographic 8 imaging was performed on gelatin-based force from ultrasonic beams can generate crawling phantoms with a modified commercial ultrasound waves as well. Since crawling waves from scanner. Three groups of radio-frequency (RF) radiation force can be synthesized at arbitrary echo frames were reconstructed from fully frequencies, they can be used to measure the synthetic aperture data. In the first group, all 128 change of shear speed as a function of frequency. transmission elements (corresponding to a lateral Recent research from the laboratory of Professor beamwidth of 0.22 mm at the center of the field Kevin Parker aims to measure the dispersion of of view) were used to reconstruct RF echo frames biological samples by using synthesized crawling with A-line densities that varied from 6.4 lines/ waves from radiation force. mm to 51.2 lines/mm. In the second group, the A GE LOGIQ 9 system has been modified for size of the aperture was varied to produce RF acoustic radiation crawling wave experiments. echo frames with lateral beamwidths ranging from A specially designed sequence produces push/ 0.22 mm to 0.43 mm and a fixed A-line density scan pulses to obtain displacement data at points of 25.6 lines/mm. In the third group, sparse inside the region of interest. Scanned biological arrays with varying number of active transmission phantoms include gelatin-oil phantoms (10%– elements (from 2 to 128) were used to reconstruct 50% oil and 10%–20% gelatin), veal livers, and RF echo frames, whose A-line density and lateral human livers embedded in a gelatin background. beamwidth were fixed to 25.6 lines/mm and IQ data are averaged over several runs to 0.22 mm, respectively. Applying a two- minimize the background noise. Cross-correlation dimensional displacement estimator to the pre- of IQ data sets provides displacement data sets and post-deformed RF echo frames produced that are further processed to generate crawling displacement elastograms. Axial and lateral strain waves at different frequencies, nominally 80 to elastograms were computed from displacement 450 Hz. elastograms with a least squares strain estimator. Local speed estimations are performed on The quality of axial and lateral strain elastograms synthesized crawling waves over a frequency improved with increasing applied strain and range of 85 to 400 Hz for each of the phantoms A-line density but decreased with increasing to produce the mean and SD of the shear speed lateral beamwidth and deteriorated as the number inside the medium at different frequencies. Two of active transmission elements in the sparse parameters are derived for further analysis: shear arrays were reduced. This work demonstrated speed at the median frequency and the dispersion that the variance incurred when estimating the slope over an interval of 100 Hz. Veal liver, for lateral component of displacement was reduced example, showed about 1.6 to 2.1 m/s of shear considerably when elastography was performed speed with a dispersion slope of 0.2 to 0.85 with a synthetic aperture ultrasound imaging m/s per 100 Hz. The results were compared system. Satisfactory axial and lateral strain with the composition of the samples, and fat elastograms were produced using a sparse array was identified as increasing the dispersion. In with as few as 16 active transmission elements. conclusion, synthesized crawling waves from radiation force can be used to measure the dispersion of biological samples, which indicates Measuring dispersion of a biological medium the composition of the biomaterials. with crawling waves synthesized from ultrasonic radiation force Zaegoo Hah, PhD, Brady Mills, BS, Christopher Hazard, MD, Kevin J. Parker, PhD, Deborah Rubens, MD Crawling waves can be generated with the radiation force from ultrasonic beams. Crawling waves generated can be analyzed to provide local shear speed and elasticity. Although most crawling wave experiments have used mechanical sources, recent studies showed that radiation

9 compared for mode of delivery, perineal tear, Obstetrics & Gynecology Ultrasound Unit pelvic muscle avulsion, and peripartum urinary Tulin Ozcan, MD and fecal dysfunction rates.

The UR OB/GYN Ultrasound Unit provided Evaluation of the presence of a subchorionic clinical service at multiple sites including Strong hematoma on first trimester ultrasound and Memorial Hospital, Highland Hospital, Rochester midtrimester transvaginal cervical length: A General Hospital, FF Thompson Hospital and our facility at Red Creek Drive. The total number retrospective cohort of examinations was 12,780, including 10,619 Erin M Lemcke-Berno RDMS, MPH, David obstetric, and 2,261 gynecological scans. Invasive Hackney, MD procedures included 213 amniocenteses for Both first trimester intrauterine events and a karyotype or lung maturity, 109 chorionic villus decreased second trimester cervical length samplings, and 135 sonohysterograms and 25 have been associated with an increased risk other procedures including OR guidance for of subsequent spontaneous preterm birth. minor gynecological procedures, intracardiac However, potential associations between the KCL injections or cyst aspirations. Interpretation two have not yet been previously explored. The of ultrasound examinations at FF Thompson objective of this study was to determine if first Hospital are continued utilizing a combination trimester subchorionic hematomas (SCHs) or of telemedicine and onsite service. The Unit also self-reported vaginal bleeding was associated continued to provide ultrasound and consulting with a subsequent decrease cervical length at services to Rochester General Hospital OB/GYN 16-20 weeks. Retrospective cohort of all patients Department. Additional equipment has been with both a second trimester transvaginal cervical obtained to improve the quality of 2D and to length and first trimester ultrasound at the increase the utilization of 3D and 4D scanning University of Rochester ultrasound department in both obstetrics and gynecology. Examples of over a six-month period during which screening ongoing research projects are provided below. cervical lengths were obtained in all patients undergoing anatomic surveys. Cervical lengths Impact of pelvic oor musculature on were compared in subjects with or without a SCH peripartum outcomes: A prospective study and/or clinical vaginal bleeding and adjusted for Tulin Ozcan, MD, Veruna Raizada, MD, potential confounders. 353 ethnically diverse G Buschbaum, MD subjects fulfilled the inclusion criteria, of whom 40 had a first trimester SCH, 53 reported an The aim of this project is to investigate the episode of first trimester vaginal bleeding and 18 impact of pelvic floor muscle contraction on the had both. There were no significant differences labor and delivery outcomes. The hypothesis in cervical length for subjects with or without is that primiparous women who are able to a SCH (p=0.42), clinical bleeding (p=0.23) or increase the size of their pelvic floor hiatus both (p=0.38). Linear regression did not identify with maximal valsalva are more likely to have any statistically significant associations between a successful normal vaginal delivery and less intrauterine bleeding and cervical length when likely to have pelvic floor muscle avulsions and adjusted for confounders. peripartum urinary and fecal dysfunctions. Term Analyses did not validate our hypotheses. primiparous patients admitted for early labor who There were no significant associations between are candidates for vaginal delivery or admitted the presence of a first trimester subchorionic for induction of labor are included in the study. hematoma and second trimester cervical Three dimensional ultrasound volume data sets shortening, or with bleeding of any type and are obtained of the pelvic floor muscle at rest, cervical length. Thus, the two preterm birth risk squeeze and valsalva using a transperineal probe factors appear to be independent of one another, before active labor and 6 weeks postpartum. The and the increased risk of preterm delivery pelvic floor muscle hiatus dimensions which associated with early bleeding is not mediated include dynamic pelvic floor muscle hiatal through cervical shortening. length and area with various maneuvers will be

10 Effect of imaging parameters on estimates of and the displacement SNR. We have been able shear modulus using a single tracking to identify the appropriate imaging parameters location ARFI method to select during Etana Elegbe, MS, Stephen McAleavey, PhD different conditions. This is significant Ultrasound elastography is of increasing clinical because selecting significance because it provides a relatively the appropriate low cost method for producing image contrast imaging parameters that is associated with disease and distinct can improve the from conventional modalities (X-ray, US, MRI). precision of our Acoustic radiation force elastography methods estimates, which are particularly attractive because of the ability ultimately enhances to directly interrogate the tissue at the region elastographic image of interest. In addition, the propagation of the quality. induced shear waves in soft tissue, generally occurs on a time scale that is long enough to BME graduate allow for adequate motion tracking without the student Etana Elegbe need for elaborate hardware. On the other hand, the generated shear waves are rather quickly attenuated, and, in the case of dispersive media, Prostate cancer detection using distorted. Consequently, the algorithm and choice 3-dimensional vibration sonoelastography: of imaging parameters can affect the ability to Ex vivo and in vivo results accurately and precisely determine the true Benjamin Castaneda, PhD, K. Westesson, Liwei velocity of the induced shear waves. An, PhD, Jorge Yao, M.D., L. Baxter, Jean In the past, we developed a Single- Joseph, MD, Kevin Hoyt, PhD, John Strang, MD, Track-Location (STL) ARFI method and have Deborah Rubens, MD, Kevin J. Parker, PhD identified speckle noise as a significant source of measurement variance in shear wave velocity Vibration sonoelastography (VS) is an elasticity estimation methods that rely on ultrasonic imaging technique that has shown promise for tracking of tissue motion at two or more locations cancer detection in ex vivo prostate glands. (the Multiple-track-location methods). The STL A recent study from the Parker lab compared ARFI algorithm determines the shear velocity of VS performance in prostate cancer detection a material by pushing in two locations a known between ex vivo and in vivo experiments. Eleven distance apart and determining the difference patients underwent VS examination prior to their in arrival time of the induced shear waves. We scheduled radical prostatectomy. Vibration was have shown success in measuring the shear induced by a specially designed plate with 2 wave velocity and shear modulus of both mildly mechanical actuators driven by a low-frequency dispersive materials (such as tissue mimicking harmonic signal (70–140 Hz). In vivo ultrasound phantoms) as well as dispersive materials (such as (US) and VS volume data were acquired excised porcine tissue). We have also successfully using a GE LOGIQ 9. After surgery, the same monitored heat-induced changes (water and prostate gland was received and embedded in a rf-ablations) in excised porcine liver tissue over gelatin mold. External low-frequency vibration time. (combination of 105, 140, 175, and 210 Hz) was More recently, we have been investigating applied by a mechanical piston. Ex vivo US and the effect of processes that result in the distortion VS volume data were acquired. After imaging, the of the shear waves, SNR of the displacement data, entire gland was step sectioned using a whole- and sampling errors. Specifically, we have been mount histologic method. A pathology volume investigating the effect of the distance between was reconstructed and registered to the US the pushing locations, the distance from the and elastographic volumes. To assess detection pushing location to the tracking location, the performance, cancer and benign prostatic ratio of the width of the push beam to that of hyperplasia (BPH) findings from the in vivo and the track beam, the frequency of the push beam ex vivo volumes were compared in size and

