Saluran saraf biokejuruteraan dan balutan untuk pembaikan saraf periferi anggota atas
Referencias
References to studies included in this review
References to studies excluded from this review
References to ongoing studies
Additional references
References to other published versions of this review
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | Study type: RCT Follow‐up: 18 months | |
| Participants | Participants: 12 (6 intervention, 6 control) Injury: < 1 week following injury, complete median or ulnar nerve injury, or both, at the wrist/forearm level Age range (years): 15–58 Sex: 1 female, 11 male | |
| Interventions | Intervention: PHB wrap (6 participants, total number of nerves unclear) Control: epineural end‐to‐end suturing (6 participants, total number of nerves unclear) | |
| Outcomes | Outcomes measured at 3, 6, 9, 12, and 18 months Motor recovery (MMT, grip and pinch strength, motor neurography, EMG) Sensory recovery (BMRC score S0–S4, thermal threshold, 2‐PD, sensory neurography, morphological assessment of sensory neuropeptides of skin biopsies) Functional recovery (sensorimotor test, Sollerman hand function test, 4 question form) Safety (adverse events, complications) | |
| Funding | Study sponsored by AstraTech AB, Sweden, manufacturers of PHB wrap | |
| Conflicts of interest | Stated no conflicts | |
| Notes | Results from sensory neurography were excluded from the final analysis due to missing data. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Low risk | Sealed envelope, opened at time of surgery. |
| Random sequence generation (selection bias) | Low risk | Computerised randomisation with a block size of 10 participants. |
| Blinding of participants and personnel (performance bias) | Low risk | All assessors and participants were unaware of the type of treatment. |
| Blinding of outcome assessment (detection bias) | Low risk | All assessors and participants were unaware of the type of treatment. |
| Incomplete outcome data (attrition bias) | Unclear risk | 1 participant did not have the primary outcome (BMRC sensory recovery) measured at 18‐month follow‐up. Detail was provided of incomplete data sets. The discussion advised careful interpretation of results in which missing data resulted in < 5 participants. |
| Selective reporting (reporting bias) | High risk | All predetermined outcome measures commented on. Report provided data only on those demonstrating a significant difference between groups and data were discarded for median nerve injuries in 2 participants who had > 1 nerve repaired. |
| Other bias | Low risk | No other specific risks of bias. |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Follow‐up: 12 months | |
| Participants | Participants: 30 (17 intervention, 13 control) Injury: unknown time from injury, complete nerve injury distal to the wrist Age range (years): 18–75 Sex: 7 female, 23 male | |
| Interventions | Intervention: poly(DL‐lactide‐caprolactone) (Neurolac) nerve guide (21 nerve repairs in 17 participants) Control: end‐to‐end suturing (13 nerve repairs in 13 participants). | |
| Outcomes | Outcomes measured at 3, 6, 9, and 12 months Sensory recovery (static and moving 1‐ and 2‐PD) Safety (adverse events, complications) | |
| Funding | Study supported by Polyganics, manufacturers of Neurolac nerve guide | |
| Conflicts of interest | Awarded funding support by company who makes conduits. | |
| Notes | Nerve lesions were subgrouped according to defect length (< 4 mm, 4–8 mm, and 8–20 mm). Each subgroup had its own randomisation. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Low risk | Allocation made in operating theatre after exploration of wound, nurse opened concealed envelope. |
| Random sequence generation (selection bias) | Unclear risk | Detail of sequence generation not provided. |
| Blinding of participants and personnel (performance bias) | Unclear risk | Participants may have been aware of intervention following allocation. |
| Blinding of outcome assessment (detection bias) | Unclear risk | Assessors may have been aware of treatment. |
| Incomplete outcome data (attrition bias) | Unclear risk | Detail not provided of incomplete data, number of participants at time points not provided. No comment on number who attended follow‐up. |
| Selective reporting (reporting bias) | Low risk | Results for all expected outcome measures were reported. |
| Other bias | Unclear risk | Randomisation of participants (with nerves from same participant receiving the same treatment) producing a unit‐of‐analysis error. 4 participants had 2 nerve grafts, and it is unclear how these paired data impacted the results. |
| Study characteristics | ||
| Methods | Study type: RCT Follow‐up period: 24 months | |
| Participants | Participants: 43 participants (22 intervention, 21 control) Injury: < 72 hours following injury, complete nerve laceration of the median or ulnar nerves or both in the distal third of the forearm Age range (years): 21–66 Sex: 9 female, 22 male (demographics provided for those attending 2‐year follow‐up) | |
