Neoplasms

All Conditions

Nervous System Diseases

Neuroma

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

Anti-Arrhythmia Agents

Channel Blockers

Central Nervous System Depressants

All Drugs and Chemicals

Lidocaine

The control group received traditional amputation.The proximal nerve is blocked with lidocaine and cut off. The end of the nerve retracted as far as possible and the bleeding point is ligated if necessary.

The experimental group received regenerative peripheral nerve interface（RPNI） surgery.

Each RPNI unit consists of nerve stump and free autologous muscle graft that is cut off from healthy muscle of the amputated limb. The muscle graft is approximately 30×15×5 mm.The ends of the transected nerve are placed within the muscle belly of the free muscle grafts in an orientation that is parallel to the muscle fibers. Next, the nerve is secured distally with 6-0 non-absorbable monofilament sutures in an epimysial-to-epineurial fashion. The nerve is then wrapped around completely via muscle graft and epimysial securing sutures. All RPNI units are placed in areas remote from the surgical incision and from the weight-bearing surface of the limb.

preventive regenerative peripheral nerve interface reconstruction

Guangxue Li

The trial will be carried out in Peking University People's Hospital. The whole trial will last 3 years. Amputees from orthopedics and vascular surgery will be distributed into two groups randomly and receive different treatments including traditional resection and regenerative peripheral nerve interface(RPNI) surgery.The pain outcome,the impact of post-amputation pain on life and the utilization rate of prostheses will be collected to study the efficacy, safety and prognosis of preventive regenerative peripheral nerve interface reconstruction in amputees.

Investigators believe that RPNI can effectively reduce the incidence of post-amputation pain, reduce the degree of pain, improve the wearing rate of prostheses, and help patients return to normal life.

The investigator who perform the operations cannot be blinded because of the use of manual techniques.

The Efficacy of Preventive Regenerative Peripheral Nerve Interface(RPNI) Reconstruction in Amputees

The Efficacy, Safety and Prognosis of Preventive Regenerative Peripheral Nerve Interface(RPNI) Reconstruction in Amputees: Study Protocol for a Cohort Study

Patient-Reported Outcomes Measurement Information System (NRS, PROMIS) were used to assess postamputation pain.The intensity of pain is described by 11 points from 0 (painless) to 10 (the most severe pain).

Whether the subject wears a prosthetic limb, and if so, what kind of prosthetic limb is worn.

Whether there is tumor recurrence or metastasis.

The medical outcomes study-short from(MOS-SF 36) is used to evaluate the difference between the RPNIs group and the control group in the quality of life after amputation.The SF-36 scale consists of 36 questions with eight dimensions:physiological function, role-physiological, physical pain, general health, vitality, social function, role-emotional, and mental health. The scoring method was used for each dimension, ranging from 0 to 100 points. The higher the score, the better the health status.

Peking University People's Hospital

Deputy Chief Physician

Symptoms and General Pathology

Behaviors and Mental Disorders

Pain

Phantom Limb

Neuralgia

Perceptual Disorders

Neurobehavioral Manifestations

Neurologic Manifestations

Pain, Postoperative

Postoperative Complications

Peripheral Nervous System Diseases

Neuromuscular Diseases

The surgical procedure comprises three steps: preparation of the donor nerve, identification of a motor branch to the targeted muscle, and nerve coaptation. To prepare the donor nerve, the surgeon will identify the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Next, the surgeon will identify a motor branch to a nearby target muscle and will confirm muscle contraction using a hand-held nerve stimulator. The motor branch to the target muscle will be transected as close as possible to its entry point without tension. In the final step, the previous nerve stump from which the neuroma was resected will be transferred and coapted to the newly severed motor branch that innervates the target muscle and secured by 2-3 non-resorbable monofilament sutures. The surgery time is approximately 2-3 hours and it takes place in the hospital.

The RPNI procedure involves construction of a residual peripheral nerve split into several nerve fascicles and implanted into free skeletal muscle grafts. First, the surgeon identifies the nerve with a painful neuroma and resect the neuroma up to healthy fascicles. Then, a longitudinal intraneural dissection will be performed exposing its fascicles. Next, autologous muscle grafts will be harvested from a healthy donor site, and the dissected nerve stumps will be placed parallel to the muscle fibers. The nerve stump will be secured to the muscle graft, thereafter the graft will be wrapped around the nerve stump and anchored in the folded graft, thus creating an RPNI. This will be repeated for each fascicle obtained from splitting the transected nerve. Lastly, the RPNIs will be placed in a protected area. The surgery time is approximately 2-3 hours and it takes place in the hospital.