11 position to 3D pathology. maturation are shown in Table 1. One sample Ten cases were analyzed (1 case was was allowed to continue maturation and was discarded due to poor contact between the imaged using a Matec Micro Electronics PSS-18 gland and transducer).Tumors detected with VS acoustic scanning system fitted with a 130 MHz showed good agreement in size with findings in focused immersion transducer housed in the histology. When only tumors >4 mm in diameter Center for Integrated Manufacturing Studies at RIT (as measured on histology) were considered for (Figure 1). Maturity of the biofilm over the time analysis, in vivo VS showed 83% accuracy, 91% span of the study was corroborated with increase sensitivity, and 81% specificity, whereas ex vivo in biofilm thickness and IBC values, shift in center VS showed 82% accuracy, 75% sensitivity, and frequency and narrowing of the bandwidth. 84% specificity. This study evaluated the entire Future investigations will involve studying prostate, by fusing volumes from in vivo and different strains subject to a similar experimental ex vivo VS experiments to histology, permitting protocol. Newer and more sophisticated quality quantification and localization of tumors. Both metrics will be developed and used to evaluate experiments presented similar performance in changes in the biofilm over time. We expect to cancer detection (>80% accuracy for tumors be able to identify unique signatures that will >4 mm in diameter). These results are an help us distinguish one strain from another. The improvement over gray scale US but not yet changes observed in the acoustic signals from sufficient to replace biopsy. the three batches can be used as a benchmark to compare to different strains in isolation and in High-frequency ultrasound characterization combination with epithelial cells. The experiment of biofilms described above demonstrates the efficacy of Maria Helguera, PhD high frequency ultrasound as a diagnostic tool in testing properties of biological materials. RCBU member Maria Helguera is investigating the use of ultrasound for biofilm characterization. Table 1. Change in properties as biofilm matures. This project is in collaboration with Dr. Michael Batch Batch Batch 1 2 3 Pichichero of Rochester General Hospital Research Early Mid Old Early Mid Old Early Mid Old

Institute and Dr. Robert Osgood of Biomedical Fo (MHz) 14.3 13.43 10.9 14.04 12.82 11.9 14.08 13.92 13.01

