Neoplasms

All Conditions

Nervous System Diseases

Neuroma

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Neoplasms by Histologic Type

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)

University of Michigan

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

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

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

Standard Post-Amputation Surgical Care: Briefly, the transected nerves will be blindly tucked into surrounding bulky soft tissue to protect the nerve ends before the wound is closed.

Briefly, each transected nerve is identified after amputation using 6-0 Prolene suture and is dissected proximally for length. With minimal dissection, a nerve stimulator is used to identify functional motor nerve branches. Near the point where the motor branch enters the muscle, the motor nerve branch is transected and an end-to-end coaptation is performed with a nearby tagged amputated nerve.

Briefly, a muscle graft (usually from the amputated limb) is wrapped around the clean ends of the transected nerve(s).

Targeted Muscle Re-innervation involves re-routing transected nerve ends to functional motor nerves proximal to the site of amputation.

Targeted Muscle Re-innervation

Regenerative Peripheral Nerve Interface involves placing transected nerve ends in harvested muscle grafts.

Regenerative Peripheral Nerve Interface

Standard post-amputation surgical care involves placing transected nerve ends into muscle/soft tissue proximal to the site of amputation.

Standard Post-Amputation Surgical Care

Deborah Noble

The purpose of this study is to analyze the efficacy of novel interventions in post-amputation surgical care (specifically Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interface) on post-amputation pain and functional outcomes at the time of amputation. These novel interventions have been shown to be successful in treating the downstream effects of amputations (pain, phantom limb pain, neuroma pain, etc.), but has not been studied in a randomized manner at the time of amputation.

The investigators plan a randomized control trial of all eligible patients undergoing major limb amputation at Parkland Memorial Hospital. Eligible patients undergoing an amputation will be consented for all possible interventions and randomized to either receive Targeted Muscle Re-Innervation (TMR), Regenerative Peripheral Nerve Interface (RPNI), or standard post-amputation surgical care at the time of their operation. Key pre-operative data including patient sex, age, BMI, past medical history, past surgical history, medications, allergies, social history, social support systems, exposure to narcotic medication, and reason for amputation will be analyzed. Intra-operatively, patients randomized to the treatment arm will receive TMR or RPNI and the transected nerve ends addressed will be recorded. Post-operative data that will be recorded include hospital stay, complications related to the procedure, complications leading to reoperation, functional results, need for pain medication, incidence of phantom limb pain, incidence of painful neuromas, length of follow-up, and all adverse events/complications. Analyses will be conducted using data obtained from patient medical records from the Parkland Health \& Hospital System.

Effect of Prophylactic TMR and RPNI on Neuroma and Phantom Limb Pain

Prophylactic Treatment of Neuroma and Phantom Limb Pain With Targeted Muscle Reinnervation (TMR) and Regenerative Peripheral Interface (RPNI) at the Time of Major Limb Amputation: A Randomized Control Trial

The primary outcome measure of the study will the incidence of phantom limb pain in each group over the course of the recovery period.

Pain intensity score is measured bv PROMIS (Patient Reported Outcomes Measurement Information System) Scores via patient questionnaires administered at follow-up visits. Possible scores range from 1-5 where higher scores indicate worse outcome (pain severity).

Pain interference score as measured by PROMIS (Patient Reported Outcomes Measurement information System) scores via patient questionnaires administered at follow-up visits. Possible scores range from 1-5, where higher scores indicate worse outcome (pain interference).

Pain behavior score measured by PROMIS (Patient Reported Outcomes Measurement Information System) questionnaire that pertains to subject social health. Raw summed score from 8 to 40, where 40 represents severely maladaptive pain behavior.

Narcotic medical use post-operatively as measured by MME (Morphine Milligram Equivalent) Score This is a tool to condense and standardize the patient's narcotic pain regimen.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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
Effect of Prophylactic TMR and RPNI on Neuroma and Phantom Limb Pain	NCT05344261	Amputation Neuroma Amputat... Phantom Limb Pa... Residual Limbs	Targeted Muscle... Regenerative Pe... Standard Post-A...	18 Years -	University of Texas Southwestern Medical Center
Effect of Prophylactic TMR and RPNI on Neuroma and Phantom Limb Pain	NCT05344261	Amputation Neuroma Amputat... Phantom Limb Pa... Residual Limbs	Targeted Muscle... Regenerative Pe... Standard Post-A...	18 Years -	University of Texas Southwestern Medical Center

Spots Global Cancer Trial Database for rpni

Every month we try and update this database with for rpni cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for rpni

Every month we try and update this database with for rpni cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for rpni cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.