Targeted Muscle Reinnervation at the Time of Amputation Decreases Recurrent Symptomatic Neuroma Formation.

BACKGROUND: Targeted muscle reinnervation (TMR) is an effective technique for the prevention and management of phantom limb pain (PLP) and residual limb pain (RLP) among amputees. The purpose of this study was to evaluate symptomatic neuroma recurrence and neuropathic pain outcomes between cohorts undergoing TMR at the time of amputation (ie, acute) versus TMR following symptomatic neuroma formation (ie, delayed). METHODS: A cross-sectional, retrospective chart review was conducted using patients undergoing TMR between 2015 and 2020. Symptomatic neuroma recurrence and surgical complications were collected. A subanalysis was conducted for patients who completed Patient-Reported Outcome Measurement Information System (PROMIS) pain intensity, interference, and behavior scales and an 11-point numeric rating scale (NRS) form. RESULTS: A total of 105 limbs from 103 patients were identified, with 73 acute TMR limbs and 32 delayed TMR limbs. Nineteen percent of the delayed TMR group had symptomatic neuromas recur in the distribution of original TMR compared with 1% of the acute TMR group ( P < 0.05). Pain surveys were completed at final follow-up by 85% of patients in the acute TMR group and 69% of patients in the delayed TMR group. Of this subanalysis, acute TMR patients reported significantly lower PLP PROMIS pain interference ( P < 0.05), RLP PROMIS pain intensity ( P < 0.05), and RLP PROMIS pain interference ( P < 0.05) scores in comparison to the delayed group. CONCLUSIONS: Patients who underwent acute TMR reported improved pain scores and a decreased rate of neuroma formation compared with TMR performed in a delayed fashion. These results highlight the promising role of TMR in the prevention of neuropathic pain and neuroma formation at the time of amputation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Non degradation of chitosan and initial degradation of collagen nerve conduits used for protection of nerve coaptations.

BACKGROUND: Nerve conduits are either used to bridge nerve gaps of up to 3 cm or to protect nerve coaptations. Biodegradable nerve conduits, which are currently commercially available, include Chitosan or collagen-based ones. As histological aspects of their degradation are highly relevant for the progress of neuronal regeneration, the aim of this study was to report the histopathological signs of such nerve conduits, which were removed during revision surgery. MATERIALS AND METHODS: Either Chitosan (n = 2) or collagen (n = 2) nerve conduits were implanted after neuroma resection and nerve grafting (n = 2) or traumatic nerve lesion after cut (n = 1) or crush injury (n = 1) in two females and two men, aged between 17 and 57 years. Revision surgery with removal of the nerve conduits was indicated due to persisting neuropathic pain and sensorimotor deficits, limited joint motion, or neurolysis with hardware removal at a median time of 17 months (range: 5.5-48 months). Histopathological analyses of all removed nerve conduits were performed. RESULTS: A scar neuroma was diagnosed in one out of four patients. Mechanical complication occurred in one patient after nerve conduit implantation bridged over finger joints. Intraoperatively no or only initial signs of degradation of the nerve conduits were observed. Chitosan conduits revealed largely unchanged shape and structure of chitosan, and coating of the conduit by a vascularized fibrous membrane. The latter contained deposits taken up by macrophages, most likely representing dissolved chitosan. Characteristic histopathologic features of the degradation of collagen conduits were a disintegration of the compact collagen into separate fine circular strands, No foreign body reaction was observed in all removed nerve conduits. CONCLUSIONS: Both Chitosan nerve conduits have not been degraded. The collagen nerve conduits showed a beginning degradation process. Furthermore, wrapping the repaired nerve with a nerve conduit did neither prevent adhesions nor improved nerve gliding. Therefore, biodegradation in time should be particularly addressed in further developments of nerve conduits.

Nerve Capping Techniques for Neuroma Management: A Comprehensive Literature Review.