| Interventions | Intervention: collagen nerve guide conduit (23 nerves in 22 participants) Control: end‐to‐end suturing or nerve grafting (22 nerves in 22 participants, 21 direct repairs and 1 sural nerve graft). Note: data for sural nerve graft subsequently excluded from analysis. | |
| Outcomes | Outcomes measured at 3, 6, 12, 18, and 24 months RMI Motor action potential Sensory action potential Safety (adverse events and complications) | |
| Funding | No funding source declared | |
| Conflicts of interest | Nerve conduit company employee featured on authorship | |
| Notes | Nerve gap > 20 mm was an exclusion criterion. Trialists performed only 1 nerve grafting, which was excluded from the final analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | Quote: "We opened the randomization envelopes at the time of surgery after having measured the nerve gap and found the lacerations suitable for direct end‐to‐end suture or implantation of a short nerve graft." |
| Random sequence generation (selection bias) | Unclear risk | Details of sequence generation not provided. |
| Blinding of participants and personnel (performance bias) | Low risk | The participants and postoperative personnel were blinded to the treatment and subjective outcomes used. |
| Blinding of outcome assessment (detection bias) | Low risk | The evaluators were blinded to the treatment. |
| Incomplete outcome data (attrition bias) | Unclear risk | 11 participants did not have follow‐up at 24 months. 1 died, and the others did not attend follow‐up. Therefore, data were analysed for 18/22 participants in the conduit repair group and 13/21 participants in the direct suture group at 24 months. However, we judged the risk of bias unclear because there was no reported systematic difference in the way participant groups were followed up. There was only 1 participant with a nerve gap injury repaired using autologous nerve graft and the data were excluded from analysis. We deemed this a low risk of attrition bias in itself. We graded the risk of attrition bias overall as unclear as the reasons for loss to follow‐up were not detailed. |
| Selective reporting (reporting bias) | Low risk | All outcome measures were reported. |
| Other bias | Unclear risk | Nerve gaps were compared to direct repair. Length of defects repaired in the conduit group unclear. Quote: "We measured the nerve gaps to ensure that they did not exceed 20 mm but we did not record the measurements for further analysis." Comment: this could conceivably bias results to favour direct repair but we did not consider this a major concern. 1 participant underwent 2 nerve repairs (unit of randomisation was the participant). It is unclear how authors dealt with non‐independence of data in analysis. |
| Study characteristics | ||
| Methods | Study type: RCT Follow‐up: 60 months | |
| Participants | Participants: 30 participants (17 intervention, 13 control) Injury: < 48 hours following injury, complete transection of the median or ulnar nerve at wrist or distal forearm (< 10 cm from the wrist) Age range (years): 12–72 Sex: 4 female, 26 male | |
| Interventions | Intervention: silicone tube (17 nerve repairs in 17 participants) Control: epineural end‐to‐end suturing (13 nerve repairs in 13 participants) | |
| Outcomes | Outcomes measured at 3, 6, 12, 24, 36, 48, and 60 months BMRC grading for sensory recovery Sensory and motor neurophysiology RMI | |
| Funding | Supported by grants from the Swedish Research Council, Swedish Brain Foundation, Faculty of Medicine, Lund University | |
| Conflicts of interest | Did not state any conflict of interest. | |
| Notes | 17 participants underwent neurophysiological assessment. We requested raw data, which was provided and facilitated meta‐analysis at the 24‐month time point. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Low risk | Concealment was performed with sealed envelopes. It is uncertain at what point this was opened; however, all surgeries were performed within the first 48 hours following injury. |
| Random sequence generation (selection bias) | Unclear risk | Detail of sequence generation not provided. |
| Blinding of participants and personnel (performance bias) | Unclear risk | It is unclear if participants were blinded. |
| Blinding of outcome assessment (detection bias) | High risk | The examiner was actively blinded during the first follow‐up year; however, due to small‐study size and close follow‐up, blinding was broken by 5‐year follow‐up. |
| Incomplete outcome data (attrition bias) | Low risk | Only 2/30 participants failed to make the 5‐year follow‐up, 1 from the conduit repair and 1 from the standard repair group. All analysis was performed as intention‐to‐treat and there were no deviations from random allocation. |
| Selective reporting (reporting bias) | Low risk | Results for all expected outcomes were reported. |
| Other bias | Low risk | No other specific areas of risk of bias. |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Follow‐up: 12 months | |
