Regenerative Peripheral Nerve Interface Research Articles

Prophylactic Regenerative Peripheral Nerve Interface (RPNI) Surgery in Pediatric Lower Limb Amputation Patients.

To evaluate the prophylactic effect of Regenerative Peripheral Nerve Interface (RPNI) surgery on pediatric post-amputation pain. Chronic post-amputation pain is a debilitating and refractory sequela of limb amputation affecting up to 83% of pediatric patients with limb loss, resulting in disability and decreased quality of life. We postulate that prophylactic RPNI surgery performed during amputation may decrease the incidence of symptomatic neuroma and development of phantom limb pain, as well as limit analgesic use among pediatric patients with limb loss. Retrospective chart review was performed on pediatric patients between the ages of 8 and 21 years who underwent major lower limb amputation with and without RPNI surgery. Documented neuroma and phantom limb pain scores as well as analgesic use was recorded. Narcotic use was converted to milligrams morphine equivalents per day (MME/day) while overall analgesic use was converted to Medication Quantification Scale version III (MQSIII) scores. Analysis was performed using Stata. Forty-four pediatric patients were identified; 25 RPNI patients and 19 controls. Seventy-nine percent of control patients developed chronic post-amputation pain versus 21% of RPNI patients (P<0.001). Among the patients who developed post-amputation pain, 20% of controls developed clinical neuroma pain, compared to 0% of RPNI patients (P<0.001). Additionally, RPNI patients demonstrated a significant decrease in pain score (P=0.007) and narcotic usage (P<0.01), compared to controls. Overall analgesic use did not vary significantly between groups. Prophylactic RPNI surgery shows promise for pediatric patients undergoing major lower limb amputation by preventing both symptomatic neuromas and possibly the development of phantom limb pain.

Regenerative peripheral nerve interfaces (RPNIs): an overview of innovative surgical approaches

Complications following amputation can be devastating for patients, including debilitating neuropathic pain, the inability to perform activities of daily living (ADLs) or gain meaningful employment. While prosthesis use allows patients to restore independence and reintegrate into daily activities, patients often abandon these devices. Despite the immense advancements in prosthetic technology, there is still a need for an interface that can provide a natural experience with accurate and reliable long-term control. The Regenerative Peripheral Nerve Interface (RPNI) is a simple surgical technique that offers real-time control of myoelectric prosthetic devices to restore extremity function. This stable, biological nerve interface successfully amplifies efferent motor action potentials, provides sensory feedback, and offers a more functional prosthetic device experience. Based on the principles of RPNI, novel surgical approaches have been developed to expand its applications and improve outcomes. This review article summarizes the utilization of the RPNI and its recent modifications of different neural interfaces in the setting of major limb amputation and musculoskeletal injuries.

Combined Targeted Muscle Reinnervation With Regenerative Peripheral Nerve Interfaces Decreases Long-Term Narcotic Use in Amputees: A Case Control Study.

Combined targeted muscle reinnervation with regenerative peripheral nerve interfaces ("TMRpni") is a recently described nerve management strategy that leverages beneficial elements of targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) techniques. This study aimed to evaluate the effect of TMRpni on long-term opioid consumption after amputation. We hypothesize that TMRpni decreases chronic opioid consumption in amputees. This is a retrospective cohort study of all patients who underwent TMRpni between 2019 and 2021. These patients were age-matched at a 1:1 ratio with a control group of patients who underwent amputation without TMRpni. Statistical analysis was performed using SPSS Version 28.0. Thirty-one age-matched pairs of patients in the TMRpni and control groups were included. At 30 days after surgery, there was no significant difference in number of patients who required an additional refill of their opioid prescriptions (45% vs 55%, P = 0.45) or patients who continued to actively use opioids (36% vs 42%, P = 0.60). However, at 90 days after surgery, there was a significantly lower number of patients from the TMRpni group who reported continued opioid use compared with the control group (10% vs 32%, P = 0.03). This study demonstrates that TMRpni may translate to decreased rates of chronic opiate use. Continued study is indicated to optimize TMRpni techniques and patient selection and to determine its long-term efficacy.