The standard neuroma treatment, also called neuroma transposition, includes excision of the terminal neuroma and burying the nerve into an adjacent deep muscle.The standard neuroma treatment entails the excision of the terminal neuroma and then implanting the nerve into an adjacent muscle. Firstly, the surgeon will identify the nerve with a painful neuroma and thereafter resect the neuroma up to healthy fascicles. Next, the surgeon will identify a nearby muscle which is not involved in joint motion and has limited output opportunities for the nerve. The nerve will then be channeled at least 1 cm inside the muscle without applying any tension to it and secured by 1-2 non-resorbable monofilament sutures. The identified nerve with the painful neuroma will not be treated with any additional therapy than the resection (e.g., diathermy, pharmacotherapy, crushing, etc.). The surgery time is approximately 1-2 hours and it takes place in the hospital.

Surgical procedure used to rewire injured proximal nerves to motor nerves directly innervating an otherwise redundant target muscle.

Targeted Muscle Reinnervation (TMR)

Surgical procedure where the the nerve is split into fascicles and wrapped in free muscle grafts.

Regenerative Peripheral Nerve Interface (RPNI)

Surgical procedure where the neuroma is excised and the nerve stump is buried in an adjacent deep muscle.

Standard neuroma treatment, neuroma excision, and muscle burying

Emily Pettersen, MSc

Max Ortiz Catalan, PhD

Jason Ko, MD, PhD

Gregory Dumanian, MD, PhD

Ian Valerio, MD, PhD

Kyle Eberlin, MD, PhD

Paul Cederna, MD, PhD

Theodore Alexander Kung, MD, PhD

Michael Lo, MD, PhD

Michael Leung, MD, PhD

Adil Ladak, MD, PhD

Hollie Power, MD, PhD

Jacqueline Hebert, MD, PhD

Juan Manuel Breyer, MD, PhD

Paolo Sassu, MD, PhD

Francesca Pedrini, MD

Carina Reinholdt, MD, PhD

Hannes Granberg, MD

Aidan Roche, MD, PhD

Andrew Hart, MD, PhD

Lorraine Harrington, MD, PhD

This is a double-blind randomised controlled trial (RCT) which compares the effectiveness of three surgical techniques for alleviating residual limb pain (RLP), neuroma pain and phantom limb pain (PLP). The three surgical treatments are Targeted Muscles Reinnervation (TMR), Regenerative Peripheral Nerve Interface (RPNI), and an active control (neuroma excision and muscle burying). Patients will be follow-up for 4 years.

Residual limb pain (RLP), neuroma pain, and phantom limb pain (PLP) can develop after the loss of a body part and fall within the umbrella term postamputation pain. However, the underlaying causes to postamputation pain are diverse and must be addressed accordingly. Surgical treatments for RLP have become a popular approach and have shown great potential for successful outcomes. The two surgical interventions, Targeted Muscle Reinnervation (TMR) and Regenerative Peripheral Nerve Interface (RPNI), are globally used in pain management therapies.

This is a multi-centre, double-blind, superiority RCT which takes place at 9 hospitals in 7 countries:the Sahlgrenska University Hospital in Gothenburg, Sweden; the Rizzoli Orthopaedic Institute in Bologna, Italy; the University of Alberta Hospital in Edmonton, Canada; Worker Hospital in Santiago, Chile; the NHS Lothian, NHS Clyde \& Greater Glasgow, and NHS Grampian, UK; Dandenong Hospital, Monash Health in Melbourne, Australia; the Northwestern Memorial Hospital in Chicago, USA; the University of Michigan Health System in Ann Arbor, Michigan, USA; and within the Massachusetts General Hospital in Boston, USA. One hundred ten participants will be recruited and randomly assigned to one of three surgical treatments (TMR, RPNI, or control) in an equal allocation ratio (n = 37 per group). Each participant will be followed up short term (1, 3, 6, and 12 months post-surgery) and long term (2 and 4 years post-surgery). After the 12-month follow-up, the study will be unblinded for the evaluator and the participants. If the participants are unsatisfied with the outcome of the treatment, they may request one of the other treatments. In such a case, a medical evaluation and further treatment options will be discussed in consultation with the clinical investigator at the site.