BACKGROUND/AIM OF THE STUDY: Nerve capping is a method of neuroma treatment or prevention that consists of the transplantation of a proximal nerve stump into an autograft or other material cap, after surgical removal of the neuroma or transection of the nerve. The aim was to reduce neuroma formation and symptoms by preventing neuronal adhesions and scar tissue. In this narrative literature review, we summarize the studies that have investigated the effectiveness of nerve capping for neuroma management to provide clarity and update the clinician's knowledge on the topic. METHODS: A systematic electronic search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria was performed in the PubMed database combining "neuroma," "nerve," "capping," "conduit," "treatment," "management," "wrap," "tube," and "surgery" as search terms. English-language clinical studies on humans and animals that described nerve capping as a treatment/prevention technique for neuromas were then selected based on a full-text article review. The data from the included studies were compiled based on the technique and material used for nerve capping, and technique and outcomes were reviewed. RESULTS: We found 10 applicable human studies from our literature search. Several capping materials were described: epineurium, nerve, muscle, collagen nerve conduit, Neurocap (synthetic copolymer of lactide and caprolactone, which is biocompatible and resorbable), silicone rubber, and collagen. Overall, 146 patients were treated in the clinical studies. After surgery, many patients were completely pain-free or had considerable improvement in pain scores, whereas some patients did not have improvement or were not satisfied after the procedure. Nerve capping was used in 18 preclinical animal studies, using a variety of capping materials including autologous tissues, silicone, and synthetic nanofibers. Preclinical studies demonstrated successful reduction in rates of neuroma formation. CONCLUSIONS: Nerve capping has undergone major advancements since its beginnings and is now a useful option for the treatment or prevention of neuromas. As knowledge of peripheral nerve injuries and neuroma prevention grows, the criterion standard neuroprotective material for enhancement of nerve regeneration can be identified and applied to produce reliable surgical outcomes.

Regenerative peripheral nerve interface reduces the incidence of neuroma in the lower limbs after amputation: a retrospective study based on ultrasound.

BACKGROUND: Amputees suffer from symptomatic neuroma and phantom limb pain. Regenerative peripheral nerve interface (RPNI) has recently been regarded as an effective method to prevent neuroma after amputation. However, the verifications of RPNI efficacy are mostly based on subjective evaluation, lacking objective approaches. This study aims to unveil the effect of RPNI on preventing neuroma formation and provide evidence supporting the efficacy of RPNI based on ultrasound. METHODS: Amputees of lower limb at Peking University People's Hospital from July 2020 to March 2022 were analyzed retrospectively. The clinical data collected consisted of general information, pathology of primary disease, history of limb-salvage treatment, amputation level of nerve, pain scales such as the Numerical Rating Scale (NRS) and the Manchester Foot Pain and Disability Index (MFPDI). Three months after amputation, the transverse diameter, anteroposterior diameter, and cross-sectional area of neuromas in stump nerves at the end of residual limbs were measured using ultrasound and compared to adjacent normal nerves. RESULTS: Fourteen patients were enrolled in the study, including 7 in the traditional amputation group (TA group) and 7 in the RPNI group. There was no significant difference in basic information and amputation sites between the two groups. The NRS and MFPDI scores of patients in RPNI group were significantly lower than those in TA group, and decreased with the follow-up time increasing, indicating that RPNI could reduce symptomatic neuroma pain. The comparison of preoperative ultrasound and postoperative pathology showed ultrasound could reflect the size of neuroma in vivo. Independent-sample t tests indicated that the ratios of anteroposterior diameter, transverse diameter and area of the cross section of both the neuroma and adjacent normal nerve obtained via ultrasound were significantly reduced in the RPNI group. CONCLUSION: This study suggested that RPNI can effectively prevent the formation of symptomatic neuroma after amputation using ultrasound.

A Direct Comparison of Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interfaces to Prevent Neuroma Pain.

