Medical Policy

Policy Num:      07.001.174
Policy Name:    Peripheral Nerve Injury Repair Using Synthetic Conduits or Processed Nerve Allografts
Policy ID:          [07.001.174]  [Ac /B / M- / P-]  [7.01.177]

Last Review:    February 19, 2025
Next Review:    February 20, 2026
 

Related Policies:

07.001.114 - Bioengineered Skin and Soft Tissue Substitutes
07.001.067 - Nerve Graft with Radical Prostatectomy

Peripheral Nerve Injury Repair Using Synthetic Conduits or Processed Nerve Allografts 

Summary

Description

Peripheral nerve injuries are common traumatic events for which the conventional treatment is the microsurgical repair for gaps <5 mm in length. Autologous grafting is used for repairing nerve gaps of greater length. Because autologous grafts must be harvested from the patient, there is a risk of donor site complications, and the overall success rate of autografting may be limited. Therapies such as processed nerve allografts and synthetic nerve conduits are being investigated to provide improved treatment alternatives.

Summary of Evidence

For individuals with peripheral nerve injury requiring repair and closure of the nerve gap who receive processed nerve allografts, the evidence includes 2 meta-analysies, 2 randomized controlled trials (RCTs) comparing allograft to collagen conduit repair with NeuraGen, 1 comparative case series, 1 retrospective cohort study, 1 case series, and 1 registry study. All studies, with the exception of 1 non-randomized controlled trial, used Avance allografts. The evidence base consisted primarily of peripheral nerve injuries to the fingers or upper extremities. Relevant outcomes were sensory and motor function changes, quality of life, and treatment-related morbidity. In 1 RCT that compared allograft to NeuraGen synthetic conduit, allograft patients had a greater return of protective sensation rate on the static 2-point discrimination (S2PD) score but did not differ on overall S2PD score or other outcome measures. The second RCT comparing allograft to Neuragen found that S2PD favored the Avance allograft group at 1-year follow-up, but no differences were noted in moving 2-point discrimination (M2PD), Semmes Weinstein Monofilament (SWMF) test, or the Disability of the Arm and Shoulder (DASH) questionnaire. Limitations in the RCT evidence base included a lack of intention to treat (ITT) analysis, high loss to follow-up, lack of reporting power calculations, and insufficient follow-up duration. Three non-randomized comparative studies found no difference between NeuraGen (n=2) and direct surgical repair (n=2) in sensory or functional outcomes and complications compared to allograft. One meta-analysis found comparable pooled rates of S2PD and M2PD across assessed interventions, including allograft, autograft, artificial conduits, and direct surgical repair, but all estimates had extreme heterogeneity. Another meta-analysis found that meaningful recovery (≥S3 on the British Medical Research Council [BMRC] recovery grading system) was significantly higher in allograft and autografting than for synthetic conduits. Data from the ongoing Avance registry study suggested durability of outcomes and safety at more than 2 years of follow-up. There is an absence of comparison of Avance to autografting in the included literature, which is a significant limitation as this is the current standard of care for repairing peripheral nerve gap discontinuities larger than 5 mm. Additionally, substantial interventional, comparator, and outcome heterogeneity across the evidence base makes it challenging to compare outcomes across studies reliably. Randomized comparisons of allograft to autograft with sufficient follow-up using validated outcome measures are needed to evaluate the relative risk-benefit of allografting. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with peripheral nerve injury requiring repair and closure of the nerve gap who receive synthetic nerve conduits, the evidence includes 3 meta-analyses, 8 RCTs (2 comparing NeuraGen to allograft, 1 comparing Neurotube to autologous vein grafting, and 4 comparing conduit [1 Neurolac, 1 Polyhydroxybutyrate {PHB}, 1 polyglycolic acid {PGA}, and 1 silicone tube] to direct surgical repair), 1 non-randomized clinical trial, 1 comparative retrospective cohort study, 1 comparative case series, and 1 non-comparative case series. The evidence base consisted primarily of peripheral nerve injuries to the fingers or upper extremities. NeuraGen was evaluated in 3 studies, and all other synthetic conduits were represented by a single study (Neuromatrix, Neuroflex, Neurotube, Neurolac, PHB conduit, PGA conduit, and collagen-filled conduit). In 1 RCT that compared Avance allograft to NeuraGen, allograft patients had a greater return of protective sensation rate on static 2-point discrimination (S2PD), but did not differ on overall S2PD score or other outcome measures. The second RCT comparing Avance allograft to Neuragen found that S2PD favored the allograft group at 1-year follow-up, but no differences were noted in moving 2-point discrimination (M2PD), Semmes Weinstein Monofilament (SWMF) test, or the Disability of the Arm and Shoulder (DASH) questionnaire. One RCT compared Neurotube conduit to an autologous vein conduit and found similar outcomes at a 2-year follow-up, but at 1-year analysis, the motor domain of the Rosen Model Instrument (RMI) favored the autologous treatment arm. Five other trials compared different types of conduits to direct surgical repair with generally equivalent outcomes; one RCT observed a significant difference in cold intolerance, which favored the synthetic conduit group, and another found that at short (<4 mm) and long nerve gaps (> 8 mm) M2PD was better in the PGA conduit group than in direct surgical repair or autograft. Major limitations identified in the trial evidence base included an absence of participant blinding, lack of intention to treat analysis, high loss to follow-up, absence of power calculations, and short duration of follow-up. Three non-randomized comparative studies found no difference between synthetic conduits and Avance (n=2), direct surgical repair (n=1), or autograft (n=1) in sensory or functional outcomes as well as complications. A Cochrane review found that there is no clear benefit to patients treated with artificial nerve conduits or nerve wraps over direct surgical repair, and that complications may be greater for participants treated with synthetic nerve conduits or wraps. The overall evidence base was considered very uncertain, with few outcomes having more than 1 included study. One other meta-analysis found comparable pooled rates of S2PD and M2PD across assessed interventions, but all estimates had extreme heterogeneity. The third meta-analysis found that meaningful recovery (≥S3 on the British Medical Research Council [BMRC] recovery grading system) was significantly higher in allograft and autografting than for synthetic conduits. No guideline evidence was identified for synthetic nerve conduits for the treatment of peripheral nerve injuries. Many of the included trials have significant limitations, and the substantial heterogeneity in patient and intervention characteristics makes it challenging to compare outcomes reliably across studies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine the safety efficacy of synthetic allograft and nerve conduits compared with conventional treatments.

Policy Statement

The use of processed nerve allograft for the repair and closure of peripheral nerve gaps is considered investigational.

The use of synthetic nerve conduits for the repair and closure of peripheral nerve gaps is considered investigational.

Policy Guidelines

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.
 

Background

Peripheral Nerve Injury

Injuries to the peripheral nerves are common and occur in approximately 2.5% of trauma patients in the United States, with an average incidence of over 550,000 annually.^1, Based on hospital ICD-9 coding, the most commonly injured peripheral nerves reported by hospitals were the upper extremity digital nerves, ulnar nerve, radial nerve, and the brachial plexus. ^2, Functional regeneration of injured nerves requires peripheral nerve surgery to allow axon regrowth and remyelination.^3,

Conventional Treatment

Direct surgical repair (e.g. end-to-end coaptation or neurorrhaphy) is the standard of care for transected nerves when the gap distance permits tensionless suturing. However, when the size of the peripheral nerve gap precludes tensionless direct surgical repair, the standard of care is nerve autograft.^4,Alternatives to autografting are being investigated to bridge nerve discontinuities to avoid complications from harvesting (e.g., pain or numbness) at the donor site as well as issues such as nerve fascicle mismatch and damage to the autograft from tissue handling.^3,

Alternative Treatments

Allogenic nerve grafts are derived from human donors and are generally used to bridge gaps resulting from peripheral nerve injuries that are >5 mm.^4, Allogenic grafts are preferred for their potential to minimize donor site morbidity, as they eliminate the need for autografts. Allogenic grafts also address the challenge of obtaining a sufficient graft length as they are available in multiple lengths and diameters; this is particularly relevant in cases where the injury site is extensive. Before transplantation, allografts undergo processing to ensure immunological compatibility and reduce the risk of rejection, allowing for successful integration into the recipient's nervous system. ^5,

Synthetic nerve conduits are hollow tubular structures designed to bridge nerve gaps caused by injury or trauma, providing a supportive environment for the regrowth of damaged nerve fibers.^6, They are available in various biocompatible materials, lengths, and diameters and are designed to degrade over time. The conduits serve as guidance channels for regenerating nerves, facilitating directional growth, and preventing scar tissue formation.^3,Conduits are generally used for nerve gap repairs of < 5 mm.^4,

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, title 21, parts 1270 and 1271. Avance Nerve Grafts subject to these regulations.