The study design is chosen to be able to follow RLP, neuroma pain and PLP intensity before and after surgical treatment as well as to investigate how pain develops up to four years post-surgery. The evaluation methods in the study are based on previously used methods in the literature for RLP-, neuroma- and PLP-related pain research. The questionnaires are previously used in clinical settings.

Surgical Treatments for Postamputation Pain

Difference in residual limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.

Difference in neuroma pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-month follow-up visit.

Difference in phantom limb pain intensity will be measured by numerical rating scale (NRS, 0-10), where 0 - no pain and 10 - worst imaginable pain, between baseline period and at the 12-months follow-up visit.

Vastra Gotaland Region

Göteborg University

Chalmers University of Technology

Istituto Ortopedico Rizzoli

Hospital del Trabajador de Santiago

NHS Lothian

NHS Greater Clyde and Glasgow

NHS Grampian

Northwestern Memorial Hospital

University of Michigan

Massachusetts General Hospital

Dandenong Hospital

The Bionics Institute of Australia

University of Alberta

Center for Bionics and Pain Research

Professor

This arm includes patients with transhumeral amputation that will receive the e-OPRA implant system.

The e-OPRA is an implant system that provides an alternative to traditional socket prostheses by establishing a direct, load-bearing link between the patient's skeleton and a prosthesis for transhumeral amputees. The anchorage element of the system is implanted directly into the bone while the electrodes that provide control signals for the prosthesis are implanted into muscle grafts on the transhumeral amputation.

e-OPRA (electronic-Osseoanchored Prosthese for the Rehabilitation of Amputees)

This early feasibility study proposes to evaluate use of the electronic-Osseoanchored Prostheses for the Rehabilitation of Amputees (e-OPRA) device, a transhumeral implant system for direct skeletal anchorage of amputation prostheses, with a test prosthesis. The e-OPRA System is being investigated to better understand the ability to improve the functionality of the prosthesis and enhance the sense of embodiment of the prosthesis itself. This will be a 10 subject Early Feasibility Study in which the primary objective is to capture preliminary safety and effectiveness information on the implanted e-OPRA system. With the addition of electrodes to the muscle segments, this biological interface allows for both the extraction of fine motor control signals from the nerve fascicles and the generation of sensory percepts via electrical stimulation of the muscles. In addition, electrodes placed on muscles within the residuum with native vascularization and innervation also allow the extraction of critical motor control signals and the generation of sensory feedback through muscle stimulation. The electrical activity recorded from these muscle segments (called electromyography or EMG) is specific to certain movements and can be used to determine precisely how a person wants to move their arm and hand. Use of the e-OPRA device with the well-documented neuro-electronic capabilities of EMG control systems provides an alternative to traditional socket prostheses by establishing a direct, loadbearing link between the patient's skeleton and prosthesis.

An Osseoanchored Percutaneous Prosthesis Study Evaluating Stable Neural Signal Transmission in Subjects With Transhumeral Amputations

Efficacy will be evaluated by signal-to-noise ratio during maximum voluntary contraction of at least two independent myoelectric signals.

Safety will be evaluated by assessing the adverse event type, incidence, timing, severity, treatment, outcome, and relationship to the device.

The number of subjects achieving 2 or more degrees of freedom summarized using frequency and percentage

Change in Pain Level as measured by SF-36 survey Pain will be assessed using the SF-36 survey instrument, to be filled out by the participant before and after each surgical procedure performed and at a minimum of once per month while electrodes remain implanted. Scores range from 0 - 100 Lower scores = more disability, higher scores = less disability.

Change in Pain Level as measured by LANSS survey Pain will be assessed using the LANSS survey instrument, to be filled out by the participant before and after each surgical procedure performed and at a minimum of once per month while electrodes remain implanted. A score greater than 12 (From 0 to 15) indicates neuropathic pain.

Measured by the participant performing the SHAP at each experimental visit. A higher score indicates increased upper limb functionality.

Measured by the participant performing the AM-ULA at each experimental visit. A higher score indicates increased upper limb functionality.

Measured by the participant performing the UEFT at each experimental visit. A higher score indicates increased upper limb functionality.

Change in Pain Level as measured by LANSS survey Pain will be assessed using the LANSS survey instrument, to be filled out by the participant before surgery and at each experimental visit. The Numeric Rating Scale measures (adult, pediatric, parent proxy) each consist of a single item rating pain on average over the past 7 days from 0 (no pain) to 10 (worst pain you can think of). The items are not calibrated and do not produce a T-score. Instead, raw response scores (0 to 10) should be used for analyses.