| Participants | Participants: 98 participants with 136 nerve transections (62 intervention, 74 control) Injury: complete transection of a sensory nerve distal to the distal wrist crease (common or proper digital nerves) Age range (years): 17–65 Sex: 26 female, 72 male Timing of repair: varied < 72 hours (112 nerves), 4–20 days (15 nerves), > 20 days (9 nerves) | |
| Interventions | Intervention: polyglycolic acid conduit (62 nerves in 54 participants) Control: end‐to‐end suturing or nerve grafting (74 nerves in 52 participants) | |
| Outcomes | Outcomes measured at 3, 6, 9, and 12 months Sensory recovery (static and moving 2‐PD) Safety (adverse events, complications) | |
| Funding | No funding source declared. | |
| Conflicts of interest | RA Weber and colleagues have no stated conflicts of interest. | |
| Notes | Each nerve transection was randomised individually. Nerve gap, if any, was ≤ 3 cm Reporting of patient functional outcomes were grouped based on last follow‐up time (i.e. 3, 6, or 9 months); as such, data were not in a useable format for meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment (selection bias) | Unclear risk | Allocation concealment was performed with sealed envelopes at time of surgery after exploration of wound. |
| Random sequence generation (selection bias) | Unclear risk | Detail of sequence generation not provided. |
| Blinding of participants and personnel (performance bias) | Low risk | Randomisation performed in theatre following exploration. Each nerve was randomised individually. |
| Blinding of outcome assessment (detection bias) | Low risk | The therapist making the assessments was blinded to treatment. |
| Incomplete outcome data (attrition bias) | High risk | Postoperative sensory measurements were obtained detailing 46/62 nerves in the conduit participant group and 54/74 nerves in the standard repair group. For participants who did not return for the complete 12‐month follow‐up, the result of their last visit, whether at 3, 6, or 9 months was carried forward and used to determine their outcome. |
| Selective reporting (reporting bias) | Low risk | Results for all expected outcomes were reported. |
| Other bias | Unclear risk | Randomisation of nerves. It is unclear if there is unit‐of‐analysis bias. There was no apparent adjustment for non‐independence of multiple nerve repairs in same participant. Number of nerve surgeries per participant:
|
1‐PD: 1‐point discrimination; 2‐PD: 2‐point discrimination; BMRC: British Medical Research Council; EMG: electromyography; MMT: manual muscle test; PHB: poly(R)‐3‐hydroxybutyrate; RCT: randomised controlled trial; RMI: Rosén Model Instrument.
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| Insufficient patient compliance and data collection led to study termination. No published data. | |
| Methodology did not meet inclusion criteria. Time points for follow‐up different for device repair and standard repair cohorts. | |
| Follow‐up limited to 6 months. |
Characteristics of ongoing studies [ordered by study ID]
| Study name | CoNNECT: a study of sutureless nerve repair |
| Methods | Interventional 3‐arm RCT powered for equivalence. Computer randomisation. Participants and observers blinded. |
| Participants | Patients aged 16–75 years with a traumatic complete digital nerve injury between the wrist and middle of the affected finger < 10 days old |
| Interventions | Stitching injured nerve ends directly together Stitching nerve ends directly together and placing a nerve conduit around it Placing the injured nerve ends together without stitches and using the nerve conduit to maintain their position and heal |
| Outcomes | Primary outcome measure Sensory recovery using static and moving 2‐PD (tactile gnosis) for each repaired nerve. The comparable area on the opposite hand will be tested for static and moving 2‐PD to act as a baseline for assessment of recovery. These measurements will allow the modified Weber score to be calculated. This will be assessed at weeks 2, 6, 12, 26, and 52. Secondary outcome measures Monofilament pressure thresholds (innervation density), assessed using the WEST Monofilaments Upper extremity disability and symptoms, assessed using the DASH score Self‐rated health, assessed using the EQ‐5D Nerve irritation, assessed using differential Tinel's sign Pain, assessed using a VAS Cold intolerance, assessed using a VAS Hyperaesthesia, assessed using a VAS Site of repair, measured in mm from the hyponychium of the same digit (the duration of each repair will be recorded) For suture repairs, the quality of the repair will be recorded using the visual grading scale for suture‐only nerve repair For common digital nerve repair, the outcome for each digital nerve territory will be recorded Each assessed at weeks 2, 6, 12, 26, and 52 |
| Starting date | 1 February 2017 |
| Contact information | |
| Notes | Retrospectively registered |
| Study name | Comparison of processed nerve allograft and collagen nerve cuffs for peripheral nerve repair (RECON) |
| Methods | Multicentre, prospective, randomised, participant‐ and evaluator‐blinded comparative study of nerve cuffs and Avance nerve graft evaluating recovery outcomes for the repair of nerve discontinuities |
| Participants | 220 participants enrolled, aged 18–65 years |
