Matthew O'Donnell - US grants

Ultrasound imaging has had limited success in cancer diagnosis because of its inability in routinely detecting low contrast lesions. The ability to detect low contrast objects, as well as present fine spatial detail, is directly related to the size of the basic imaging voxel (i.e., 3-D resolution cell). Due to sound velocity inhomogeneities in the body and th lack of large contiguous acoustic windows, conventional imaging systems hav been restricted to relatively small active apertures, resulting in poor resolution. Results from intraoperative ultrasound suggest, however, that imaging undistorted by body wall effects may produce images capable of actually surpassing other diagnostic tests for the detection of cancer. It is the long-term objective of the research proposed here to overcome the technical problems associated with large apertures, permitting the detectio of low contrast objects using conventional transcutaneous imaging. In particular, large active area (>2500 mm2) 2-D- conformal arrays will be explored for ultrasound imaging deep in the body with resolution approachin an acoustic wavelength. Recent progress in phase aberration correction methods, developed primarily for reduction of beam forming artifacts due to propagation through inhomogeneous media raises the possibility of high quality imaging using conformal arrays. It is the purpose of the research plan proposed here to systematically study the key technical problems inherent in the development of such array systems. Consequently, four major areas of research will be addressed. First phase aberration correction algorithms will be extended to handle both 2-D arrays and large time delay excursions across the imaging aperture. Second, methods for obtaining accurate phase aberration measurements and optimal beams in the presence of a large number of "dead" channels will be studied. Because of the discontinuous character of acoustic windows into the body, large area arrays will generate greatly improved clinical image quality only if optima performance is preserved in the presence of a large number of acoustically inactive elements. Third, 2-D array geometries and conformal array construction methods will be examined to aid the development of clinically relevant conformal probes. And fourth, images of phantoms and in vitro tissue specimens will be constructed to test the hypothesis that a high performance large aperture conformal array system will enhance the detection of low contrast lesions.

Changes in soft tissue elasticity are usually related to pathological processes. Because of this, palpation is still widely used for diagnosis. Its efficacy, however, is limited to abnormalities located relatively close to the skin surface. The goal of quantitative elasticity imaging is to develop surrogate, remote palpation, thus expanding its range to include deep lying lesions. The elastic properties of any continuous medium such as tissue can be assessed through precise measurement of mechanical deformations throughout that medium induced by forces applied at the surface. Using modern medical imaging devices to precisely measure internal motion, it should be possible to estimate and even image elastic properties of internal organs. In competition with other imaging modalities, ultrasound has two major advantages for elasticity imaging; it is inherently real-time and speckle artifacts limiting the quality of conventional images provide excellent markers for accurate tracking of tissue motion. Elasticity can be imaged, therefore, by measuring motion with an ultrasound speckle tracking algorithm, followed by reconstruction of the elasticity distribution. Although some other imaging systems, particularly real- time ultrasound, must be used to monitor tissue motion, elasticity imaging represents a fundamentally new diagnostic modality. To investigate quantitative elasticity imaging for medical diagnosis, a research plan addressing the important clinical problem of renal inflammation and scarring has been formulated. Preliminary data support the hypothesis that kidney elasticity changes with renal damage and concomitant scarring before renal problems are detectable by traditional diagnostic techniques such as laboratory measurements of renal function. Therefore, quantitative elasticity imaging may be valuable in detecting and quantifying scar for conditions such as kidney transplant rejection where rejection is difficult to quantify from functional measurements alone. Based on the results of these studies, it is the long range goal of this research program to develop a sensitive diagnostic technique based on quantitative elasticity imaging permitting surrogate palpation of deep lying lesions.

