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

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

• To assess and compare the effects and complication rates of licensed bioengineered nerve conduits or wraps for surgical repair of traumatic peripheral nerve injuries of the upper limb.

• To compare effects and complications against the current gold surgical standard (nerve autograft).

Background

Traumatic peripheral nerve injury occurs in domestic, industrial or military trauma, and can also occur during birth. The estimated frequency is 1 per 1000 in Europe, with the greatest prevalence in working age adults (Wilson 2003). Traumatic injuries can be lacerating, crushing or stretching in nature and are most commonly sustained by males, with more than 50% of these occurring in the workplace (Thorsén 2012). Major peripheral nerve trauma has significant socioeconomic cost, and outcomes remain very poor in terms of pain, time to achieve plateau outcome, psychosocial impact, and return of function (Rosberg 2005; Kretschmer 2009).

The current clinical standards of epineurial repair and nerve allografting were reaching widespread adoption by 1975 (Smith 1964; Terzis 1975; Lundborg 2005). Some closed injuries can recover without surgery, but when nerves are divided, ruptured, or severely compressed they may require decompression, repair, or reconstruction. The current gold standard technique is direct, tension‐free microsurgical repair, with use of nerve autografts when segmental defects arise (Millesi 1990). Despite considerable refinements in microsurgical technique nerve healing is slow and extended periods of denervation result in muscle atrophy and trophic skin changes. Misdirection of regenerating axons results in failure to re‐innervate target organs and can lead to painful neuroma formation. The overwhelming majority of patients do not achieve complete functional recovery, as current strategies for peripheral nerve repair and reconstruction fail to adequately address the neurobiology of injury and of nerve regeneration (Lundborg 2000; Lundborg 2005; Hart 2011).

An extensive preclinical literature has documented translationally relevant strategies to enhance nerve regeneration (Faroni 2015; Gaudin 2016). However, to date, clinical studies have been restricted to the use of bioengineered nerve wraps and bioengineered nerve conduits. The purpose of nerve wraps is to minimise suture‐associated fibrosis, reduce axonal escape, and provide narrow gaps known to facilitate neurite bridging across repair sites. Conduits remove the need for nerve autograft harvest, along with the associated donor site scarring, sensory loss, pain, and risk of symptomatic neuroma (Wiberg 2003; Martin 2014).

Description of the condition

The peripheral nervous system is a complex network of afferent (sensory) and efferent (motor) axons that connect cell bodies located in the central nervous system with peripheral (sensory input) and effector organs (such as muscles). Axons are situated within the endoneurium of peripheral nerves, which is an extracellular matrix (ECM) basal lamina produced by Schwann cells. Schwann cells ensheath one or more axons depending upon whether they myelinate the axons they ensheath. They myelinate a single larger axon serving motor supply, proprioception, and fine touch sensation, and ensheath multiple unmyelinated axons in Remak bundles (Salzer 2012). Other specialised connective tissue layers provide support and mechanical protection, and guide regeneration after axons cross the site of an injury. The perineurium surrounds several axons and endoneurial tissue forming a fascicle, and the outermost layer, the epineurium, envelopes several fascicles to form the nerve bundle.

Peripheral nerve injury has been classified according to severity, to assist in making prognosis and management decisions (Seddon 1942; Sunderland 1951; Lundborg 2005). Under the widely used Seddon classification, neurapraxia is interruption of conduction without loss of axonal integrity and full recovery is expected. Axonotmesis is interruption of axonal continuity, with preservation of epineurium and perineurium structure, following which there is Wallerian degeneration of the axon distal to the site of injury. Axonal regeneration is possible following axonotmesis, as the connective tissue scaffold remains to provide topographical guidance. Recovery time is lengthy, since axons regrow at approximately 1 mm/day. Neurotmesis is complete disruption of the axon and connective tissue layers. In neurotmesis, loss of distal motor and sensory function is complete and surgery is necessary to approximate the two ends of the injury and facilitate recovery. We will consider only neurotmesis in this review.

Following neurotmesis, the distal nerve stump undergoes Wallerian degeneration, a co‐ordinated debris‐clearing event. Schwann cells de‐differentiate, proliferate, and migrate, forming bands of Büngner, as they prepare to guide future axonal outgrowth from the proximal stump (Lundborg 1994; Hart 2011; Allodi 2012). Loss of axonal continuity causes the retrograde axonal transport system to fail, leading to a cascade of molecular and genetic changes within the injured neurons. Axonal transport failure culminates either in neuronal cell death, or in the adoption of a regenerative phenotype and the extension of neurites into the site of injury (Terenghi 2011; Hart 2011).

