Background: Postamputation pain affects a large number of individuals living with major limb loss. Regenerative peripheral nerve interfaces are constructs composed of a transected peripheral nerve implanted into an autologous free muscle graft. The authors have previously shown that regenerative peripheral nerve interfaces can be used to treat symptomatic end neuromas that develop after major limb amputation. In this study, they investigated the potential of prophylactic interfaces to prevent the formation of symptomatic neuromas and mitigate phantom limb pain. Methods: Patients who underwent limb amputation with and without prophylactic regenerative peripheral nerve interface implantation were identified. A retrospective review was performed to ascertain patient demographics, level of amputation, and postoperative complications. Documentation of symptomatic neuromas and phantom limb pain was noted. Results: Postoperative outcomes were evaluated in a total of 90 patients. Forty-five patients underwent interface implantation at the time of primary amputation, and 45 control patients underwent amputation without interfaces. Six control patients (13.3 percent) developed symptomatic neuromas in the postoperative period compared with zero (0.0 percent) in the prophylactic interface group (p = 0.026). Twenty-three interface patients (51.1 percent) reported phantom limb pain, compared with 41 control patients (91.1 percent; p < 0.0001). Conclusions: Prophylactic regenerative peripheral nerve interfaces in major limb amputees resulted in a lower incidence of both symptomatic neuromas and phantom limb pain compared with control patients undergoing amputation without regenerative peripheral nerve interfaces, suggesting that prevention of peripheral neuromas following amputation may diminish the central pain mechanisms that lead to phantom limb pain. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Pain is a central feature of soft tissue trauma, which under certain contexts, results in aberrant osteochondral differentiation of tissue-specific stem cells. Here, the role of sensory nerve fibers in this abnormal cell fate decision is investigated using a severe extremity injury model in mice. Soft tissue trauma results in NGF (Nerve growth factor) expression, particularly within perivascular cell types. Consequently, NGF-responsive axonal invasion occurs which precedes osteocartilaginous differentiation. Surgical denervation impedes axonal ingrowth, with significant delays in cartilage and bone formation. Likewise, either deletion of Ngf or two complementary methods to inhibit its receptor TrkA (Tropomyosin receptor kinase A) lead to similar delays in axonal invasion and osteochondral differentiation. Mechanistically, single-cell sequencing suggests a shift from TGFβ to FGF signaling activation among pre-chondrogenic cells after denervation. Finally, analysis of human pathologic specimens and databases confirms the relevance of NGF-TrkA signaling in human disease. In sum, NGF-mediated TrkA-expressing axonal ingrowth drives abnormal osteochondral differentiation after soft tissue trauma. NGF-TrkA signaling inhibition may have dual therapeutic use in soft tissue trauma, both as an analgesic and negative regulator of aberrant stem cell differentiation.

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Peripheral nerve injury remains a major cause of morbidity in trauma patients. Despite advances in microsurgical techniques and improved understanding of nerve regeneration, obtaining satisfactory outcomes after peripheral nerve injury remains a difficult clinical problem. There is a growing body of evidence in preclinical animal studies demonstrating the supportive role of stem cells in peripheral nerve regeneration after injury. The characteristics of both mesoderm‐derived and ectoderm‐derived stem cell types and their role in peripheral nerve regeneration are discussed, specifically focusing on the presentation of both foundational laboratory studies and translational applications. The current state of clinical translation is presented, with an emphasis on both ethical considerations of using stems cells in humans and current governmental regulatory policies. Current advancements in cell‐based therapies represent a promising future with regard to supporting nerve regeneration and achieving significant functional recovery after debilitating nerve injuries.