Measured by the participant filling out the DASH questionnaire before surgery and at each experimental visit every 3 months. A score closer to 1 indicates higher functionality. The DASH Outcome Measure is scored in two components: the disability/symptom section (30 items, scored 1-5) and the optional high performance Sport/Music or Work section (4 items, scored 1-5). The raw is transformed to a zero-to-100 scale, with an average score closer to 100 meaning higher disability (unable to perform tasks).

Measured by the participant assigning a number 1-10 of their pain while viewing the DVPRS. A score close to of 0 indicates zero pain, and a score of 10 indicates maximum pain as bad is it can be.

Measured by the participant filling out the EQ-5D-5L before surgery and at each experimental visit every 3 months. Each question is scored from 1-5, with 5 having the most difficulty in that area.

University of California, San Francisco

Robert Oneal Professor of Plastic Surgery, Chief of the Section of Plastic Surgery

In this arm, participants will have an initial surgery to place partial muscle grafts on the amputated nerves. After a healing period, the participant will have a shorter surgical procedure to implant the electrodes onto the muscle grafts and in residual muscles. After another healing period, experiments with prosthetic control and sensory feedback will begin.

In this arm, participants have already had partial muscle grafts placed on the amputated nerves to control neuroma growth. The participant will have a short surgical procedure to implant the electrodes onto the muscle grafts and in residual muscles. After a healing period, experiments with prosthetic control and sensory feedback will begin.

The device, a bipolar percutaneous intramuscular electromyography electrode, is intended for use in upper-limb amputation patients who have received the regenerative peripheral nerve interface surgical procedure, in order to enable the use of advanced prosthetic arms and hands.

a bipolar percutaneous intramuscular electromyography electrode

Paul Cederna, M.D.

Mona Moore

This is a single center, 10 subject early feasibility study in which the primary objective is to ensure the safety of percutaneous intramuscular electrodes implanted in surgically-created RPNI constructs (free muscle grafts attached to the amputated nerves) in subjects with upper limb amputation. The secondary objectives are to assess the efficacy of the electrodes in recording electromyographic signals from the RPNI grafts and in delivering electrical stimulation to the RPNI grafts to evoke sensory percepts.

This study will enroll people who have had upper limb amputations or are planning to have upper limb amputations. Each participant who does not already have RPNI grafts at the time of enrollment will have RPNI grafts implanted on branches or fascicles of nerves of the upper extremity. Several or all RPNI grafts will have a single bipolar electrode implanted in the muscle tissue, with the proximal end tunneled to a percutaneous exit point on the residual limb. Additional electrodes may be placed in innervated muscles in the residual limb, in order to provide a control comparison as well as to provide additional input during prosthesis control experiments. Electrodes will remain implanted for up to 7 years, with a minimum of 2 study visits per month to perform prosthesis control and sensory feedback experiments. Study endpoint will be assessed at a minimum of once per month while electrodes remain implanted. After a maximum of 7 years, electrodes will be explanted and the study ended after a 1 week follow-up.

The results of this study will inform the final design of the electrodes to be implanted long-term in RPNI grafts to provide an increased number of degrees of freedom for prosthetic control and sensory and proprioceptive feedback. This will drastically improve the functionality of the prosthesis, enhance the sense of embodiment of the prosthesis itself, and enable future investigation of a fully-implanted (non-percutaneous) prosthesis control system.

Short-term Implanted Electrodes Following Regenerative Peripheral Nerve Surgery for Improving Prosthetic Limb Control Signals

Pain will be assessed using the SF-36 survey instrument, to be filled out by the participant before and after each surgical procedure performed and at a minimum of once per month while electrodes remain implanted. Two questions related to pain with a score closer to 0 means a pain increase

Pain will be assessed using the LANSS survey instrument, to be filled out by the participant before and after each surgical procedure performed and at a minimum of once per month while electrodes remain implanted. A score greater than 12 indicates neuropathic pain.

Phantom pain will be assessed using the Phantom Limb Questionnaire, to be filled out by the participant before and after each surgical procedure performed and at a minimum of once per month while electrodes remain implanted. This 9-item instrument measures phantom pain on a scale of 0-4, where 0-no pain at all and 4=very severe pain.