Description of the intervention

Current microsurgical methods employ epineurial sutures to approximate nerve ends with minimal tension, with or without the use of human fibrin glue (Dahlin 2008). The use of vein grafts, and other autologous tissue, to wrap the repair site has been described, but is not common practice. Where there is a gap defect, the surgeon interposes nerve autograft. The autograft is obtained by excision of functionally less important sensory nerves, creating a donor defect. Sensory nerve grafts are not a perfect system to promote motor nerve regeneration (Brushart 1993). Autologous donor nerve availability may be insufficient in large proximal injuries, such as brachial plexus injury (Millesi 2007). Even under optimal experimental conditions, less than 50% of regenerating axons successfully cross the site of surgical repair (Welin 2008).

The interventions considered here are alternative approaches to neurosynthesis, which work by approximating nerve stumps to one another within a tubular nerve conduit or by wrapping a sheet of material around the stumps to entubulate the repair site. A nerve conduit can also be used instead of an autologous nerve graft to bridge a gap defect. Designed to encourage directed regeneration and prevent axonal escape (Hart 2011), these constructs are not biologically functionalised. Pre‐clinical research indicates that future functionalisation (by patterning, cellularisation, or the incorporation of bioactive molecules) could enhance the regenerative ability of the ingrowing cells (Dahlin 2001). These products are beginning to be used in clinical trials and practice. However, there is a paucity of data to examine their efficacy and little comparative outcome data.

Nerve wrap

A nerve wrap is a form of direct neurosynthesis, using a sheet of material that is formed into a tube around the approximated nerve stumps. The composition and manufacturer of the nerve wrap, and mechanism of securing it (e.g. sutures or glue) vary, as do the injury mechanism, preoperative delay, intraoperative details, concomitant injuries, and postoperative care. These will be taken into account in this review if possible.

Nerve conduit

A nerve conduit involves reconstruction of a gap defect by the placement of proximal and distal nerve stumps into a tubular repair construct. The composition and manufacturer of the nerve conduit, and mechanism of securing it (e.g. sutures or glue) vary, as do the injury mechanism, preoperative delay, intraoperative details, concomitant injuries, and postoperative care. In addition, the length of nerve gap (and therefore, the length of the conduit employed to bridge the defect) is potentially important to the outcome of the repair.

How the intervention might work

Nerve wraps and tubular conduits present means by which to approximate nerve stumps within a biologically‐enhanced microenvironment, which minimises fibrosis and the potential for ingrowth of external scar tissues. These products can provide directional growth cues, and prevent dissipation of pro‐regenerative trophic and tropic factors away from the repair site. As a result, these constructs may reduce axonal escape or misdirection, improve regeneration into the distal nerve, and enhance functional recovery. Tubular conduits also offer the possibility of avoiding nerve autograft harvest, and thereby avoid the potential morbidity of that procedure (Hallgren 2013).

Why it is important to do this review

Around three million peripheral nerve repairs are performed each year (Life Science Intelligence 2009). Conduits and nerve wraps carry a significantly higher cost per item than microsurgical sutures for nerve repair. Widespread adoption of these products potentially presents a considerable economic challenge to healthcare services, and if the evidence for functional benefit is uncertain, inequalities of access could ensue. Patients will be worse off if complication profiles prove worse for these products than for standard treatments, and if the indications for their use widen uncritically.

Several inert bioengineered conduits and nerve wraps, manufactured from a variety of materials, are now clinically licensed. However, we lack comparative clinical trial data comparing functional outcomes and complication profiles between products (Meek 2008; Kehoe 2012), and data comparing these techniques with nerve autograft are limited. This review aims to provide a valuable resource to clinicians and participants in identifying and synthesising the evidence on the potential role of bioengineered conduits and wraps in the management of peripheral nerve injury.

A number of factors are known to influence nerve healing including gap length, type of nerve, age, smoking status, graft type and delay to surgery (Hart 2011; Birch 2015; Camara 2015; Hundepool 2015). We will also attempt to explore the effect of these factors on graft success in a subgroup analysis.

A well‐planned review of the performance of these devices compared to the current clinical gold standard is necessary to aid the clinician in identifying the potential role of bioengineered conduits and wraps in the management of peripheral nerve injury. Furthermore, critical analysis of current research will inform the design of future studies. This review will focus on nerve repair and reconstruction in the upper limb. However, we anticipate that our findings will have broader application to several other areas of surgical nerve repair, including, but not limited to, head and neck, lower limb, urological, and composite tissue allotransplantation procedures.