42. Clinical Outcomes Of Prophylactic Regenerative Peripheral Nerve Interface (RPNI) Surgery In Pediatric Lower Limb Amputation Patients

42. Clinical Outcomes Of Prophylactic Regenerative Peripheral Nerve Interface (RPNI) Surgery In Pediatric Lower Limb Amputation Patients

Reconstructive surgery for phantom and residual limb pain in post-conflict settings

Traumatic amputations remain one of the most frequent and disturbing wounds of armed conflict. In this scenario, most amputees develop residual and phantom limb pain, impacting their quality of life. There are several elective surgical procedures available for both conditions, such as neuroma excision followed by nerve reconstruction, nerve relocation, e.g., surgically implanting a transected nerve into a muscle, nerve transfers in cases of associated paralysis, and most recently, regenerative peripheral nerve interface surgery. Whenever possible in the post-conflict phase, a coordinated effort between traveling humanitarian surgeons specializing in reconstructive microsurgery and local healthcare providers is essential for successfully treating phantom and chronic residual limb pain in post-conflict amputees. While providing a detailed logistical framework for global humanitarian missions is beyond the scope of this article, we provide a brief perspective on a topic of utmost importance for reconstructive surgeons worldwide: the high-quality care and treatment of refugees and those whose lives have been impacted by conflict, disaster, or displacement.

Economic Cost-Benefit Analysis of Nerve Implanted into Muscle versus Targeted Muscle Reinnervation versus Regenerative Peripheral Nerve Interface, for Treatment of the Painful Neuroma.

This study investigated the relative cost utility of three techniques for the management of symptomatic neuromas after neuroma excision: (1) implantation of nerve into muscle, (2) targeted muscle reinnervation (TMR), and (3) regenerative peripheral nerve interface (RPNI). The costs associated with each procedure were determined using Common Procedural Terminology codes in combination with data from the Centers for Medicaid and Medicare Services Physician and Facility 2020 Fee Schedules. The relative utility of the three procedures investigated was determined using changes in Patient-Reported Outcomes Measurement Information System (PROMIS) and Numeric Rating Scale (NRS) pain scores as reported per procedure. The relative utility of each procedure was reported in terms of quality-adjusted life years (QALYs), as is standard in the literature. The least expensive option for the surgical treatment of painful neuromas was nerve implantation into an adjacent muscle. In contrast, for the treatment of four neuromas, as is common postamputation, TMR without a microscope was found to cost $50,061.55 per QALY gained, TMR with a microscope was found to cost $51,996.80 per QALY gained, and RPNI was found to cost $14,069.28 per QALY gained. While RPNI was more expensive than nerve implantation into muscle, it was still below the standard willingness-to-pay threshold of $50,000 per QALY, while TMR was not. Evaluation of costs and utilities associated with the various surgical options for the management of painful neuromas suggest that nerve implantation into muscle is the least expensive option with the best improvement in QALY, while demonstrating comparable outcomes to TMR and RPNI with regard to pain symptoms.

Regenerative peripheral nerve interface in the prevention and treatment of post-amputation pain: a systematic review

Regenerative peripheral nerve interface in the prevention and treatment of post-amputation pain: a systematic review

Merging Humans and Neuroprosthetics through Regenerative Peripheral Nerve Interfaces.

Limb amputations can be devastating and significantly affect an individual's independence, leading to functional and psychosocial challenges in nearly 2 million people in the United States alone. Over the past decade, robotic devices driven by neural signals such as neuroprostheses have shown great potential to restore the lost function of limbs, allowing amputees to regain movement and sensation. However, current neuroprosthetic interfaces have challenges in both signal quality and long-term stability. To overcome these limitations and work toward creating bionic limbs, the Neuromuscular Laboratory at University of Michigan Plastic Surgery has developed the Regenerative Peripheral Nerve Interface (RPNI). This surgical construct embeds a transected peripheral nerve into a free muscle graft, effectively amplifying small peripheral nerve signals to provide enhanced control signals for a neuroprosthetic limb. Furthermore, the RPNI has the potential to provide sensory feedback to the user and facilitate neuroprosthesis embodiment. This review focuses on the animal studies and clinical trials of the RPNI to recapitulate the promising trajectory toward neurobionics where the boundary between an artificial device and the human body becomes indistinct. This paper also sheds light on the prospects of the improvement and dissemination of the RPNI technology.

