Regenerative Peripheral Nerve Interfaces for the Treatment of Painful Neuromas in Major Limb Amputees

The Regenerative Peripheral Nerve Interface (RPNI) is a novel strategy to prevent neuroma formation in transected peripheral nerves. The RPNI consists of a residual peripheral nerve that is implanted into a free skeletal muscle graft either at the time of limb amputation or after excision of a terminal neuroma bulb. The sprouting axons of the nerve readily reinnervate the free muscle graft, thereby greatly reducing the chance of neuroma formation.

This investigation has a prospective cohort study design involving major lower limb amputees drawn from both the University of Michigan Health Systems and VA Health System of Ann Arbor. To objectively evaluate the effect of RPNI surgery on patients' perception of pain and to measure other health-related quality of life metrics relating to neuroma pain, this clinical trial will utilize specific, validated patient-reported outcomes measures (PROMs) to assess targeted domains in patients with major limb amputation. These survey instruments will determine: 1) patterns of pain medication use, including the use of opioids, 2) functional status and use of a prosthetic device, 3) changes in neuroma pain quality, 4) limitations in activities of daily living due to neuroma pain, 5) depression and anxiety relating to neuroma pain.

Study Overview

• Status: Completed
• Conditions: Amputation Neuroma
• Intervention / Treatment: Procedure: Amputation with Regenerative Peripheral Nerve Interfaces (RPNI); Other: Amputation Without RPNI

• Study Type: Observational
• Enrollment (Actual): 132

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Ann Arbor, Michigan, United States, 48105
      • Department of Veterans Affairs Ann Arbor Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Participants were recruited from plastic surgery, orthopedic surgery, and vascular surgery clinics.

Description

Inclusion Criteria:

• Major lower limb amputation (chronic pain treatment group only)
• Symptomatic residual limb neuroma (chronic pain treatment group only)
• Undergoing a major lower limb amputation (prophylactic pain treatment group only)

Exclusion Criteria:

• History of chronic amputation-related pain (prophylactic pain treatment group only)
• History of regenerative peripheral nerve interface (RPNI)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Chronic Amputation Pain; Participants who were existing amputees who had chronic neuroma pain at the amputation site.	Procedure: Amputation with Regenerative Peripheral Nerve Interfaces (RPNI); Free-muscle graft over cut nerve ends for treatment of neuromas at site of an amputation.; Other Names: RPNI
Prophylactic Treatment Group; Participants who had a lower extremity amputated during the study and were prophylactically treated for pain.	Procedure: Amputation with Regenerative Peripheral Nerve Interfaces (RPNI); Free-muscle graft over cut nerve ends for treatment of neuromas at site of an amputation.; Other Names: RPNI; Other: Amputation Without RPNI; Standard of care for lower-extremity amputation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Orthotics and Prosthetics Users Survey (OPUS)	The OPUS was a self-report questionnaire consisting of five modules. It can be used for prosthetic and orthotic programs for quality assessment, to maintain awareness of improvement in activities, to evaluate changes in patient's functional status and quality of life, and to assess satisfaction with devices and services. This study used the Functional Status Measure module, which was a 20-question survey that used a Likert scale ranging from 1 (very easy) to 5 (cannot do this activity).	Up to 12 months postoperatively
Pain Cognition Scale (PCS)	The PCS evaluated the relationship between thoughts and pain. The PCS was a 13-question survey that used a Likert scale ranging from 0 (not at all) to 4 (all the time). Total score ranged from 0 (no pain catastrophizing) to 52 (highest level of pain catastrophizing), with a score of 30 indicating a clinically high level of pain catastrophizing.	Up to 12 months postoperatively
Short-form McGill Pain Questionnaire 2 (SF-MPQ-2)	The SF-MPQ-2 was a pain assessment tool that measured both neuropathic and non-neuropathic pain. It used 22 descriptors, grouped into four subscales (continuous, intermittent, neuropathic, and affective) along with a Present Pain Intensity (PPI) scale. The descriptors and PPI all used a Likert scale that ranged from 0 (none) to 10 (worst possible). The SF-MPQ-2 was scored by calculating the average ratings for each of the four subscales and the total pain score and averaging all 22 item ratings, resulting in a score ranging from 0 (none) to 10 (worst possible).	Up to 12 months postoperatively
Patient-Reported Outcomes Measurement Information System (PROMIS) - Pain Interference	The PROMIS was a system of standardized, scientifically validated questions used to measure a patient's physical, mental, and social health status. The PROMIS pain interference short form had 6 questions ranging from 1 [not at all] to 5 [very much]. The PROMIS was scored by summing the values of the responses within each short form. The raw score was converted to a standardized T-score using specific scoring tables found in the instrument's scoring manual.	Up to 12 months postoperatively
PROMIS - Neuropathic Pain Quality	The PROMIS was a system of standardized, scientifically validated questions used to measure a patient's physical, mental, and social health status. The PROMIS neuropathic pain quality short form had 5 questions ranging from 1 [not at all] to 5 [very much]. The PROMIS was scored by summing the values of the responses within each short form. The raw score was converted to a standardized T-score using specific scoring tables found in the instrument's scoring manual.	Up to 12 months postoperatively
PROMIS Pain Intensity	The PROMIS was a system of standardized, scientifically validated questions used to measure a patient's physical, mental, and social health status. The PROMIS pain intensity short form had 3 questions ranging from 0 [had no pain] to 5 [very severe]. The PROMIS was scored by summing the values of the responses within each short form. The raw score was converted to a standardized T-score using specific scoring tables found in the instrument's scoring manual.	Up to 12 months postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Health Questionnaire-9 (PHQ-9) - Depression	The PHQ-9 was a nine-question self-report questionnaire used to screen for depression, diagnose its severity, and monitor treatment response. Each of the nine questions was scored on a four-point scale from 0 ("Not at all") to 3 ("Nearly every day"). The PHQ-9 asked about the frequency of specific depressive symptoms over the past two weeks, with a total score ranging from 0 to 27, with scores below 5 indicating no depression and scores above 20 indicating severe depression.	Up to 12 months postoperatively
General Anxiety Disorder-7 (GAD-7) - anxiety	The GAD-7 was a seven-item questionnaire used to screen for and measure the severity of generalized anxiety disorder (GAD). It asked about symptoms like feeling nervous, worrying too much, and trouble relaxing, with responses scored from 0 to 3 for each of the seven questions. The total score, ranging from 0 to 21, is interpreted to indicate the level of anxiety: 0-4 (minimal), 5-9 (mild), 10-14 (moderate), and 15-21 (severe).	Up to 12 months postoperatively
Fibromyalgia Survey Questionnaire (FSQ)	The FSQ was a tool used to assess the key symptoms of fibromyalgia by evaluating widespread pain and the severity of other somatic symptoms. It was comprised of two tools, the widespread pain index (WPI) subsection and the symptom severity score (SSS), which were summed to get a result. The WPI asked participants to mark off from a list of 19 potential pain locations on a body diagram. which were summed. The total score ranged from 0 to 19. The SSS evaluated the severity of three major symptoms and the severity of other somatic symptoms. The SSS consisted of 6 questions with a total score ranging from 0 to 12. The total range of both tools combined was 0 to 31, with a total score of ≥13 supporting a diagnosis of fibromyalgia.	Up to 12 months postoperatively

Collaborators and Investigators

• Sponsor: University of Michigan
• Investigators: Principal Investigator: Theodore Kung, MD, University of Michigan

Publications and helpful links

General Publications

• Lee JC, Kubiak CA, Best CSW, Hamill JB, Ki J, Kim HM, Roth RS, Kozlow JH, Tinney MJ, Geisser ME, Cederna PS, Kemp SWP, Kung TA. Regenerative Peripheral Nerve Interface Surgery to Treat Chronic Postamputation Pain: A Prospective Study in Major Lower Limb Amputation Patients. Ann Surg Open. 2025 Jan 7;6(1):e535. doi: 10.1097/AS9.0000000000000535. eCollection 2025 Mar.

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2017
• Primary Completion (Actual): June 26, 2023
• Study Completion (Actual): June 26, 2023

Study Registration Dates

• First Submitted: December 2, 2025
• First Submitted That Met QC Criteria: December 2, 2025
• First Posted (Actual): December 16, 2025

Study Record Updates

• Last Update Posted (Actual): December 16, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Surgical Procedures, Operative; Orthopedic Procedures; Amputation, Surgical
• Other Study ID Numbers: HUM00120915

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No