Objectives

• To assess and compare the effects and complication rates of licensed bioengineered nerve conduits or wraps for surgical repair of traumatic peripheral nerve injuries of the upper limb.

• To compare effects and complications against the current gold surgical standard (nerve autograft).

Methods

Criteria for considering studies for this review

Types of studies

We will include parallel group randomised controlled trials (RCTs) and quasi‐RCTs of nerve repair in the upper limb using a bioengineered wrap or conduit, with at least 12 months of follow‐up.

Where RCTs are unavailable, we will provide narrative discussion of large cohort studies that satisfy minimum quality criteria, namely adequate description of the following:

• injury (mixed/motor/sensory nerve, adult/child/neonate, mechanism, location, size, and concomitant injuries sustained);

• surgical procedure (gap length to be reconstructed, length of inserted nerve conduit or graft);

• neurosynthesis technique (e.g. suture or fibrin glue);

• outcome assessment (timing relative to injury, blinding measures used, detail of measure(s) used and how applied);

• rate of dropout from study.

We will include studies reported as full‐text, those published as abstract only, and conference reports. We will apply no restrictions as to language of publication. We will not perform a formal non‐randomised studies meta‐analysis and we will describe the non‐randomised studies in the discussion section only.

Types of participants

We will consider for inclusion studies of adults and children with a peripheral nerve transection. We will consider the influence of participant age on nerve healing via subgroup analysis (four groups: less than 12 years, 12 to 25 years, 26 to 40 years, over 40 years), as it has been well documented that outcomes following nerve injury decline with advancing age (Rosén 1994; Rosén 2001; Lundborg 2003; Chemnitz 2013; Paprottka 2013; Chemnitz 2015). We do not expect that controlled studies will include participants with obstetric brachial plexus palsy; however, if they do we will report this, and consider such participants as a separate subgroup.

Where information is available, subgroup analysis will also evaluate the impact of smoking versus non‐smoking, and gender on our predefined outcomes (Stenberg 2014).

We will note details of co‐morbidities and exclude participants with the following co‐morbidities or characteristics, which have a significant impact on nerve healing (Kalomiri 1994):

• pre‐existing peripheral neuropathy of any sort;

• previous nerve injury to the peripheral nerve being repaired;

• multilevel nerve injury;

• metabolic conditions, drug therapy, or other concomitant conditions known to impair nerve healing, such as diabetes (Stenberg 2014), thyroid disease, autoimmune disease, allo‐transplant recipients, malignancy, HIV/AIDS, or chemotherapy.

Types of interventions

Direct neurosynthesis (i.e. no gap)

We will include trials comparing peripheral nerve repair using different nerve wraps or conduit products, or comparing one product against the current gold standard of direct microsurgical nerve repair.

Gap reconstruction of peripheral nerve injury

We will include trials comparing different nerve conduits for the reconstruction of equivalent gaps, or comparing nerve conduit with autologous nerve graft (the current gold standard of autologous nerve graft with microsurgical repair onto the proximal and distal nerve stumps).

We will consider subgroups of length of gap defect, based on critical gap lengths in previous animal and human studies (Ruijs 2005; Hart 2011; Camara 2015), as follows:

• no gap;

• < 3 cm gap;

• > 3 cm gap.

We will consider trials in which participants receive co‐interventions, provided that they are provided to each group equally.

Types of outcome measures

The outcomes listed below and further detailed in Appendix 1 are not eligibility criteria for this review, but are outcomes of interest within whichever studies we include. We will evaluate outcome measures at ≤ six months, 12 months and 24 months; where studies report outcome measures at different post‐operative periods, these will be grouped into subgroups for inclusion in meta‐analyses (i.e. < six months, six ‐ 12 months, 12 ‐ 24 months, > 24 months).

Primary outcomes

The co‐primary outcome measures will be the British Medical Research Council (BMRC) grading at 24 months for:

• muscle strength, using manual muscle testing (MMT);

• sensory recovery.

For motor function, we will report the BMRC grades of abductor pollicis brevis and abductor digiti minimi to assess median and ulnar nerve function, respectively, as these are both commonly used to assess motor function of the hand in clinical trials. Studies indicate that MMT correlates well with functional outcome and electrophysiological assessments (Brandsma 1995; Sahin 2014).

Secondary outcomes

• BMRC grading for muscle strength by MMT, and sensory recovery at ≤ six months, 12 months and 24 months.

