mRNA-containing fibrous conduits for repair of long-gap peripheral nerve injury

Project Summary/Abstract Peripheral nerve injury remains a significant problem in the United States and among the Veteran population. Even after decades of research, there are few clinically available approaches to treat long-gap peripheral nerve injury. Often, long-gap peripheral nerve repair is facilitated through harvest and placement of sural nerve autografts into the injury site. Sural nerve isolation induces donor site morbidity, and some patients are unable to donate neural tissue due to other co-morbidities (such as diabetes). As alternatives to the autografts, nerve allografts and biomaterial scaffolds have emerged as possible approaches to supplant the autograft. However, allografts require extensive decellularization processes, and it is challenging to find size-matched allografts for patients. Biomaterial conduits can be shaped into appropriate sizes. Many biomaterial conduits lack sufficient extracellular matrix to promote extensive regeneration of axons. In total, autograft, allograft, and biomaterial strategies routinely fail to completely rescue lost function. Thus, new strategies are needed to advance the field. Biomaterial conduits that consist of aligned, electrospun fibers robustly promote axonal regeneration in preclinical models of peripheral nerve injury. Fibrous materials are produced using synthetic, degradable polymers that contain no extracellular matrix. Schwann cells migrating into the injury site are responsible for producing sufficient ECM to foster robust regeneration. Unfortunately, Schwann cells immediately after peripheral nerve injury reduce their production of key growth factors, such as neurotrophin-3 (NT-3). Therefore, Schwann cells are unable to produce sufficient factors to create ECM and growth factors to robustly induce regeneration. Inclusion of exogenous stem cells and Schwann cells that release regenerative factors or use of biomaterials that release growth factors improve regeneration in preclinical models. However, cellular explants from donor tissue require immunosuppression, and it is difficult to release proteins from degradable polymers (which typically require harsh chemicals for polymer synthesis). Harsh chemicals used to fabricate biomaterial scaffolds denature growth factors, requiring investigation of alternative approaches. In this SPiRE application, we propose to develop mRNA-releasing fibrous scaffolds and assess the ability of the mRNA-releasing scaffolds to promote peripheral regeneration in a pre-clinical injury model. In total, the development of new biomaterial approaches to treat peripheral nerve injury may lead to new tools capable of promoting robust peripheral nerve regeneration for the Veteran population.