A number of synthetic conduits and protective nerve wraps have been approved through the FDA 510k process for individuals undergoing peripheral nerve repair (Table 1). This list includes products for which this reference medical policy did not find any published, peer-reviewed research that satisfied the PICO (Population, Intervention, Comparison, Outcome) criteria.

Table 1. FDA 510K Approved Synthetic Conduits and Wraps for Peripheral Nerve Repair

Rationale

This evidence review was created in January 2023 with a search of the PubMed database. The most recent literature update was performed through November 15, 2023.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Processed Nerve Allograft

Clinical Context and Therapy Purpose

The purpose of processed nerve allografts in individuals with peripheral nerve injuries is to provide a treatment option that is an alternative to or an improvement on existing standard therapies such as autologous nerve grafting in injuries where the discontinuity is >5 mm. These allografts spare individuals with nerve injuries the need to harvest autologous grafting material and negate the potential for donor site defects.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with peripheral nerve injuries requiring the repair and closure of peripheral nerve gaps generally > 5mm.

Interventions

The therapy being considered is processed, nerve allografts (Avance, Axogen, Inc). Avance nerve graft is a sterile, processed human nerve allograft that is indicated for the repair of peripheral nerve discontinuities to support axonal regeneration across the gap.^5, A proprietary cleansing process removes specific proteins, cells, and cellular debris but spares the extracellular matrix (ECM), providing structural support for cellular migration and regenerating axons.^5, Avance is available in multiple lengths from 5 to 70 mm, and multiple diameters. The allograft is stored frozen with a shelf life of up to three years, but upon thawing, it must be transplanted within 12 hours. Surgical implantation of the allograft connects the distal and proximal ends of a severed peripheral nerve via suturing. Post-surgery, the allograft is revascularized and remodeled into the patient's own tissue.

Comparators

To repair peripheral nerves, standard therapies include direct microsurgical repair with nerve sutures in small gaps, or autologous nerve grafting when direct suturing is not possible due to the size of the gap.

Outcomes

The outcomes of interest are improvements in sensory recovery (British Medical Research Council [BMRC] grade, Semmes Weinstein Monofilament [SWMF] testing, 2-point static and moving discrimination [S2PD and M2PD]), function (BMRC grade, Rosen Model Instrument [RMI]), quality of life (Disability of the Arm and Shoulder [DASH] questionnaire), and treatment-related morbidity. Outcome scales and interpretation are reported in the Appendix.

The S2PD test measures the narrowest gap at which two separate points applied to the skin can be distinguished as two rather than one. S2PD evaluates innervation density, which is important for assessing hand function, particularly precision sensory grip and constant touch. The M2PD test is performed similarly, except the assessor moves the points over the skin surface rather than performing the test at a static location. Normal values are ≤ 5 mm for the S2PD and ≤ 2 mm for M2PD tests, and lower scores indicate a more positive result. The SWMF test measures touch pressure in a standardized way using filaments of variable diameters and pressing them in the assessment area just to the point of bending; sensation with lower diameters indicates a better result. These tests are often used as components of composite sensory and motor outcomes scale such as the RMI or BRMC grade. On the BMRC scale, meaningful recovery was generally defined as an S3 or M4 rating or better.

Follow-up at 1 year is of interest to adequately assess sensory and functional recovery where there are sizable nerve discontinuities at the time of surgery and to allow for the identification of delayed adverse events.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Two meta-analyses evaluated processed nerve allografts (PNA) and synthetic nerve conduits for peripheral nerve injuries to fingers or peripheral nerve injuries in various locations (finger, hand, upper extremity, head, neck, or lower extremity).[Zhang Y, Hou N, Zhang J, et al. Treatment options.... 023; 18(1): 675. PMID 37700356][Lans J, Eberlin KR, Evans PJ, et al. A Systematic.... 1(5): 814e-827e. PMID 36728885] The characteristics of the meta-analyses are provided in Table 3, and the results are provided in Table 4. The meta-analysis of peripheral nerve injuries of the finger found similar ranges in pooled sensory and motor outcomes between PNA, autograft, synthetic conduits, or direct surgical repair. The meta-analysis of injuries to various peripheral nerve locations showed that more patients treated with PNA or autograft had meaningful sensory recovery compared to synthetic nerve conduits. However, conduit repairs and direct surgical repair would only apply to short nerve gap repairs so all treatment groups were not applicable across all gaps and nerve types in the included studies. Both analyses showed substantial heterogeneity for all pooled estimates. This variability, along with differences in patient populations (e.g. nerve gap length, location of nerve injury, cause and number of injuries, and the time from injury to nerve repair), limit drawing conclusions from these findings.

Zhang et al (2023) included a total of 66 studies which pooled data on PNA, synthetic conduits (polyglycolic acid [PGA] conduit or collagen conduit), autografting (muscle-in-vein graft, vein graft, or autologous nerve graft), and direct surgical repair (end to end or end to side coaptation) for the treatment of peripheral nerve defects of the finger. ^7,Treatment groups varied substantially by the size of the nerve defect treated. The authors provided pooled estimates for static 2-point discrimination test (S2PD), moving 2-point discrimination test (M2PD), Mackinnon and Dellon modified British Medical Research Council (BMRC) scale, and Semmes-Weinstein monofilament (SWMF) testing stratified by each of these treatment categories. The proportion of significant recovery, defined as achieving a level of S3 or higher on the Mackinnon and Dellon scale, was consistent across various studies. On average, PNA showed a recovery rate of 78%, PGA and collagen-based synthetic nerve conduits exhibited recovery rates of 74% and 83%, respectively. The recovery rates ranged from 77% to 84% for the three different types of autografts. In surgical procedures, end-to-end and end-to-side direct repairs demonstrated recovery rates of 79% and 98%, respectively. The pooled estimates had overlapping confidence intervals for all interventions and reported outcomes, but no statistical comparison between groups was made. High heterogeneity, according to the I² statistic, was observed for all pooled within-group estimates for all outcome measures. In addition to this statistical heterogeneity, the studies had significant variations in nerve gap length, type of injury, number of injuries, and time of injury to repair. The included body of evidence had methodological shortcomings due to pooling data from many case reports or series and fewer comparative studies or RCTs. Reporting on outcomes by length of injury and type of injury is insufficient in the meta-analysis to determine the relative impact on each treatment group. Most included studies did not report complications, but in a pooled analysis,14 studies reported neuroma (artificial conduit: 2 articles, n=3; autograft repair: 7 articles, n=7; and direct surgical repair: 3 articles, n=4), cold stimulation in 13 studies (autograft repair: 10 articles, n=47; nerve sutures: 3 articles, n=3), 17 studies reporting paresthesia (artificial conduit: 3 articles, n=1; autograft repair:11 articles, n=14; and nerve sutures: 3 articles); post-operative infections 6 studies (artificial conduit: 3 articles, n=5; nerve allograft: 2 articles, n=4; autograft repair:1 articles, n=1); 13 articles reported pain (artificial conduit: 2 articles, n=1; nerve allograft: 3 articles, n=9; autograft repair: 6 articles, n=12; and nerve sutures: 2 articles, n=1).