DESCRIPTION (Adapted from Applicant's Abstract): Changes in soft tissue elasticity are usually related to pathological processes. Because of this, palpation is still widely used for diagnosis. Efficacy, however, is limited to abnormalities located relatively close to the skin surface. The fundamental goal of elasticity imaging is to develop surrogate, remote palpation. Using sensitive ultrasound speckle tracking procedures, controlled surface deformations, and quantitative reconstruction algorithms developed over the first funding period, elasticity imaging has emerged as a potentially new diagnostic modality providing information about the mechanical properties of internal organs. In particular, results of studies during the first funding period support the hypothesis that changes in kidney elasticity due to renal damage and concomitant scarring can be detected with elasticity imaging before problems are identified by traditional diagnostic techniques such as laboratory measurements of renal function. Based on these results, a research plan has been developed to address the important clinical problem of noninvasively detecting kidney transplant rejection. The proposed program includes fundamental studies of both optimal elasticity imaging methods and kidney elasticity. In addition, an elasticity imaging system appropriate for clinical studies will be designed and built to monitor the internal elastic properties of the transplanted kidney. This system will be tested on a group of human subjects with normally functioning renal allografts. Results from this group will be compared to elasticity images from a different group with abnormally functioning allografts. The overall program is designed to critically test the hypothesis that elasticity imaging can noninvasively detect fibrosis in a renal allograft well before functional measurements sense abnormalities.

DESCRIPTION (Adapted from Applicant's Abstract): Percutaneous interventions are now the primary means of managing coronary artery disease, where over one million procedures, including over 500,000 coronary stents, were performed during 1999. Despite these advances, restenosis continues to be a major limitation of percutaneous coronary revascularization procedures. Even in the best cardiac catheterization labs between 10-20 percent of treated lesions must be revascularized. Intravascular ultrasound (IVUS) is routinely used in many of these laboratories to guide procedures. Although image quality has improved steadily, still only about 7-8 percent of total procedures use this technology. The primary reason for this low rate is that an IVUS study can add appreciable time to a procedure without significantly improving the outcome. This will change only when IVUS can efficiently guide interventions with improved outcomes. The long range goal of this research program remains to manage nearly every aspect of coronary artery interventions with intravascular ultrasound (IVUS). It focuses on the common mechanical interventions of balloon angioplasty (PCTA) and endovascular stenting. However, the methods are general and can apply to other procedures such as ablation/vaporization and brachytherapy. Based on progress during the initial funding period, it now appears that IVUS can provide key information about anatomical and elastic properties of the artery wall flow and flow dynamics within the lumen. Given these developments, an ambitious research plan has been developed to address how IVUS can help manage nearly every aspect of coronary artery interventions. For the mechanical interventions of balloon angioplasty and endovascular stenting, the applicants hypothesize that IVUS can identify the mechanical properties of arterial lesions, guide and monitor both PCTA and stent deployment to minimize tissue injury while insuring full stent extensions, assess flow dynamics pre- and post-interventions, and determine the likelihood of restenosis. In addition, an integrated IVUS delivery will be constructed to perform mechanical interventions under full ultrasound guidance, including real-time elasticity and flow monitoring. Such a catheter is key to optimizing stent deployment while minimizing tissue injury and subsequent restenosis. In addition, an integrated device can dramatically reduce the number of catheters employed during a typical procedure.