RPNI tissue degeneration will be assessed by changes in pain scores (see above) and measurements of recording efficacy.

Recording efficacy will be assessed using two signal quality measures:

1. Peak-to-peak signal amplitude during maximum voluntary contraction
2. Signal-to-noise ratio during maximum voluntary contraction

Electrode migration outside of the implanted RPNI graft or muscle will be assessed by changes in recording efficacy, as described above, and by ultrasound examination as necessary. Electrode extrusion and implantation complications will be assessed by adverse events reported by both the participant and the study physicians. At each study visit, the participant will be asked to report any issues, and will have a basic examination of the affected limb performed by study physicians and/or trained staff.

Efficacy will be assessed, for each implanted electrode using two calculated signal quality measures: Peak-to-peak signal amplitude during maximum voluntary contraction and signal-to-noise ratio during maximum voluntary contraction.

Stimulation data will be recorded at least once per month while electrodes remain implanted. Stimulation threshold will be determined using the range of sensory feedback necessary to evoke a sensory percept.

National Institute of Neurological Disorders and Stroke (NINDS)

Robert Oneal Professor and Chief of Plastic Surgery; Professor, Biomedical Engineering

In this operation, the surgeon will make a skin incision and carefully identify nerves that were likely to have been injured during the amputation surgery. These nerves are then "cleaned up" to be rerouted and connected to smaller nerves that control individual muscles. The connection to nerves that run into muscles is thought to be helpful in directing the nerve healing process and reducing the risk of developing pain in the future. This operation takes 2 - 4 hours and occurs in the hospital. Follow up requires six to seven clinic visits with the surgeon over the course of one year, at which time standard questionnaires will be used to assess pain.

In this operation, the surgeon will make a skin incision and carefully identify nerves that were likely to have been injured during the amputation surgery. The nerves are then "cleaned up" to enhance the possibility of healthy healing. Then the surgeon takes a small sample from a muscle (usually one close by to the nerves that are being operated on but sometimes through a second incision in the arm or leg, depending on the exact medical situation) and form something called a "muscle graft". The muscle graft is used to wrap the cleaned ends of the nerves mentioned above. This is thought to be helpful in directing the nerve healing process and reducing the risk of developing pain in the future. This operation takes 1 - 3 hours and occurs in the hospital. Follow up requires six to seven clinic visits with the surgeon over the course of one year, at which time standard questionnaires will be used to assess pain.

In this operation, the surgeon will make a skin incision and carefully identify nerves that were likely to have been injured during the amputation surgery. The nerves are then "cleaned up" to enhance the possibility of healthy healing. The surgeon will then identify a local muscle along with a small artery and vein that supply blood to part of the muscle. A small sample of muscle, still attached to the artery and vein, is then created. The nearby nerves are then nestled into this segment of muscle that is still connected to the artery and vein. This is thought to be helpful in directing the nerve healing process and reducing the risk of developing pain in the future. This operation takes 2 - 4 hours and occurs in the hospital. Follow up requires six to seven clinic visits with the surgeon over the course of one year, at which time standard questionnaires will be used to assess pain.

Surgical procedure to connect injured proximal nerve stumps to motor nerve branches directly innervating a muscle

Surgical procedure to wrap the ends of injured nerves in small muscle grafts

RPNI

Surgical procedure that creates a small muscle graft that is both denervated and vascularized, which will then receive the damaged nerve ending

VDMT

Sami Tuffaha, MD

Amputees often suffer from relentless pain and disability resulting from symptomatic neuromas within the amputation stumps. When conservative measures fail to address these symptoms, two contemporary surgical approaches to treat symptomatic neuromas have become the most popular. Targeted muscle reinnervation (TMR) is a procedure which involves transferring the injured proximal nerve stump into a terminal nerve branch entering muscle, such that the axons from the proximal nerve stump will regenerate into the muscle and thereby prevent neuroma recurrence. Regenerative peripheral nerve interfaces (RPNIs) are muscle grafts placed on the proximal nerve stumps that serve as targets for the regenerating axons from the proximal nerve stumps.

While TMR and RPNIs have demonstrated promise for the treatment of symptomatic neuromas, prospective comparative data comparing outcomes with these two approaches is lacking.

The investigators have recently developed a novel approach to treat symptomatic neuromas that provides vascularized, denervated muscle targets (VDMTs) for the axons regenerating from the severed proximal nerve stump to reinnervate. This is accomplished by islandizing a segment of muscle on its blood supply and ensuring complete denervation prior to implanting the neighboring transected nerve stump into this muscle. VDMTs offer theoretical benefits in comparison to RPNIs and TMR that the investigators also aim to test in the proposed study.

