Lori A. Setton - US grants

9510401 Setton This project is a Research Planning Grant made to help increase the number of new women investigators participating in National Science Foundation (NSF) research programs, and to facilitate preliminary studies and other activities related to the development of competitive NSF research proposals. This project will seek to quantify the state of swelling- induced residual stress and strain in the anulus fibrosus, a part of the intervertebral (spinal) disc. Disc degeneration causes great discomfort to a large number of individuals and results of the investigation are expected to generate new knowledge for consideration of appropriate tissue substitutes or chemical treatments to alleviate disc degeneration. The Principal Investigator is expected to submit a full research proposal to NSF subsequent to the completion of this project. Gilbert B. Devey August 16, 1995

9703299 Setton Cartilaginous tissues, such as the intervertebral disc, articular cartilage and meniscus, have a limited blood supply and low cell density and so are particularly susceptible to degeneration induced by aging and daily wear. Current treatment options for degenerating tissues include fusion of the joint to prevent further motion, or replacement of the joint with an artificial prosthetic. These treatments are limited in their effectiveness, however, and are appropriate only for repair of end-stage disease. There is a great need for new methods of restoring the mechanical function in these cartilaginous tissues. Our long- term interest is in developing a tissue-engineered approach to controlling function in the intervertebral disc with a focus on inhibiting or reversing progressive degeneration. In this 4-year plan, we propose a comprehensive research activity and complementary educational program focused on biomechanics and tissue engineering with application to the intervertebral disc. Our research plan is focused on studies of a mechano-chemical coupling mechanism in the intervertebral disc which influences tissue function through biochemical composition. This coupling mechanism gives rise to swelling-induced residual stress and strain fields in the anulus fibrosus of the intervertebral disc which may be important in contributing to the load-bearing functions of the intervertebral disc. The primary objective of this research plan is to determine the function of these residual stress and strain fields in the anulus fibrosus, as well as in synthetic biomaterials with potential for disc repair. The motivating hypothesis is that these residual stresses and strains significantly contribute to the mechanical function of the intervertebral disc by improving its ability to provide for compressive load-bearing in the spine. A set of design criteria based on residual stresses, residual strains, and compressive behavior will be defined for the anulus fibrosus, and used to engineer a novel biomaterial for tissue repair in the intervertebral disc. The proposed research plan is organized about four specific aims. First, new experimental methods will be developed to quantify the residual strain fields in the native anulus fibrosus. Second, theoretical model advancements will be pursued to calculate the residual stress fields in the native anulus fibrosus. Third, experiments will be performed to directly test the hypothesis that residual stresses and strains modify the compressive load-bearing behavior of the anulus fibrosus. Fourth, these methods will be applied to evaluate synthetic biomaterials supplied through industrial collaborations for their utility in intervertebral disc repair. Teams of industrial and academic collaborators will work together to develop and evaluate new biomaterials for restoring mechanical function in the intervertebral disc. A complementary educational plan in biomechanics and tissue engineering has been designed for students at the high school, undergraduate and graduate levels. First, an internship program will be organized for second-year undergraduate students from underrepresented minority backgrounds. The broad objective of this aim is to maintain interest in a subset of students who suffer from low retention rates in the undergraduate engineering education. Second, the undergraduate and graduate engineering curriculum will be revised to expand course offerings in biomechanics. The broad objective of this aim is to provide a direct channel for incorporating applied research in educational programs at the undergraduate and graduate level. Third, a new hands-on biomechanics laboratory will be developed for high school students as part of the Women in Engineering Outreach Program at Duke. The broad objective of this aim is to provide female high school students with a problem- solving and confidence-building experience in engineering, and expose them to female faculty and engineering graduate students in leadership roles. The integration of these research and education plans is expected to promote partnerships for the transfer of engineering research to the industrial sector, to increase the numbers of underrepresented minorities and women in engineering, to better prepare these students for achieving excellence in engineering in an academic or industrial setting, and to expose a broad base of students to the excitement of discovery and learning that is characteristic of research in engineering. ***

The intervertebral disc is a cartilaginous tissue with highly ordered architecture, consisting of layers of Type I/II collagen fibers with successive orientations of +30 and -30 degrees to the transverse plane. The tissue is susceptible to degeneration secondary to injury and aging, characterized by a loss of the preferential collagen orientation, and replacement of the healthy tissue with a fibrous isotropic matrix. Conventional MR techniques for diagnosing degeneration in the disc have relied on detection of signal changes associated with decreased water content. Diffusion tensor microscopy is expected to provide a novel, structure-based mechanism for detecting cartilage degeneration and remodeling. In collaboration with the Center's goals in developing the methodology of diffusion tensor microscopy, healthy and spontaneously degenerating intervertebral discs of guinea pigs will be studied. Efforts will be focused on obtaining high resolution diffusion-weighted micrographs of the tissue, and corroborating the eigenvectors of the diffusion tensor with independent histological examination.

