Intervertebral Disc Degeneration and Cross-Talk with the Nervous System

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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.