The investigators' objective is to enroll amputees with symptomatic neuromas into a prospective study in which amputees will be randomized to undergo TMR, RPNI, or VDMT and subsequently monitored for pain and disability for 1-year post-operatively. The investigators' specific aims are as follows: 1) Test the hypothesis that VDMTs are more effective than TMR and RPNIs with regards to treating pain and disability associated with symptomatic neuromas; 2) Provide the first level one, prospective data directly comparing the efficacy of TMR and RPNIs.

Extremity amputations are common operations both in the United States and other areas of the world. It is estimated that there are nearly 2 million adults living in the United States alone. Etiologies for extremity amputation are diverse but the most common indications include complications of type 2 diabetes, non-diabetic peripheral vascular disease, trauma, and oncologic conditions. Given the increasing prevalence of several of these pathologies, conservative estimates suggest that the population of people living with an amputated limb will likely double within the next several decades.

Patients who undergo limb amputation are at significant risk of developing chronic neuropathic pain as a result of symptomatic neuroma formation, due in large part to the abundance of sizeable nerves within the extremities that are necessarily transected as part of the procedure. There are two distinct forms of pain experienced by patients who have undergone major extremity amputations. Residual limb pain is the more straightforward form of post-amputation pain attributable to neuroma formation within the amputation stump. Following peripheral nerve transection, axons regenerating from the proximal stump tend to form aggregates of disorganized neural growth called neuromas. Some neuromas will produce severe, intractable pain causing significant impairment in prosthetic fit and function, activities of daily living, and quality of life. Some estimates place the prevalence of residual limb pain attributable to neuroma formation as high as 75%. The other form of pain is known as phantom limb pain. While the underpinnings of phantom limb pain are the subject of ongoing debate, it is thought by many to arise from chronic stimulation of the cerebral cortex with painful inputs from peripheral neuromas, leading to unpredictable and poorly characterized reorganization of the cortex. Informed estimates of phantom limb pain prevalence as high as 85% have been reported. Successful prevention and treatment of symptomatic neuromas in the setting of limb amputation is therefore of paramount importance given the central role in the pathogenesis of chronic post-amputation limb pain encompassing both residual limb pain and phantom limb pain.

Treatment options for chronic post amputation pain caused by symptomatic neuromas are diverse. Medical options for both phantom limb pain and residual limb pain have been met with limited success. Despite the widespread use, the utility of neuromodulating medications, such as gabapentin, has been called into question by recent large scale meta-analyses that failed to demonstrate meaningful improvements. Neurotoxins, such as botulinum toxin, have also been studied and found to offer limited, if any, pain resolution.

One of the most commonly used surgical approaches to treat and prevent symptomatic neuromas involves burying the proximal nerve stump into nearby muscle. There is a widely-held misconception that burying a proximal nerve stump into muscle will prevent a neuroma from forming. However, elegant animal studies have proven that regeneration of a neuroma is virtually guaranteed because innervated muscle will not accept additional innervation from regenerating neurons.

In the past decade, two other surgical treatments for chronic post-amputation limb pain have come into vogue. Targeted muscle reinnervation (TMR) was initially pioneered as a means of providing intuitive control of advanced prostheses and only later observed to reduce neuroma pain. TMR involves transferring the proximal nerve stump of the injured nerve into a nearby distal motor branch. Early results are promising. A recently published randomized, controlled trial demonstrated the superiority of the TMR approach over the 'bury in muscle' approach, so much so that the trial concluded prematurely due to the superiority of the TMR compared to the historical technique.

The other recently developed and widely popularized option for surgical treatment of chronic post-amputation limb pain involves creation of a regenerative peripheral nerve interface (RPNI). Similar to TMR, the RPNI was initially conceived as a method to provide an interface with an advanced neuroprosthetic prior to being employed as a treatment strategy for neuromas. RPNIs are muscle grafts that are coapted to the ends of severed proximal nerve stumps. This technique has gained popularity because of its technical simplicity and promising early clinical data. In contrast to the 'bury in muscle' approach, RPNIs are denervated at the time of harvest and have been shown to accept reinnervation via direct neurotization from the proximal nerve stump.