| Interventions | Intervention: processed nerve allograft (human) Active comparator: collagen nerve cuff |
| Outcomes | Recovery of static 2‐PD assessed by discriminator (in mm) (time frame: 12 months) |
| Starting date | June 2015 |
| Contact information | L Scott Levin, University of Pennsylvania |
| Notes |
| Study name | Nerve repair using hydrophilic polymers to promote immediate fusion of severed axons and swift return of function |
| Methods | Randomised, single‐blind, parallel‐group |
| Participants | Planned recruitment: 18 People with diagnosis of Sunderland Class 5 traumatic neuropathy (transection injury) of a digital nerve in the upper extremity who are candidates for immediate surgical repair, within 72 hours of injury or 48 hours if the injury requires nerve grafting. Participants are required to have no significant comorbidities to prevent immediate repair and be willing to comply with treatment and evaluation schedule. People with peripheral nerve injuries complicated by significant vascular or orthopaedic damage were eligible. Exclusion criteria: gross contamination of injuries, inadequate soft tissue coverage, or planned staged repair; diabetes, diagnosed neuromuscular disease, undergoing chemotherapy, radiotherapy, or other treatments known to affect the growth of the neural and vascular system; people enrolled in another investigational study, those unlikely to complete the normal regimen of occupational therapy; time of injury outside study parameters |
| Interventions | 3 'no intervention' groups (no medication used)
3 experimental groups (with PEG‐assisted axonal fusion technique)
Quote: "For the control groups, epineural repair or interposition grafting will be undertaken in the standard end‐to‐end fashion using interrupted nylon suture after irrigation of the wound with normal saline as deemed necessary by the operating surgeon. For the experimental group, the nerve(s) will be repaired using standard suture neurorrhaphy techniques and a 149.25 mM (50%) solution of PEG 3.35 kD in sterile water will then be irrigated onto the neurorrhaphy site for one minute. Following this, the approximated nerve ends will be irrigated with sterile water gently for 2 minutes. All wounds will be closed in the fashion deemed appropriate by the operating surgeon." |
| Outcomes | Return of nerve function as measured by (Medical Research Council Classification) (time frame: 12 months) |
| Starting date | 1 September 2015 |
| Contact information | Wesley Thayer, Julia Yao, Vanderbilt University Medical Centre |
| Notes |
| Study name | Chitosan nerve tube for primary repair of traumatic sensory nerve lesions of the hand (CNT) |
| Methods | To evaluate whether the additional use of a chitosan nerve tube in primary microsurgical repair of traumatic sensory nerve lesions of the hand has an effect on convalescence and functional results. |
| Participants | Adults aged 18–67 years with a sensory nerve defect in the hand |
| Interventions | Chitosan nerve tube Gold‐standard repair |
| Outcomes | Static 2‐PD of injured finger measured with compasses 6 months after intervention (primary outcome) Static 2‐PD of injured finger/sensibility (checking participants' ability to recognise filaments of different calibres) at other follow‐ups (3, 6, 12, and 24 months after intervention). DASH‐score (at 3, 6, 12, and 24 months after intervention). Patients' individual disability in activities of daily living will be measured with the DASH questionnaire. Grip strength (at 3, 6, 12, and 24 months after intervention). Grip strength of both hands will be measured with a dynamometer and will be compared to the opposite side. Range of motion of the injured finger (at 3, 6, 12, and 24 months after intervention). Range of motion of the injured finger measured with a goniometer for small joints and will be compared to the opposite side. Pain (VAS) (at 3, 6, 12, and 24 months after intervention). Participants will self‐report pain on VAS, ranged from 0 (no pain) up to 10 (maximum of pain) Cold intolerance (grades: 0 = hinders function; 1 = disturbing; 2 = moderate; 3 = none/minor) (at 3, 6, 12, and 24 months after intervention). The examiner will question the participant about cold intolerance (grades: 0 = hinders function; 1 = disturbing; 2 = moderate; 3 = none/minor) Hypersensitivity (grades: 0 = hinders function; 1 = disturbing; 2 = moderate; 3 = none/minor) (at 3, 6, 12, and 24 months after intervention). The examiner will stroke the dysfunctional area and question the participant about cold hypersensitivity (grades: 0 = hinders function; 1 = disturbing; 2 = moderate; 3 = none/minor) Existence of neuromas (at 3, 6, 12, and 24 months after intervention). The existence of a neuroma will be assessed clinically and by neurosonography. |
| Starting date | 1 July 2015 |
| Contact information | florian.neubrech@bgu‐ludwigshafen.de |
| Notes |
2‐PD: 2‐point discrimination; DASH: Disabilities of the Arm, Shoulder and Hand; EQ‐5D: Euro‐Qol 5 Dimension; PEG: polyethylene glycol; VAS: visual analogue scale; WESY: Weinstein Enhanced Sensory Test.