Small animal models are attractive for studying the pathogenesis of osteoarthritis (OA) and for screening pharmacological agents and surgical strategies for treatment of OA. Articular cartilage exhibits dramatic changes in composition, metabolism and structure with OA which are associated with an impaired mechanical function as a weight-bearing material. Presently, there is no information on cartilage mechanics in small animal models (e.g., mice, rat, guinea pig) due to the limitations inherent in testing small tissue samples. In this project, we propose to quantify changes in cartilage mechanical properties in three small animal models of OA: (1) a guinea pig model of spontaneous OA; and two mouse models which exhibit early onset of degenerative joint disease (2) a mutant mouse model with a type XI collagen defect; and (3) a mutant mouse model with a type IX collagen defect. We hypothesize that disruption of the cartilage matrix, quantified as a decrease in the cartilage elastic modulus, is an early event in the progression of OA in these animal models. We propose to develop a new noncontacting method to determine the mechanical properties of cartilage in small animal joints. Aim number 1 is to develop a chemical loading (swelling) experiment to determine material properties (elastic modulus and Poisson's ratio) of articular cartilage from the hip and knee joints of guinea pigs and mice. In preliminary tests of canine cartilage samples (1-4 mm thickness), material properties determined using this method were shown to be equivalent to those determined in a traditional tensile test, and to be capable of detecting changes in cartilage mechanics with joint degeneration. In this project, this method will be proportionally scaled for the testing of cartilage harvested from small animal models (50 -500 mum thickness) with use of bright-field and epifluorescence microscopy. Aim number 2 is to quantify the temporal change in cartilage material properties in the guinea pig model of spontaneous OA. Aim number 3 is to quantify differences in cartilage material properties in joints from wild-type and mutant mice with type XI and type IX collagen defects. The temporal changes in cartilage mechanics will also be studied in these models by quantifying material properties at early, middle and late stages of disease. This project will provide the first available data on degeneration-induced loss of cartilage function in the guinea pig and mouse joints. This data is expected to yield new insights into the pathogenesis of OA as well as the mechanical role of collagen types XI and IX in cartilage.

DESCRIPTION: (verbatim) Cells of the intervertebral disc (IVD) exhibit little capacity for functional matrix repair in situ, which may contribute to the progressive nature of disc degeneration. IVD cells respond to mechanical stimuli with altered biosynthesis in manner that depends on zone of cell origin (anulus fibrosus, transition zone or nucleus pulposus), although the mechanisms governing these responses are poorly understood. The central hypothesis of this proposal is that zonal variations in the local mechanical environment of IVD cells are dominant in regulating zonal variations in disc cell metabolism. Our preliminary analytical and finite element analyses suggest that the micromechanical environment of disc cells depends on four parameters: (1) the anisotropic, nonlinear and multiphasic properties of the extracellular matrix; (2) applied loading conditions; (3) cell mechanical properties; and (4) three-dimensional cell geometry. In this study, we propose a set of experiments to quantify zonal variations in these four parameters and to incorporate them in a computational model of IVD cell micromechanics. Independent tests will be performed to quantify material properties of the cell and extracellular matrix using materials testing and micropipette aspiration techniques. Three-dimensional cell geometry and the local boundary conditions in the IVD under compression will be obtained using confocal laser scanning microscopy. A finite element model of the micromechanical environment of IVD cells will be developed, which incorporates nonlinear, anisotropic and biphasic material behaviors and the measured material and geometric data. Finite element model predictions of the local mechanical environment of IVD cells under compression in the intact IVD (in situ), and isolated cells cultured in a three-dimensional alginate matrix (ex situ), will be obtained to precisely determine important local mechanical stimuli such as stress, strain, fluid pressure and fluid flow. To construct new and precise relationships between these stimuli and IVD cell metabolism, corresponding experiments to measure zonal variations in gene expression and biosynthesis of collagens and agrecan will be performed on intact IVD and cell-alginate constructs under compression. Comparison of data for in situ and ex situ experiments is expected to reveal the relative contributions of cell morphology, matrix properties and loading conditions to the micromechanical environment and metabolic response of IVD cells. Furthermore, the experimental and computational data to be obtained in this project will define new relationships between precisely determined mechanical stimuli and IVD cell metabolism that are prerequisite to understanding the mechanisms that govern cellular response to mechanical stimuli in vivo.