Abstract

The University of Washington (UW) requests funding for the Northwest Alliance for Access
to Science, Technology, Engineering and Mathematics (STEM) to increase the quantity and
quality of people with disabilities in STEM careers.
Intellectual Merit and Qualifications of Partners
The lead agency is the UW's award-winning DO-IT (Disabilities, Opportunities, Internetworking
and Technology) program, which has conducted successful NSF PPD projects since 1992.
Regional site teams at the two largest STEM research institutions in the State of Washington, the
UW and Washington State University (WSU), will collaborate with K-12 and postsecondary
schools, employers, and leading STEM research institutions in neighboring states - the
University of Idaho, the University of Oregon, Oregon State University, and the University of
Alaska in Anchorage and Fairbanks. The project will partner with ENTRY POINT! to place STEM
postsecondary students with disabilities in paid internships. It will collaborate with MESA
(Mathematics, Engineering, Science Achievement) adapting for students with disabilities the
hands-on science activities and teacher training strategies it uses with racial/ethnic minority and
female students. The Alliance builds on established collaborations and brings together practices
that have proven successful individually, to create a unique, comprehensive set of interventions.
Objectives and examples of interventions include:
1. The Northwest Alliance will increase the number of students with disabilities pursuing
STEM academic programs and careers. Interventions: Motivational college/career transition
and STEM fairs for precollege students and STEM academic/career activities for college
students that identify participants for the AccessSTEM Team in objective 2 interventions.
2. The Alliance will provide on-going support and encourage high school and college
students with disabilities who show interest and aptitude in STEM with peer and
mentor interaction, work experiences, and other activities as they transition to college,
graduate school, and employment. Interventions: Students join the AccessSTEM Team to
engage in an on-line community, mentoring, fields trips, research, paid internships, and other
activities to assure their success in STEM careers and promote the success of others.
3. The Alliance will provide precollege educators and staff with strategies, tools and
support to create more inclusive programs for students with disabilities, where they are
encouraged to pursue STEM studies and careers. Interventions: Training and curriculum
materials through established networks of MESA, Educational Services Districts, teacher
training programs, and professional organizations; provide educators with opportunities to
work with students who have disabilities.
4. The Alliance will help STEM postsecondary faculty, support staff, counselors, and
employers fully include students with disabilities in their courses and programs and create
accessible facilities and electronic resources. Interventions: Opportunities for faculty to
receive training and work with students with disabilities in research; assistance in making
facilities, equipment, distance learning, and Web pages accessible.
Each intervention is associated with measurables that provide evidence of effectiveness. The
National Center on Postsecondary Educational Supports (NCSPES) will evaluate project
outcomes and impacts, conduct research on factors that promote success for students with
disabilities, describe replication models, and help disseminate results.
Broader Impacts Resulting from the Northwest Alliance
Collaborations with MESA and other programs will broaden the participation of racial/ethnic
minorities and females with disabilities in STEM. Wide distribution of a replication model, curriculum
materials, and other project products and creation of a searchable Knowledge Base on the project
Web site will enhance scientific and technological understanding and maximize project impact.
Project outcomes will benefit society by making STEM opportunities available to all citizens and
increasing the number of STEM professionals and leaders who have disabilities.

DESCRIPTION (provided by applicant): Among all atherosclerotic lesions, vulnerable plaque is particularly lethal and its sudden rupture typically leads to intraluminal thrombus, directly linked to a variety of clinical manifestations such as stroke and acute coronary syndromes. These rupture-prone plaques usually consist of a large lipid-rich core in the central portion of the eccentrically thickened intima and a thin fibrous cap. Reliable, noninvasive imaging tools are needed to identify these potentially fatal plaques before their disruption. We have developed a technique, called microwave-induced thermal imaging (MITI), to image tissue dielectric and thermal properties with potentially high spatial and contrast resolution. Under a reasonable set of assumptions, the imaging parameter is simply the product of the microwave absorption coefficient (alpha) with the derivative of the sound speed with respect to temperature (lambda). Generally, water-bearing tissue can be easily distinguished from lipids based on lambda, which can be particularly valuable in plaque composition characterization and vulnerability assessment. Consequently, we rename MITI thermal strain imaging (TSI) to indicate our new focus on the imaging parameter lambda in the model. This also allows us to explore other energy delivery methods in addition to microwaves without degrading system performance. We propose to test TSI for high-risk plaque identification in peripheral arteries, especially the carotid. If successful, it will represent a high performance, cost-effective, noninvasive alternative to current techniques such as IVUS, OCT, ultrafast computed tomography (UFCT) and magnetic resonance imaging (MRI). This revised R21 application presents a plan to test TSI as a potentially noninvasive, simple, and cheap imaging tool providing information about arterial plaque vulnerability with high spatial and contrast resolution. It is the aim, therefore, of the work proposed here to address the following issues in detail. 1.) Construct a heating source fully integrated with an ultrasound imaging system to provide controlled energy delivery to tissue equivalent phantoms and excised tissue samples during routine ultrasound scanning. Both ultrasound and microwave heating sources will be investigated. 2.) Develop robust pulse sequence and data acquisition schemes for controlled heating with simultaneous ultrasonic imaging. 3.) Develop signal processing methods to remove the effects of unwanted tissue motion during TSI data acquisition. Like all high precision speckle tracking methods, TSI is susceptible to tissue motion artifacts. Methods must be developed to identify and minimize these artifacts. 4.) Demonstrate that TSI can separate water-bearing tissues from lipids in images similar to methods developed for magnetic resonance imaging but with high spatial resolution for peripheral vascular applications. 5.) Demonstrate on excised arterial samples that TSI can identify the lipid pool within an arterial plaque. The results of these preliminary experiments will test TSI as an imaging technique for vulnerable plaque detection. If it proves viable, we will develop an RO1 proposal to build an integrated imaging system combining ultrasound with a controlled heat source and explore the possibility of noninvasive, in vivo highrisk plaque identification in the carotid and other peripheral arteries.