BACKGROUND AND OBJECTIVES: Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) surgeries manage neuroma pain; however, there remains considerable discord regarding the best treatment strategy. We provide a direct comparison of TMR and RPNI surgery using a rodent model for the treatment of neuroma pain. METHODS: The tibial nerve of 36 Fischer rats was transected and secured to the dermis to promote neuroma formation. Pain was assessed using mechanical stimulation at the neuroma site (direct pain) and von Frey analysis at the footpad (to assess tactile allodynia from collateral innervation). Once painful neuromas were detected 6 weeks later, animals were randomized to experimental groups: (a) TMR to the motor branch to biceps femoris, (b) RPNI with an extensor digitorum longus graft, (c) neuroma excision, and (d) neuroma in situ. The TMR/RPNIs were harvested to confirm muscle reinnervation, and the sensory ganglia and nerves were harvested to assess markers of regeneration, pain, and inflammation. RESULTS: Ten weeks post-TMR/RPNI surgery, animals had decreased pain scores compared with controls ( P < .001) and they both demonstrated neuromuscular junction reinnervation. Compared with neuroma controls, immunohistochemistry showed that sensory neuronal cell bodies of TMR and RPNI showed a decrease in regeneration markers phosphorylated cyclic AMP receptor binding protein and activation transcription factor 3 and pain markers transient receptor potential vanilloid 1 and neuropeptide Y ( P < .05). The nerve and dorsal root ganglion maintained elevated Iba-1 expression in all cohorts. CONCLUSION: RPNI and TMR improved pain scores after neuroma resection suggesting both may be clinically feasible techniques for improving outcomes for patients with nerve injuries or those undergoing amputation.

Sexually Dimorphic Pattern of Pain Mitigation Following Prophylactic Regenerative Peripheral Nerve Interface (RPNI) in a Rat Neuroma Model.

BACKGROUND: Treating neuroma pain is a clinical challenge. Identification of sex-specific nociceptive pathways allows a more individualized pain management. The Regenerative Peripheral Nerve Interface (RPNI) consists of a neurotized autologous free muscle using a severed peripheral nerve to provide physiological targets for the regenerating axons. OBJECTIVE: To evaluate prophylactic RPNI to prevent neuroma pain in male and female rats. METHODS: F344 rats of each sex were assigned to neuroma, prophylactic RPNI, or sham groups. Neuromas and RPNIs were created in both male and female rats. Weekly pain assessments including neuroma site pain and mechanical, cold, and thermal allodynia were performed for 8 weeks. Immunohistochemistry was used to evaluate macrophage infiltration and microglial expansion in the corresponding dorsal root ganglia and spinal cord segments. RESULTS: Prophylactic RPNI prevented neuroma pain in both sexes; however, female rats displayed delayed pain attenuation when compared with males. Cold allodynia and thermal allodynia were attenuated exclusively in males. Macrophage infiltration was mitigated in males, whereas females showed a reduced number of spinal cord microglia. CONCLUSION: Prophylactic RPNI can prevent neuroma site pain in both sexes. However, attenuation of both cold allodynia and thermal allodynia occurred in males exclusively, potentially because of their sexually dimorphic effect on pathological changes of the central nervous system.

Comparison of surgical techniques used for prevention of neuroma in order to make more clear the role of the epineurium. An experimental study.

AIM: Several studies have been conducted for the prevention of neuroma and recently published experimental studies include interventions on epineurium. The techniques which include interventions on epinerium were compared to reveal the role of epinurium in neuroma prevention. MATERIAL E METHODS: 55 Sprague-Dawley rats were divided into five groups. Two of the groups were negative and positive controls. The proximal nerve stump was left "free" in the negative control group, while the stump was implanted in a muscle pocket in the positive control group following sciatic nerve transection. Experimental groups include epineural ligation, epineural stripping and epineural capping procedures. Follow-up period was six months. After sacrification of the rats, histopathologic and immunohistochemical examinations were conducted as well as real-time PCR studies for the assessment. Statistical analysis was performed. RESULTS: The most prominent neuroma formation was detected in the epineural capping group, while the least neuroma was observed in the epineural ligation group. DISCUSSION: Statistically significant differences were obtained when the three experimental groups were compared with both control groups. Interestingly there was no significant difference in-between the control groups in terms of preventing neuroma formation. CONCLUSION: epineural ligation group were found to be superior to both control groups as well as experimental groups. Use of epineural capping was concluded to increase the formation of neuroma rather than preventing. Intramuscular implantation of nerve stump had no preventive effect on neuroma formation. KEY WORDS: Capping, Epineurium, Ligation, Neuroma, Stripping.

Digital Nerve Management and Neuroma Prevention in Hand Amputations.

