Collaborative Research: Glial scar morphology informed tunable biomimetic platforms toward spinal cord injury repair

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Spinal cord injury (SCI) results in loss of cells and blood supply, disruption of brain connectivity to various tissues, and formation of a dense scar around the injury site, ultimately resulting in permanent loss of mobility. There are no proven clinical solutions or pharmaceutical interventions to reverse SCI. To develop successful treatment options for SCI, it is important to first understand the physical, chemical, and biological changes occurring over time in the injured tissues. This information would in turn help in developing improved mimics of such injured tissues (combining important structural, mechanical, and inflammatory aspects) to test the response of various cells resident to the spinal cord, as well as to evaluate the efficacy of pharmaceutical drugs in promoting tissue regeneration to ultimately improve the success of downstream clinical applications. Successful implementation of these objectives will lead to the development and validation of physiologically-relevant integrated systems that improve our fundamental understanding of SCI, while also enabling new testing platforms. The broader impact of this work will include the generation of new insights into how nerve cell outgrowth and targeting is inhibited in an inflammatory SCI tissue, and may be overcome for reparative benefit, specifically in the context of SCI. Besides opportunities for research dissemination to the scientific community, this project will lead to training of diverse undergraduate and graduate students through development of research/educational modules and through the auspices of established summer internship/outreach programs at the investigators’ respective institutions.Injury to the central nervous system (CNS) has profound, long-term physiological consequences due to the tissue’s low innate regenerative ability and formation of a glial scar around the injury site. This scar has large soft regions, is inhibitive to axonal/neurite outgrowth, confers an anti-regenerative environment, and is marked by gliosis and production of inhibitory chondroitin sulfate proteoglycans. The underlying mechanisms for such altered characteristics at the injury site are unclear. The goals of this study are to (1) elucidate and correlate spinal cord tissue-scale mechanical properties, architecture, and mechanochemical signaling at key phases following CNS injury, and (2) identify the mechanochemical response of CNS cells to scar-like physical properties measurable via defined signaling pathways, altered membrane tension, and tension-regulated behaviors. This multi-disciplinary, comprehensive strategy establishes hitherto undefined multi-scale relationships between glial scar structure, micromechanical properties, ECM composition, and CNS cell mechanochemical responses. The newly identified glial scar characteristics will be utilized to develop tunable biomimetic hydrogels for the isolation of CNS cell function, mechano-chemical profiles, membrane tension, and regulated behaviors, towards mimicking the acute injury phase in a humanized in vitro platform. The broader research impacts of this project include generation of new mechanistic insights into how cell functions are dysregulated in an inflammatory milieu, while offering new targets for regeneration. By emphasizing mechanobiological knowledge-driven formulation of glial scar-biomimetic scaffolds, this project represents a paradigm shift in CNS repair and regeneration strategies.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.