DESCRIPTION (provided by applicant): Maintenance of healthy intervertebral disc function depends on preservation of the anatomic integrity and function of the nucleus pulposus (NP). Aging-related cell losses leave the disc with little ability to respond to injury or aging-related changes such as loss of disc height or hydration, disc fissures or extrusion, all features associated with symptomatic intervertebral disc disorders. Cell supplementation to the disc is now of great interest, using autologous, progenitor and other cells that carry the potential to regenerate NP-like matrix in vivo. Little is known of unique and specific cellular characteristics required for regenerating NP-like matrix, however, and there are few technical strategies available to assist this goal in vitro or in vivo. We have identified unique features of immature NP cells to be their adhesion to specific laminins, and their expression of laminin-binding receptors and laminin-associated proteins. These unique features have been identified in three species (porcine, rat and human NP) and include an ability to bind to laminin-1 and laminin-10, to express both integrin and non-integrin laminin receptors, and to express a laminin associated protein. Furthermore, laminin binding protects cells from serum deprivation-induced cell apoptosis and promotes formation of extracellular matrix that uniquely contains laminin and these associated receptors. We propose to synthesize new biomaterials that promote laminin binding for primary NP cells and adult progenitor (hADAS) cells, in order to stimulate regeneration of a distinct, NP-like extracellular matrix. In Aim 1, we will select human and porcine NP cell populations for their attachment to laminin or cell-binding laminin peptides and encapsulate them in 3D polypeptide hydrogels composed of laminins and elastin-like polypeptides (ELPs). Newly synthesized matrix will be studied for its expression of specific laminin-associated and other NP matrix markers. Cell attachment strength and receptor expression will also be studied. Differences in the quantity or quality of matrix, attachment strength and receptor expression profile, amongst cell populations will be modeled using artificial neural networks and tested to determine if laminin binding promotes an enhanced capacity to regenerate the NP. In Aim 2, we will design fusion proteins of cell-binding laminin peptides and ELPs that function as 3D scaffolds. Preservation of the 3D hydrogel-forming ELP domain, together with introduction of a cell- binding domain unique to NP cells, is proposed to promote the regeneration of NP-like matrix. The significance of this work will be the design of a new cell-instructive biomaterial that, combined with a readily accessible cell source, can serve as an effective, broadly available therapeutic option for NP-like matrix regeneration for the treatment of pathological NP changes.

[unreadable] DESCRIPTION (provided by candidate): N/A [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The anti-inflammatory drugs, IL-1 receptor antagonist (IL1Ra) and TNF-alpha blocking antibodies, have been shown to dramatically modify the progression of inflammatory joint disease. While these drugs have significant potential to impact treatment of osteoarthritis, serious side effects associated with the required systemic administration protocol limits their application to single joint pathology in osteoarthritis. There is a need for an effective mechanism to deliver these drugs directly to the joint space, while providing for the high concentrations and frequent dosing suggested for drug effectiveness. The objective of this study is to develop a novel intra-articular drug delivery system that will be effective for delivering these disease-modifying drugs directly to the joint space. Elastin-like polypeptides (ELPs) will serve as the basis for the newly developed drug delivery system, whereby ELPs are thermally triggered to form large, micron size aggregates at body temperature upon injection into the joint space. We propose that these aggregates can entrap protein drugs and thus serve as a "depot" for drug release over time. We further propose two specific mechanisms by which ELPs can serve as drug carriers for these protein drugs: (1) by physical entrapment of the protein drug following mixing and thermally-initiated aggregate formation (> 35 degrees C), or (2) by design of an ELP-drug fusion protein that will undergo aggregate formation when thermally-initiated. In this project, we propose work to study these two concepts applied to the release of one protein drug, IL1Ra, as a first proof-of-concept. We propose work to: (1) synthesize ELPs that physically entrap IL1Ra into aggregates and evaluate the kinetics of IL1Ra biodistribution in a rat model; and (2) synthesize fusion proteins of ELPs and IL1Ra and similarly evaluate IL1Ra biodistribution in the rat. The protein drugs released from the ELPs, either as soluble drug or fusion protein, will also be evaluated in vitro to determine kinetics of release, binding activity to target (IL-1 receptor 1) and biological activity in regulating T-lymphocyte proliferation. It is our central hypothesis that intra-articular injection of an ELP-based "drug depot" for IL1Ra will increase the half-life of this important disease-modifying drug in the joint space, and thus provide the potential to serve as a highly effective treatment for osteoarthritis. [unreadable] [unreadable] [unreadable]