BACKGROUND: Hand and digit amputations represent a relatively common injury affecting an active patient population. Neuroma formation following amputation at the level of the digital nerve can cause significant disability and lead to revision surgery. One method for managing digital nerves in primary and revision partial hand amputations is to perform interdigital end-to-end nerve coaptations to prevent neuroma formation. METHODS: All patients with an amputation at the level of the common or proper digital nerves that had appropriate follow-up at our institution from 2010 to 2020 were included. Common or proper digital nerves were managed with either traction neurectomy or digital end-to-end neurorrhaphy. The primary outcome was the development of a neuroma. Secondary outcomes included revision surgery, complications, and visual analog pain scores. RESULTS: A total of 289 nerves in 54 patients underwent hand or digital amputation in the study period. Thirteen hands with 78 nerves (27%) underwent direct end-to-end coaptation with a postoperative neuroma incidence of 12.8% compared with 22.7% in the 211 nerves that did not have a coaptation performed. Significantly fewer patients reported persistent pain if an end-to-end coaptation was performed (0% vs. 11.8%, P < .01). The prevalence of depression and workers compensation status was significantly higher in in patients with symptomatic neuromas than in patients without symptomatic neuromas (P < .01). CONCLUSIONS: Digital nerve end-to-end neurorrhaphy is a method for neuroma prevention in partial hand amputations that results in decreased residual hand pain without increase complications. Depression and worker's compensations status were significantly associated with symptomatic neuroma formation.

Development of an acellular nerve cap xenograft for neuroma prevention.

Neuroma formation following limb amputation is a prevalent and debilitating condition that can deeply affect quality of life and productivity. Several approaches exist to prevent or treat neuromas; however, no approach is either consistently reliable or surgically facile, with high rates of neuroma occurrence and/or recurrence. The present study describes the development and testing of a xenogeneic nerve cap graft made from decellularized porcine nerve. The grafts were tested in vitro for cellular removal, cytotoxicity, mechanical properties, and morphological characteristics. The grafts were then tested in rat sciatic nerve gap reconstruction and nerve amputation models for 8 weeks. Gross morphology, electrophysiology, and histopathology assessments were performed to determine the ability of the grafts to limit pathologic nerve regrowth. In vitro testing showed well decellularized and demyelinated nerve cap graft structures without any cytotoxicity from residual reagents. The grafts had a proximal socket for the proximal nerve stump and longitudinally oriented internal pores. Mechanical and surgical handling properties suggested suitability for implantation as a nerve graft. Following 8 weeks in vivo, the grafts were well integrated with the proximal and distal nerve segments without evidence of fibrotic adhesions to the surrounding tissues or bulbous outgrowth of the nerve. Electrophysiology revealed absence of nerve conduction within the remodeled nerve cap grafts and significant downstream muscle atrophy. Histologic evaluation showed well organized but limited axonal regrowth within the grafts without fibrous overgrowth or neuromatous hypercellularity. These results provide proof of concept for a novel xenograft-based approach to neuroma prevention.

Controlling axonal regeneration with acellular nerve allograft limits neuroma formation in peripheral nerve transection: An experimental study in a swine model.

BACKGROUND: Symptomatic neuromata are a common indication for revision surgery following amputation. Previously described treatments, including traction neurectomy, nerve transposition, targeted muscle re-innervation, and nerve capping, have provided inconsistent results or are technically challenging. Prior research using acellular nerve allografts (ANA) has shown controlled termination of axonal regrowth in long grafts. The purpose of this study was to determine the ability of a long ANA to prevent neuroma formation following transection of a peripheral nerve in a swine model. MATERIALS AND METHODS: Twenty-two adult female Yucatan miniature swine (Sus scrofa; 4-6 months, 15-25 kg) were assigned to control (ulnar nerve transection only, n = 10), treatment (ulnar transection and coaptation of 50 mm ANA, n = 10), or donor (n = 2) groups. Nerves harvested from donor group animals were treated to create the ANA. After 20 weeks, the transected nerves including any neuroma or graft were harvested. Both qualitative (nerve architecture, axonal sprouting) and quantitative histologic analyses (myelinated axon number, cross sectional area of nerve tissue) were performed. RESULTS: Qualitative histologic analysis of control specimens revealed robust axon growth into dense scar tissue. In contrast, the treatment group revealed dwindling axons in the terminal tissue, consistent with attenuated neuroma formation. Quantitative analysis revealed a significantly decreased number of myelinated axons in the treatment group (1232 ± 540) compared to the control group (44,380 ± 7204) (p < .0001). Cross sectional area of nerve tissue was significantly smaller in treatment group (2.83 ± 1.53 mm2 ) compared to the control group (9.14 ± 1.19 mm2 ) (p = .0012). CONCLUSIONS: Aberrant axonal growth is controlled to termination with coaptation of a 50 mm ANA in a swine model of nerve injury. These early results suggest further investigation of this technique to prevent and/or treat neuroma formation.

