An injectable acellular nerve graft as a platform for treating spinal cord injury
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Spinal cord injury (SCI) affects a quarter million people in the US, and there is currently no clinical treatment option. Approximately 60% of clinical SCI results from spinal cord contusion, which causes formation of a growth-inhibitory cavity. Research with experimental SCI models has shown spinal axons can regenerate despite this cavity if supplied with appropriate conditions. Two strategies have proven particularly successful: grafting segments of peripheral nervous tissue and transplanting pro-regenerative cells such as peripheral nerve Schwann cells. While implanting fresh nerve tissue risks immune rejection, this challenge can be overcome by removing immunogenic tissue components through decellularization. Unfortunately, decellularization also eliminates the benefits of resident nerve Schwann cells, and transplanting purified Schwann cells after SCI requires the addition of a scaffold for effective cell survival. Tumor-derived Matrigel is often used experimentally to support Schwann cell therapy. For successful translation into humans, however, more clinically-relevant alternatives are needed. Acellular nerve grafts are currently available clinically for peripheral nerve repair and therefore have potential to be such an alternative, although they require some modification to be compatible with contusion injury. Contusion cavities necessitate scaffolds be applied using minimally-invasive techniques such as injection. Additionally, injectable scaffold are easier to incorporate with other therapeutics such as cells. The goal of this dissertation was to develop and evaluate an injectable acellular nerve graft as a potential intervention for treating contusion SCI. This thermally-gelling nerve scaffold was shown to approximate the chemical composition of native nerve tissue and was optimized to match the mechanical properties of rat neural tissue. Injectable nerve scaffolds were biocompatible with Schwann cells in vitro and promoted a regenerative immune response in vivo in a rat model of cervical contusion SCI. Delivery of injectable nerve alone supported axon growth into and beyond the SCI lesion after 8 weeks. In collaboration with Dr. Mary Bunge at the Miami Institute to Cure Paralysis, transplanting Schwann cells in injectable nerve promoted equivalent yet faster recovery compared to using Matrigel. This injectable acellular nerve graft is therefore a clinically-relevant alternative to Matrigel for enhancing Schwann cell therapy and promoting recovery following traumatic SCI.