| Coverage Policy Manual | |
| Policy #: | 2024003 |
| Category: | Medicine |
| Initiated: | July 2024 |
| Last Review: | April 2024 |
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| Peripheral Nerve Injury Repair Using Synthetic Conduits or Processed Nerve Allograft | |
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| Description: |
Peripheral nerve injuries are common traumatic events for which the conventional treatment is the microsurgical repair for gaps less than 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.
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 (Brattain, 2014). 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 (Karsy, 2019). Functional regeneration of injured nerves requires peripheral nerve surgery to allow axon regrowth and remyelination (Mankavi, 2023).
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 (Buncke, 2022). 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 (Mankavi, 2023).
Alternative Treatments
Allogenic nerve grafts are derived from human donors and are generally used to bridge gaps resulting from peripheral nerve injuries that are greater than 5 mm (Buncke, 2022). 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 (Axogen Inc., 2023).
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 (Parker, 2021). 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 (Mankavi, 2023). Conduits are generally used for nerve gap repairs of less than 5 mm (Buncke, 2022).
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.
FDA 510K Approved Synthetic Conduits and Wraps for Peripheral Nerve Repair
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Policy/ Coverage: |
Effective July 15, 2024
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of processed nerve allograft for the repair and closure of peripheral nerve gaps does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, the use of processed nerve allograft for the repair and closure of peripheral nerve gaps is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
The use of synthetic nerve conduits for the repair and closure of peripheral nerve gaps does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, the use of synthetic nerve conduits for the repair and closure of peripheral nerve gaps is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
A review of literature was performed with a search of the PUBMED databases through November 15, 2023. Following is a summary of the key literature to date.
Processed Nerve Allograft
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.
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 (Axogen, 2023). 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 (Axogen, 2023). 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.
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, 2023; Lans, 2023). 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 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 (Zhang, 2023). 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 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 (Lans, 2023). 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.
Randomized Controlled Trials
Isaacs et al published the results of a multicenter, double-blind RCT comparing conduit and processed nerve allograft (PNA) for peripheral nerve repairs of the fingers (Isaacs, 2023). 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 (NCT01809002).
Means et al reported the results of a multicenter, double-blind pilot RCT comparing hollow collagen conduits to PNA for peripheral nerve repairs of the fingers (Means, 2016). 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).
Nonrandomized Studies
Three non-randomized comparative studies were identified, including 1 case series and 2 non-randomized clinical trials that evaluated PNA (Rbia, 2019; He, 2015; Ducic, 2017). Rbia et al 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 (Rbia, 2019). 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. 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 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 (He, 2015). 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). 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 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 (Ducic, 2017). 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.
Many observational case reports and case series are available on treating peripheral nerve discontinuities with processed nerve allografts (Brooks, Cho, 2012; Dunn, 2021; Guo, 2013; Taras, 2013; Leckenby, 2021; Isaacs, 2014; Rinker, 2017; Zhu, 2017; Carlson, 2018; Safa, 2019; Safa, 2020; Peters, 2023; Karabekmez, 2009; Rinker, 2015). 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 performed a single-center, retrospective review of outcomes from Avance PNA for peripheral nerve injuries from April 2009 to October 2017 (Leckenby, 2021). A total of 129 patients with 171 nerve allografts met the study inclusion criteria. 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). 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 published results from the multi-center, Retrospective Avance Nerve Graft utilization, Evaluations, and outcomes in peripheral nerve injury Repair (RANGER) registry (Safa, 2020). 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. 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.
Synthetic Nerve Conduits
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.
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. The device received FDA 510k approval on April 24, 2014. It provides a protective environment for peripheral nerve repair after injury. 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 (Buncke, 2022).
Neuroflex is a resorbable, flexible type I collagen conduit that encases peripheral nerve injuries and protects the neural environment. 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. 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. 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 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. 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. 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.
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, 2023; Lans, 2023). The meta-analyses are relevant to both processed nerve allografts and synthetic nerve conduits. 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 (Thomson, 2022). 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. 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). 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.
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, 2023; Means, 2016; Boeckstyns, 2013; Rinker, 2011; Aberg, 2009; Bertleff, 2005; Lundborg, 2004; Wever, 2005).
Processed Nerve Allograft
The preceding section on processed nerve allografting reported the two trials that compared nerve conduits to allografts (Isaacs, 2023; Means, 2016). Isaacs et al 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 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 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 (Rinker, 2011). 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. 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, 2013; Rinker, 2011; Aberg, 2009; Bertleff, 2005; Lundborg, 2004; Wever, 2005). 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 (Boecksytns, 2013). 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, 2004). 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, 2005). No significant differences were noted between the conduit and direct surgical repair in 2 remaining RCTs (Aberg, 2009; Bertleff, 2005).
Boeckstyns et al 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 (Boecksytns, 2013). 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 reported a prospective, assessor-blinded pilot RCT comparing resorbable polyhydroxybutyrate (PHB) to conventional end-to-end repair in wrist and forearm nerve discontinuities (Aberg, 2009). 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. 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 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 (Bertleff, 2005). 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 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 (Lundborg, 2004). 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 published the results of a multicenter, double-blind RCT comparing PGA conduit to standard nerve repair for digital nerve reconstruction (Weber, 2005). 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.
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, 2019; Ducic, 2017). In a case series by Rbia et al, 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, 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 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 (Saeki, 2018). 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.
Observational Studies
Numerous observational case reports and case series are available on the treatment of peripheral nerve discontinuities with synthetic conduits (Arnaout, 2014; Bushnell, 2008; Chiriac, 2012; Dienstknecht, 2013; Farole, 2008; Haug, 2013; Kusuhara, 2019; Lohmeyer, 2007; Nakamura, 2020; Schmauss, 2014; Takeda, 2023; Li, 2017; Lohmeyer, 2014; Mackinnon, 1990; Patel, 2018; Thomsen, 2010). 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 reported results from a retrospective chart review of all patients who received Neuragen conduits (Integra Lifesciences) at a single center (Wangensteen, 2010). 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%). 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 greater percentage 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.
National Institute for Health and Care Excellence (NICE)
In 2017, NICE published guidance on processed nerve allografting to repair peripheral nerve discontinuities (NICE, 2017). 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 previously. NICE also evaluated two other smaller case series, which were not included in the review of evidence due to the availability of higher-quality evidence. The following were among the recommendations issued:
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below.
Summary of Ongoing Key Trials
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