DESCRIPTION (provided by applicant): Over the last several years we have developed a technology to optically generate ultrasound using laser pulses absorbed in thin polymer films. This approach produces ultrasonic intensity comparable to piezoelectric counterparts and is especially attractive for high-frequency applications. We have also developed a complementary technology for sensitive ultrasonic detection using resonant optical detectors. High-frequency ultrasound incident on these devices modulates the resonance condition and alters the intensity of a continuous wave (CW) laser beam probing the structure. The fundamental hypothesis of this proposal is that these technologies will produce very small, all-optical ultrasonic transducers enabling high spatial resolution imaging. Therefore, the primary goal of the research program described in this application is to develop a new intravascular imaging technology embedding a miniature, high-resolution ultrasonic imaging array within the tip of a guidewire used to deliver therapeutic catheters (typically 0.35 mm in diameter). A guidewire-based ultrasonic bio-microscopy (UBM) system would combine high resolution ultrasound imaging with conventional X-ray fluoroscopy in the baseline catheterization system. A wide range of technical and scientific issues must be investigated to fully exploit the capabilities of optoacoustic transduction. Therefore, it is the further aim of this application to address the following issues. 1.) Optimize optically absorbing polymer structures for efficient ultrasonic generation from 1-100 MHz. Particular emphasis will be placed on constructing optoacoustic transducers that can operate as arrays at these frequencies. 2.) Optimize polymer etalons for sensitive optical detection of ultrasound from 1-100 MHz. Particular emphasis will be placed on constructing etalons that can operate as arrays over these frequencies. 3.) Design, construct, and optimize a single element optoacoustic microscopy transducer. This device will serve as a test vehicle for all-optical ultrasonic transducers. In addition, it will be integrated into a high-performance UBM system for ophthalmology and dermatology applications. 4.) Design, construct, and optimize an all-optical, high-frequency ultrasonic array for UBM. This device will serve as a test vehicle for optical integration technologies. In addition, it will represent a significant advance for UBM by enabling real-time 3-D imaging. 5.) Design, construct, and optimize an all-optical, high-frequency ultrasonic array with dimensions that can fit within a conventional guidewire to guide coronary artery interventions.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The central aim of this proposal is to understand ultrafast light-DNC interactions as monitored by high frequency ultrasound. In particular, we will use ultrasonic micrsocopy to monitor the photodisruption process transducing site-targeted nanoparticles into a detectable microbubble. Our short-term goal is to detect molecular agents targeted to squamous cell cancers and to monitor therapy applied to these cells. We propose to investigate two photodisruption regimes: one near threshold in which the UOB process can be carefully controlled to produce detectable microbubbtes with little cellular injury (i.e., minimally invasive); the second at a different set of optical parameters where the UOB processes can be highly destructive, killing labeled cells for therapeutic purposes, ff both regimes can be established, then ultrasonic detection of DNC promoted photodisruption can provide a sensitive tool for both site-targeted molecular imaging and molecular therapeutics. [unreadable] [unreadable] It is the aim, therefore, of the work proposed here to address the following issues in detail. [unreadable] [unreadable] 1.) Characterize LIOB and resultant microbubbles in water, water-based gels, and tissue culture using high-frequency ultrasound. In particular, the ultrasound system will monitor photodisruption thresholds, system parameters for minimally invasive transient bubble creation, system parameters for invasive and stable bubble creation, system parameters determining bubble size, and system parameters determining bubble temperature. [unreadable] 2.) Determine the necessary composition and structure of DNC particles that have minimal LIOB thresholds. Detailed structural studies will be performed on all compositions showing enhanced breakdown characteristics. [unreadable] 3.) Determine the range of optical parameters controlling LIOB thresholds and photodisruption characteristics in DNC solutions and DNC loaded tissue-equivalent gelatin phantoms, including wavelength, optical fluence per pulse, repetition rate, and total number of pulses. [unreadable] [unreadable] If these studies demonstrate that we can control DNC-promoted LIOB to operate either as a minimally invasive sensor or a highly localized disruptor, and we can sensitively monitor both processes with high frequency ultrasound, we will develop an RO1 proposal for site-targeted molecular imaging and therapy monitoring of squamous cell cancers, a rapidly growing and very important clinical problem. [unreadable] [unreadable]