Sciences at RIT. The study employs biofilms BW (MHz) 4.19 3.89 3.58 3.21 2.38 2.14 3.86 3.22 2.85 grown in vitro on silastic substrates to determine IBC (mm-1) 16.3 1.71 1.74 3.25 7.25 15.15 9.055 0.91 3.24 the feasibility of detecting and characterizing Thickness n/a 119.8 219.43 10 80.2 88.06 18.2 45.25 65.56 parameters such as biofilm thickness, backscatter (µm) coefficient, integrated backscatter, shift of center frequency and reduction of bandwidth. These parameters are needed to understand image Figure 1. 130 MHz C- properties and design an efficient non-invasive scan of a 19-day old protocol to identify biofilms, map their progression biofilm. Scanned area over time, and differentiate between single-species is 4 mm2. and multiple-species biofilms. A single element focused transducer (F number 1.5) was fully characterized and used to study the acoustic properties of biofilms. The transducer had a center frequency of 15 Investigating cavitation in vivo MHz and a 50 percent -3dB/echo bandwidth. Diane Dalecki, PhD, Carol H. Raeman, AAS, Three independent batches of Non-typeable Sally Z. Child, MS, Neo Jang, MS, Haemophilus influenzae, NTHi, harvested from Sheryl M. Gracewski, PhD the middle ear fluid of a case of AOM were A long-standing area of collaborative research studied over a period of one week. Each batch was between Professor Sheryl Gracewski and probed over three phases during the entire span Professor Diane Dalecki centers on understanding of the study. The three phases were named 'Early', acoustic cavitation in vivo. The work has direct ‘Middle’, and ‘Old’ corresponding to samples that relevance to the response of contrast agents to are 1-3 days old, 3-5 days old and 5-7 days old, ultrasound exposure. Ultrasound contrast agents respectively. Changes in these parameters due to 12 are suspensions of gas-filled microbubbles. Ultrasound contrast agents currently enhance (NAFLD) is the most common cause of the capabilities of diagnostic imaging and are chronic liver dysfunction in Western countries also providing new avenues for therapeutic and can progress to end stage liver disease as a applications of ultrasound. Research efforts result of non-alcoholic steatohepatitis (NASH). focus on developing an understanding of the Current understanding of the pathophysiological physical and biological mechanisms of interaction progression from NAFLD to NASH is incomplete. of acoustic fields with tissues containing The gold standard for measuring intrahepatic fat microbubble contrast agents. content is liver biopsy followed by histologic Microbubble contrast agents can increase analysis. This procedure can increase patient risk the likelihood of bioeffects of ultrasound and discomfort, be logistically cumbersome and associated with acoustic cavitation. Ongoing subject to interpretive errors upon analysis. The work from the Dalecki lab continues to ability to effectively measure hepatic fat content investigate ultrasound-induced bioeffects of is essential for both evaluating livers for transplant microbubble contrast agents in biological and diagnosing all stages of NAFLD. systems. Previous work has demonstrated that The objective of recent work in the Parker the presence of ultrasound contrast agents lowers laboratory is to demonstrate the correlation the threshold for ultrasound-induced premature between hepatic steatosis and shear speed cardiac contractions, and capillary rupture in frequency dependence (dispersion) of viscoelastic various organs and tissues. Results of a series liver tissue. A non-invasive technique using of mechanistic investigations are consistent crawling waves (CrWs) to measure both the with the hypothesis that acoustic cavitation stiffness and fat content of liver samples is is the mechanism for the production of these employed. bioeffects of ultrasound and microbubble contrast Excised mouse and human liver specimens agents. Sheryl Gracewski and her laboratory are were examined using CrW sonoelastography. developing unique capabilities to computationally Phantoms were prepared by embedding the simulate the response of microbubbles to sound samples in a porcine gelatin background exposure within a confining blood vessel. In (8–11%). Two vibration sources were positioned recent work, the dynamics of microbubbles in at each side of the phantom with the ultrasound vessels were modeled using a lumped parameter transducer scanning from the top. CrWs model for a five-degree-of-freedom system, were driven at frequencies ranging from accounting for the compliance of the tube and 100-300 Hz by offsetting a small frequency the coupled response of two microbubbles. difference between two sources. CrW data was Two different simulation approaches are also de-noised and sinusoidal curve fitting was applied employed: 1) an axisymmetric coupled boundary to a similar ROI in each frame to determine the element and finite element code, and 2) finite relative wavelength. Wavelengths were then element models developed in COMSOL used to calculate respective shear velocities at Multiphysics. Ongoing work in the Gracewski lab each frequency for a given sample. The rate of continues the development of more sophisticated increase in shear velocity over a frequency band computational models of bubble dynamics. was collected to reveal the dispersion of each Experimental measurements and observations specimen. within the Dalecki lab are used to validate the In ob/ob genetically obese mice (n=10), the simulation results from the Gracewski lab in order mean dispersion slope was 0.15+/-0.015 cm/ to obtain new insights into the nonlinear bubble sec per 100 Hz, compared to lean ob/- littermates dynamics that can occur within blood vessels. (n=10) at 0.075+/-0.02 cm/sec per 100 Hz. Histologic analysis using H&E and oil red O Using crawling wave sonoelastography for staining confirms steatosis up to 65% in ob/ the measurement of intrahepatic fat content ob animals and 0% to <5% in ob/- animals. Brady Mills, BS, Christopher Barry, MD, Additionally, human liver scans from patients Zaegoo Hah, PhD, Deborah Rubens, MD, over a range of steatosis and fibrosis suggests this Kevin J. Parker, PhD method can discriminate degrees of steatosis (e.g., Hepatic steatosis affects 31% of the U.S. minimal <20%, moderate 20–40%, and severe population and as much as 67% of those who >40%) as well as fibrosis. are obese. Non-alcoholic fatty liver disease CrW sonoelastography is potentially a non- 13 invasive, cost effective and efficient technique the gels ranged from homogeneously distributed for grading not only the stiffness but also the fat cells to loosely aggregated bands of cells to more content of liver tissue. This method has promise densely packed cell bands as the radiation force as a safe and effective way to assess liver health in magnitude increased (Figure 1, panel A). As such, both the realm of liver transplant patients as well cell band density was controlled by varying the as the general population. radiation force magnitude of the USWF. Spacing between adjacent cell bands was controlled by Ultrasound standing wave fields pattern utilizing a different frequency USWF (Figure cells and affect vascular network formation 1, panel B). Additionally, in related work, the in engineered tissues extracellular matrix protein fibronectin was co- Kelley A. Garvin, MS, Denise C. Hocking, PhD, localized to cell bands by binding fibronectin Diane Dalecki, PhD to the cell surface prior to USWF exposure. In Advances in the field of tissue engineering this way, the spatial organization of proteins, hold great promise in saving the lives of the and other biologically active molecules, can be hundreds of thousands of patients currently controlled using our USWF technology. Taken awaiting organ transplantation. In the Dalecki together, these data indicate that our USWF and Hocking laboratories, ultrasound-based technology has the ability to create complex technologies for the fabrication of engineered spatial patterns of cells and proteins within tissue are actively being developed to aid in the engineered tissue constructs, and therefore, holds advancement of this field. These technologies promise in aiding the field of tissue engineering in are aimed at overcoming two of the major reconstructing tissues with complex organization challenges hindering progress in the field of tissue in a laboratory setting. engineering – reconstructing complex tissue In previous work, we utilized our USWF organization in a laboratory setting, and forming technology to demonstrate that USWF-induced a vascular system within engineered tissue to patterning of endothelial cells (the cells that line maintain cell viability and function of large, the inner wall of blood vessels) into multicellular three-dimensional tissue constructs. We have planar bands led to the rapid and extensive developed a novel ultrasound standing wave field vascularization of the three-dimensional collagen (USWF)-based technology to spatially pattern gel. To further investigate whether the initial cells and extracellular matrix proteins within USWF-induced pattern of cells affects vascular three-dimensional, collagen-based engineered network formation or morphology, collagen gels tissue and have utilized this technology to with various spatial patterns of endothelial cells accelerate the formation of extensive vascular were created using our USWF technology and networks throughout the three-dimensional both the rate of formation and morphology of volume of tissue constructs. vascular networks within the gels were analyzed. Acoustic radiation forces associated with the Constructs with loosely aggregated bands of development of an USWF can actively direct cells developed anastomosing networks with a cells in suspension into multicellular planar tortuous morphology within 4 days post-exposure. bands that are perpendicular to the direction of These networks were present throughout the sound propagation and that are spaced at half- three-dimensional volume of the construct and wavelength intervals. To maintain the USWF- were maintained at least 10 days post-fabrication induced spatial pattern of cells after removal (Figure 2). Anastomosing network formation of the sound field, cells were suspended in was delayed until day 10 in constructs initially an unpolymerized type-I collagen solution, containing densely packed cells bands. Networks and the solution was allowed to polymerize in these samples exhibited a vascular-tree like into a gel during USWF exposure. By varying morphology with large, lumen-containing areas the magnitude of the acoustic radiation force and smaller branching capillary-like structures experienced by the cells, as well as utilizing emerging from these areas (Figure 2). In contrast, different acoustic frequencies, various spatial any vascular network formation in sham-exposed patterns of multicellular planar bands were samples initially containing a homogeneous created within three-dimensional collagen gels distribution of cells was confined to a thin layer using our USWF technology (Figure 1, next page). at the gel bottom and not present throughout The USWF-induced patterns produced within the three-dimensional volume of the engineered 14 tissue (Figure 2). Similar results were observed Comparing the performance of plane wave for constructs fabricated at a different frequency and sparse array elastography imaging where the initial spacing between adjacent bands systems of cells was decreased (Figure 2). Taken together, Sangmithra Korukonda, MS, and Marvin M. these data indicate that the initial density of Doyley, PhD USWF-induced cell bands, but not the initial spacing, affects both the rate of formation and Non-invasive vascular elastography (NIVE) morphology of vascular networks within collagen- imaging of the carotid artery provides quantitative based engineered tissue. As such, the spatial information on vessel morphology and its organization of endothelial cells was shown mechanical properties. This information may be to influence the vascularization of engineered used to characterize plaque vulnerability. In this tissue in vitro. Therefore, not only can we use work, we compare sparse array and plane wave our USWF technology to produce various spatial imaging to perform ultrafast elastographic imaging patterns of cells within engineered tissue for of the carotid artery. A SONIX RP commercial reconstructing complex tissue organization, ultrasound scanner (Ultrasonix Corp., Vancouver, USWF-patterning can also be used to effectively Canada) equipped with an L14–5/38 linear and rapidly create vascular networks within array probe was configured to acquire engineered tissue with complex network (1) sparse array data with only 7 active transmit morphologies. elements and 128 receive elements, and (2) plane wave data by transmitting simultaneously with all 128 elements and receiving in parallel with all elements. Elastographic imaging was performed on vessel phantoms at intra-luminal pressure differences ranging from 4-20 mm Hg. Three-dimensional data sets were acquired by translating the transducer along the long axis of the phantoms in increments of 2 mm. Axial and lateral displacement images were computed by applying 2D cross-correlation to the beam formed Figure 1. Various spatial patterns of cells created within radio-frequency (RF) echo frames obtained at three-dimensional engineered tissue using USWF technology. different pressures. Radial and circumferential Patterns ranging from homogeneously distributed cells, to loosely aggregated planar bands of cells, to more densely elastograms were obtained from the gradients of packed cell bands produced at 1 MHz (A) and 2 MHz (B). the displacement estimates. Scale bar, 200 µm. Strain elastograms were obtained with both plane wave and sparse array imaging methods over the range of pressures employed in this study. Figure 1 (next page) shows representative examples of elastograms obtained from a cross- section of a phantom containing a soft plaque (4 o’clock). The plaque appears as a localized region of high strain, which is clearly demarcated in the radial (a) and circumferential (b) strain elastograms obtained with the sparse array. In the case of the homogeneous elastograms, higher variance was observed in the plane wave elastograms as compared to the sparse array elastograms, particularly in the lateral sectors. In conclusion, Figure 2. Various complex vascular network morphologies sparse array imaging is a promising elastography created within three-dimensional engineered tissue using USWF technique that can image the carotid artery in technology. Multiphoton microscopy images showing vascular network morphology (red, vessel walls; blue, cell nuclei) as real time at ultrafast frame rates. While plane dense and tortuous for initially loosely aggregated cell bands wave imaging has greater speed and higher signal but as vascular tree-like for constructs initially containing more power, sparse array imaging has greater sensitivity densely packed cells bands. Homogeneous cell distributions to tissue motion, particularly in the lateral present in sham samples did not develop networks throughout direction. In addition, with the high acquisition the three-dimensional construct. Scale bar 200 µm. 15 speeds, 3D data can be acquired to improve the scan of a 2.25 cm2 region in the paper was diagnostic value of this technique. investigated using non-contact ultrasound pulse- echo techniques at 1 MHz. Six different classes a of papers that have been used in the construction of LPTFT were analyzed. Figures 1a and 1b (below) show results for two paper substrates. It can be seen that the structure of the papers and fiber orientation are easily detected using this technique. The next step in this project entails quantitative analysis of the backscattered data to extract characteristic parameters for each paper sample. Figure 1a. From left to right: Paper “D”, C-scan of top surface, B-scan image; b