The Pratt School of Engineering (Pratt) at Duke University proposes an effective program to increase the diversity, including gender diversity - in the engineering academy. Pratt's success in hiring outstanding women faculty in engineering was accomplished by reserving one to two faculty lines each year at the School level for departments and strategic initiative leaders to compete for by recruiting targets of opportunity. TOPS is more than a recruiting strategy. It is an effective and sustainable methodology for attracting underrepresented faculty to the engineering academy. It consists of developing a longitudinal database of outstanding under-represented students at various stages of their graduate studies (with a focus on minority women), tracking their progress, having consistent interactions with these students over time, encouraging them to pursue an academic career, making home visits to their respective institutions, inviting them to Duke for visits, and ultimately recruiting them into the academy. TOPS aims to overcome a key entry barrier--the inclusion factor.

To help transform the engineering discipline, the TOPS methods and results are disseminated to the engineering and science communities through the TOPS web site, coaching clinics, and research publications. The TOPS program collaborates with complementary programs. Pratt plans to recruit faculty who are applying their talents, in part, to improve the quality of life, life without pain, without fear, and in harmony with the environment.

Intellectual Merits: Through the TOPS program, important social research presents
data regarding critical mass versus tokenism; comparative studies on the experiences of students and faculty within Pratt to a comparison group of equivalents in science departments; and evaluate the perception that engineering is a masculine field and is not a people-oriented discipline. TOPS is committed to a rigorous assessment and study of the proposed methods, techniques, and impacts.

Broader Impacts: Through TOPS, Pratt develops Best Practices for recruiting, retaining, and
advancing under-represented, particularly female, faculty in engineering and science. The dissemination of these Best Practices are expected to positively impact engineering and science disciplines, and the nation by enhancing the country's ability to solve problems and create a better world.

In the first funding cycle, Project 2 was successful in elucidating the nature of OA changes in mice carrying genetic mutations for key fibrillar collagens, including types IX and XI collagen. In the absence of type IX collagen, we learned that complete erosion of joint cartilage occurs with concomitant changes in animal behavior, cartilage biomechanics and chemistry. For Project 2, we take the finding of pro-inflammatory cytokines in the serum of OA patients, as well as our mouse models of OA, and turn towards developing a targeted intervention appropriate for OA based on delivering anti-inflammatory compounds to the joint. Antiinflammatory drugs that attenuate IL-1[unreadable] and TNFa activity have therapeutic potential for OA but require high protein doses and cause significant side effects when administered via intravenous or subcutaneous injection for inflammatory disease. Strategies that utilize low protein doses and provide for sustained release have great potential to achieve value in the clinic as a treatment for OA. In Project 2, we propose to develop and evaluate the utility of an in situ forming, intra-articular 'drug 'depot'that can provide for local and sustained delivery of anti-inflammatory protein drugs for the treatment of OA. We have previously constructed thermally responsive drug depots the drugs, IL-1 receptor antagonist (IL1Ra) or soluble TNF receptor (sTNFRII), conjugated to a thermally responsive peptide. We have shown that these thermally responsive peptide "tags", composed from elastin sequences called ELPs, spontaneously form a depot upon injection into the joint space that provide for a 25-fold increase in the half-life of the administered protein and 75% reduction in peak serum exposure. In Aim 1, we propose studies to evaluate the following for both ELP-IL1Ra and ELP-sTNFRII: (a) in vitro bioactivity against cytokines in primary synoviocytes;(b) in vivo biodistribution following delivery to the rat knee joint;(c) in vitro immunotoxicity;and (d) in vivo efficacy in mediating inflammatory joint disease caused by overexpression of IL-1[unreadable] and/or LPS injection in the joint space. In Aim 2, we propose to evaluate the disease-modifying effects of ELP-IL1 Ra and ELP-sTNFRII in a joint instability model of OA with the following measures: (a) gross and histological joint appearances;(b) synovial fluid and serum biomarkers (through Core B);and (c) parameters of gait and pain perception. We hypothesize that thermally responsive ELPs conjugated to these anti-inflammatory drugs will contribute to long drug half-lives in the joint space while retaining bioactivity, reducing serum drug exposure and modifying disease in these pre-clinical models of OA. The results of this 5-year project are expected to advance a novel drug depot strategy to easily deliver drugs to the joint, advancing the application of disease-modifying drugs with significant systemic side effects for the treatment of OA.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our goal is to investigate the delivery of rat intervertebral disc (IVD) cells in a rat model of disc degeneration. The cells will be delivered to live rat tails (IVD) percutaneously. The cells will be labelled with a fluorescent marker (nanoparticles, Kodak optical imager) to allow us to define the specific location of the implanted cells. We also aim to define the migratory patterns of the injected cells to assist in developing improved methods of cell delivery to IVD. The ability to track implanted cells over a time course will be a significant addition to ongoing efforts in improving cell based delivery methods. Cells may be delivered alone or with a cell delivery vehicle (hydrogel scaffold) developed in our laboratory to maintain the implanted cells in the desired locations. We will plan a longitutional imaging study where the implanted cells will be imaged at 24hrs, 3 days, 7 days and 14 days to determine both the duration of labeling as well as migratory patterns of implanted cells.