Secondary Trigger Point Deactivation Surgery for Nerve Compression Headaches: A Scoping Review.

Primary trigger point deactivation surgery has been successful in reducing or eliminating nerve compression headaches between 79% and 90% of the time. The aim of this review article was to discuss the factors that contribute to index trigger point deactivation surgery failure, the importance of reevaluating trigger points following failure, and the options for secondary surgery. A literature search was performed using a combination of keywords involving "chronic headache" and "nerve deactivation surgery," in databases until February 2023. Data of 1071 patients were evaluated and included (11 articles). The failure rate after index trigger point deactivation surgery occurs is approximately 12%, primarily due to incomplete primary trigger point deactivation. Secondary trigger points may not appear until the primary trigger is eliminated, which occurs in 17.8% of patients. Reevaluation of previously diagnosed trigger points as well as uncovered trigger points and additional preoperative testing is indicated to help determine candidacy for further surgical deactivation. To address scarring that could contribute to failure, corticosteroid injection, acellular dermal matrix, adipofascial fat, or expanded polytetrafluoroethylene sleeves have been described with beneficial effects. For neuroma management, regenerative peripheral nerve interface, targeted muscle reinnervation, a combination of both, relocation nerve grafting, or nerve capping have also been described. Neurectomy can be performed when patients prefer anesthesia and/or paresthesia over current pain symptoms. Secondary trigger point deactivation surgery is indicated when there is suspicion of incomplete deactivation, internal scarring, neuroma, or newly-diagnosed trigger points.

Regenerative Peripheral Nerve Interface Surgery for the Management of Chronic Posttraumatic Neuropathic Pain.

Chronic pain resulting from peripheral nerve injury remains a common issue in the United States and affects 7 to 10% of the population. Regenerative Peripheral Nerve Interface (RPNI) surgery is an innovative surgical procedure designed to treat posttraumatic neuropathic pain, particularly when a symptomatic neuroma is present on clinical exam. RPNI surgery involves implantation of a transected peripheral nerve into an autologous free muscle graft to provide denervated targets to regenerating axons. RPNI surgery has been found in animal and human studies to be highly effective in addressing postamputation pain. While most studies have reported its uses in the amputation patient population for the treatment of neuroma and phantom limb pain, RPNI surgery has recently been used to address refractory headache, postmastectomy pain, and painful donor sites from the harvest of neurotized flaps. This review summarizes the current understanding of RPNI surgery for the treatment of chronic neuropathic pain.

Management of Neuropathic Pain with Neurectomy Combined with Dermal Sensory Regenerative Peripheral Nerve Interface (DS-RPNI).

Neuropathic pain affects a large percentage of the U.S. population and leads to tremendous morbidity. Numerous nonsurgical and surgical treatments have been utilized to try and manage neuropathic pain with varying degrees of success. Recent research investigating ways to improve prosthetic control have identified new mechanisms for preventing neuromas in both motor and sensory nerves with free muscle and dermal grafts, respectively. These procedures have been used to treat chronic neuropathic pain in nonamputees, as well, in order to reduce failure rates found with traditional neurectomy procedures. Herein, we focus our attention on Dermal Sensory-Regenerative Peripheral Nerve Interfaces (DS-RPNI, free dermal grafts) which can be used to physiologically "cap" sensory nerves following neurectomy and have been shown to significantly decrease neuropathic pain.

Regenerative Peripheral Nerve Interface (RPNI) Surgery for Mitigation of Neuroma and Postamputation Pain.

