Bioengineered nerve conduits and wraps for peripheral nerve repair of the upper limb

Suzanne E Thomson; Nigel YB Ng; Mathis O Riehle; Paul J Kingham; Lars B Dahlin; Mikael Wiberg; Andrew M Hart

doi:10.1002/14651858.CD012574.pub2

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Figure 1

Study PRISMA flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Forest plot of comparison: 1 Repair using bioengineered device versus standard nerve repair, outcome: 1.5 Integrated functional outcome, assessed with Rosén Model Instrument.

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Figure 4

Forest plot of comparison: 1 Repair using bioengineered device versus standard nerve repair, outcome: 1.9 Adverse events.

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Figure 5

Forest plot of comparison: 1 Repair using bioengineered device versus standard nerve repair, outcome: 1.10 Device removal or revision.

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Analysis 1.1

Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 1: Sensory recovery at ≥ 24 months

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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

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Analysis 1.3

Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 3: Motor Rosén at 12–24 months

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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

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Analysis 1.5

Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 5: Integrated functional outcome, assessed with Rosén Model Instrument

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Analysis 1.6

Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 6: Touch threshold, measured by Semmes‐Weinstein Monofilament

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Analysis 1.7

Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 7: Cold intolerance

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Analysis 1.8

Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 8: Sensory nerve action potential (SNAP)

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Analysis 1.9

Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 9: Adverse events

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Analysis 1.10

Comparison 1: Repair using bioengineered device versus standard nerve repair, Outcome 10: Device removal or revision

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Summary of findings 1. Bioengineered devices compared to standard techniques for peripheral nerve repair of the upper limb

Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Repair using bioengineered devices versus standard techniques
Patient or population: people undergoing peripheral nerve repair of the upper limb Setting: upper limb peripheral nerve injury Intervention: bioengineered devices Comparison: standard repair
Outcomes	Risk with standard repair	Risk with bioengineered devices	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Muscle strength at ≥ 24 months assessed with: BMRC Grading (manual muscle testing, score 0–5, where 0 = no movement, 5 = normal)	Not reported
Sensory recovery at ≥ 24 months assessed with: BMRC Grading (score S0–S4, where S0 = no sensation, S4 = normal) Follow‐up: 2 years	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 (0.43 lower to 0.49 higher)	—	28 (1 RCT)	⊕⊝⊝⊝ Very low^a,b	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 assessed with: RMI (scale from 0 to 3, higher score better) 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 (2 RCTs)	⊕⊕⊝⊝ Low^c,d	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 assessed with: Semmes‐Weinstein monofilament (score 0–1, where higher score is better) Follow‐up: 24 months	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)	⊕⊝⊝⊝ Very low^a,e	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 assessed with: DASH PROM Scale from: 0 (good) to 100 (poor) Follow‐up: 24 months	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 (5 RCTs)	⊕⊝⊝⊝ Very low^f,g,h	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 (5 RCTs)	⊕⊝⊝⊝ Very low^f,h	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 High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded twice for imprecision, because of the very small sample size. ^bDowngraded once for study limitations; outcome assessor blinding was broken beyond the first follow‐up year, representing a high risk of bias, and we judged two domains, including allocation concealment, at unclear risk of bias. ^cDowngraded once for imprecision because of the small sample size and the CIs did not rule out an effect (in favour of standard repair). ^dDowngraded once for study limitations; in one study, outcome assessor blinding was broken beyond the first follow‐up year, representing a high risk of bias. Across both studies, multiple domains, including allocation concealment in both studies, were at unclear risk of bias. ^eDowngraded once for indirectness due to subjective nature of the test, and one study found the test results too heterogeneous to be reported. ^fDowngraded twice for very serious imprecision because of the wide CIs. ^gDowngraded once for indirectness. We planned to report serious adverse events, but the studies did not classify adverse events as serious or non‐serious. ^hDowngraded once for study limitations. All trials were either at high risk of bias or unclear risk of bias in multiple domains. ⁱWe added secondary surgeries for unplanned device removal to the summary of findings table as a change from protocol, as this outcome is important in decision‐making.

Summary of findings 1. Bioengineered devices compared to standard techniques for peripheral nerve repair of the upper limb

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Table 1. Cost of devices

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.

Table 1. Cost of devices

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Table 2. Registered studies evaluating bioengineered nerve wraps/conduits

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. NCT01526681	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) NCT02970864	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) NCT01573650	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) NCT02359825	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) NCT02459015	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. NCT01809002	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) NCT02718768	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) NCT02372669	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) NCT03359330	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) NCT03780855	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) NCT03673449	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) ISRCTN97234566	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 NCT02480777	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 NCT03964129	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.

Table 2. Registered studies evaluating bioengineered nerve wraps/conduits

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Comparison 1. Repair using bioengineered device versus standard nerve repair

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]

Comparison 1. Repair using bioengineered device versus standard nerve repair

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