Lans et al (2023) included 35 studies comparing processed nerve allograft, synthetic nerve conduit, and autograft for treating peripheral nerve defects in the hand, arm, head and neck, or lower extremity. Although nerve repairs involving the lower extremities and the head or neck areas were part of the study, they only constituted 1.3% and 2%, respectively of the overall study population. The studies on allografts and autografts covered a similar range of nerve gap lengths, whereas synthetic conduits were limited to studies with nerve gaps less than 1.5 cm. The meaningful recovery rate (≥ S3 on the BMRC scale) was significantly higher in the allograft (82%) and autograft (72%) groups than in the synthetic conduit group (62%). Subgroup analyses of meaningful recovery rate by gap length (≤30 mm or >30 mm) and motor type (sensory or motor) revealed no differences between the allograft and autograft groups. All reported estimates had high heterogeneity, but the I² values were not reported for the primary endpoint of overall meaningful sensory recovery by repair type. In addition to this statistical heterogeneity, the studies had significant variations in nerve gap length, type of injury, number of injuries, and time of injury to repair. The included body of evidence had methodological shortcomings due to pooling data from many case reports or series and fewer comparative studies or RCTs. Reporting on outcomes by injury type is insufficient in the meta-analysis to determine the relative impact on each treatment group.

Table 2. Comparisons of Trials/Studies Included in SR & MA for Peripheral Nerve Allograft and Synthetic Conduit

* Only trials of processed nerve allograft or synthetic nerve conduit are reported.
M-A: meta-analysis; SR: systematic review.

Table 3. SR & M-A Characteristics for Processed Nerve Allograft and Synthetic Conduit

M-A: meta-analysis; NR: not reported; SR: systematic review.

Table 4. SR & M-A Results for Processed Nerve Allograft and Synthetic Conduit

CI: confidence interval; M-A: meta-analysi; MIV: muscle in vein; NNT: number needed to treat; NR: not reported; PGA: polyglycolic acid; PNA: processed nerve allograft; RR: risk ratio; SR: systematic review.

Randomized Controlled Trials

Isaacs et al (2023) published the results of a multicenter, double-blind RCT comparing conduit and processed nerve allograft (PNA) for peripheral nerve repairs of the fingers.^37, Study characteristics and results are summarized in Tables 5 and 6. A total of 220 participants were recruited who were randomized 1:1 to PNA (n=112, Avance allograft, AxoGen, Inc) or to NeuraGen nerve conduit (Integra Lifesciences); 183 patients completed at least 1 acceptable post-surgery visit between 6 and 15 months post-repair. The primary endpoint was static 2-point discrimination (S2PD), and the authors determined that to achieve 80% power in the larger gap group and 95% power in the shorter gap group, a total of 88 subjects needed to be enrolled. The mean patient age was 38.5 years, and baseline characteristics were similar between groups. A higher proportion of patients treated with PNA for nerve gap distances between 15 and 25 mm achieved superior mean S2PD scores at the last follow-up (6.1mm vs 7.5mm; p<.05). The authors also found a greater percentage of participants receiving PNA had a return of protective sensation on the Semmes Weinstein Monofilament (SWMF) recovery in both short (5 to 14 mm) and long (15 to 25 mm) gaps (p<.05), but no difference in the mean or median values at last follow-up. No significant differences were noted in M2PD evaluations at the last follow-up. Complications occurred in 17 patients treated with PNA and 10 patients whose nerve gaps were bridged with conduits; the most common complications were infection, wound healing problems, and the need for surgical re-intervention. Physician satisfaction was high in both groups but was statistically significantly greater in the PNA group for handling properties of the implant, ability to properly size the implant, and overall satisfaction (p<.05), with no differences observed for the ease of implantation for the devices. Limitations of the study include evaluating patients who had follow-up appointments from 6 to 15 months rather than the desired 12-month follow-up period, not adjusting statistical significance for multiple comparisons, and limitations in describing the baseline level of discontinuities and etiology of injuries in each group (Tables 7 & 8) (NCT01809002).

Means et al (2016) reported the results of a multicenter, double-blind pilot RCT comparing hollow collagen conduits to PNA for peripheral nerve repairs of the fingers.^23, Study characteristics and results are summarized in Tables 5 and 6. A total of 23 participants were recruited who were randomized 3:2 to processed nerve allograft (n=14, Avance allograft, Axogen, Inc) or to hollow collagen nerve conduit (n=9, Neurogen, Neuromatrix, or Neuroflex, Stryker Orthopedics); 5 patients were lost to follow-up before 12-month assessment (22%). The primary endpoint was s2PD. The mean patient age was 42 years in the PNA group and 38 years in the conduit group, with average nerve gap lengths of 12.8±4.6 and 12.2±4.5, respectively. At 12 months follow-up, participants treated with PNA had a greater improvement on S2PD testing compared to conduit (5mm versus 8 mm; p<.05). The authors also reported a non-significant difference favoring PNA on M2PD testing at 12 months follow-up (5mm versus 7 mm; p>.05). No significant differences in the rate of participants achieving S3+ or S4 on medical research council classification (MRCC) was observed between groups. SWMF testing revealed that at 12 months, the PNA group had more favorable results (3.6 mm versus 4.4mm; p<.05), and all patients in the PNA group had recovery of protective sensation compared to 75% in the conduit group. Disability of the Arm, Shoulder, and Hand (DASH) assessment yielded no significant differences between groups, as did the mean pain intensity (p>.05). Study limitations included a small sample size with no power calculations in determining the number of participants needed to recruit to detect a difference in S2PD, and high loss to follow-up with a greater proportion in the PNA group (NCT00948025).

Table 5. Summary of Key RCT Characteristics for Processed Nerve Allograft

NR; not reported; RCT: randomized controlled trial.

Table 6. Summary of Key RCT Results for Processed Nerve Allograft

BMRC: British Medical Research Council; CI: confidence interval; HR: hazard ratio; IQR: interquartile range; M2PD: moving 2-point discrimination; NNT: number needed to treat; NR: not reported; NS: non-significant; OR: odds ratio; PGA: polyglycolic acid; PNA: processed nerve allograft; RCT: randomized controlled trial; RR: relative risk ; S2PD: static 2-point discrimination; SD: standard deviation; SWMF: Semmes-Weinstein Monofilament testing.

The purpose of the study limitations tables (see Tables 7 and 8) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 7. Study Relevance Limitations for Processed Nerve Allograft

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 8. Study Design and Conduct Limitations for Processed Nerve Allograft

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Nonrandomized Studies

Three non-randomized comparative studies were identified, including 1 case series and 2 non-randomized clinical trials that evaluated PNA.^25,15,39, Rbia et al (2019) published a case series of patients who underwent peripheral nerve injury reconstruction of the finger with either Avance PNA (n=18) or Neuragen collagen nerve conduit (n=19) from 2005 to 2015 at a single center in the Netherlands in adult patients who underwent 1 or more nerve reconstructions with a nerve gap after resection (Table 9)^25,. The mean age at surgery was 38 years in the collagen conduit group and 41 years for patients treated with PNA; gap lengths in the conduit and PNA groups were 14 mm and 18.4 mm, respectively. The primary outcome of S2diPD was reported as a mean of 9.8±3.8 mm at 12 months follow-up in the conduit group and 8.5±3.7 in PNA (Table 10). Excellent sensory recovery was reported in 48% of collagen conduit implantations and 39% of PNA patients. No significant differences in S2PD or degree of sensory recovery by Mackinnon classification were observed. At 12 months follow-up, the authors reported no instances of graft rejection or extrusion of conduit. The rate of other adverse events was low and included one instance each of neuroma and allodynia with complex regional pain syndrome in the PNA group and one infection in the collagen conduit implanted group (p=.378). Limitations of the study include lack of randomization and blinding, absence of power calculations, and retrospective nature of the study.