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 disability1-3. 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. 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. 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. 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. 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 postoperatively4,5. 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. 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.

Electrical Stimulation of Regenerative Peripheral Nerve Interfaces (RPNIs) Induces Referred Sensations in People With Upper Limb Loss.

Individuals with upper limb loss lack sensation of the missing hand, which can negatively impact their daily function. Several groups have attempted to restore this sensation through electrical stimulation of residual nerves. The purpose of this study was to explore the utility of regenerative peripheral nerve interfaces (RPNIs) in eliciting referred sensation. In four participants with upper limb loss, we characterized the quality and location of sensation elicited through electrical stimulation of RPNIs over time. We also measured functional stimulation ranges (sensory perception and discomfort thresholds), sensitivity to changes in stimulation amplitude, and ability to differentiate objects of different stiffness and sizes. Over a period of up to 54 months, stimulation of RPNIs elicited sensations that were consistent in quality (e.g. tingling, kinesthesia) and were perceived in the missing hand and forearm. The location of elicited sensation was partially-stable to stable in 13 of 14 RPNIs. For 5 of 7 RPNIs tested, participants demonstrated a sensitivity to changes in stimulation amplitude, with an average just noticeable difference of 45 nC. In a case study, one participant was provided RPNI stimulation proportional to prosthetic grip force. She identified four objects of different sizes and stiffness with 56% accuracy with stimulation alone and 100% accuracy when stimulation was combined with visual feedback of hand position. Collectively, these experiments suggest that RPNIs have the potential to be used in future bi-directional prosthetic systems.

Pediatric Regenerative Peripheral Nerve Interface and Targeted Muscle Reinnervation at the Time of Major Lower Extremity Amputation: 1 Year Outcomes

Pediatric Regenerative Peripheral Nerve Interface and Targeted Muscle Reinnervation at the Time of Major Lower Extremity Amputation: 1 Year Outcomes

Regenerative Peripheral Nerve Interface Surgery and Targeted Muscle Reinnervation for the Treatment of Chronic Pain in Limb Amputees.

Regenerative Peripheral Nerve Interface Surgery and Targeted Muscle Reinnervation for the Treatment of Chronic Pain in Limb Amputees.

Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interfaces for Prophylactic Pain Control in Neurofibromatosis Type 1 Amputees.

Neurofibromatosis type 1 (NF1) is an inherited multisystem disorder that affects one in 2500 to one in 5000 people. Neurofibromas are the second-most common benign peripheral nerve sheath tumors arising from Schwann cells and are associated with neurofibromatosis. Chronic pain and opioid use is elevated in patients with NF1 when neurofibromas are associated with sensory nerves. Surgical excision is the primary treatment of neurofibromas when they become large, malignant, or painful, but they are associated with high rates of recurrence. Targeted muscle reinnervation and regenerative peripheral nerve interfaces are two prophylactic surgical techniques that are used to prevent neuroma-associated residual limb and phantom pain in amputees. Both techniques stimulate physiologic regeneration of the nerve via trophic stimulus from denervated muscle. This case report describes two patients with NF1 who underwent targeted muscle reinnervation and/or regenerative peripheral nerve interfaces at the time of amputation. Despite the abnormality of the peripheral nerves involved, both patients had excellent postoperative outcomes with minimal pain. This experience advocates for the use of prophylactic nerve management techniques in neurofibromatosis patients despite baseline nerve pathology.

Improving outcomes in traumatic peripheral nerve injuries to the upper extremity.

Peripheral nerve lesions of the upper extremity are common and are associated with devastating limitations for the patient. Rapid and accurate diagnosis of the lesion by electroneurography, neurosonography, or even MR neurography is important for treatment planning. There are different therapeutic approaches, which may show individual differences depending on the injured nerve. If a primary nerve repair is not possible, several strategies exist to bridge the gap. These may include autologous nerve grafts, bioartificial nerve conduits, or acellular nerve allografts. Tendon and nerve transfers are also of major importance in the treatment of nerve lesions in particular with long regeneration distances. As a secondary reconstruction, in addition to tendon transfers, there is also the option for free functional muscle transfer. In amputations, the prevention of neuroma is of great importance, for which different strategies exist, such as target muscle reinnervation, regenerative peripheral nerve interface, or neurotized flaps. In this article, we give an overview of the latest methods for the therapy of peripheral nerve lesions.