? DESCRIPTION (provided by applicant): Nucleus pulposus (NP) cells of the intervertebral disc are derived from notochord and synthesize a soft, gelatinous matrix containing numerous collagen, proteoglycan and laminin species. With age, NP cells become more fibroblast-like and lose their ability to synthesize and repair this NP-specific extracellular matrix. We have previously shown that environmental cues of molecular composition and substrate stiffness can be manipulated to promote elevated matrix synthesis for the NP cell. In particular, we have developed a laminin-presenting hydrogel that can promote increased expression for many molecular markers of the healthy, biosynthetically active NP cell (e.g, brachyury, integrin ?3, laminin, and elevated sGAG), but only when crosslinked to be soft (<0.5 kPa) as opposed to stiff (>0.9 kPa). Our overall hypothesis is that environmental cues of soft stiffness and laminin engagement can be exploited to promote re-expression of the healthy, biosynthetically active NP cell phenotype for cells of the adult, degenerate human NP. In Specific Aim 1, we will determine if young and/or adult degenerate human NP cells have elevated expression of NP-specific molecular markers, elevated NP-specific matrix biosynthesis, and NP-related transcription factor activity following culture upon laminin-functionalized polyethylene (PEG) hydrogels of varying stiffness (0.3 -50 kPa). NP-specific markers will be measured with mRNA, protein and biochemical assays following guidance from a consensus paper by the Spine Research Interest Group (Risbud et al. 2015, JOR). In Specific Aim 2, we will determine if cell recognition peptides have an ability to promote elevated expression of NP-specific markers for young and/or adult degenerate human NP cells when cultured upon peptide-functionalized PEG hydrogels. We have identified four cell recognition peptides derived from integrin-binding and laminin-derived domains that promote human NP cell attachment and elevated sGAG synthesis when attached to soft hydrogel substrates. We will vary ratios of these four peptides upon PEG substrates of optimal stiffness identified from Specific Aim 1, and measure the expression of NP-specific molecular markers over time (as for Specific Aim 1). In Specific Aim 3, we test if an optimal PEG-laminin or PEG-peptide hydrogel can preserve the re-expression of the healthy NP cell phenotype for degenerate human NP cells following delivery to the pathological environment of the degenerated intervertebral disc. Adult, degenerate NP cells will be preconditioned upon PEG-laminin or PEG- peptide substrates, then delivered into degenerated discs in a nude rat model with an injectable, in situ crosslinking version of the PEG hydrogel as a cell carrier. Cell residence time (luminescence), disc height, and NP-specific markers will be evaluated to test if the PEG-LM or PEG-peptide hydrogel can support preservation of the healthy NP cell phenotype for these degenerate NP cells in the native disc. Completion of this study would identify environmental cues that can promote re-expression of a healthy, biosynthetically active NP cell with application to primary adult NP cells and progenitor cells for cell-mediated regeneration of the degenerate disc.