He et al (2013) conducted a multicenter, single-blinded, non-randomized controlled trial of acellular nerve allografting (n=72) compared standard direct surgical repair or, in cases where the gap was > 10 mm, autograft (n=81) of the damaged nerve.^15, The mean age of patients was 33±11.1 years in the allograft group and 36.9±13.4 years in the control group (p=.047); the mechanism of injury (cut, contusion, avulsion, squeeze, or electrical) also varied between groups. The mean length of the nerve graft was 1.8±.82 cm (range 1 to 5 cm). Seven participants (4%) were lost to follow-up and not included in the analysis. Power calculations suggested that 70 patients needed to be recruited in each group to have 80% power at a 95% significance level to detect an expected ±15% difference in the primary outcome of the SWMF test. All surgeries were reported as successful. In both neural and patient-level assessments, S2PD scores were significantly different between groups, with the control group having fewer excellent reconstruction outcomes (p<.01) (Table 10). Only 78 patients were included in the safety evaluation, which found that 6 patients (8%) had mild wound pain for 2 weeks post operation and 3 patients (4%) had mild redness; no reports of pain, itching, local erythema, urticaria, rash or other allergic symptoms were observed at 1-month follow-up. At 6-month follow-up, two patients had required secondary tenolysis (8%). Limitations of the study include lack of randomization and single-blinding, imbalanced baseline patient characteristics, and short duration of follow-up.

Ducic et al (2012) published a retrospective cohort study of patients treated with either Avance PNA (n=8), NeuraGen conduit repair (n=27) compared to autograft (n=11) or end-to-end direct surgical repair (n=8) for upper extremity peripheral nerve reconstruction.^39, Participants were treated from 2003 to 2009 and were evaluated using the Quick Disability of the Arm, Shoulder, and Hand (QuickDASH) questionnaire. The average age of participants was 46.4 years of age, and the nerve gap length within each group was highly variable but not compared statistically (mean range 0 mm to 37.5 mm). Minimum follow-up was greater than 2 years, although the timing of outcome assessment is unclear. QuickDASH scores did not vary significantly between groups (P=.56), and no complications were reported. Limitations of the study include the retrospective nature of the study design, imbalanced baseline characteristics, and a lack of statistical analysis for between-group comparisons of interest.

Table 9. Summary of Key Nonrandomized Trials OR Observational Comparative Study Characteristics for Processed Nerve Allograft

NR: not reported; PNA: processed nerve allograft.

Table 10. Summary of Key Nonrandomized Trials OR Observational Comparative Study Results for Processed Nerve Allograft

BMRC: British Medical Research Council; CI: confidence interval; HR: hazard ratio; IQR: interquartile range; M2PD: moving 2-point discrimination; NNT: number needed to treat; NR: not reported; NS: non-significant; OR: odds ratio; PGA: polyglycolic acid; PNA: Processed decellularized nerve allograft; RCT: randomized controlled trial; RR: relative risk; S2PD: static 2-point discrimination; SD: standard deviation; SWMF: Semmes-Weinstein Monofilament testing.

Observational studies

Many observational case reports and case series are available on treating peripheral nerve discontinuities with processed nerve allografts.^{40,41,42,13,34,18,38,28,43,44,29,45,46,16,27,} Because higher quality evidence is available, only larger studies (N≥75) with commercially available interventions and longer-term follow-up over 6 months were summarized.

Leckenby et al (2020) performed a single-center, retrospective review of outcomes from Avance PNA for peripheral nerve injuries from April 2009 to October 2017.^18, A total of 129 patients with 171 nerve allografts met the study inclusion criteria (Table 11). The mean age of surgery was 45 years (range 18 to 82 years) with an average follow-up period of 13 months. On the BMRC sensory rating scale, 77% of patients achieved a sensory outcome score of S3 or above, and 36% achieved a motor score of M3 or above and were deemed to have meaningful recovery (MR) (Table 12). Longer grafts and grafts used in lower limbs were associated with poorer outcomes compared to shorter grafts and grafts of the upper extremity (p<.05). Median numeric rating scale pain scores decreased from a pre-operative value of 7 (range 3 to 10) to 3 (range 0 to 7; p<.05). The authors noted that no patient developed a higher level of pain or diminished level of sensation in the post-surgical observation period.

Safa et al (2019) published results from the multi-center, Retrospective Avance Nerve Graft utilization, Evaluations, and outcomes in peripheral nerve injury Repair (RANGER) registry.^45, The study is ongoing, but at the time of publication, 385 subjects with 624 nerve repairs had sufficient follow-up and were included in the outcome analysis (Table 11). The mean patient age was 42 years (range 6 to 83 years), and although injuries to regions other than the upper extremity were eligible for inclusion, only 28 (7.3%) of patients had lower extremity nerve repairs, and 4 (1%) had repairs of nerves in the head and neck region. The mean follow-up time was 417 days (range 120 to 3,286 days). Overall, 82% MR was achieved across sensory, mixed, and motor nerves in gaps up to 70mm. No adverse events were reported over the study period. For upper extremity repair, significant differences were noted in the mechanism of injury between complex injuries (74%), lacerations (85%), and neuroma resections (100%; p=.03) and by the gap length (MR: <15 mm, 91%; 15-29 mm, 84%; 30-49 mm, 78%; 50-70mm, 69% (p<.05) (Table 12). By body region, MR was reported in 83% of the upper extremity, 53% of the lower extremity, and 100% of head/neck repairs (p=.01). Assessment of MR found no differences according to nerve type, time-to-repair discontinuity, and smoking status. Overall, there were reoperations in 31 subjects (8%), and adverse events were reported in 39 subjects (3.7%) drawn from the safety population, which included a total of 1041 subjects, many of which weren’t yet included in the outcome evaluation population due to lack of sufficient follow-up.

Table 11. Summary of Key Case Series Characteristics for Processed Nerve Allograft

Table 12. Summary of Key Case Series Results for Processed Nerve Allograft

Section Summary: Processed Nerve Allograft

For individuals with peripheral nerve injury requiring repair and closure of the nerve gap who receive processed nerve allografts, the evidence includes 2 meta-analyses, 2 randomized controlled trials (RCTs) comparing allograft to collagen conduit repair with NeuraGen, 1 comparative case series, 1 retrospective cohort study, 1 case series, and 1 registry study. All studies, with the exception of 1 non-randomized controlled trial, used Avance allografts. The evidence base consisted primarily of peripheral nerve injuries to the fingers or upper extremities. Relevant outcomes were sensory and motor function changes, quality of life, and treatment-related morbidity. In 1 RCT that compared allograft to NeuraGen synthetic conduit, allograft patients had a greater return of protective sensation rate on the static 2-point discrimination (S2PD) score but did not differ on overall S2PD score or other outcome measures. The second RCT comparing allograft to Neuragen found that S2PD favored the Avance allograft group at 1-year follow-up, but no differences were noted in moving 2-point discrimination (M2PD), Semmes Weinstein Monofilament (SWMF) test, or the Disability of the Arm and Shoulder (DASH) questionnaire. Limitations in the RCT evidence base included a lack of intention to treat (ITT) analysis, high loss to follow-up, lack of reporting power calculations, and insufficient follow-up duration. Three non-randomized comparative studies found no difference between NeuraGen (n=2) and direct surgical repair (n=2) in sensory or functional outcomes and complications compared to allograft. One meta-analysis found comparable pooled rates of S2PD and M2PD across assessed interventions, including allograft, autograft, artificial conduits, and direct surgical repair, but all estimates had extreme heterogeneity. Another meta-analysis found that meaningful recovery (≥S3 on the British Medical Research Council [BMRC] recovery grading system) was significantly higher in allograft and autografting than for synthetic conduits. Data from the ongoing Avance registry study suggested durability of outcomes and safety at more than 2 years of follow-up. There is an absence of comparison of Avance to autografting in the included literature, which is a significant limitation as this is the current standard of care for repairing peripheral nerve gap discontinuities larger than 5 mm. Additionally, substantial interventional, comparator, and outcome heterogeneity across the evidence base makes it challenging to compare outcomes across studies reliably. Randomized comparisons of allograft to autograft with sufficient follow-up using validated outcome measures are needed to evaluate the relative risk-benefit of allografting. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Synthetic Nerve Conduits