Hybrid Bionic Nerve Interface for Application in Bionic Limbs.

Intuitive and perceptual neuroprosthetic systems require a high degree of neural control and a variety of sensory feedback, but reliable neural interfaces for long-term use that maintain their functionality are limited. Here, a novel hybrid bionic interface is presented, fabricated by integrating a biological interface (regenerative peripheral nerve interface (RPNI)) and a peripheral neural interface to enhance the neural interface performance between a nerve and bionic limbs. This interface utilizes a shape memory polymer buckle that can be easily implanted on a severed nerve and make contact with both the nerve and the muscle graft after RPNI formation. It is demonstrated that this interface can simultaneously record different signal information via the RPNI and the nerve, as well as stimulate them separately, inducing different responses. Furthermore, it is shownthat this interface can record naturally evoked signals from a walking rabbit and use them to control a robotic leg. The long-term functionality and biocompatibility of this interface in rabbits are evaluated for up to 29 weeks, confirming its promising potential for enhancing prosthetic control.

Vascularized Denervated Muscle Targets for Headache Surgery-Presentation and Surgical Management.

Patients with substantial trauma to their occipital nerves and those with recurrent or persistent chronic headaches after occipital nerve decompression surgery require transection of their greater occipital and/or lesser occipital nerves to control debilitating pain. Current techniques, such as burying the transected nerve stump in nearby muscle, do not prevent neuroma formation, and more advanced techniques, such as targeted muscle reinnervation and regenerative peripheral nerve interface, have demonstrated only short-term anecdotal success in the context of headache surgery. Vascularized denervated muscle targets (VDMTs) are a novel technique to address the proximal nerve stump after nerve transection that has shown promise to improve chronic nerve pain and prevent neuroma formation. However, VDMTs have not been described in the context of headache surgery. Here authors describe the etiology, workup, and surgical management of 2 patients with recurrent occipital neuralgia who developed vexing neuromas after previous surgery and were successfully treated with VDMTs, remaining pain-free at 3-year follow-up.

Google Trends Analysis of Peripheral Nerve Disease and Surgery

Despite advances in the surgical management of peripheral nerve pathologies over the past several decades, it is unknown how public awareness of these procedures has changed. We hypothesize that Google searches for peripheral nerve surgery have increased over time. Google Trends was queried for search volumes of a list of 40 keywords related to the following topics in peripheral nerve surgery: spasticity, nerve injury, prosthetics, and nerve pain. Monthly relative search volume over the first 5years of the study period (2010-2014) was compared with that of the last 5years (2018-2022) of the study period. Search volumes for keywords "nerve injury," "nerve laceration," "peripheral nerve injury," "nerve repair," "nerve transfer", "neuroma," "neuroma pain," "nerve pain," "nerve pain surgery," and "neuroma pain surgery" all increased more than 10% points in relative search volume over the study period (P < 0.0001 for each keyword). In contrast, searches for "rhizotomy," "spasticity surgery," "targeted muscle reinnervation," "bionic arm," and "myoelectric prosthesis" either decreased or remained stable. Technical terms such as "selective neurectomy," "hyperselective neurectomy," "regenerative peripheral nerve interface," and "regenerative peripheral nerve interface surgery" did not have adequate search volume to be reported by Google Trends. The increase in Google searches related to nerve injury and pain between 2010 and 2022 may reflect increasing public recognition of these clinical entities and surgical techniques addressing them. Technical terms relating to nerve pain are infrequently searched, surgeons should use plain English terms for online discovery. Interest in spasticity and myoelectric prosthetics remains stable, indicating an opportunity for better public outreach.