Local Environment Induces Differential Gene Expression in Regenerating Nerves.

INTRODUCTION: Approximately 80% of amputations are complicated by neuromas. Methods for neuroma management include nerve translocation into bone and implantation into skeletal muscle grafts, which have also facilitated the development of regenerative neural interfaces to enable fixation of prosthetics with motor and sensory feedback. However, molecular-level differences between nerves in these environments have not been investigated. This study aimed to elucidate the physiology of regenerating nerves in different settings by assessing gene expression. MATERIALS AND METHODS: New Zealand white rabbits underwent transfemoral amputation with sciatic nerve transposition into the femur or tacked to skeletal muscle. At 5 wk, ribonucleic acid (RNA) sequencing of samples of distal nerve terminating in bone or muscle and nerve of the contralateral limb (control) identified differentially expressed genes (DEGs) and biochemical pathways (α = 0.05). RESULTS: Three samples of nerve housed in bone, four of nerve tacked to muscle, and seven naïve controls were analyzed. Relative to controls, nerve housed in bone had little within-group variation and 13,028 DEGs, and nerve tacked to muscle had dramatic within-group variation and 12,811 DEGs. These samples upregulated the following pathways: lysosome, phagosome, antigen processing/presentation, and cell adhesion molecule. Relative to nerve housed in bone, nerve tacked to muscle had 12,526 DEGs, demonstrating upregulation of pathways of B-cell receptor signaling, focal adhesion, natural killer-cell mediated cytotoxicity, leukocyte transendothelial migration, and extracellular matrix-receptor interactions. CONCLUSIONS: Nerve housed in bone has a more predictable molecular profile than does nerve tacked to muscle. Thus, the intramedullary canal may provide a more reliable setting for neuroma prevention and neural interfacing.

Techniques to prevent symptomatic neuroma in digital amputations.

The occurrence of a symptomatic neuroma on a digital amputation stump, whether traumatic or not, is a frequent complication that affects the patient's quality of life. The objective of this study was to analyze the complications inherent to the various techniques used to manage the nerves when performing digital amputation. We compared different surgical nerve management techniques to determine if one technique is more effective than another in preventing neuroma occurrence. We reviewed 105 patients over a 5-year period. A DN4 score greater than 4 and the modified Tinel test (percussion) showing a trigger zone allowed us to clinically diagnose symptomatic neuroma-related pain. We found 23 symptomatic neuromas out of 131 digital amputations. Twelve neuromas were found when the nerves had been neglected (12/33), eight were found in nerves treated by stripping (8/60), three when nerves were treated by stripping and thermal ablation (3/18). No neuroma was found in the five cases of centrocentral union of the two proper palmar digital nerves, in the 5 nerves buried in the bone or in the 9 nerves subjected to thermal ablation only. Management of the nerve is essential for the prevention of neuromas in digital amputations. New techniques such as bone burial and centrocentral union of the two stumps appear to be particularly effective.

"Decreasing Postamputation Pain with the Regenerative Peripheral Nerve Interface (RPNI)".

Over 185,000 limb amputations are performed in the United States annually, many of which are due to the sequelae of peripheral vascular disease. Symptomatic neuromas remain a significant source of postamputation morbidity and contribute to both phantom limb (PLP) and residual limb pain (RLP). While many interventions have been proposed for the treatment of symptomatic neuromas, conventional methods lead to a high incidence of neuroma recurrence. Furthermore, these existing methods do not facilitate an ability to properly interface with myoelectric prosthetic devices. The Regenerative Peripheral Nerve Interface (RPNI) was developed to overcome these limitations. The RPNI consists of an autologous free muscle graft secured around the end of a transected nerve. The muscle graft provides regenerating axons with end organs to reinnervate, thereby preventing neuroma formation. We have shown that this simple, reproducible, and safe surgical technique successfully treats and prevents neuroma formation in major limb amputations. In this paper, we describe RPNI surgery in the setting of major limb amputation and highlight the promising results of RPNIs in our animal and clinical studies.