Data and analyses
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Sensory recovery at ≥ 24 months Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.1  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 1: Sensory recovery at ≥ 24 months | ||||
| 1.1.1 At 5 years | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.03 [‐0.43, 0.49] |
| 1.2 Muscle strength, assessed with BMRC motor grading at 12–24 months Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 1.2  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 2: Muscle strength, assessed with BMRC motor grading at 12–24 months | ||||
| 1.2.1 At 18 months | 1 | 11 | Mean Difference (IV, Random, 95% CI) | 0.40 [‐0.38, 1.18] |
| 1.3 Motor Rosén at 12–24 months Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 1.3  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 3: Motor Rosén at 12–24 months | ||||
| 1.3.1 At 24 months | 2 | 60 | Mean Difference (IV, Random, 95% CI) | ‐0.09 [‐0.24, 0.05] |
| 1.3.2 At 12 months | 1 | 35 | Mean Difference (IV, Random, 95% CI) | ‐0.15 [‐0.18, ‐0.12] |
| 1.4 Sensory recovery, assessed with BMRC sensory grading at 12–24 months Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 1.4  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 4: Sensory recovery, assessed with BMRC sensory grading at 12–24 months | ||||
| 1.4.1 At 18 months | 1 | 11 | Mean Difference (IV, Random, 95% CI) | 0.93 [‐0.09, 1.95] |
| 1.5 Integrated functional outcome, assessed with Rosén Model Instrument Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.5  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 5: Integrated functional outcome, assessed with Rosén Model Instrument | ||||
| 1.5.1 At 5 years | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.23 [0.07, 0.38] |
| 1.5.2 At 24 months | 2 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.17 [‐0.38, 0.05] |
| 1.5.3 At 12 months | 2 | 65 | Mean Difference (IV, Fixed, 95% CI) | ‐2.29 [‐2.49, ‐2.09] |
| 1.6 Touch threshold, measured by Semmes‐Weinstein Monofilament Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| Analysis 1.6  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 6: Touch threshold, measured by Semmes‐Weinstein Monofilament | ||||
| 1.6.1 At 24 months | 1 | 32 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.06, 0.08] |
| 1.6.2 At 12 months | 2 | 65 | Mean Difference (IV, Fixed, 95% CI) | 0.05 [‐0.07, 0.17] |
| 1.7 Cold intolerance Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 1.7  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 7: Cold intolerance | ||||
| 1.7.1 At 24 months | 1 | 32 | Mean Difference (IV, Random, 95% CI) | 0.11 [‐0.08, 0.30] |
| 1.8 Sensory nerve action potential (SNAP) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| Analysis 1.8  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 8: Sensory nerve action potential (SNAP) | ||||
| 1.8.1 At 24 months | 2 | 60 | Mean Difference (IV, Random, 95% CI) | ‐0.08 [‐1.89, 1.73] |
| 1.8.2 At 12 months | 2 | 61 | Mean Difference (IV, Random, 95% CI) | 0.23 [‐0.58, 1.03] |
| 1.9 Adverse events Show forest plot | 5 | 213 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.15 [1.74, 29.42] |
| Analysis 1.9  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 9: Adverse events | ||||
| 1.10 Device removal or revision Show forest plot | 5 | 256 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.61 [1.48, 39.02] |
| Analysis 1.10  Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 10: Device removal or revision | ||||
Study PRISMA flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Forest plot of comparison: 1 Repair using bioengineered device versus standard nerve repair, outcome: 1.5 Integrated functional outcome, assessed with Rosén Model Instrument.
Forest plot of comparison: 1 Repair using bioengineered device versus standard nerve repair, outcome: 1.9 Adverse events.
Forest plot of comparison: 1 Repair using bioengineered device versus standard nerve repair, outcome: 1.10 Device removal or revision.
