An Injectable Recombinant Polypeptide Scaffold for Peripheral Nerve Repair

About This Grant

PROJECT SUMMARY The objective of this proposal is to investigate the ability of an injectable polypeptide scaffold to improve patient outcomes after peripheral nerve repair. Peripheral nerve injuries (PNI) affect >20 million people in the US alone, with $150 billion in healthcare costs annually, and are a cause of devastating functional disability and chronic pain in those affected. The gold-standard treatment for PNI is primary neurorrhaphy when a tension-free repair approach is feasible; otherwise, secondary options such as autografts, decellularized allografts, or nerve conduits are used. However, regardless of approach, only about half of patients achieve meaningful sensorimotor recovery and the majority of patients continue to experience chronic pain. Lack of success is generally attributed to a poor microenvironment for neuroregeneration which must simultaneously be able to provide neovascularization, low inflammation, cell infiltration, and successful neuroaxonal migration. Current treatment strategies fail to address all these needs. Motivated by this clear clinical need, we will investigate the applicability of partially ordered polypeptides (POPs) to improve outcomes after peripheral nerve repair. POPs are a unique platform of biomaterials that transition from an injectable liquid at room temperature to a physically crosslinked, porous network at body temperature. POPs are highly biocompatible, integrating into the surrounding tissue, initiating remodeling, cell infiltration, and vascularization. Further, their ability to phase transition under the action of body temperature, letting them be injected as a low-viscosity liquid, allows for easy handling and integration in the operating room, and their scalable manufacturing process means that POPs have the capability to be a clinically translatable product. Our central goal will be to demonstrate that POPs is uniquely suited to provide the needed mechanical support and well-vascularized microenvironment essential for successful neuroaxonal regeneration. Our strategy will include tailoring the POPs biomaterial formulation to have the correct porous microarchitecture, mechanical properties, and promotion of beneficial local signaling for peripheral nerve repair applications. We will then investigate the ability of POPs to augment outcomes following peripheral nerve repair in models of rat sciatic nerve injury. Functional and histological testing will be performed and compared to current gold-standard primary neurorrhaphy and commercially available products. If this proposal is successful, it will provide a strong foundation to commence large animal testing and begin scale-up for translation into clinical application. The improvement of surgical outcomes following peripheral nerve repair by application of POPs has the potential for a transformative impact for patients with peripheral nerve injuries by reducing long-term disability and chronic pain.