Figure 1b. From left to right: Paper “E”, C-scan of top surface, B-scan image

Figure 1. 3-D visualization of strain within a heterogeneous vessel phantom obtained using ultrasound based sparse array elastography. An eccentric soft plaque is located on the phantom's inner lumen at the 4 o'clock cross-section, which is subjected to a 5 mm Hg pressure difference. Pairs Self-assembled microtissues as a model of sparse array images (pre- and post-deformation) were system to assess ultrasound-induced acquired along the vessel long axis at increments of 2 mm. conformational changes in extracellular Cross-correlation analysis was performed to obtain the displacement estimates between consecutive ultrasound RF matrix proteins image pairs. The displacements were then used to compute Carlos Sevilla, MS, Diane Dalecki, PhD, radial (a) and circumferential (b) vessel strains. Regions of Denise C. Hocking, PhD localized high strain in the 4 o'clock sectors of the vessel clearly indicate the presence of the soft plaque (Plot scales Wound healing is mediated by complex (a) and (b) are [-3 0] and [0 3], respectively). and dynamic interactions between cells and Non-contact ultrasound characterization of their surrounding extracellular matrix (ECM). paper substrates Disruptions in the healing process can lead to chronic wounds that may impair quality of life Maria Helguera, PhD or result in death. Fibronectin is a principal In collaboration with Ricardo Costa, CENIMAT, component of the ECM and is thought to play Universidade de Nova Lisboa, Portugal, the a role in wound healing. Soluble fibronectin Helgeura lab is investigating the use of ultrasound is polymerized into insoluble ECM fibrils via a for characterization of paper substrates. Latest tightly regulated, cell-dependent process. In turn, developments in the field of lignocellulose thin ECM fibronectin stimulates several cell functions film transistors (LPTFT) have demonstrated that critical for wound repair, including proliferation. it is possible to construct electronic nanoscale Recent data suggest that ECM fibronectin may components on top of micrometric structures. exist in various conformational states that produce There is a need for consistent results and it has different cellular behaviors. The Hocking and been determined that the fiber orientation in Dalecki laboratories are investigating whether commercial papers affect performance. A raster ultrasound, and its associated mechanical 16 forces, can be used to promote the healing of Measuring circumferential and radial chronic wounds. To this end, we developed an component of displacement using a non-rigid in vitro model of tissue formation by combining registration based displacement estimator compliant, polymerized collagen-I substrates with Shayin Jing, MS, Michael S. Richards, PhD, the cell-mediated assembly of fibronectin matrix Marvin M. Doyley, PhD fibrils. Fibronectin matrix assembly stimulated Intravascular ultrasound elastography is emerging the formation of multicellular structures with tall as an imaging modality that can visualize the (~50 µm) dome-like central cores surrounded by radial strain distribution within vascular tissues cells that extended onto the collagen substrate. providing new diagnostic information that Immunofluorescence microscopy studies revealed cardiologists may use to detect rupture prone that fibronectin fibrils were present throughout atherosclerotic plaques. Since plaques typically the microtissues, whereas proliferating cells were rupture in areas where the circumferential stress confined to the microtissue periphery (Figure is high, it should prove useful to develop methods 1). Collagen and fibronectin fibrils also co- to measure both the radial and circumferential localized only at the microtissue periphery (Figure component of displacement. The goal of recent 2). Blocking fibronectin-collagen interactions work from the Doyley lab was to investigate completely inhibited cell proliferation, indicating the feasibility of developing elastographic that cell proliferation in response to fibronectin is methods for visualizing the circumferential strain dependent on the co-polymerization of collagen within vascular tissue using a single-element and fibronectin fibrils. Ongoing experiments will rotating catheter. In these studies, elastography determine if ultrasound exposure can alter the imaging was performed on homogeneous conformational state of collagen fibrils to enhance and heterogeneous vessel phantoms using a fibronectin-collagen interactions and, in turn, commercially available intravascular ultrasound stimulate cell proliferation. scanner (ILABTM, Boston Scientific) that was Figure 1. equipped with a 40 MHz rotating element Immunfluorescence catheter. The phantoms were pressurized image captured using a dynamic pressurization system (peak using two-photon to peak 20 mmHg, 1 Hz) during elastographic microscopy showing the spatial imaging. A non-rigid image registration based organization of method was developed to obtain both radial fibronectin (white), and circumferential displacements, based proliferating cells on which radial and circumferential strain (red), and cell nuclei (blue) within elastograms were computed. Since a single three-dimensional element rotating transducer was used, non- microtissues. uniform rotation distortion (NURD) exists that will induce additional circumferential motion. The magnitude of NURD is dependent on the catheter position; in this study the magnitude Figure 2. of the non-uniform distortion was estimated to Immunfluorescence be +1-2° from the angular location. To make image captured the method feasible when NURD exists, an using two-photon microscopy incompressibility constraint was introduced showing fibronectin in the image registration method procedure. (green). Collagen Phantom studies were performed to investigate fibrils (blue) were the feasibility of the method. Figure 1 (next visualized using page) shows representative examples of radial second harmonic generation. Areas and circumferential strain images obtained from of co-localization a homogeneous vessel phantom. Figure 2 (next appear white. page) shows representative examples of radial and circumferential strain images obtained from a heterogeneous phantom that contained a soft

17 plaque. The result of this preliminary investigation Three-dimensional image analysis and suggests that circumferential strain images can be visualization of vasculature in engineered computed using a registration based displacement tissues estimator with a commercially available IVUS Maria Helguera, PhD, Mohammed Yousef imaging system. Hussien, MS, Kelley A. Garvin, MS, Denise C. 1a Hocking, PhD, Diane Dalecki, PhD The Dalecki and Hocking laboratories have demonstrated that ultrasound standing wave fields can non-invasively control the spatial distribution of cells within three-dimensional, collagen-based engineered tissues (see related story on page 14). Their studies indicated that ultrasound- induced alignment of mouse embryonic myofibroblasts in collagen gels increases cell contractility and cell-mediated extracellular 1b matrix reorganization. Further, noninvasive organization of endothelial cells within collagen gels accelerates the formation of capillary sprouts that mature into branching networks throughout the three-dimensional hydrogel. Multi-photon microscopy imaging techniques were employed to visualize these branching networks, as shown below in Figure 1. Both the rate of formation and morphology of the resultant vascular network are dependent upon the ultrasound field parameters used to produce the cellular alignment.

Figure 1. Multi-photon z-projection microscopy images show different vascular networks produced in response to different ultrasound standing wave field parameters used for cell 2b patterning. Left: 1 MHz, 0.15 MPa, Right: 1 MHz, 0.05 MPa

Figure 2. 3-D visualization of two co-registered data sets. Cell nuclei are stained with DAPI (blule) and endothelial cells are stained with anti-CO31 antibodies (red).

Figure1. (a) radial strain image of a homogeneous phantom; (b) circumferential strain of a homogeneous phantom. Figure2. (a) radial strain image of a heterogeneous phantom; (b) circumferential strain of a heterogeneous phantom. 18 This collaborative multidisciplinary project disruption and the risk of hemorrhage limit the draws on the expertise of Dr. Maria Helguera peak pressures practical. Moreover, the use to develop image processing approaches to of long pulses degrades the axial resolution quantify properties of engineered tissues. In achievable. In recent work from the Doyley lab, one project, the Helguera lab is developing a novel excitation strategy using preemphasized interactive 3-D visualization tools that provide chirps for microbubble insonation was employed actual volume of vaculature in engineered to significantly enhance subharmonic signal tissues, as shown in Figure 2 (previous page). from UCA. Therefore, low peak pressures can Furthermore, Dr. Helguera is investigating be employed to obtain high contrast resolution 3-D textural and volumetric image analysis and the axial resolution can be restored by pulse techniques for characterizing the multi-photon compression. This technique was validated by microscopy image stacks. In recent work, the numerical simulations and flow studies at high Helguera lab implemented an algorithm to transmit frequencies (20 MHz). High spatial and quantitatively analyze the texture and morphology contrast resolution achievable by this technique of vasculature in engineered tissues produced may significantly enhance the clinical potential by the Dalecki and Hocking labs. Textural and for functional imaging of coronary atherosclerosis. volumetric parameters were able to differentiate quantitatively the vascular networks produced with different ultrasound standing wave fields of different pressure amplitudes. The Helguera lab is currently working on a stand-alone graphical user interface tool that will support scientists working in this field. A coded excitation technique for functional imaging of coronary atherosclerosis using ultrasound contrast agents Himanshu Shekhar, MS, Marvin M. Doyley, PhD Acute coronary syndromes may occur when life–threatening atherosclerotic plaques rupture in the advanced stages of cardiovascular disease. There is increasing evidence that plaque neovascularization accelerates the progression and disruption of atherosclerotic plaque. Plaque neovessels may be detected by subharmonic intravascular ultrasound (IVUS) imaging with ultrasound contrast agents (UCAs). The assessment of plaque neovascularity and perfusion at high spatial and contrast resolution may help identify those most at risk of acute coronary syndromes. While theoretical considerations dictate the use of high peak pressures and long excitation pulses for obtaining Figure 1. Demonstrattion that chirp-coding of the ultrasonic high contrast transmitted pulse can improve the sensitivity and axial subharmonic resolution of high-frequency subharmonic imaging. IVUS images, Chirp-coded excitation shows improved subharmonic to microbubble fundamental ratio computed from the frequency response of ultrasound contrast agent backscatter (a), and improves the ECE graduate axial resolution by almost two-fold (b). student, Himanshu Shekhar 19 Crawling wave detection of prostate cancer: imaging, oil exploration, mapping the ocean floor, Preliminary in vitro results and harbor surveillance. Underwater sound over Liwei An, PhD, Brady Mills, BS, Zaegoo Hah, a broad frequency range can be produced from PhD, Shuo Mao, MS, Jorge Yao, MD, Jean a variety of sources including sonar systems and Joseph, MD, Deborah Rubens, MD, John Strang, underwater blasts. The Dalecki lab continues MD, Kevin J. Parker, PhD to investigate the interaction of underwater A focus of investigation in the Parker laboratory sound fields with biological tissues. The Naval is to develop signal and image processing Submarine Medical Research Laboratory methods to derive an accurate estimation of local (NSMRL) in Groton, CT have been collaborators tissue elasticity using the crawling wave (CrW) and supporters of projects in this area. An sonoelastography method. The task is to reduce understanding of the interaction of underwater noise and to improve the contrast of the elasticity sound fields with biological systems is necessary map. The protocol of the CrW approach was first to develop safe exposure guidelines for humans, tested on heterogeneous elastic phantoms as a marine mammals, and fish exposed to these model of prostate cancers. Then the contrast- acoustic fields. to-noise ratio of the estimation was calculated Over the years, our laboratory has been iteratively with various sequences of algorithms working to quantify the thresholds for sound- to determine the optimal signal processing induced damage to tissues containing gas and settings. Finally, the optimized signal processing identify the physical mechanisms for tissue was applied to ex vivo prostate cancer detection. damage. The air-filled lung is particularly The comparison of the segmented elasticity map sensitive to underwater sound exposure. We and the histology tumor outline was made by have investigated the response of murine lung quadrants to evaluate the diagnostic performance to underwater sound exposure for frequencies of the protocol. Furthermore, the CrW approach spanning over four orders of magnitude (i.e., was combined with amplitude-sonoelastography ~100 Hz to 1000 kHz). Sheryl Gracewski has to achieve a higher specificity. developed both analytical and computational Results of this study demonstrated the models to predict the acoustic fields within the feasibility of the proposed approach for clinical exposure chambers of our experimental acoustic applications. In the application to ex vivo prostate systems. Using both an acoustic scattering cancer detection, the established approach technique and a pulse-echo ranging technique, was tested on 43 excised prostate glands. The we have shown that the response of the lung combination of the CrW approach and amplitude- is maximized for exposure at the resonance sonoelastography achieved an accuracy of over frequency of the lung. At the resonance frequency 80% for finding tumors larger than 4 mm in of the lung, the threshold for damage to the lung diameter. The elasticity values and contrast found and surrounding tissues is lowest. by the CrW approach were in agreement with the Through a collaborative project, the Dalecki previous results derived from mechanical testing. lab and Hydroacoustics, Inc. (HAI) investigated In summary, crawling waves can be applied to the effects of underwater acoustic impulses on detect prostate cancer with accuracy approaching mammalian systems. Air gun technology, water 80% and can quantify the stiffness or shear tanks, and measurement facilities at HAI were modulus of both cancerous and noncancerous used to generate underwater acoustic impulses tissues. The technique therefore shows promise for our bioeffects investigations. The Dalecki lab for guiding biopsies to suspect regions that are completed a series of experimental investigations otherwise difficult to identify. on the effects of underwater acoustic impulses on murine lung in vivo. The Dalecki lab Interactions of underwater sound fields and also collaborated with the laboratory of John biological tissues Olschowka, Ph.D. (Neurobiology and Anatomy) Diane Dalecki, PhD, Sheryl Gracewski, PhD, to study the effects of underwater acoustic John Olschowka, PhD, Sally Z. Child, MS, Carol impulse fields on the mammalian brain and spinal H. Raeman, AAS cord. The results of this work are relevant to Underwater sound fields are used for numerous establishing safety guidelines for swimmers and commercial and military applications, including divers exposed to underwater sound fields.