The "AccessSTEM: The Northwest Alliance for Students with Disabilities in Science, Technology, Engineering, and Mathematics - Phase II (AccessSTEM2)" project will increase the associate, baccalaureate, and graduate science, technology, engineering and mathematics (STEM) degree attainment of individuals with disabilities in the Seattle, WA region. The primary institution, the University of Washington (UW), is partnering with Bellevue Community College (BCC), Seattle Central Community College (SCCC), and all high schools within the Seattle Public Schools system to accomplish this goal.

The AccessSTEM-Phase 2 Alliance will increase the associate, baccalaureate and graduate STEM degree attainment of students with disabilities by attending to the following four objectives:

1. Implement changes within awardee and partner postsecondary institutions (UW, BCC, SCCC) to make STEM programs more welcoming and accessible to students with disabilities (e.g., more accessible websites and science labs, STEM publications that encourage the participation of students with disabilities);

2. Create and expand engagement of stakeholders (precollege STEM educators, disability services, veteran associations, projects that broaden participation in STEM, and industry and career services) in fostering STEM education and careers that are welcoming and accessible to people with disabilities;

3. Implement evidence-based practices (e.g., mentoring, peer support, internships) to increase numbers of individuals with disabilities moving through critical junctures to STEM associate, baccalaureate, and graduate degrees and careers; and

4. Support and expand an online resource center that shares research and promising practices worldwide.

Strategic interventions are needed to achieve gender parity in the faculty ranks of science and engineering disciplines. Wooing women faculty in STEM from one university to another is, nationally, a zero-sum game. Instead of recruiting women away from other universities, there is a mostly-untapped pool of Ph.D.-level women scientists and engineers in industry and research laboratories. Many are very accomplished at their research, which is the primary figure of merit for success at Research-Extensive universities. With the proper mix of information, networking, and support, they could become very successful professors. The goal of this project is to increase the pool of women faculty available to all universities by providing professional development to Ph.D.-level women in industry or research laboratories. In particular, we will host a two-day workshop each year over a three-year period to provide practical tools and support to women who are interested in making the transition to academia. We will specifically target women who are a minimum of three-four years past their Ph.D. and/or postdoctoral position. The attendees and speakers will form a community who can support each other during the job application period, the interview process, the startup negotiations, and the first years in academia. In summary, the project will develop "On Ramps into Academia."

Intellectual Merit: It is of great interest to determine the challenges, skills, and resources needed for people to successfully make the transition from industry or national laboratories to academia. The assessment plan, which is strongly directed at outcomes evaluation, will help identify concrete best practices to encourage women into faculty pathways. By providing the necessary skills and advice to help women make successful transitions from industry to academia, UW ADVANCE will help develop a third pathway into academia, in addition to the current practices of hiring new Ph.D.s and postdoctoral fellows and hiring women away from other universities. This third pathway into academia is an original approach to recruitment and a creative way to expand the pool of women faculty in STEM.

Broader Impacts: This project will expand the national pool of women faculty in STEM disciplines. Even a small increase of STEM women faculty can improve the image of the disciplines and encourage more women to pursue them.

