Development of a peripheral nerve specific extracellular matrix-based hydrogel and its use in augmenting peripheral nerve injury and repair

Peripheral nerve injury commonly results in loss of neuromuscular function, often resulting in significant impact upon both quality of life and cost of care for patients. One promising target for improving patient outcomes is the use of a peripheral nerve specific extracellular matrix hydrogel (PNM) as an injectable, regenerative support. It has been long understood that the extracellular matrix (ECM) not only provides structural support but also regulates cell growth, survival, maturation, differentiation, and development of resident cells. The objective of this dissertation was to develop and characterize a decellularized peripheral nerve hydrogel, investigate its effect on key properties of peripheral nerve regeneration, and finally assess its ability to enhance return to function in several peripheral nerve injury models. We found that PNM provides a tissue-specific microenvironment which is conducive to nerve repair, including: nerve specific growth factors that are chemotactic signals for Schwann cells, promote neurite outgrowth, as well as factors that modulate the macrophage inflammatory response to injury. When employed as a lumen filler for conduit repair of peripheral nerve defects, a switch in the ratio of M1:M2 phenotype macrophages was observed, a phenomenon associated with improved nerve growth and promotion of Schwann cell migration across a gap defect. This was associated with improved function over time in non-critical common peroneal and sciatic nerve defects. Furthermore, we provided proof-of-concept for the use of PNM in treating nerve crush injuries. The injection of the PNM hydrogel directly into the nerve injury was found to be safe with no impact on downstream function. The application of PNM to the crush injury resulted in enhanced return to function and a more robust axon regrowth across the injury. In conclusion, we developed an injectable material that provides a regeneration promoting, tissue-specific microenvironment at the site of injury. The material has shown the ability to promotes recruitment of alternately activated, M2 macrophages, enhance Schwann cell migration, and axon extension. Finally, the use of PNM has enhanced recovery and return to function in numerous peripheral nerve injury models. PNM shows promise in augmenting current surgical practices for peripheral nerve injury and repair and has the potential to significantly improve quality of life for affected patients.