20 TISSUE ELASTICITY CONFERENCE HIGHLIGHTS

major step. That important step was the creation of specialized scanners for conducting clinical research on thousands of patients in some of the most highly respected medical centers around the world. In retrospect, the evolution of the field is a superb case study of translational research, developing from ‘bench to bedside.’ This conference series has, by design, served as the place where researchers, clinicians, industry leaders, and students from around the world could trade ideas and discuss the latest advances, while creating an archival record of their progress. The international participation in the Conference Celebrating its Tenth Anniversary, the International now includes virtually all global entities engaged Tissue Elasticity Conference displayed mugs from the in research, development, commercialization and the previous conferences. practice in the field.” The Tenth International Tissue Elasticity As with previous conferences, the tutorial series Conference was held in Arlington, Texas on the technical and clinical progress over the from October 12–15, 2011. Co-organized by last 10 years as well as potential for the future Kevin Parker (RCBU past Director), the annual was continued by Drs. Jeffrey Bamber (UK) and conference provided an international forum for Mark Palmeri (US). The conference also included the advancement of knowledge and methods for the popular format of the formal Poster Session, the measurement and imaging of elastic properties where each presenter has the opportunity to give a brief oral summary of his/her poster. of tissues with ultrasound. RCBU members Alex Partin, Michael Richards, Kevin J. Parker, and Next year's conference will be held October 2–5, Marvin Doyley attended the conference. 2012 in Deauville, France. Please visit www. Dr. Parker, along with co-founder Jon Ophir, elasticityconference.org for more in formation. provided the opening remarks at the conference. In their joint welcoming statement in the proceedings, Dr. Parker and Dr. Ophir wrote, “This year we celebrate the 10th Anniversary of the annual International Tissue Elasticity Conference. In the 1990s we saw a remarkable development of technologies and approaches for imaging various elastic properties of tissues. The 2000’s have seen a continuation RCBU members Alex Partin, Michael Richards, of innovative Kevin J. Parker, and Marvin Doyley at the Tenth approaches, with International Tissue Elasticity Conference in Conference Co-Founder the addition of a Arlington, Texas in October 2011. Kevin J. Parker 21 RCBU NEWS In Memoriam: New Ultrasound Patent Wesley Nyborg Robert C. Waag and Jeffrey The biomedical ultrasound P. Astheimer have been community sadly lost issued a new patent. Patent one of its most important US 7,867,166, Statistical pioneers. Wesley Nyborg estimation of ultrasonic passed away on September propagation parameters for 24, 2011 at the age of 94. aberration correction, was Wes was a member of the issued on January 11, 2011, and Physics Department at the abstract was published in July, 2011 (J Acoust the University of Vermont Soc Am. 2011, 130(1):641). for over 50 years. Wes’ seminal theoretical Maria Helguera was invited to and experimental work forms the foundation join the Scientific Advisory Board for our understanding of the biological effects of the International Conference of ultrasound. He developed fundamental on Education, Research and theories of the physical mechanisms of Innovation, Madrid, Spain. interaction of ultrasound with tissues including acoustic cavitation, ultrasound heating, and acoustic radiation force. He was a member Denise Hocking was appointed of the National Academy of Engineering, and to serve a four-year term on the was recognized with the highest awards from Bioengineering, Technology, numerous scientific societies. Wes was a Charter and Surgical Sciences (BTSS) Member of the RCBU and was a long-time friend Study Section of the National and colleague for many of us. Institutes of Health (NIH) Center Dr. Edwin Carstensen, Founding Director for Scientific Review (CSR). of the RCBU, remembered Dr. Nyborg thus: "Wes was my longest and in many ways my Vikram Dogra was appointed editor-in-chief most important professional friend. Wes rightly of The Journal of Clinical Imaging Science deserves the title, father of bioacoustics. Others (JCIS) (www.clinicalimagingscience.org). This dabbled in the field before him but in total peer-reviewed, multidisciplinary journal covers selfless effort and intellectual superiority he all aspects of imaging, including technical was the first and best. After a flurry of interest innovations, review articles, case reports, in the mid-20th century, there was a time in original research, and pictorial essays, enabling the late ‘60s when he and Floyd Dunn kept the radiologists to clearly comprehend concepts field alive. As it later flourished and became and practices, and encouraging further research a mainstay of diagnostic medicine, he almost and technical advances. The primary aim of singlehandedly forced the ultrasound community The Journal of Clinical Imaging Science is to to consider the safety of ultrasound exposure. provide free access to medical information, "There really aren’t words adequate to especially to developing countries that do not praise Wes as a friend. He was always positive have the resources to join the imaging societies or and helpful in his interactions with colleagues. subscribe to the journals. Our decade together producing the bioeffects volumes for National Council for Radiation Protection was one of the richest scientific Marvin Doyley was invited to experiences of my life." join the Editorial Board of the The RCBU and the wider biomedical Journal of Electronic Imaging ultrasound community will miss Wes dearly. as an expert in ultrasound imaging.

22 RCBU AWARDS Kevin Parker Receives Students Awarded at Undergraduate Lifetime Achievement Award Research Exposition Kevin Parker, The work of several RCBU students was Dean Emeritus recognized at the annual University of Rochester of the School of Undergraduate Research Exposition 2011. Engineering & Aaron Zakrzewski (ME 2011), a UR/Xerox Applied Sciences Undergraduate Fellow mentored by Mechanical at the University Engineering Professor Sheryl Gracewski, gave of Rochester and an oral presentation of his research titled Natural past director of frequency of bubbles within rigid and compliant the Rochester tubes, which received a Deans’ Award for Center for Undergraduate Research in Engineering and Biomedical Applied Sciences. Jasmine Carvalho (BME 2011) Ultrasound from the Dalecki Lab presented her work titled (RCBU) was Investigations of Ultrasound Parameters to awarded the Promote Spatial Organization of Cells in Three- Hajim School Dimensional Engineered Tissues. Vlabhav Kakkad Left: Kevin J. Parker, Dean Emeritus Lifetime (BME 2011) from the McAleavey Lab presented of the School of Engineering and Achievement his work titled Experimental Implementation of Applied Sciences, and Right, Rob Award. The Clark, Dean of the Hajim School of Shear Wave Induced Phase Encoding Imaging. Engineering and Applied Sciences award recognizes Professor Parker’s Speaking at the long-standing contributions to the School of Engineering and Engineering and Applied Sciences. Dean Rob Applied Sciences Clark presented the award and recognized Symposium Talks: Professor Parker’s outstanding scientific research (left to right) accomplishments, patents, teaching, and Benjamin Freedman dedicated service to the university, including (BME 2011), Kelli Dean of the School of Engineering and Applied Summers (BME Sciences, Chair of the Department of Electrical 2011), and Aaron and Computer Engineering, and Director of the Zakrzewski (ME 2011). Rochester Center for Biomedical Ultrasound. Student Research Recognized at Acoustical Vlabhav Kakkad Society of America Meeting (BME 2011) with his RCBU student member Himanshu Shekhar poster, Experimental was awarded Second Place in the Best Student Implementation of Paper in the Biomedical Acoustics Competition Shear Wave Induced at the 161st Meeting of the Acoustical Society of Phase Encoding America, held in June in Seattle, Washington. Imaging. Himanshu was recognized for his research titled, A Coded Excitation Technique for the Jasmine Carvalho (BME Functional Imaging 2011) in front of her of Coronary poster, Investigations of Atherosclerosis Ultrasound Parameters Using Ultrasound to Promote Spatial Organization of Cells Contrast Agents. in Three-Dimensional Himanshu Shekhar Engineered Tissues.

23 INNOVATION The RCBU is continually advancing novel concepts in ultrasound technology. Recent news, and some of the patents that originated at the RCBU are summarized below. For more information, contact the University of Rochester Offices of Technology Transfer at (585) 275- 3998 or http://www.urmc.rochester.edu/technology-transfer/.

