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Background: A neuroma occurs when a regenerating transected peripheral nerve has no distal target to reinnervate. Symptomatic neuromas are a common cause of postamputation pain that can lead to substantial disability 1-3 . Regenerative peripheral nerve interface (RPNI) surgery may benefit patients through the use of free nonvascularized muscle grafts as physiologic targets for peripheral nerve reinnervation for mitigation of neuroma and postamputation pain., Description: An RPNI is constructed by implanting the distal end of a transected peripheral nerve into a free nonvascularized skeletal muscle graft. The neuroma or free end of the affected nerve is identified, transected, and skeletonized. A free muscle graft is then harvested from the donor thigh or from the existing amputation site, and the distal end of each transected nerve is implanted into the center of the free muscle graft with use of 6-0 nonabsorbable suture. This can be done acutely at the time of amputation or as an elective procedure at any time postoperatively., Alternatives: Nonsurgical treatments of neuromas include desensitization, chemical or anesthetic injections, biofeedback, transcutaneous electrical nerve stimulation, topical lidocaine, and/or other medications (e.g., antidepressants, anticonvulsants, and opioids). Surgical treatment of neuromas includes neuroma excision, nerve capping, excision with transposition into bone or muscle, nerve grafting, and targeted muscle reinnervation., Rationale: Creation of an RPNI is a simple and reproducible surgical option to prevent neuroma formation that leverages several biologic processes and addresses many limitations of existing neuroma-treatment strategies. Given the understanding that neuromas will form when regenerating axons are not presented with end organs for reinnervation, any strategy that reduces the number of aimless axons within a residual limb should serve to reduce symptomatic neuromas. The use of free muscle grafts offers a vast supply of denervated muscle targets for regenerating nerve axons and facilitates the reestablishment of neuromuscular junctions without sacrificing denervation of any residual muscles., Expected Outcomes: Articles describing RPNI surgery for postamputation pain have shown favorable outcomes, with significant reduction in neuroma pain and phantom pain scores at approximately 7 months postoperatively 4,5 . Neuroma pain scores were reduced by 71% and phantom pain scores were reduced by 53% 4 . Prophylactic RPNI surgery is also associated with substantially lower incidence of symptomatic neuromas (0% versus 13.3%) and a lower rate of phantom limb pain (51.1% versus 91.1%) 5 compared with the rates in patients who did not undergo RPNI surgery., Important Tips: Ask the patient preoperatively to point at the site of maximal tenderness, as this can serve as a guide for where the symptomatic neuroma may be located. The incision can be made either through the previous site of the amputation or directly over the site of maximal tenderness longitudinally. The pitfall of incising directly over the site is creating another incision with its attendant risk of wound infection.Excise the terminal neuroma with a knife until healthy-appearing axons are visualized.The free nonvascularized skeletal muscle graft can be obtained from local muscle (preferred) or from a separate donor site. A separate donor site can introduce donor-site morbidity and complications, including hematoma and pain.The harvested skeletal muscle graft should ideally be approximately 35 mm long, 20 mm wide, and 5 mm thick in order to ensure survivability and to prevent central necrosis. The harvesting can be performed with curved Mayo scissors.The peripheral nerve should be implanted parallel to the direction of the muscle fibers, and the epineurium should be secured to the free muscle graft at 1 or 2 places. One suture should be utilized to tack the distal end of the epineurium to the middle of the bed of the muscle graft. Another suture should be utilized to start the wrapping of the muscle graft around the nerve using a bite through the muscle, a bite through the epineurium of the proximal end of the nerve, and another bite through the other muscle edge in order to form a cylindrical wrap around the nerve.Wrap the entire muscle graft by taking only bites of muscle graft around the nerve to secure the muscle graft in a cylindrical structure using 2 to 4 more sutures.Avoid locating the RPNI near weight-bearing surfaces of the residual limb when closing. The RPNI should be in the muscular tissue, deep to the subcutaneous tissue and dermis.Do perform intraneural dissection for large-caliber nerves to create several (normally 2 to 4) distinct RPNIs, to avoid too many regenerating axons in a single free muscle graft., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSEST/A434)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)