The role of growth factors in peripheral nerve regeneration and opportunities for next-generation biological therapeutics.

Regeneration after peripheral nerve injury (PNI) involves complex processes that are often insufficient to facilitate full functional recovery. In particular, PNI stimulates the release of a multitude of growth factors with critical spatial and temporal specificity to aid in regeneration by affecting axons, glia, immune cells, and vasculature. Depending on the severity of the injury, however, these endogenous processes may be inadequate to support regeneration, leaving patients with life-long sensory and motor deficits. Current treatments in these cases attempt to modify the regenerative environment, and many involve direct or indirect growth factor modulations to stimulate and sustain regenerative processes. For example, surgical interventions in the case of segmental defects may involve nerve conduits, which passively sequester and concentrate local growth factors, or nerve autografts, which provide autologous Schwann cells that actively secrete growth factors to drive axonal growth. Other strategies include electrical stimulation and physical therapy, each altering growth factor release to enhance axonal regeneration and functional innervation, respectively. Next-generation biological therapeutics including biomaterial-growth factor release systems and tissue engineered nerve grafts are emerging as potential regenerative scaffolds capable of presenting both structural and trophic cues. This review describes the critical role that growth factors play in orchestrating regenerative processes after PNI while highlighting novel therapeutics that are leveraging the unique capabilities of specific growth factors to augment peripheral nerve regeneration and facilitate functional recovery. Impact statement. This review describes the critical role that growth factors play after peripheral nerve injury by detailing the primary growth factors involved, the effects of their release over time and space, and how advanced regenerative therapies are leveraging these mechanisms to enhance nerve regeneration and functional recovery.