U.S. Patents • Sonoelasticity Imaging Estimators U.S. Patent No. 5,086,775, issued to Ron • Statistical Estimation of Ultrasonic Propagation Huang, Robert Lerner, and Kevin Parker on Parameters for Aberration Correction February 11, 1992 U.S. Patent No. 7,867,166 issued to Robert Waag and Jeffrey Astheimer on January 11, 2011 • Butterfly Search Technique U.S. Patent No. 5,419,331 issued to S. Kaisar • Real Time Visualization of Shear Wave Alam and Kevin J. Parker on May 30, 1995 Propagation in Soft Materials with • Smart Endotracheal Tube Sonoelastography U.S. Patent No. 5,785,051 issued to Jack U.S. Patent No. 7,444,875 issued to Zhe Wu Mottley and Randy Lipscher on July 29, 1998 and Kevin J. Parker on November 4, 2008 • Finite Amplitude Distortion-Based University of Rochester is a Leader in Inhomogeneous Pulse Echo Ultrasonic Technology Commercialization Imaging The University of Rochester has a long-standing tradition U.S. Patent No. 7,104,956 issued to of being at the forefront of innovation and scientific Ted Christopher on September 12, 2006 research. In the 2011 fiscal year, the University received • System for Model-Based Compression of $415 million in research funding. The UR Offices Speckle Images of Technology Transfer received over 120 invention U.S. Patent No. 5,734,754 issued to disclosures, including several non-invasive diagnostic and therapeutic methods and tools. The University was Kevin J. Parker on March 31, 1998 granted 27 new U.S. patents, 22 foreign patents, and • Blue Noise Mask successfully completed 22 licensing agreements. To U.S. Patent Nos. 5,111,310 (1992); 5,477,305 propel some of these UR technologies forward on the (1995); 5,708,518 (1998); 5,543, 941 (1996); path of commercialization, the University has instituted and 5,726,772 (1998) issued to Kevin J. Parker a new Technology Development Fund to accelerate and Theophano Mitsa translation of scientific and engineering research into commercial opportunities. • Thin-Film Phantoms and Phantom Systems The UR is consistently rated as one of the best U.S. Patent No. 5,756,875 issued to Daniel B. educational institutions in the nation for patent licensing Phillips and Kevin J. Parker on May 26, 1998 and revenue, according to the Association for University Technology Managers (AUTM). The AUTM U.S. • System and Method for 4D Reconstruction and Licensing Activity Survey is an annual report of the Visualization technology transfer activity of top universities, research U.S. Patent No. 6,169,817 issued to institutions, and teaching hospitals across the nation. In Kevin J. Parker, Saara Totterman, and 2011, UR royalty revenue exceeded $41.8 million. The Jose Tamez-Pena on January 2, 2001 technological advances of members of the Rochester • The Acoustic Filter Center for Biomedical Ultrasound continue to contribute U.S. Patent No. 5,334,136 issued to to the UR’s success. Karl Schwarz, Richard Meltzer, and Charles The University of Rochester Offices of Technology Transfer play an important role in facilitating the transfer Church on August 2, 1994 of University research results and innovative ideas to • Multiple Function Infant Monitor the commercial marketplace. For more information, and U.S. Patent No. 5,479, 932 issued to Joseph to view the 2011 UR Technology Commercialization Higgins, E. Carr Everbach, Kevin J. Parker on Annual Report, visit the University of Rochester Office of January 2, 1996 Technology Transfer at http://www.urmc.rochester.edu/ technology-transfer/.

24 RCBU MEMBER EDUCATION

Training Completed BME Senior Design Students Wei Jiang received his Ph.D. degree in Electrical Tackle Ultrasound Problem and Computer Engineering,from the University For the last ten years, senior biomedical of Rochester in May 2011. His PhD dissertation, engineering students have helped real-life Ultrasound Focusing by Use of Apertures with customers solve bioengineering problems through Different Pitches a two-semester Senior Design course taught by and Ultrasound RCBU member Amy Lerner and Scott Seidman. Imaging by Use In 2011, BME seniors Andreana Echter, Eileen of a Hemispheric Hansen, Katherine Prokop, and Frank Yeung Transducer Array was became interested in a problem presented by supervised by Robert RCBU members Professor Marvin Doyley and C. Waag, PhD. Michael Richards, Ph.D. The Doyley Lab is Wei Jiang, Ph.D. and working to develop image processing techniques Robert C. Waag, Ph.D. for Intravascular Ultrasound (IVUS) as a tool to better understand plaque structure and to predict New Ultrasound Course Offered the likelihood of plaque rupture. The senior RCBU member Andrew design team, supervised by RCBU Director Diane Hesford offered a new course, Dalecki, Ph.D., developed CoroFlow, a coronary ECE 492—Computational artery perfusion system. Methods. The course covered The CoroFlow Team designed and developed computational techniques a prototype device to perfuse the coronary for the solution of numerical arteries of excised hearts for IVUS imaging of problems with applications of atherosclerotic plaques. The perfusion systems the techniques in acoustic and consist of two primary units. The Heart Unit is electromagnetic wave propagation and scattering. comprised of a holder to secure an excised heart Professor Hesford is a Research Assistant for IVUS imaging, and a chamber to submerge Professor in the Department of Electrical and the heart in a bathing fluid. The Plumbing Computer Engineering and his areas of expertise Unit provides flow through the coronary artery include diagnostic ultrasound imaging, acoustic via a specially designed cannula system that aberration estimation and correction, acoustic and incorporates the IVUS transducer and allows for electromagnetic forward and inverse scattering, contrast agent infusion. The final prototype was fast algorithms, parallel systems, computational delivered to the Doyley Lab at the end of the wave physics, and general-purpose GPU semester. computing. Summer Acoustics Course Once again RCBU visiting professor David RCBU member Shweta Bhatt, M.D. participated Blackstock offered his popular summer acoustics in the creation of the Maintenance of course. Dr. Blackstock, from the University of Certification examination for the American Board Texas at Austin, is a leading expert in acoustics of Radiology, and RCBU Associate Director Dr. and the author of one of the leading textbooks in Deborah Rubens and Dr. Bhatt were oral board physical acoustics. examiners in ultrasound. "I loved this class," says Karla Mercado, a BME graduate student and member of the Dalecki RCBU member Dr. Vikram Dogra, along with lab. "Dr. Blackstock took complicated concepts international colleagues, continues his leadership and made them easy to understand. I definitely with Medical Imaging Partnership, (MIP). MIP is benefited from the course because it laid the basic a non-profit organization engaged in providing foundation for ultrasound, and what I learned medical imaging equipment, training, and will help me with the rest of the my research by education in medical diagnostic imaging to providing me with a more intuitive understanding developing countries around the world. of ultrasound research. We were blessed to have Dr. Blackstock to teach this summer." 25 EDUCATION

Biomedical Ultrasound (BME 251/451) Elasticity (ME449)) Presents the physical basis for the use of high- Presents an analysis of stress and strain, frequency sound in medicine. Topics include equilibrium, compatibility, elastic stress-strain acoustic properties of tissue, sound propagation relations, and material symmetries. Additional (both linear and nonlinear) in tissues, interaction of topics include torsion and bending of bars, ultrasound with gas bodies (acoustic cavitation and plane stress and plane strain, stress functions, contrast agents), thermal and non-thermal biological applications to half-plane and half-space problems, effects, ultrasonography, dosimetry, hyperthermia, wedges, notches, and 3D problems via potentials. and lithotripsy. Nonlinear Finite Element Analysis (BME 487)) Advanced Biomedical Ultrasound (BME 453) Examines the theory and application of nonlinear Investigates the imaging techniques applied in state- finite element analysis in solid and biosolid of-the-art ultrasound imaging and their theoretical mechanics. Topics include generalization of FE bases. Topics include linear acoustic systems, concepts, review of solid mechanics, nonlinear spatial impulse responses, the k-space formulation, incremental analysis, displacement-based methods of acoustic field calculation, dynamic FE formulation for large displacements and focusing and apodization, scattering, the statistics of large strains, nonlinear constitutive relations, acoustic speckle, speckle correlation, compounding incompressibility and contact conditions, rubber- techniques, phase aberration correction, velocity like materials, biomechanical materials, and estimation, and flow imaging. solution methods. Medical Imaging–Theory and Implementation (ECE 452) Biomedical Optics (BME 492) Provides an introduction to the principles of X-ray, Introduces the major diagnostic methods in CT, PET, MRI, and ultrasound imaging. The emphasis biomedical optics. The course emphasizes is on providing linear models of each modality, spectroscopy (absorption, fluorescence, Raman, which allows linear systems and Fourier transform elastic scattering), photon migration techniques techniques to be applied to analysis problems. (steady-state and time-resolved), and high- resolution subsurface imaging (confocal, multi- Fundamentals of Acoustical Waves (ECE 432) photon, optical coherence tomography). Essential Introduces acoustical waves. Topics include acoustic methods of multivariate data analysis are taught in wave equation; plane, spherical, and cylindrical the context of spectroscopy. wave propagation; reflection and transmission at boundaries; normal modes; absorption and Physiological Control Systems (BME 428) dispersion; radiation from points, spheres, cylinders, Focuses on the application of control theory to pistons, and arrays; diffraction; and nonlinear physiological systems. Presents modern control acoustics. theory in the context of physiological systems that use feedback mechanisms. Begins with an MR Imaging: From Spins to Brains (BME 513) R overview of linear systems analysis, including Introduces the physics of magnetic resonance (MR) Laplace transforms and transfer functions. imaging and reviews its application to medical Discusses the response dynamics of open- and imaging. Provides a comprehensive background of closed-loop systems such as the regulation of the MR imaging technique and its application to cardiac output and level of glucose, stability medical or research issues. Discusses how the MR analysis, and identification of physiological control technique takes advantage of physiological principles systems. and tissue structure to provide diagnostic images ( for clinicians and researchers. Introduces functional Models and Simulations of Biomedical Systems brain imaging and related issues in data analysis. (BME 267/467) Biosolid Mechanics (BME 483) Introduction to analytical modeling and computational simulations of systems. Examples This course examines the application of engineering will include cardiovascular, respiratory, muscle, mechanics to biological tissues, including bone, soft neural and population models. Analytical models tissue, cell membranes, and muscle. Other topics for several physiological systems will be studied, include realistic modeling of biological structures, and simulations will be written in Matlab. including musculoskeletal joints and tissues, investigations of the responses of biological tissues to All courses are not offered each semester. See the mechanical factors, and experimental methods and University of Rochester Undergraduate and Graduate material models. Bulletins or www.rochester.edu for more information. 26 SELECTED 2011 PUBLICATIONS