To address possible limitations of the strategies described above, the investigators propose using muscle targets similar to RPNIs but maintaining vascularity - a vascularized, denervated muscle target (VDMT). This is accomplished by raising a portion of muscle on a vascular leash in proximity to the transected nerve. Perforating branches from larger blood vessels that perfuse adjacent muscle can be found in abundance throughout the extremities. Any nerves traveling with the vascular leashes will be divided to ensure complete denervation of the muscle. Therefore, VDMTs will be receptive to reinnervation from the implanted proximal nerve stump, maintain vascularity such that the VDMTs can be large enough to supply an abundance of sensory receptors (spindle cells, Golgi apparati, etc) to accept regenerating axons, and avoid the use of a nerve coaptation. In short, the VDMT offers possible enhancements to the surgical techniques currently in use.

In terms of surgical outcomes, there is a robust body of data surrounding the TMR and RPNI operations, with some more recent reports providing pre- and post-operative pain scores for the individual operations. With the exception of one study that prospectively compared TMR to the historical gold standard of neuroma excision and implantation into surrounding tissue, there is a startling lack of prospective data on pain outcomes. Furthermore, the investigators are not aware of prospective, head-to-head comparative data for RPNI vs TMR. Robust, prospective, comparative data is now needed to validate the VDMT approach and assess its efficacy in comparison to the other established techniques.

It is of prime importance to surgeons who perform extremity amputations (eg orthopedic surgeons, vascular surgeons, trauma surgeons, plastic surgeons, and podiatrists) as well as those who perform salvage procedures for post-amputation extremity pain to understand the potential of these operations in treating this pain. Physicians are still lacking evidence-based treatment guidelines. With the generation of this data, surgeons and patients can make more informed decisions about which operative intervention provides the highest likelihood of durable, significant pain relief.

Surgical Treatments for Neuroma Pain in Amputees

A Randomized Trial Comparing Surgical Treatments for Neuroma Pain in Amputees

Pain score will be assessed using the numerical pain score (0-10) with 0 representing no pain and 10 representing the worst pain.

The Plastic Surgery Foundation

Johns Hopkins University

Traction neurectomy - of digital sensory nerves at the time of amputation.

Targeted Muscle Reinnervation - of digital sensory nerves at the time of amputation

Regenerative Peripheral Nerve Interface - of digital sensory nerves at the time of amputation

The type of procedure performed on the digital nerve at the time of amputation

Digital nerve procedure

Joshua Adkinson, MD

Scott N Loewenstein, MD

Finger amputations are common and may be complicated by debilitating nerve pain. This study seeks to determine if nerve pain after digital amputation can be more effectively prevented with either of two new surgical techniques-targeted muscle reinnervation (TMR) or regenerative peripheral nerve interfaces (RPNI)-compared to standard treatment by traction neurectomy (TN).

Patients who require proximal amputations will have the opportunity to enroll in the study, will be randomized intraoperatively to receiving one of the aforementioned treatments, and will be followed at 3 and 6 month for outcome measures.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
The Efficacy of Preventive Regenerative Peripheral Nerve Interface(RPNI) Reconstruction in Amputees	NCT05554900	Amputation Neur...	preventive rege...	6 Years -	Peking University People's Hospital
Surgical Treatments for Postamputation Pain	NCT05009394	Residual Limb P... Amputation Neur... Phantom Limb Pa... Pain, Neuropath... Pain, Nerve	Targeted Muscle... Regenerative Pe... Standard neurom...	18 Years -	Center for Bionics and Pain Research
An Osseoanchored Percutaneous Prosthesis Study Evaluating Stable Neural Signal Transmission in Subjects With Transhumeral Amputations	NCT03957226	Amputation Neur... Amputation Prosthesis User	e-OPRA (electro...	22 Years - 65 Years	University of Michigan
Short-term Implanted Electrodes Following Regenerative Peripheral Nerve Surgery for Improving Prosthetic Limb Control Signals	NCT03260400	Amputation Neur... Amputation	a bipolar percu...	22 Years - 65 Years	University of Michigan
Surgical Treatments for Neuroma Pain in Amputees	NCT04204668	Pain, Neuropath... Amputation Neur... Phantom Limb Pa...	TMR RPNI VDMT	18 Years -	Johns Hopkins University
Pain After Proximal Digital Amputation Prevention	NCT04378062	Pain Amputation Neur... Amputation	Digital nerve p...	18 Years -	Indiana University

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