Clinical Context and Therapy Purpose

The purpose of nerve conduits in individuals with peripheral nerve injuries is to provide a treatment option that is an alternative to or an improvement on existing standard therapies, such as direct surgical repair for shorter nerve gaps and autologous nerve grafting in injuries larger than 5 mm. These synthetic devices spare individuals with nerve injuries the need to harvest autologous grafting material and negate the potential for donor site defects as well as protect the area of injury by blocking external inhibitory factors during axon regeneration. The FDA has approved multiple synthetic nerve conduits and wraps through the 510k process, including some for which this reference medical policy found no peer-reviewed, published research meeting the PICO (Population, Intervention, Comparison, Outcome) criteria.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with peripheral nerve injuries requiring the repair and closure of peripheral nerve gaps.

Interventions

The therapy being considered are synthetic nerve conduits (NeuraGen [Integra, Lifesciences], Neuroflex [Stryker Orthopedics], Neurolac [Polyganics, BV], Neurotube [Synovis Micro]) for peripheral nerve injuries requiring nerve gap repair and closure.

NeuraGen is a resorbable hollow nerve conduit designed for the repair of peripheral nerve discontinuities where gap closure is achievable by flexion of the extremity.(Integra, Lifesciences) The device received FDA 510k approval on April 24, 2014.(NeuraGen FDA 510(k)) It provides a protective environment for peripheral nerve repair after injury.(NeuraGen® Nerve Guide (integralife.com) The NeuraGen Nerve Guide is designed to be an interface between the nerve and surrounding tissue, creating a conduit for axonal growth across a nerve gap. NeuraGen’s semi-permeable type 1 collagen membrane allows for controlled resorption, appropriate nutrient diffusion, and retention of representative Nerve Growth Factor. It is available in different lengths and diameters to meet varied implantation needs. Conduits are generally used most commonly for nerve gap repairs of < 1 cm.^4,

Neuroflex is a resorbable, flexible type I collagen conduit that encases peripheral nerve injuries and protects the neural environment.(Stryker Neuroflex) It is designed to prevent the ingrowth of scar tissue and the formation of neuromas. The corrugated walls of the conduit allow it to bend up to approximately 60 degrees without forming an occlusion. The device received FDA 410k approval on April 03, 2014, and is indicated for peripheral nerve discontinuities where gap closure can be achieved by flexion of the extremity or at the end of the nerve in the foot to reduce the formation of symptomatic or painful neuroma. (Neuroflex FDA 510(k)) The device is available in differing lengths and diameters.

Neurolac is a synthetic nerve guide designed for the reconstruction of peripheral nerve discontinuities up to 20 mm.(Polyganics B.V.) It received FDA 510k approval on October 20, 2011 and is indicated for the reconstruction of a peripheral nerve discontinuity up to 20 mm in patients who have sustained a complete nerve division.(Neurolac FDA 510(k)) Neurolac provides guidance and protection to regenerated axons and prevents the ingrowth of fibrous tissue into the nerve gap during nerve regeneration. It retains its initial mechanical properties up to 10 weeks, providing support and protection to the healing nerve, and after this period, rapid loss of mechanical strength and gradual reduction in mass occurs. The final degraded products are resorbed, metabolized, and excreted by the body. Neurolac is available in different internal diameters, making it suitable for small nerves that require precise suturing in a small and defined area.

The Neurotube (Synovis Micro) is an absorbable woven polyglycolic acid mesh tube designed for primary or secondary peripheral nerve repair or reconstruction.(Synovis Micro) It received FDA 510k approval on August 28, 1998, for the indication of peripheral nerve injuries where the nerve gap is more than or equal to 8 mm, but less than or equal to 30 mm.(Neurotube FDA 510(k)). The device is contraindicated for anyone with a known allergy to polyglycolic acid. The walls of the Neurotube are corrugated for strength and flexibility, preventing the tube from collapsing under normal physiological soft tissue pressures.

Comparators

To repair peripheral nerves, standard therapies include microsurgical repair with nerve sutures in small gaps or when direct suturing is not possible due to the size of the gap, autologous nerve grafts are used. Several studies compared processed nerve allografts and synthetic conduits either as part of a systematic review and meta-analysis or a primary study. These studies are reported in detail in the section on processed nerve allografts and summarized in this section on synthetic nerve conduits.

Outcomes

The outcomes of interest are improvements in sensory recovery (British Medical Research Council [BMRC] grade, Semmes Weinstein Monofilament [SWMF]testing, 2-point static and moving discrimination [S2PD and M2PD]), function (BMRC grade, Rosen Model Instrument), quality of life (Disability of the Arm and Shoulder [DASH] questionnaire), and treatment-related morbidity. Outcome scales and interpretation are reported in the Appendix.

The S2PD test measures the narrowest gap at which two separate points applied to the skin can be distinguished as two rather than one. S2PD evaluates innervation density, which is important for assessing hand function, particularly precision sensory grip and constant touch. The M2PD test is performed similarly, except the assessor moves the points over the skin surface rather than performing the test at a static location. Normal values are ≤ 5 mm for the S2PD and ≤ 2 mm for M2PD tests, and lower scores indicate a more positive result. The SWMF test measures touch pressure in a standardized way using filaments of variable diameters and pressing them in the assessment area just to the point of bending; sensation with lower diameters indicates a better result. These tests are often used as components of composite sensory and motor outcomes scale such as the RMI or BRMC grade. On the BMRC scale, meaningful recovery was generally defined as an S3 or M4 rating or better.

Follow-up at 1 year is of interest to adequately assess sensory and functional recovery where there are sizable nerve discontinuities at the time of surgery and to allow for the identification of delayed adverse events.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Two meta-analyses evaluated processed nerve allografts (PNA) and synthetic nerve conduits for peripheral nerve injuries to fingers or peripheral nerve injuries in various locations (finger or hand, upper extremity, head and neck, and lower extremity).[Zhang Y, Hou N, Zhang J, et al. Treatment options.... 023; 18(1): 675. PMID 37700356][Lans J, Eberlin KR, Evans PJ, et al. A Systematic.... 1(5): 814e-827e. PMID 36728885] The meta-analyses are relevant to both the first and second PICO and are summarized in more detail in the previous section on processed nerve allografts (Tables 2-4).The meta-analysis of peripheral nerve injuries of the finger found similar ranges in pooled sensory and motor outcomes between PNA, autograft, synthetic conduits, or direct surgical repair. The meta-analysis of injuries to various peripheral nerve locations showed that more patients treated with PNA or autograft had meaningful sensory recovery compared to synthetic nerve conduits. However, conduit repairs and direct surgical repair would only apply to short nerve gap repairs so all treatment groups were not applicable across all gaps and nerve types in the included studies. Both analyses showed substantial heterogeneity for all pooled estimates. This variability, along with differences in patient populations (e.g. nerve gap length, location of nerve injury, cause and number of injuries, and the time from injury to nerve repair), complicates drawing conclusions from these findings.