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 1: Sensory recovery at ≥ 24 months
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 2: Muscle strength, assessed with BMRC motor grading at 12–24 months
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 3: Motor Rosén at 12–24 months
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 4: Sensory recovery, assessed with BMRC sensory grading at 12–24 months
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 5: Integrated functional outcome, assessed with Rosén Model Instrument
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 6: Touch threshold, measured by Semmes‐Weinstein Monofilament
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 7: Cold intolerance
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 8: Sensory nerve action potential (SNAP)
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 9: Adverse events
Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 10: Device removal or revision
| Repair using bioengineered devices versus standard techniques | ||||||
| Patient or population: people undergoing peripheral nerve repair of the upper limb | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with standard repair | Risk with bioengineered devices | |||||
| Muscle strength at ≥ 24 months | Not reported | |||||
| Sensory recovery at ≥ 24 months | The mean sensory recovery assessed with BMRC sensory grading in the standard repair group at 2 years was 2.75 points | The mean sensory recovery assessed with BMRC sensory grading at 2 years with bioengineered devices was 0.03 points higher | — | 28 (1 RCT) | ⊕⊝⊝⊝ | There may be no difference in therapeutic effect on sensory recovery with bioengineered devices compared to standard repair at 24 months, but the evidence is very uncertain. |
| Integrated functional outcome at ≥ 24 months Follow‐up: 2 years | The mean integrated functional outcome (RMI score) in the standard repair group was 1.875 | The mean integrated functional outcome (RMI score) with bioengineered devices was 0.17 lower (0.38 lower to 0.05 higher) | — | 60 | ⊕⊕⊝⊝ | There may be little or no difference in RMI with bioengineered devices compared to standard repair at 24 months to 5 years. At 5 years, the RMI may be slightly better after device repair than standard repair (MD 0.23, 95% CI 0.07 to 0.38; 1 RCT, 28 participants). |
| Touch threshold (score 0–1, where higher score is better) | Mean touch threshold score in the standard repair group was 0.81 | The mean touch threshold score with bioengineered devices was 0.01 higher (0.06 lower to 0.08 higher) | — | 32 (1 RCT) | ⊕⊝⊝⊝ | There may be little or no difference in touch threshold measured by Semmes‐Weinstein monofilament test with bioengineered nerve conduits compared to standard repair at 24 months. Semmes‐Weinstein monofilament test contributed to RMI data in 2 studies at 12 months. 1 further study planned to use this outcome measure but found it to be imprecise and did not report data. |
| Impact on daily living | No studies employed DASH PROM. | |||||
| Adverse events assessed as: adverse events (serious and non‐serious) Follow‐up: range 3 months to 5 years | 10 per 1000 | 68 per 1000 (17 to 280) | RR 7.15 (1.74 to 29.42) | 213 participants | ⊕⊝⊝⊝ | Use of bioengineered devices may increase adverse events compared to standard repair techniques, but the evidence is very uncertain. 2 studies included in this analysis had no adverse events. 1 study provided no information on adverse events in the standard repair group. |
| Specific serious adverse events: further surgery (device removal or revision)i assessed as: any unplanned secondary surgery to remove device Follow‐up: range 3 months to 5 years | 12/129 devices required further surgery (device removal) in the bioengineered devices group; 0/127 procedures required further surgery in the standard repair group | RR 7.61 (1.48 to 39.02) | 256 repairs | ⊕⊝⊝⊝ | The use of bioengineered devices may require more revision (device removal or revision) than standard repair but the evidence is uncertain. Unplanned removal of 12/44 devices (1/21 poly(DL‐lactide‐caprolactone) (Neurolac) devices, 8/17 silicone devices and 3/6 polyglycolic acid devices. 2 studies included in this analysis required no device removal. | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BMRC: British Medical Research Council; CI: confidence interval; DASH PROM: Disability of Arm Shoulder and Hand Patient‐Reported Outcome Measure; MD: mean difference; RCT: randomised controlled trial; RMI: Rosén Model Instrument; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded twice for imprecision, because of the very small sample size. | ||||||