DESCRIPTION (provided by applicant): Most cancer deaths are caused by metastasis, a process whereby primary tumor cells spread to non-adjacent organs mainly by penetrating the walls of blood vessels and circulating through the bloodstream. Patients would have a much greater opportunity for long-term survival if these circulating tumor cells (CTCs) could be sensitively and specifically detected to guide disease management. However, CTCs are too rare for easy detection and quantification. Photoacoustic (PA) imaging following magnetic capture of circulating tumor cells has been proposed to address this problem, but the method is limited in contrast specificity due to strong PA signals from blood. Magnetomotive photoacoustic imaging (mmPA), a new molecular imaging modality developed in our group, introduced dynamic manipulation into traditional PA imaging. Similar to conventional PA, mmPA retains the high resolution and penetration of ultrasound (US), and can measure optical absorption in tissue. Unlike conventional PA, magnetomotive manipulation with simultaneous US/PA imaging of agents incorporating magnetic nanoparticles (MNPs) enables direct visualization of the signal generating object and can dramatically reduce background signals from strong optical absorbers such as blood. We hypothesize that biologically targeted, coupled magnetic nanoparticles can be used to identify, accumulate, and manipulate CTCs circulating in the vasculature using a combination of magnetic trapping and mmPA imaging. If successful, this technique can lead to a non-invasive system to accumulate CTCs, enabling highly sensitive CTC detection with a simple system appropriate for ultimate clinical translation. To test this hypothesis, a research plan with five specific aims has been developed. The first is to demonstrate that coupled MNPs targeted to mimics of circulating rare cells can be identified, accumulated, and manipulated in a vascular phantom using a combination of magnetic trapping and mmPA imaging. In the second aim, we will develop an effective magnetic trapping approach that can be easily integrated with a real-time US/PA imaging system appropriate for potential clinical applications in the peripheral vasculature. The third aim, in which a highly magnetic and NIR-absorbing coupled nanoprobe will be synthesized and characterized, is focused on developing the appropriate contrast agent for this application. Before performing in vivo tests, the fourth aim will demonstrate trapping and manipulation of targeted cells in circulation using an in vitro model of flow in a peripheral vessel. Finally, the overall approach will be validated i vivo by demonstrating trapping and manipulation of targeted cells in circulation using a murine model of metastatic cell trafficking in the vasculature. The overall goal of the proposed research plan is to help provide the background required to construct a prototype integrated system and to design studies helping translate mmPA technology into the clinic. This is a necessary first step in developing a robust system for metastatic disease management.

Project Summary/Abstract Ischemic heart disease remains the top cause of death in the world. Acute myocardial infarction (MI) causes regional dysfunction which places remote areas of the heart at a mechanical disadvantage resulting in long term adverse left ventricular (LV) remodeling and complicating congestive heart failure (CHF). The course of MI and post-MI remodeling is complex and includes vascular and myocellular injury, acute and chronic inflammation, alterations of the extracellular matrix (ECM) and angiogenesis. Stress echocardiography is a clinically established, cost-effective technique for detecting and characterizing coronary artery disease and myocardial injury by imaging the LV at rest and after either exercise or pharmacologically-induced stress to reveal ischemia and/or scar. In our previous effort on this project, we developed quantitative 3D differential deformation measures for stress echocardiography from 4DE-derived LV strain maps taken at rest and after dobutamine stress. These measures can localize and quantify the extent and severity of LV myocardial injury and reveal ischemic regions. We now propose that improved versions of these same measures can be used for both targeting of therapy and outcomes assessment in the treatment of adverse local myocardial remodeling following MI. We choose a particular up and coming therapeutic strategy as an exemplar: the local delivery of injectable hydrogels within the MI region that are intended to alter the biomechanical properties of the LV myocardium, as well as inflammation, and thereby help to minimize adverse remodeling. Our new, robust approach for estimating improved dense displacement and differential deformation measures is based on an innovative data-driven, deep feed-forward, neural network architecture that employs domain adaptation between data from labeled, carefully-constructed synthetic models of physiology and echocardiographic image formation (i.e. with ground truth), and data from unlabeled noisy in vivo porcine or human echocardiography (missing or very limited ground truth). Training is based on tens of thousands of four-dimensional (4D) image-derived patches from these two domains, initially based on displacements derived separately from shape-based processing of conventional B-mode data and block-mode, speckle-tracked processing of raw radio-frequency (RF) data; and later based on learning directly from B-mode and RF image intensity information. After non-rigid registration of rest and stress 4DE image sequences, quantitative 4D differential deformation parameters will be derived from porcine and human echocardiographic test data. These parameters will be derived at baseline, and at several timepoints after delivery of injectable hydrogels into the MI region. The ability of the differential deformation parameters derived from 4D stress echocardiography to guide local delivery of injectable hydrogels in a MI region and assess/predict outcomes will then be determined in a hybrid acute/chronic porcine model of MI and post-MI remodeling. The technique will be translated to humans and evaluated by measuring the reproducibility and the relationship to remodeling of our new robust, deep learning-based differential deformation parameters in a small cohort of subjects.