Injury or trauma to the knee, hip, or ankle is a well-documented contributor to premature onset of joint degeneration and osteoarthritis (OA). Nuclear factor kappa B (NF-?B) is a transcription factor that has early involvement in post-traumatic OA by activating genes involved in extracellular matrix catabolism and joint inflammation. Increased NF-?B activity has also been implicated in the development of pain following joint injury and other musculoskeletal pathologies. Despite the availability of numerous compounds that inhibit NF-?B, pharmacologic inhibition of NF-?B via systemic administration or even local delivery to the joint has not been successful in the treatment of OA. We hypothesize that intra-articular delivery of NF-?B antagonists from a safe, sustained-release carrier (silk) will have value in attenuating pain related sensitivities, joint dysfunction, and progressive joint pathology in a non-surgical, intra-articular fracture model of OA. We have previously identified a strong correlation between NF-?B activity and pain-related sensitivity in a model of inflammatory joint injury using the NF-?B-luciferase reporter mouse. Here, we will similarly track NF-?B activity, but in a mouse model of closed tibial fracture as a non-surgical model of joint injury which is known to progress to OA. In Specific Aim 1, we will evaluate the temporal and spatial development of NF-?B activity, pain- related sensitivities, and joint dysfunction in mice following intra-articular fracture out to 8 weeks. We will identify relationships between systemic and local NF-?B activation, patterns for sensitivity, gait and weight- bearing, and arthritis progression following joint fracture. Results will identify ?therapeutic windows? for timing of intra-articular drug delivery in Specific Aim 3. In Specific Aim 2, we will optimize silk fibroin microparticle depots for sustained release of two small molecule NF-?B inhibitors, SC-514 or PHA-408. We have previously demonstrated increased residence times for silk fibroin microparticles when delivered to the joint space, but have not incorporated a drug for sustained release. Silk fibroin microparticles (10-60 microns) will be fabricated specific to each NF-?B inhibitor, and tested to verify high drug loading and sustained release out to 4 weeks. In Specific Aim 3, we will evaluate if a single, intra-articular injection of SC-514 or PHA-408-loaded silk fibroin microparticles can attenuate NF-?B activation, pain-related sensitivities, joint dysfunction, and joint pathology after intra-articular fracture. Intra-articular injections of drug-loaded microparticles will be administered to the injured limb at either early or late times after injury, with longitudinal monitoring of effects on NF-?B activation, pain-related sensitivities, joint dysfunction and arthritis development. Results will reveal whether either compound, and at which time, can modulate defined outcome measures of arthritis symptoms and/or pathology progression in this model of OA. This work will establish a safe, sustained release strategy for the local treatment of OA that can advance utility for an entire class of small molecule NF-?B antagonists with a high likelihood for treating pathology and/or pain development in patients with OA.

The Biomedical Engineering Society (BMES) Annual Meeting will be held in Phoenix, AZ, October 11-14, 2017. This award will fund several competitive travel grant programs as well as professional development activities targeted at underrepresented groups and those that may not otherwise be able to participate in the conference. The competitive travel grant programs include: students (12), career development awards for underrepresented post-doctoral trainees and young professionals, including junior faculty (20); and NSBE members interested in biomedical engineering who have not previously been BMES members (25). In addition, funding is sought for a Career Pathways in Biomedical Engineering session and a High School Visitation program for students from Phoenix high schools that do not have enhanced STEM programs and targeting underrepresented groups. Finally, a small amount of funding is sought for 5 poster awards. The meeting will feature 19 Program Tracks with the theme "Engineering Personalized Medicine and Therapies." Approximately 800 oral presentations, 1600 poster presentations and over 4,000 participants are anticipated. The BMES Annual Meeting serves as a primary vehicle for scientific sharing and dissemination of the latest advances in biomedical engineering, as well as a facilitator of important cross-fertilizations between the life sciences and engineering technologies, which foster a multi-disciplinary approach in the practice of Biomedical Engineering. The travel awards will afford the opportunity for young investigators and investigators from underrepresented groups to attend the Annual Meeting, be informed on the latest scientific and technological advances in Biomedical Engineering, and help support BMES members involved in research and training focused on health disparities and minority health. The partnership with NSBE is specifically targeted at supporting underrepresented engineers with an interest in biomedical engineering.