| Device trade name | Material | Cost for device to repair 10 mm gap, 2 mm diameter |
|---|---|---|
| NeuroTube | Polyglycolic acid | GBP 580 exc of VAT (November 2018) |
| Neurogen PNG220 | Type I collagen | GBP 689.26 exc of VAT (Nov 2018) |
| Neurolac (Polyganics) | poly(DL‐lactide‐ε‐caprolactone) | No reply November 2018 [email protected] and info@polyganics emailed further 7 January 2019 further 18 May 2019 |
| Salubridge | Polyvinyl alcohol | No reply November 2018 [email protected] emailed further 7 January 2019 further 18 May 2019 |
| Axoguard | Porcine small intestine submucosa | USD 1000 equivalent to GBP 789.04 (April 2019) |
| Avance Axogen | Decellularised cadaveric nerve | USD 1800 equivalent to GBP 1420.28 (April 2019) |
| RevoInerv (NG02‐0203) | Porcine Type I and III collagen, bovine Type I | GBP 348 exc of VAT (January 2019) |
| exc: exclusive; GBP: Great British pounds; USD: United States dollars; VAT: value added tax. | ||
| Conduit/name | Study detail | Outcomes measured | Status | Study design |
|---|---|---|---|---|
| Registry of Avance Nerve Graft Evaluating utilization and outcomes for the Reconstruction of peripheral nerve discontinuities (RANGER) Avance, Axogen Inc. | Avance vs standard practice (epineurial suture or autologous nerve graft). Aim 5000 participants, 36 months' follow‐up | Adverse events, "improvement in function, return of meaningful recovery" | Recruiting, estimated completion December 2020, extended to December 2025 | Observational retrospective registry |
| Polynerve University of Manchester (UK) | Polynerve repair of nerve gaps 5–20 mm Aim 16 participants, 12 months' follow‐up | Adverse reactions (Clavien‐Dindo classification), 2‐PD, SWM | Recruitment complete, 17 participants, estimated completion August 2019 | Prospective observational cohort |
| Fibrin wrap or conduit University Hospital Basel (Switzerland) | Fibrin wrap or conduit vs standard practice (epineurial suture or autologous nerve graft) direct repair or > 5 mm gap digital nerves. Aim 48 participants, 6 months' follow‐up | 2‐PD, SWM, electroneurography | Recruiting, estimated completion December 2022 | Interventional case control |
| Hydrophilic polymers at repair site Vanderbilt University (Nashville, Tennessee) | Repair and topical polyethylene glycol (MiraLAX (MERCK) at repair site vs repair alone (epineurial suture or autologous nerve graft)). Within 48 hours of injury. Aim 18 participants 12 months' follow‐up | Return of nerve function as measured by BMRC classification. | Recruiting, estimated completion March 2020 | Interventional RCT |
| Reaxon Siemers, Medovent, GmBH (Germany) | Reaxon vs standard practice (epineurial suture or autologous nerve graft) < 26 mm gap digital nerves. Within 3 months of injury. Aim 76 participants, study terminated | 2‐PD, cold intolerance, Hoffmann‐Tinel‐Test, adverse reactions | Recruiting, estimated completion December 2018. January 2019 update Terminated (study was stopped due to slow participant recruitment and insufficient participant compliance) | Interventional RCT |
| Comparison of processed nerve allograft and collagen nerve cuffs for peripheral nerve repair (RECON) Axogen Inc. | Human nerve allograft vs bovine collagen repair cuff Aim 220 participants 12 months' follow‐up | 2‐PD | Recruiting Estimated completion November 2021 | Interventional RCT |
| A multicentre prospective observational study of nerve repair and reconstruction associated with major extremity trauma Johns Hopkins (Baltimore, Maryland) | Partial or complete upper extremity nerve injury, all repair types. Aim 250 participants 24 months' follow‐up | Extensive list of primary and secondary outcome measures with 2‐year follow‐up period – detail available | Active, not recruiting Estimated completion September 2022 | Prospective observational cohort |
| Chitosan nerve tube for primary repair of traumatic sensory nerve lesions of the hand (CNT) BG Unfallklinik (Frankfurt, Germany) | Chitosan nerve tube vs standard repair sensory nerves of the hands Aim 100 participants 24 months' follow‐up | 2‐PD, DASH, grip strength, range of motion, pain, cold intolerance, hypersensitivity, existence of neuromas, adverse events | Recruiting Last update July 2017 | Interventional RCT |
| Mid‐term effect observation of biodegradable conduit small gap tubulisation repairing peripheral nerve injury Peking University People's Hospital (Beijing, China) | Repair of peripheral nerve injury in the upper extremities using a biodegradable conduit Aim 150 participants 36 months' follow‐up | BMRC grading SHEN Ning‐jiang score | Active Estimated completion December 2021 | Prospective observational cohort |
