Directed functional reinnervation to curb nociception and enable sensation

Peripheral nerve injuries lead to diminished function and pain via nociplastic phenomena. We propose a new strategy called directed functional reinnervation, in which nerves are reassigned to new peripheral targets with the intention of altering circuit function. Here, we redirect the saphenous sensory nerve into a skeletal muscle graft to curb nociplasticity and provide benign sensations or useful inputs for prosthetic applications. Electrophysiological functional characterization demonstrated robust afferent responses to mechanical stimulation of the muscle. Immunofluorescence staining indicated widespread innervation of various synapses within the muscle graft. With immediate graft placement, the injured nerve's dorsal root ganglia revealed comparable levels of nociceptive markers to uninjured nerves, suggesting a molecular basis for the prevention of pain sensitization. These findings contribute to the mechanism by which skeletal muscle grafts alleviate neuropathic pain and can be used as a sensory transmitter in conjunction with neural interfaces.