Alvarez DM, Bhatt S, Dogra VS. Sonographic Hedegard WC, Bhatt S, Saad W, Rubens D, spectrum of tunica albuginea cyst. J Clin Imaging Dogra V. Hepatic arterial waveforms on early Sci. 1:5; 2011. posttransplant Doppler ultrasound. Ultrasound Q. 27:49-54; 2011. An L, Mills B, Hah Z, Mao S, Yao J, Joseph J, Rubens DJ, Strang J, Parker KJ. Crawling wave Helguera M, Baum KG, Schmidt E, Rafferty K, detection of prostate cancer: Preliminary in vitro Krol A. Evaluation of novel genetic algorithm results. Med Phys. 38:2563-71; 2011. generated schemes for PET/MRI image fusion. Journal of Digital Imaging. 24:1031-1043; 2011. Barry CT, Mills B, Hah Z, Mooney RA, Ryan CK, Rubens DJ, Parker KJ. Shear wave dispersion Hesford AJ, Waag RC. Reduced-rank measures liver steatosis. Ultrasound Med Bio. approximations to the far-field transform in the 38:2: 75-182; 2011. gridded fast multipole method. J Comput Phys. 230:3656-3667; 2011. Baum KG, Menezes G, Helguera M. Simulation of high-resolution magnetic resonance images on Hubeny CM, Sykes JB, O’Connell A, Dogra VS. the IBM Blue Gene/L supercomputer using SIMRI. Pilomatrixoma of the adult male breast: A rare International Journal of Biomedical Imaging. tumor with typical ultrasound features. J Clin doi:10.1155/2011/305968, 2011. Imaging Sci. 1:12; 2011.

Bhatt S, Jafri SZ, Wasserman N, Dogra VS. Jang NW, Zakrzewski A, Rossi C, Dalecki D, Imaging of non-neoplastic intratesticular masses. Gracewski S. Natural frequencies of two bubbles Diagn Interv Radiol.17:52-63; 2011. in a compliant tube: Analytical, simulation, and experimental results. J Acoust Soc Am. 130:3347- Carstensen EL, Gracewski SM, Dalecki D. Shear 56; 2011. strain from irrotational tissue displacements near bubbles. J Acoust Soc Am. 130:3467-71; 2011. Korukonda S, Doyley MM. Estimating axial and lateral strain using a synthetic aperture Elegbe EC, Menon MG, McAleavey SA. elastographic imaging system. Ultrasound Med Comparison of two methods for the generation Biol. 37:1893-908; 2011. of spatially modulated ultrasound radiation force. IEEE Trans Ultrason Ferroelectr Freq Control. Lee V, Alvarez MD, Bhatt S, Dogra VS. 58:1344-54; 2011. Median arcuate ligament compression of the celiomesenteric trunk. J Clin Imaging Sci. 1:8; Garvin KA, Dalecki D, Hocking DC. 2011. Vascularization of three-dimensional collagen hydrogels using ultrasound standing wave fields. Lefort CT, Wojciechowski K, Hocking DC. Ultrasound Med Biol. 37:1853-64; 2011. N-cadherin cell-cell adhesion complexes are regulated by fibronectin matrix assembly. J Biol Hah Z, Hazard C, Mills B, Barry C, Rubens Chem. 26:286:3149-60; 2011. D, Parker K. Integration of crawling waves in an ultrasound imaging system. Part 2: Signal Loberant N, Bhatt S, Messing E, Dogra VS. processing and applications. Ultrasound Med Bio. Bilateral testicular epidermoid cysts. J Clin 38: 312-323; 2011. Imaging Sci. 1:4; 2011.

Hazard C, Hah Z, Rubens D, Parker K. Mihmanli I, Kantarci F, Dogra VS. Endoanorectal Integration of crawling waves in an ultrasound ultrasonography. Ultrasound Q. 27:87-104; 2011. imaging system. Part 1: System and design Onur MR, Wandtke B, Yao JL, Dogra VS. considerations. Ultrasound Med Bio. 38: 2; 296- Paratesticular solitary plasmacytoma. J Clin 311; 2011. Imaging Sci. 1:52; 2011.

27 2011 PUBLICATIONS 2011 PRESENTATIONS

Parker KJ. The evolution of vibration Barry C, Mills B, Hah Z, Mooney R, Safadjou S, sonoelastography. Current Medical Imaging Reviews. Ryan C, Rubens D, Parker K. Ex vivo and in vivo 7:283-291; 2011. ultrasonographic hepatic steatography measurements correlate with histologic estimates of liver fat content. Parker KJ, Doyley MM, Rubens DJ. Imaging the Presented at the American Association for the Study elastic properties of tissue: The 20 year perspective. of Liver Diseases: The Liver Meeting, San Francisco, Phys Med Biol. 56:R1-R29; 2011. CA, November 2011.

Paspulati RM, Turgut AT, Bhatt S, Ergun E, Dogra VS. Barry C, Mills B, Hah Z, Mooney R, Safadjou S, Ultrasound assessment of premenopausal bleeding. Ryan C, Rubens D, Parker K. Ultrasonic hepatic Obstet Gynecol Clin North Am. 38:115-47.; 2011. steatography: A noninvasive method to measure intrahepatic fat content. Presented at the American Perera E, Bhatt S, Dogra VS. Complications of denver Transplant Congress, Philadelphia, PA, May 2011. shunt. J Clin Imaging Sci. 1:6; 2011. Castaneda B, Westesson K, An L, Yao J, Baxter Perera E, Bhatt S, Dogra VS. Cystic duct remnant L, Joseph J, Hoyt K, Strang J, Rubens D, Parker syndrome. J Clin Imaging Sci. 1:2; 2011. K. Prostate cancer detection using 3-dimensional Perera E, Bhatt S, Dogra VS. Traumatic ectopic vibration sonoelastography: Ex vivo and in vivo dislocation of testis. J Clin Imaging Sci. 1:17; 2011. results. Presented at the AIUM Annual Convention, New York, NY, April 2011. Richards MS, Doyley MM. Investigating the impact Doyley MM. A model-based approach to quasi– of spatial priors on the performance of model-based static, harmonic and transient elastography. IVUS elastography. Phys Med Biol. 21;56:7223-46; Presented at the Tenth Annual International Tissue 2011. Elasticity Conference, Arlington, TX, October 2011. Rothschild J, Bhatt S, Dogra VS. Renal collision Doyley MM. Model-based elastography: Problems tumor in association with xanthogranulomatous and opportunities. Presented at the Workshop on pyelonephritis. J Clin Imaging Sci. 1:9; 2011. Biomechanical Engineering, Renssalaer Polytechnic Institute Inverse Problems Center, Troy, NY, April 2011. Roy DC, Wilke-Mounts SJ, Hocking DC. Chimeric fibronectin matrix mimetic as a functional growth- Eisenbrey J, Sridharan A, Lobel B, deMuinck E, and migration-promoting adhesive substrate. Forsberg F, Doyley M. Comparison of parametric Biomaterials 32:2077-87; 2011. contrast-enhanced fundamental and subharmonic intravascular ultrasound for plaque identification. Wang H, Weaver JB, Perreard II, Doyley MM, Presented at the AIUM Annual Convention, New Paulsen KD. A three-dimensional quality-guided York, NY, April 2011. phase unwrapping method for MR elastography. Phys Med Biol. 56:3935-52; 2011. Garvin KA, Carvalho JJ, Hocking DC, Dalecki D. Ultrasound technology for cell patterning and vascularization of three-dimensional engineered tissue. Presented at the Tissue Engineering and Regenerative Medicine International Society Annual Meeting, Houston, TX, December 2011. Garvin KA, Dalecki DC, Hocking D. Vascular network formation within collagen hydrogels fabricated with different spatial organizations of endothelial cells using ultrasound-based cell patterning techniques. Presented at the North American Vascular Biology Organization’s Vascular Matrix Biology and Bioengineering Workshop III, Hyannis, MA, October 2011.