The Cochrane Collaboration published another meta-analysis of bioengineered nerve conduits and wraps for repairs of peripheral nerves of the upper extremity.^47, The authors included only RCTs or quasi-RCT experimental studies and found 5 which included the desired interventions and had follow-up periods of at least 12 months. A total of 213 participants were included in the studies, which compared nerve reconstruction with artificial wraps or conduits to standard repair either with direct end-to-end epineural repair or with autologous nerve grafting.(Table 14) Sensory recovery assessed with the British Medical Research Council (BMRC) grading scale was higher in the wrap or conduit group than in standard repair with very low certainty of evidence on Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) at 12 months (mean difference [MD],.03; range, -0.43 to 0.49) and 24 months follow-up (MD,.01; 95% CI, -0.06 to 0.08). (Table 15) Rosen model instrument (RMI) comparisons between conduit or wrap versus standard repair revealed no between-group differences through 24 months (MD, -0.17; 95% CI, -0.38 to 0.05; p=.13) and was determined to have low certainty of evidence; findings at 5 years follow-up in a single study found a greater improvement in the conduit or wrap group, but the estimate also had low certainty of evidence (MD, 0.23; 95% CI, 0.07 to 0.38). The rate of adverse event occurrence may be greater in patients treated with nerve wraps or conduits than with standard techniques, but the evidence had a GRADE rating reflected a very low certainty of evidence (risk ratio [RR], 7.15; 95% CI, 1.74 to 29.42). The authors also sought BMRC muscle strength scores, which were not reported in the included studies. The authors concluded that based on the currently available high-quality evidence, the use of currently available nerve repair devices is not supported over the standard of care due to heterogeneity in included participants, the pattern of injury, timing of repair, timing of outcome assessment, and choice of outcome measurement scales.

Table 13. Comparisons of Trials/Studies Included in SR & MA for Synthetic Nerve Conduits

Table 14. SR & M-A Characteristics for Synthetic Nerve Conduits

Table 15. SR & M-A Results for Synthetic Nerve Conduits

BMRC: British Meidcal Research Council; CI: confidence interval; MIV: muscle in vein; NA: not applicable; NNT: number needed to treat; PGA: polyglycolic acid; PNA: processed nerve allograft; RMI: Rosen Model Instrument; RR: risk ratio.CI: confidence interval; NNT: number needed to treat.

Randomized Controlled Trials

Eight RCTs were identified that compared nerve conduits to processed nerve allografting (n=2), autologous vein conduit (n=1), or direct surgical repair(n=5) and are presented based on comparator. [Isaacs J, Nydick JA, Means KR, et al. A Multicente.... 48(9): 904-913. PMID 37530686][Means KR, Rinker BD, Higgins JP, et al. A Multicen.... ; 11(2): 144-51. PMID 27390554][Boeckstyns ME, Sørensen AI, Viñeta JF, e.... 38(12): 2405-11. PMID 24200027][Rinker B, Liau JY. A prospective randomized study.... ; 36(5): 775-81. PMID 21489720][Aberg M, Ljungberg C, Edin E, et al. Clinical eval.... 62(11): 1503-9. PMID 18938119][Bertleff MJ, Meek MF, Nicolai JP. A prospective cl.... 5; 30(3): 513-8. PMID 15925161][Lundborg G. Alternatives to autologous nerve graft.... 004; 36(1): 1-7. PMID 15083383][Weber RV, Mackinnon SE. Bridging the neural gap. C.... ): 605-16, viii. PMID 16139631]

Processed Nerve Allograft

The preceding section on processed nerve allografting reported the two trials that compared nerve conduits to allografts.[Isaacs J, Nydick JA, Means KR, et al. A Multicente.... 48(9): 904-913. PMID 37530686][Means KR, Rinker BD, Higgins JP, et al. A Multicen.... ; 11(2): 144-51. PMID 27390554] Isaacs et al (2023) compared Avance allograft to NeuraGen synthetic conduit and found that allograft patients had a greater return of protective sensation rate on the static 2-point discrimination (S2PD) as well as overall S2PD score for gaps > 12mm. No other differences were noted in moving 2-point discrimination (M2PD), Disability of the Arm and Shoulder (DASH) questionnaire score, or complications between groups. Means et al (2016) compared Avance allograft to Neuragen in peripheral nerve finger repairs and found that S2PD favored the Avance group at 1-year follow-up, but no differences were noted in M2PD, Semmes Weinstein Monofilament (SWMF) test, or DASH score. Limitations in the RCT evidence base included a lack of intention to treat (ITT) analysis, high loss to follow-up, lack of reporting power calculations, and insufficient follow-up duration.

Autologous Vein Conduit

Rinker et al (2011) published the findings from a multicenter, single-blind RCT comparing polyglycolic acid nerve conduit with autogenous vein conduits for the repair of digital nerves gaps ≤3 cm.^26, A total of 42 patients were randomized 1:1 to nerve conduit (n=41, Neurotube, Synovis Life Technologies, Inc) or to autogenous vein conduit (n=35); 5 patients were lost to follow-up before 6-month evaluation and not included in the analysis. The mean patient age was 33 years in the PGA conduit group and 38 years in the vein conduit group, with mean nerve gap lengths of 9.1±4.6 mm and 10.3±4.8 MMS, respectively. Reported baseline characteristics were balanced between groups. The primary endpoint was 2-point discrimination testing, and the authors calculated that to detect a predicted mean difference of 25% with 80% power at the 95% confidence level, a total of 28 participants needed to be enrolled. No differences in static or moving 2-point discrimination were observed at 6 months follow-up between groups (Table 17). A subgroup analysis based on gap length (< 10 mm and ≥ 10 mm) also found no statistically significant between-group differences. A numerically greater number of complications occurred in the synthetic conduit group (8%) compared to the vein conduit group (3%), but no statistical comparison was reported. These events in the PGA conduit group included 2 implant extrusions and 1 infection, with 1 infection in the vein conduit group. Limitations included a lack of intention to treat analysis and higher loss to follow-up for 12-month post-operative estimations.

Direct Surgical Repair

Five RCTs compared various synthetic nerve conduits (Neurolac [n=1], NeuraGen [n=1], PHB conduit [n=1], PGA conduit [n=1] or silicone conduit [n=1]) to direct surgical repair of peripheral nerve injuries of the hand or upper extremity. [Boeckstyns ME, Sørensen AI, Viñeta JF, e.... 38(12): 2405-11. PMID 24200027][Aberg M, Ljungberg C, Edin E, et al. Clinical eval.... 62(11): 1503-9. PMID 18938119][Bertleff MJ, Meek MF, Nicolai JP. A prospective cl.... 5; 30(3): 513-8. PMID 15925161][Lundborg G. Alternatives to autologous nerve graft.... 004; 36(1): 1-7. PMID 15083383][Weber RV, Mackinnon SE. Bridging the neural gap. C.... ): 605-16, viii. PMID 16139631] One RCT found that direct surgical repair performed better than Neuragen on the motor domain components of the Rosen score at 1 year follow-up, but no significant differences were noted in this or other outcomes at 2 years of follow-up.[Boeckstyns ME, Sørensen AI, Viñeta JF, e.... 38(12): 2405-11. PMID 24200027] Another RCT reported that cold intolerance favored the silicone conduit group over conventional repair, but the other elements of the Rosen composite score were not significantly different between groups.[Lundborg G. Alternatives to autologous nerve graft.... 004; 36(1): 1-7. PMID 15083383] A third RCT found that conduit repair did not improve overall S2PD or M2PD, but when stratified for gaps <4mm and gaps >8mm, the conduit group outperformed standard repair on M2PD.[Weber RV, Mackinnon SE. Bridging the neural gap. C.... ): 605-16, viii. PMID 16139631] No significant differences were noted between the conduit and direct surgical repair in 2 remaining RCTs.[Aberg M, Ljungberg C, Edin E, et al. Clinical eval.... 62(11): 1503-9. PMID 18938119][Bertleff MJ, Meek MF, Nicolai JP. A prospective cl.... 5; 30(3): 513-8. PMID 15925161]

