Investigating the Mechanism of Conditioning Versus Postoperative Electrical Stimulation to Enhance Nerve Regeneration: One Therapy, Two Distinct Effects

ABSTRACT Regeneration after peripheral nerve injury is often insufficient for functional recovery. Postoperative electrical stimulation (PES) following injury and repair significantly improves clinical outcomes; recently, conditioning electrical stimulation (CES), delivered before nerve injury, has been introduced as a candidate for clinical translation. PES accelerates the crossing of regenerating axons across the injury site, whereas CES accelerates the intrinsic rate of axonal regeneration; thus, it is likely that their mechanisms are distinct. The large body of literature investigating the mechanisms of electrical stimulation has not differentiated between CES and PES. In this review, we investigate the CES and PES paradigms within the existing literature, distinguish their mechanistic insights, and identify gaps in the literature. A systematic literature review was conducted, selecting articles identifying the pro‐regenerative effects of electrical stimulation in the setting of peripheral nerve injury. As a mechanistic template, both paradigms implicate cation channels for the initiation of numerous signaling pathways that together upregulate regeneration‐associated genes. CES and PES feature some overlap; activation of PI3K and MAPK signaling pathways, and upregulation of BDNF, GAP43, and GFAP are similar. Currently, the inflammatory environment in which PES is administered predominantly differentiates these mechanisms. However, gaps within the literature complicate the comparison between paradigms. Systematic review revealed the mechanisms for both CES and PES paradigms remain fragmented; though much of the literature assumes the involvement of particular signaling pathways, the evidence remains limited. Though it is likely there is overlap between mechanisms, further investigation is needed.