The overall aims of this award are to support the professional development of students and underrepresented groups. Through a series of travel awards, a Career Pathways Session, a high school visitation program, and poster awards, this grant will provide opportunities for increased diversity among the meeting attendees and participation in the meeting's networking and diversity activities. BMES is the premier biomedical engineering conference in the United States, covering all areas within the broad discipline. It brings together researchers with backgrounds in engineering and biomedical science to discuss the latest advances in the field and support the professional development of the next generation of biomedical engineers.

This award will support two special sessions related to NSF funding: "BMES-NSF Special Session on CAREER and Unsolicited Awards" and ?BMES-NSF Special Session on Graduate Research Fellowships Program.? Both of these sessions are outside of the regular program of the Annual Meeting of the Biomedical Engineering Society being held in Phoenix, AZ, October 11-14, 2017. The funding will be used to promote, convene and record the session and offset travel costs and registration fees for NSF awardees (3 research grant and 4 GRFP) and reviewers (5) who will serve as presenters, panelists, and potential mentors/collaborators for novice and emerging investigators. The CAREER/Unsolicited session builds on the success of similar sessions held at BMES annual meetings since 2013. The GRFP session was added after feedback from last year?s participants indicating a specific interest in this student-focused program. The 2017 BMES meeting will feature 19 Program Tracks with the theme "Engineering Personalized Medicine and Therapies." Approximately 800 oral presentations, 1600 poster presentations and over 4,000 participants are anticipated. The BMES Annual Meeting serves as a primary vehicle for scientific sharing and dissemination of the latest advances in biomedical engineering, as well as a facilitator of important cross-fertilizations between the life sciences and engineering technologies, which foster a multi-disciplinary approach in the practice of Biomedical Engineering.

The research grant focused session will be a 3 hour session, featuring presentations showcasing NSF funded research and researchers (2 CAREER awardees and 1 non-CAREER awardee), a Networking Reception, a Tutorial on Essential Elements to Develop a Successful NSF BME Grant, and an Interactive Grant Writing and Submission Panel Discussion, will be held on October 13, 2017. The GRFP-focused session will be 2 hours in length and will be held on October 14, 2017. It will involve 4 past GRFP recipients, from diverse graduate and undergraduate institutions, as well as past GRFP panelists. Both sessions will include time for Q&A with the audience. Both recorded sessions will be posted on the BMES website for on demand viewing.

The Biomedical Engineering Society (BMES) Annual Meeting will be held in Atlanta, Georgia, on October 17-20, 2018. This award will fund several competitive travel grant programs as well as professional development activities targeted at underrepresented groups and those that may not otherwise be able to participate in the conference. The competitive travel grant programs include: students (12), career development awards for underrepresented post-doctoral trainees and young professionals, including junior faculty (25); and National Society of Black Engineers (NSBE) members interested in biomedical engineering who have not previously been BMES members (30). In addition, funding is sought for a High School Visitation program for students from Atlanta high schools that do not have enhanced Science, Technology, Engineering and Mathematics (STEM) programs and targeting underrepresented groups. The meeting will feature 19 Program Tracks with the theme "Celebrating 50 Years of Innovation: From Discovery to Implementation." Approximately 800 oral presentations, 1600 poster presentations and over 4,000 participants are anticipated. The BMES Annual Meeting serves as a primary vehicle for scientific sharing and dissemination of the latest advances in biomedical engineering, as well as a facilitator of important cross-fertilizations between the life sciences and engineering technologies, which foster a multi-disciplinary approach in the practice of Biomedical Engineering. The travel awards will afford the opportunity for young investigators and investigators from underrepresented groups to attend the Annual Meeting, be informed on the latest scientific and technological advances in Biomedical Engineering, and help support BMES members involved in research and training focused on health disparities and minority health. The partnership with NSBE is specifically targeted at supporting underrepresented engineers with an interest in biomedical engineering.