28 SELECTED 2011 PRESENTATIONS

Hah Z, Mills B, Hazard C, Parker K, Rubens D. International Tissue Elasticity Conference, Arlington, Measuring dispersion of a biological medium with TX, October 2011. crawling waves synthesized from ultrasonic radiation Parker KJ, Hah Z, Rubens D. Vibration elastography: force. Presented at the AIUM Annual Convention, Overview and clinical results. Presented at the New York, NY, April 2011. Symposium on Ultrasonic Imaging and Tissue Hah Z, Hazard C, Mills BN, Yao J, Rubens DJ, Parker Characterization, Rosslyn, VA, June 2011. KJ. Local shear speed estimation of ex–vivo prostate Partin A, Hah Z, Mills BN, Rubens DJ, Parker KJ. A using acoustic crawling waves (arc) generated from hand-held system for quantitative mapping of elastic radiation forces. Presented at the Tenth Annual properties within a biomaterial from crawling waves International Tissue Elasticity Conference, Arlington, generated on the surface. Presented at the Tenth TX, October 2011. Annual International Tissue Elasticity Conference, Jing S, Richards MS, Doyley MM. Measuring Arlington, TX, October 2011. circumferential and radial component of displacement Richards MS, Doyley MM. Minimally constrained using a non-rigid registration based displacement reconstructions in intravascular ultrasound estimator. Presented at the Tenth Annual International elastography: Initial clinical investigation. Presented Tissue Elasticity Conference, Arlington, TX, October 2011. at the Tenth Annual International Tissue Elasticity Kaproth-Joslin K, Rubens D. Beyond portal Conference, Arlington, TX, October 2011. hypertension: Abnormalities of the portal venous Sevilla C, Dalecki D, Hocking DC. Fibronectin- system. Presented at the AIUM Annual Convention, collagen interactions promote cell proliferation New York, NY, April 2011. and determine microtissue structure. Presented at Kaproth-Joslin K, Francis C, Hobbs S, Rubens D. the Tissue Engineering and Regenerative Medicine Predictive risk score for venous thromboembolism International Society Annual Meeting, Houston, TX, in patients with malignancy: A role for prophylactic December 2011. screening. Presented at the AIUM Annual Convention, Shekhar H. A coded excitation technique for the New York, NY, April 2011. functional imaging of coronary atherosclerosis using Korukonda S, Doyley MM. Comparing the ultrasound contrast agents. Presented at the 161st performance of plane wave and sparse array Meeting of the Acoustical Society of America, Seattle, elastography imaging systems. Presented at the Tenth WA, June 2011. Annual International Tissue Elasticity Conference, Sridharan A, Eisenbrey JR, DeMuinck ED, Doyley Arlington, TX, October 2011. MM, Forsberg F. Intravascular subharmonic imaging Korukonda S, Doyley MM. Ultrafast elastography of atherosclerosis: An in vivo pilot study. Presented imaging of the carotid artery using sparse arrays. at the Symposium on Ultrasonic Imaging and Tissue Presented at the IEEE International Ultrasonics Characterization, Rosslyn, VA, June 2011. Symposium, Orlando, FL, October 2011. Tillett J, Astheimer J, Waag R. Aberration estimation McAleavey S, Kakkad V. Shear wave induced phase and correction in ultrasound imaging. Presented at encoding imaging with enhanced resolution. Presented the AIUM Annual Convention, New York, NY, April at the 2011 IEEE International Ultrasonics Symposium, 2011. Orlando, FL, October 2011. Vaidya, K, Hatfield K, Helguera M, Pichichero M. Mills B, Barry C, Hah Z, Rubens DJ, Parker KJ. Using Building parametric images of biological materials crawling wave sonoelastography for the measurement using high frequency ultrasound. International of intrahepatic fat content. Presented at the Tenth Conference on Biomedical Engineering, Manipal Annual International Tissue Elasticity Conference, University, India, 2011. Arlington, TX, October 2011. Walsh JM, Mills B, Rubens D, Parker JK, An L, Parker K. Three-dimensional vibration elastography Miller M, Hah Z. Crawling wave sonoelastography and crawling waves. Presented at the AIUM Annual of benign and malignant thyroid nodules. Presented Convention, New York, NY, April 2011. at the American Academy of Otolaryngology Head Parker KJ, Hah Z. Dispersion and distortion of and Neck Surgery Foundation Annual Meeting, San shear wave pulses. Presented at the Tenth Annual Francisco, CA, September 2011. 29 2011 RCBU Annual Report

Rochester Center for Biomedical Ultrasound Members

University of Rochester/ Electrical and Computer Engineering Pathology Strong Memorial Hospital Edwin Carstensen, PhD P. Anthony di Sant’Agnese, MD Yong Thung Cho, PhD Pharmacology and Physiology Anesthesiology Marvin Doyley, PhD Denise Hocking, PhD Paul Bigeleisen, MD Zaegyoo Hah, PhD Janine Shapiro, MD Andrew Hesford, PhD Radiation Oncology David Stern, MD Steven Huntzicker, MS Paul Okunieff, MD Jacek Wojtczak, MD Sanghamithra Korukonda, MS Surgery Biomedical Engineering Jack Mottley, PhD Christopher Barry, MD Rohit Nayak, BS Nicholas Berry, BS Urology Sally Child, MS Kevin Parker, PhD Robert Davis, MD Diane Dalecki, PhD Alexander Partin, BS Erdal Erturk, MD Etana Elegbe, MS Michael Richards, PhD Irwin Frank, MD Kelley Garvin, MS Michael Sealander, MS Jean Joseph, MD Jonathan Langdon, BS Himanshu Shekhar, MS Robert Mayer, MD Amy Lerner, PhD Jason Tillett, PhD Jeanne O’Brien, MD Stephen McAleavey, PhD Robert Waag, PhD Karla Mercado, MS Vascular Medicine Carol Raeman, AAS Emergency Medicine Charles Francis, MD Maria Randazzo, BA Jefferson Svengsouk, MD Rochester General Hospital Carlos Sevilla, MS Imaging Sciences Richard Waugh, PhD Radiology Mark James Adams, MD Robert Lerner, MD, PhD Biophysics/Biochemistry Shweta Bhatt, MD Scott Kennedy, PhD Nancy Carson, MBA, RDMS, RVT Rochester Institute of Technology Vikram Dogra, MD Center for Imaging Sciences Cardiology Unit Thomas Foster, PhD James Eichelberger, MD Maria Helguera, PhD Nina Klionsky, MD Navalgund Rao, PhD Karl Schwarz, MD Deborah Rubens, MD Sherry Steinmetz, RDMS John Strang, MD Biomedical Engineering Center for Vaccine Biology and Susan Voci, MD Daniel Phillips, PhD Immunology Eric Weinberg, MD Mitra Azadniv, PhD Jianhui Zhong, PhD Visiting Scientists David Blackstock, PhD Dermatology Immunology/Rheumatology University of Texas at Austin Alice Pentland, MD Ralf Thiele, MD E. Carr Everbach, PhD Earth and Environmental Swarthmore College Mechanical Engineering Sciences Benjamin Castaneda, PhD Asish Basu, PhD Stephen Burns, PhD Alfred Clark, Jr., PhD Pontificia Universidad Catolica Sheryl Gracewski, PhD del Peru Neo Jang, MS Zhe Wu, PhD Renato Perucchio, PhD University of California, San Diego Obstetrics and Gynecology Morton Miller, PhD Honorary Member Richard Miller, MD Floyd Dunn, PhD Tulin Ozcan, MD University of Illinois Eva Pressman, MD James Woods, MD 30 Visit: www.urmc.rochester.edu/rcbu The Rochester Center for Biomedical Ultrasound (RCBU) provides exciting opportunities for graduate and post-graduate research and training in the field of biomedical ultrasound. Research at the RCBU spans a wide range of topics in diagnostic imaging and therapeutic applications of ultrasound. With access to RCBU laboratories at the University of Rochester’s River Campus, Hajim School of Engineering and Applied Sciences, UR Medical Center, and Rochester Institute of Technology, students can tailor their own interdisciplinary training experiences. Students can pursue advanced degrees (M.S. and Ph.D.) through various departments of engineering and basic science with a research focus in biomedical ultrasound.

A wide range of relevant course offerings complements the rich research environment. Students tailor their formal coursework individually to complement their research focus and meet requirements of their home department.

The Ultrasound Journal Club is attended by an interdisciplinary group of students and faculty interested in biomedical applications of ultrasound.

The RCBU has a long history of innovation in biomedical ultrasound. Research of student members of the RCBU has led to numerous patents in ultrasound imaging and therapy.

Students have access to state-of-the-art research facilities to engage in leading-edge research in ultrasound. Core facilities in the new Goergen Hall include an ultrasound teaching laboratory, imaging and bioinstrumentation equipment, cell and tissue culture facilities, biomedical microscopy equipment, and mechanical testing apparatus.

RCBU laboratories are advancing the use of ultrasound in diagnosis and discovering new therapeutic applications of ultrasound, including: • Diagnostic imaging • Ultrasound technologies for cell & tissue engineering • Sonoelastography and elasticity imaging • Acoustic scattering and wave propagation in tissue • 3D and 4D ultrasound imaging • Ultrasound contrast agents • Acoustic radiation force imaging • Acoustic cavitation • Harmonic imaging • High frequency imaging • Nonlinear acoustics • Lithotripsy • Novel therapeutic applications • Multi-modal imaging techniques • Biological effects of ultrasound fields • Doppler ultrasound • Tissue characterization • High intensity focused ultrasound (HIFU) techniques Nonprofit U.S. Postage Paid Rochester, NY Permit No. 780 Rochester Center for Biomedical Ultrasound PO Box 270168 Rochester, NY 14627

Rochester Center for Biomedical Ultrasound

2011Annual Report