Boeckstyns et al (2013) reported the results from a multicenter, single-blind RCT comparing repair with a nerve conduit to direct suture repair for acute lacerations of mixed sensory-motor (ulnar and median) nerves.^50, Study characteristics and results are summarized in Tables 16 and 17. In total, 43 participants were recruited who were randomized 1:1 to nerve conduit (n=23, Neuragen, Integra Lifesciences) or to direct surgical repair (n=21); 11 of which were lost to follow-up before the final evaluation at 24-months follow-up and not included in the analysis. The mean patient age was 37 years in the conduit group and 33 years in the direct suture group. The operated nerves for the conduit group included 11 median and 12 ulnar nerves, with one patient having both median and ulnar nerve repair; in the direct suture group, 13 median and 8 ulnar nerves were repaired. No surgical complications of infection, extrusion of the conduit or other local adverse reaction, or development of a chronic regional pain syndrome were reported. No electrophysiological measures differed between the two treatment groups at 24-month follow-up, but at 12 months, differences in the distal motor latency and compound muscle action potential were observed, which favored direct surgical repair. Composite Rosen-Score did not vary between groups at 12 or 24-month follow-up, but the components of the motor domain (muscle force and grip strength) and overall motor domain scores favored direct surgical repair at the 12-month evaluation. Limitations include not reporting the baseline nerve gap distance a high loss to follow-up (25%), no power calculations reported, and absence of trial registration or protocol publication.

Aberg et al (2009) reported a prospective, assessor-blinded pilot RCT comparing resorbable polyhydroxybutyrate (PHB) to conventional end-to-end repair in wrist and forearm nerve discontinuities.^48, Twelve patients were randomized 1:1 to either PHB (n=6) or conventional repair (n=6); 1 patient in the PHB group was lost to follow-up (17%). Reported baseline characteristics were balanced between the two study arms. No significant difference was noted in BMRC sensory or BMRC motor scores at 18 months follow-up although the PHB group tended to have a numerically greater level of sensory and muscle recovery (Table 17). Limitations to this study were the small sample size, lack of power calculations, lack of participant blinding, no intent to treat analysis, and absence of information on the length of nerve discontinuity in each treatment group.

Bertleff et al (2005) conducted a multicenter, double-blind RCT comparing Neurolac nerve guide (Polyganics, B.V.) with standard reconstruction techniques in individuals with traumatic peripheral nerve lesions of the hand. ^49, Thirty patients with 34 nerve injuries were included and randomized 1:1 to either Neurolac (n=20) or standard of care reconstruction (n=13). No significant differences were observed on S2PD or M2PD through 12-month follow-up. Two patients in the Neurolac group (10%) needed revision surgery due to a rupture of the repaired tendon and the development of tenolysis. Limitations to this trial included lack of power calculations, uncertainty regarding participant blinding, no intention to treat analysis, absence of comparative effect calculation, and absence of information on nerve gap length at baseline.

Lundborg et al (2004) published the results of a multicenter, double-blind RCT comparing silicone tube conduit and conventional microsurgery for transection of the median or ulnar nerve at the wrist or forearm.^51, Study characteristics and results are summarized in Tables 16 and 17. Thirty participants were recruited who were randomized 1:1 to silicone tube (n=17) or to standard end-to-end epineural suturing (n=13). Outcomes were assessed at 3-, 6- and 12-month follow-ups and then yearly through 5-year follow-ups; 2 participants were lost to follow-up at the 5-year assessment 1 in each of the study arms. Outcome assessors were blinded through 1-year follow-up but not for yearly assessments after this time. The primary endpoint was BMRC grading for sensory recovery with a secondary outcome of Rosen-score. Patients ranged from 12 to 72 years of age, with an overall mean age of 33 years. No description of nerve discontinuity length within each group was reported. Early results 1 year follow-up showed a significant difference for cutaneous touch and pressure thresholds favoring the conduit group (p=.03). At 5 years of follow-up, only perceived problems from cold intolerance were significantly different between groups and favored the conduit group over conventional repair (p=.01); all other elements of the Rosen-score were not significant (SWM, s2PD, STI-test, Sollerman test [tasks 4,8 and 10], manual muscle test, grip strength, and hyperesthesia). Limitations of the trial included a lack of blinding for follow-up beyond 1 year, lack of baseline information on nerve discontinuity length for each treatment arm, lack of power calculations reported, and non-ITT analysis.

Weber et al (2000) published the results of a multicenter, double-blind RCT comparing PGA conduit to standard nerve repair for digital nerve reconstruction.^52, Study characteristics and results are summarized in Tables 16 and 17. A total of 98 participants with 136 nerve transections of the hand were randomized 1:1 to PGA conduit (n=62) or standard surgical repair (n=74). At baseline, patient gender (p=.02) and mean gap length (7.0 mm in the PGA group vs 4.3 mm in the conventional repair group; p=.01) were not balanced between treatment arms. The average length of follow-up was 9.4 months in the PGA conduit patients and 8.1 months in the control group. Sixteen (25%) nerves in the PGA group and 18 (25%) nerves in the control group were lost to follow-up. No significant differences were observed in any outcome when examining the total enrolled study population, but when stratified by length of nerve gap, nerves with gaps of 4 mm or less had better sensation when repaired with a PGA conduit (mean m2PD, 3.7±6.4 mm for PGA conduit versus 6.1 ± 6.33 mm for end-to-end repairs (p=.03). Deficits of 8 mm or greater, which necessitated an autologous nerve graft in the control arm, favored PGA tube on m2PD test (mean, 6.8±3.8 mm for PGA conduit versus 12.9±2.4 mm for conventional repair; p=.001). Three patients in the PGA group had their conduit removed. Limitations of this study include uncertainty regarding the blinding for participants, lack of power calculations, non-ITT analysis, and a high number of participants who were lost to follow-up.

Table 16. Summary of Key RCT Characteristics for Synthetic Nerve Conduit

NR; not reported; RCT: randomized controlled trial.

Table 17. Summary of Key RCT Results for Synthetic Nerve Conduit

~: indicates esimtated from figure; BMRC: British Medical Research Council; CI: confidence interval; HR: hazard ratio; IQR: interquartile range; M2PD: moving 2-point discrimination; NNT: number needed to treat; NR: not reported; NS: non-significant; OR: odds ratio; PGA: polyglycolic acid; PNA: Processed decellularized nerve allograft; RCT: randomized controlled trial; RMI: Rosen Model Instrument; RR: relative risk ; S2PD: static 2-point discrimination; SD: standard deviation; SWMF: Semmes-Weinstein Monofilament testing.

The purpose of the study limitations tables (see Tables 18 and 19) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 18. Study Relevance Limitations for Synthetic Nerve Conduit

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 19. Study Design and Conduct Limitations for Synthetic Nerve Conduit

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Nonrandomized Studies

Processed Nerve Allograft

Two non-randomized comparative studies of Neuragen compared to Avance allograft are reported in the process nerve allograft section.[Rbia N, Bulstra LF, Saffari TM, et al. Collagen Ne.... 27: e1176-e1184. PMID 31003028][Ducic I, Safa B, DeVinney E. Refinements of nerve.... 37(3): 256-263. PMID 28035702] In a case series by Rbia et al (2019), 18 patients underwent peripheral nerve reconstruction of the fingers using Avance PNA and 19 with Neuragen collagen nerve conduit. The study reported comparable sensory recovery in both groups with no significant differences. In a retrospective cohort study by Ducic et al (2012), patients with upper extremity peripheral nerve reconstructions were treated using Avance PNA, NeuraGen conduit, autograft, or direct surgical repair. The study found no significant differences in QuickDASH questionnaire scores between the groups.