The overall aims of this award are to support the professional development of students and underrepresented groups. Through a series of travel awards, a high school visitation program, and poster awards, this grant will provide opportunities for increased diversity among the meeting attendees and participation in the meeting's networking and diversity activities. BMES is the premier biomedical engineering conference in the United States, covering all areas within the broad discipline. It brings together researchers with backgrounds in engineering and biomedical science to discuss the latest advances in the field and support the professional development of the next generation of biomedical engineers.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

This award will support two special sessions related to NSF funding: "BMES-NSF Special Session on CAREER and Unsolicited Awards" and "BMES-NSF Special Session on Graduate Research Fellowships Program." Both of these sessions are outside of the regular program of the Annual Meeting of the Biomedical Engineering Society being held in Atlanta, GA, October 17-20, 2018. The funding will be used to promote, convene and record the session and offset travel costs and registration fees for NSF awardees (3 research grant and 4 GRFP) and reviewers (5) who will serve as presenters, panelists, and potential mentors/collaborators for novice and emerging investigators. The CAREER/Unsolicited session builds on the success of similar sessions held at BMES annual meetings since 2013. The GRFP session was added after feedback from 2016 participants indicating a specific interest in this student-focused program. Approximately 800 oral presentations, 1600 poster presentations and over 4,000 participants are anticipated. The BMES Annual Meeting serves as a primary vehicle for scientific sharing and dissemination of the latest advances in biomedical engineering, as well as a facilitator of important cross-fertilizations between the life sciences and engineering technologies, which foster a multi-disciplinary approach in the practice of Biomedical Engineering.

The research grant focused session will be a 3 hour session, featuring presentations showcasing NSF funded research and researchers (2 CAREER awardees and 1 non-CAREER awardee), a Networking Reception, a Tutorial on Essential Elements to Develop a Successful NSF BME Grant, and an Interactive Grant Writing and Submission Panel Discussion, will be held on October 19, 2018. The GRFP-focused session will be 2 hours in length and will be held on October 20, 2018. It will involve 4 past GRFP recipients, from diverse graduate and undergraduate institutions, as well as past GRFP panelists. Both sessions will include time for Q&A with the audience. Both recorded sessions will be posted on the BMES website for on demand viewing.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Intervertebral disc (IVD) degeneration is one of the greatest contributors to low back pain, yet how the IVD can generate pain remains poorly understood. The parent grant will pursue Specific Aims to study the development of temporal and spatial changes in neuronal function and their ?cross-talk? with changes in the degenerating IVD in a mouse model of lumbar IVD degeneration. Here, we propose a supplemental project called ?Novel Injectable Hydrogels for Localized Pain Relief in the Dorsal Root Ganglion (DRG)? that will support Ms. Sydney Neal in the design of a novel injectable drug depot in order to attenuate neuronal sensitivity with lumbar IVD degeneration. The overall goal is for Ms. Neal, a graduate student in biomedical engineering, to develop a novel chemistry that will couple the nerve growth factor (NGF) antagonist, Tanuzemab, to an injectable, gelling alginate to provide for local release of an NGF antagonist at the lumbar DRGs with IVD degeneration. In Supplemental Aim 1, Ms. Neal will modify binary mixtures of alginate and evaluate gelation kinetics and localization to the DRGs following simulated perineural delivery. In Supplemental Aim 2, Ms. Neal will develop a strategy to couple Tanezumab to alginate using an azide modification and evaluate the efficiency of coupling. In Supplemental Aim 3, Ms. Neal will evaluate the bioactivity of the drug-conjugated alginate hydrogels in isolated DRG neurons subjected to periods of incubation with NGF. Ms. Neal will be co-sponsored by Dr. Nate Huebsch who brings experience with biomaterials and drug delivery to the team, and Dr. Lori Setton who brings experience with IVD degeneration and perineural drug delivery to the team. During the period of this project, Ms. Neal will gain new and valuable skills in neuronal cell culture, genetically-encoded calcium indicators, pre-clinical models of disease development, and work closely with clinicians to increase her knowledge of treatment relevance for engineered biomaterials. Ms. Neal will further prepare an Individual Development Plan, participate in workshops for research success at Washington University, attend national conferences to present her work, and have an opportunity to participate in a national conference to mentor Black scientists. Washington University provides an excellent environment for the completion of this research project and continued professional development of Ms. Sydney Neal. Ms. Neal will work within the McKelvey School of Engineering and the School of Medicine and participate in resources of the Musculoskeletal Research Center, the Cardiovascular Research Center, and the Center for Regenerative Medicine. In all, these combined research and training activities are designed to prepare Ms. Neal for continued academic research in her post-graduate years.