| Preliminary evaluation of the clinical safety and effectiveness of the bionic nerve scaffold Xijing Hospital (China) | Preliminary evaluation of the clinical safety and effectiveness of the bionic nerve scaffold Aim 10 participants 6 months' follow‐up | 2‐PD, joint position sense and haematological tests | Recruiting Last update December 2018 | Prospective observational cohort |
| Pilot study to evaluate the reconstruction of digital nerve defects in humans using an implanted silk nerve guide Klinik für Plastische Chirurgie und Handchirurgie – UniversitätsSpital Zürich (Switzerland) | Prospective, unblinded, single‐group assignment silk nerve guide Aim 15 participants 12 months' follow‐up | Adverse events, sensory recovery 2‐PD, VAS, patient satisfaction Patient Global Impression of Change questionnaire | Recruiting Estimated completion March 2021 | Prospective observational cohort |
| CoNNECT (Conduit Nerve approximation versus Neurorrhaphy Evaluation of Clinical Outcome Trial): a study of sutureless nerve repair Queen Elizabeth Hospital Birmingham (UK) | Digital nerve injuries in upper limb, direct repair vs poly(DL‐lactide‐caprolactone) (Neurolac) nerve guide sutured vs Neurolac nerve guide no sutures Aim 240 participants 12 months' follow‐up | Static and moving 2‐PD, monofilament pressure testing, DASH, EQ‐5D, Tinel sign, pain, cold intolerance, hyperaesthesia, site, and quality of repair | Active Estimated completion January 2021 | Interventional RCT |
| Expanded access for single patient treatment of autologous human Schwann cells (ahSC) for peripheral nerve repair | Autologous, culture expanded Schwann cells seeded in Duragen collagen matrix used to repair a sciatic nerve defect | Not provided | Single participant study, 5 years' follow‐up | Single participant study |
| BMAC Nerve Allograft Study | Decellularised cadaveric nerve graft combined with unexpanded autologous bone marrow cells. Aim 15 participant recruitment, comparison to historical outcome measures obtained for Avance nerve graft. | Adverse events, Rosén Model Instrument, motor and sensory nerve conduction studies, pinch and grip strength, 1‐PD and 2‐PD | Recruiting | Single group, interventional clinical trial |
| 1‐PD: 1‐point discrimination; 2‐PD: 2‐point discrimination; DASH: disability of the arm, shoulder and hand; EQ‐5D: Euro‐Qol 5 Dimension; BMRC: British Medical Research Council; RCT: randomised controlled trial; SWM: Semmes‐Weinstein monofilament; VAS: visual analogue scale. | ||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Sensory recovery at ≥ 24 months Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 At 5 years | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.03 [‐0.43, 0.49] |
| 1.2 Muscle strength, assessed with BMRC motor grading at 12–24 months Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.2.1 At 18 months | 1 | 11 | Mean Difference (IV, Random, 95% CI) | 0.40 [‐0.38, 1.18] |
| 1.3 Motor Rosén at 12–24 months Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.3.1 At 24 months | 2 | 60 | Mean Difference (IV, Random, 95% CI) | ‐0.09 [‐0.24, 0.05] |
| 1.3.2 At 12 months | 1 | 35 | Mean Difference (IV, Random, 95% CI) | ‐0.15 [‐0.18, ‐0.12] |
| 1.4 Sensory recovery, assessed with BMRC sensory grading at 12–24 months Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.4.1 At 18 months | 1 | 11 | Mean Difference (IV, Random, 95% CI) | 0.93 [‐0.09, 1.95] |
| 1.5 Integrated functional outcome, assessed with Rosén Model Instrument Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.5.1 At 5 years | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.23 [0.07, 0.38] |
| 1.5.2 At 24 months | 2 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.17 [‐0.38, 0.05] |
| 1.5.3 At 12 months | 2 | 65 | Mean Difference (IV, Fixed, 95% CI) | ‐2.29 [‐2.49, ‐2.09] |
| 1.6 Touch threshold, measured by Semmes‐Weinstein Monofilament Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.6.1 At 24 months | 1 | 32 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.06, 0.08] |
| 1.6.2 At 12 months | 2 | 65 | Mean Difference (IV, Fixed, 95% CI) | 0.05 [‐0.07, 0.17] |
| 1.7 Cold intolerance Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.7.1 At 24 months | 1 | 32 | Mean Difference (IV, Random, 95% CI) | 0.11 [‐0.08, 0.30] |
| 1.8 Sensory nerve action potential (SNAP) Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.8.1 At 24 months | 2 | 60 | Mean Difference (IV, Random, 95% CI) | ‐0.08 [‐1.89, 1.73] |
| 1.8.2 At 12 months | 2 | 61 | Mean Difference (IV, Random, 95% CI) | 0.23 [‐0.58, 1.03] |
| 1.9 Adverse events Show forest plot | 5 | 213 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.15 [1.74, 29.42] |
| 1.10 Device removal or revision Show forest plot | 5 | 256 | Risk Ratio (M‐H, Fixed, 95% CI) | 7.61 [1.48, 39.02] |