Utilization of Techniques for Upper Extremity Amputation Neuroma Treatment and Prevention.

This study aimed to understand the current utilization of surgical approaches for nerve ending management in upper extremity amputation to prevent and treat nerve-related pain. We administered a survey to 190 of 1270 surgeons contacted by email (15% response rate) and analyzed their demographics, practice patterns, and perceptions regarding techniques for nerve ending management in upper extremity amputees. Although many surgical techniques were employed, most surgeons (54%) performed traction neurectomy during amputation and, alternatively, bury nerve into muscle if a neuroma subsequently develops (52%). Surgeons in practice less than 10 years were more likely to perform targeted muscle reinnervation (TMR) and regenerative peripheral nerve interfaces (RPNI) than surgeons in practice greater than 10 years (p<0.001). TMR and RPNI were performed more frequently for proximal amputations than distal amputations, but there is no consensus regarding the optimal timing to utilize these techniques. Surgeons commonly cited improved prosthetic control, pain, and phantom limb symptoms as reasons for performing TMR and RPNI. Increased physician compensation as a consideration was more commonly cited among TMR non-adopter than adopters (31% vs 14%, p=0.008). There is no consensus regarding techniques for the prevention or treatment of nerve ending pain in upper extremity amputees. TMR and RPNI are being utilized with increasing frequency and both patient and surgeon factors affect implementation in clinical practice.

Regenerative Peripheral Nerve Interfaces for the Treatment and Prevention of Neuromas and Neuroma Pain.

A neuroma occurs when a regenerating transected peripheral nerve has no distal target to reinnervate. This situation can result in a hypersensitive free nerve ending that causes debilitating pain to affected patients. No techniques to treat symptomatic neuromas have shown consistent results. One novel physiologic solution is the regenerative peripheral nerve interface (RPNI). RPNI consists of a transected peripheral nerve that is implanted into an autologous free skeletal muscle graft. Early clinical studies have shown promising results in the use of RPNIs to treat and prevent symptomatic neuromas. This review article describes the rationale behind the success of RPNIs and its clinical applications.

Nerve Interface Strategies for Neuroma Management and Prevention: A Conceptual Approach Guided by Institutional Experience.

In this article, the authors propose a strategy to manage and prevent symptomatic neuromas using a combination of nerve interface approaches. By using a reconstructive paradigm, these procedures provide the components integral to organized nerve regeneration, conferring both improvements in pain and potential for myoelectric control of prostheses in the future. Given the lack of evidence at this point indicating the advantage of any single nerve interface procedure, the authors propose a management approach that maximizes physiologic restoration while limiting morbidity where possible.

Dermatosensory Peripheral Nerve Interfaces: Prevention of Pain Recurrence Following Sensory Neurectomy.

Chronic pain is a significant health care problem. Many patients' pain can be linked to a neuropathic origin, diagnosed with a thorough history and physical examination, and confirmed with a diagnostic nerve block. There are new procedures designed to address neuropathic pain from symptomatic neuromas by providing physiologic targets for regenerating axons following neurectomy. Dermal wrapping of the end of a sensory nerve following transection, a technique called dermatosensory peripheral nerve interface, may provide an optimal environment to prevent neuroma pain and reduce chronic neuropathic pain.

Transradial Amputation With Pedicled Pronator Quadratus Interposition and Advanced Neuroma-Prevention Techniques.

Transradial amputation is a reconstructive option for upper-extremity trauma, infection, malignancy, and ischemia. The possible postoperative complications include residual radioulnar impingement and the development of a painful neuroma. In this report, a pedicled pronator quadratus flap interposition between the distal radius and ulna has been described. Additionally, various techniques to mitigate the development of symptomatic neuromas have been described.