Autologous Nerve Graft

Saeki et al (2018) reported the results of a multi-center, open-label, non-randomized trial of non-hollow, collagen-filled conduits (n=48) compared to autologous nerve graft (n=38) in individuals with sensory nerve defects of the wrist or more distal location on the upper extremity. ^30, Participants were recruited from 9 centers in Japan from 2010 to 2014. A non-inferiority margin of -25% between collagen conduit and allograft was assigned, and the authors determined that to have 80% power, an estimated 41 participants would be needed in each group. The allograft group contained predominately historical controls (n=31). The two treatment arms differed in the baseline characteristics of mean age (42 in the conduit group versus 36 in the autologous graft group, p=.032) and the mean size of nerve defect (12.6 in the conduit group versus 18.7 in the autologous graft group, p<.0001). At 12 months post-surgery, both groups had similar rates of sensory recovery, assessed by S2PD, of 75% (95% CI, 60% to 86%) for the artificial conduit and 73.7 (95% CI, 57% to 87%). Adverse events were reported in 70% of the nerve conduit patients, with 21% assessed as serious events, and in the autologous grafting group, 86% of participants had at least 1 adverse event, with only 5% deemed as serious. Limitations of the study include lack of randomization and blinding, generalizability of the collagen conduit intervention, use of historical control patients, and imbalanced baseline patient characteristics.

Table 20. Summary of Key Nonrandomized Trials OR Observational Comparative Study Characteristics for Synthetic Nerve Conduit

NR: not reported; PNA: Processed decellularized nerve allograft

Table 21. Summary of Key Nonrandomized Trials OR Observational Comparative Study Results for Synthetic Nerve Conduit

BMRC: British Medical Research Council; CI: confidence interval; HR: hazard ratio; IQR: interquartile range; M2PD: moving 2-point discrimination; NNT: number needed to treat; NR: not reported; NS: non-significant; OR: odds ratio; PGA: polyglycolic acid; PNA: Processed decellularized nerve allograft; RCT: randomized controlled trial; RR: relative risk ; S2PD: static 2-point discrimination; SD: standard deviation; SWMF: Semmes-Weinstein Monofilament testing.

Observational Studies

Numerous observational case reports and case series are available on the treatment of peripheral nerve discontinuities with synthetic conduits.^{9,11,12,53,54,14,17,21,55,32,56,57,19,22,58,35,} Because higher quality evidence is available, only studies with ≥75 participants, using commercially available interventions and longer-term follow-up over 6 months, were summarized.

Wangensteen et al (2010) reported results from a retrospective chart review of all patients who received Neuragen conduits (Integra Lifesciences) at a single center.^59, From 2002 to 2007, 96 patients with 126 nerve lesions were repaired; the majority of repairs were to the upper extremity (95%), non-upper extremity repairs were limited (5%). (Table 11). The mean age of the overall population was 33 years (range, 7 to 79 years), and the average nerve gap was 12.8 mm (range 2.5 to 20 mm). The average follow-up period was 256 days, and 40 nerve repairs (32%) were lost to follow-up. The total number of surgical revisions was 11 (9%), with 9 occurring in the upper extremities (8%) and a greaterpercentage in the non-upper extremities (33%). Overall, 43% of patients with either objective or subjective evaluation by electromyography, 2-point discrimination, or Semmes-Weinstein monofilament testing showed post-operative improvement.

Table 22. Summary of Key Case Series Characteristics for Synthetic Nerve Conduit

Table 23. Summary of Key Case Series Results for Synthetic Nerve Conduit

NR: not reported; SWMF:Semmes-Weinstein monofilament testing; 

Section Summary: Synthetic Conduits

For individuals with peripheral nerve injury requiring repair and closure of the nerve gap who receive synthetic nerve conduits, the evidence includes 3 meta-analyses, 8 RCTs (2 comparing NeuraGen to allograft, 1 comparing Neurotube to autologous vein grafting, and 4 comparing conduit [1 Neurolac, 1 Polyhydroxybutyrate {PHB}, 1 polyglycolic acid {PGA}, and 1 silicone tube] to direct surgical repair), 1 non-randomized clinical trial, 1 comparative retrospective cohort study, 1 comparative case series, and 1 non-comparative case series. The evidence base consisted primarily of peripheral nerve injuries to the fingers or upper extremities. NeuraGen was evaluated in 3 studies, and all other synthetic conduits were represented by a single study (Neuromatrix, Neuroflex, Neurotube, Neurolac, PHB conduit, PGA conduit, and collagen-filled conduit). In 1 RCT that compared Avance allograft to NeuraGen, allograft patients had a greater return of protective sensation rate on static 2-point discrimination (S2PD), but did not differ on overall S2PD score or other outcome measures. The second RCT comparing Avance allograft to Neuragen found that S2PD favored the allograft group at 1-year follow-up, but no differences were noted in moving 2-point discrimination (M2PD), Semmes Weinstein Monofilament (SWMF) test, or the Disability of the Arm and Shoulder (DASH) questionnaire. One RCT compared Neurotube conduit to an autologous vein conduit and found similar outcomes at a 2-year follow-up, but at 1-year analysis, the motor domain of the Rosen Model Instrument (RMI) favored the autologous treatment arm. Five other trials compared different types of conduits to direct surgical repair with generally equivalent outcomes; one RCT observed a significant difference in cold intolerance, which favored the synthetic conduit group, and another found that at short (<4 mm) and long nerve gaps (> 8 mm) M2PD was better in the PGA conduit group than in direct surgical repair or autograft. Major limitations identified in the trial evidence base included an absence of participant blinding, lack of intention to treat analysis, high loss to follow-up, absence of power calculations, and short duration of follow-up. Three non-randomized comparative studies found no difference between synthetic conduits and Avance (n=2), direct surgical repair (n=1), or autograft (n=1) in sensory or functional outcomes as well as complications. A Cochrane review found that there is no clear benefit to patients treated with artificial nerve conduits or nerve wraps over direct surgical repair, and that complications may be greater for participants treated with synthetic nerve conduits or wraps. The overall evidence base was considered very uncertain, with few outcomes having more than 1 included study. One other meta-analysis found comparable pooled rates of S2PD and M2PD across assessed interventions, but all estimates had extreme heterogeneity. The third meta-analysis found that meaningful recovery (≥S3 on the British Medical Research Council [BMRC] recovery grading system) was significantly higher in allograft and autografting than for synthetic conduits. No guideline evidence was identified for synthetic nerve conduits for the treatment of peripheral nerve injuries. Many of the included trials have significant limitations, and the substantial heterogeneity in patient and intervention characteristics makes it challenging to compare outcomes reliably across studies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Suplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Institute for Health and Care Excellence (NICE)

In 2017, NICE published guidance on processed nerve allografting to repair peripheral nerve discontinuities. [National Institutes for Health and Care Excellence.... 97. Accessed November 15, 2023] The evidence base evaluated by NICE included the RCT by Means et al (2016) and the non-randomized trial by He et al (2013), which are discussed in this medical reference policy. NICE also evaluated two other smaller case series, which were not included in our evidence review due to the availability of higher-quality evidence. The following were among the recommendations issued:

• Current evidence on the safety and efficacy of processed nerve allografts to repair peripheral nerve discontinuities is adequate to support the use of this procedure for digital nerves, provided that standard arrangements are in place for clinical governance, consent, and audit.

• The evidence on the safety of processed nerve allografts to repair peripheral nerve discontinuities in other sites raises no major safety concerns. However, current evidence on its efficacy in these sites is limited in quantity. Therefore, for indications other than digital nerve repair, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research.

• This procedure should only be done by surgeons with training and experience in peripheral nerve repair.

• Patient selection should take into consideration the site, type of nerve (motor, sensory, mixed), and the size of the defect.

• NICE encourages further research into processed nerve allografts to repair peripheral nerve discontinuities. This should include information on the type of nerve repaired, the anatomical site, the size of the defect, patient-reported outcome measures, functional outcomes, time to recovery, and long-term outcomes (12 months to 18 months).

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 24.

Table 24. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

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Codes

Policy History