• Rosén Model Instrument, a validated measure of integrated upper limb function, which evaluates function across four parameters, namely motor, sensory, dexterity and pain/discomfort (Rosén 2000) at ≤ six months, 12 months and 24 months.

• Semmes Weinstein Monofilament (SWM) testing as described by Bell‐Krotoski 1995, using five monofilament probes to apply forces and evaluate the lightest perceived force at ≤ six months, 12 months and 24 months.

• Two point discrimination (2‐PD) (moving and static), a commonly used measure (Aberg 2007) at ≤ six months, 12 months and 24 months.

• Cold intolerance, measured using the Cold Intolerance Symptom Severity score, a reliable and validated questionnaire (Carlsson 2008) at ≤ six months, 12 months and 24 months.

• Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, a validated and widely utilised participant‐reported outcome scale (Gummesson 2003; Chemnitz 2013) at ≤ six months, 12 months and 24 months.

• Sensory nerve action potential (SNAP): amplitude across the site of the nerve repair in the upper limb, measured using sensory neurography. Given the expected paucity of eligible studies, we will report SNAPs at any time point from three months after injury, giving primacy to results obtained over 12 months from injury. We will record the maximal response value obtained (microvolts) and, where provided, we will record the methodology used (e.g. orthodromic or antidromic) at ≤ six months, 12 months and 24 months.

• Cost of the device.

• Adverse events ‐ we will record any serious adverse event and the specific categories detailed in the table below.

Adverse event	Detail
1	Infection requiring antibiotics
2	Extrusion of device
3	Further surgery (washout or revision)
4	Device removal
5	Donor site pain
6	Donor site neuroma
7	Donor site slow healing
8	Donor site revision (scar or neuroma excision)

Search methods for identification of studies

Electronic searches

We will search the Cochrane Neuromuscular Specialised Register, which is maintained by the Group. The Information Specialist will search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We will search other databases using an adapted version of the MEDLINE search strategy in Appendix 2.

We will search the US National Institutes for Health Clinical Trials Registry, ClinicalTrials.gov (ClinicalTrials.gov) and the WHO International Clinical Trials Registry Portal (ICTRP) (apps.who.int/trialsearch/). We will search all databases from their inception to present, and we will impose no restriction on language of publication.

We expect most studies to have been undertaken in the last decade, but we will search for studies without date limitations. Purchase price of devices will be sought from manufacturers, accurate at the same time point immediately prior to completion of review.

Searching other resources

We will search reference lists of all primary studies and review articles for additional studies. We will search relevant manufacturers' websites and clinical trials registry for trial information. We will also review abstracts from the International Federation of Surgical Societies of the Hand, Federation of European Surgical Societies of the Hand, and the American Society for Peripheral Nerve from the last 10 years.

Data collection and analysis

Selection of studies

Two review authors (SET and NN) will independently screen titles and abstracts of all the potential studies we identify as a result of the search for inclusion. We will code them as 'retrieve' (eligible, potentially eligible or unclear) or 'do not retrieve'. We will obtain the full‐text study reports and two review authors (SET and NN) will independently screen the full‐text reports and identify studies for inclusion. They will identify and record reasons for exclusion of the ineligible studies and report the results in a PRISMA flow chart). Any disagreement will be resolved through discussion or consultation of a third person (AH, MR, or PK). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table.

We will also select studies to collect data associated with the direct and indirect cost of the use of the conduit to contextualise the efficacy and safety data. A systematic search will not be performed and a formal economic analysis will not be undertaken. Descriptive cost data only will be presented in the discussion. If data are found to construct a systematic economic analysis, these will be presented in a separate publication or a future update following the peer‐reviewed design of appropriate methodology to manage and analyse them.

Data extraction and management

We will use a data extraction form, which has been piloted on at least one study in the review, for study characteristics and outcome data. We will extract the following study characteristics.

• Methods: study design, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals, and date of study.

• Participants: Total number per treatment arm, mean age, age range, gender, occupation, hand dominance, mechanism of injury, severity of condition, length of gap, operative delay, level of injury, concomitant injury, smoking status, co‐morbidities, intraoperative detail (suture or splints), postoperative care including physiotherapy (yes or no, and any details of duration and intensity), diagnostic criteria, baseline characteristics, inclusion criteria, and exclusion criteria.

• Interventions: nerve wrap or conduit (type, delay from injury until intervention), comparison (direct repair, no wrap or autologous nerve graft), concomitant surgery.

• Outcomes: primary and secondary outcomes specified and collected, and time points reported.

• Notes: funding for trial, and notable conflicts of interest of trial authors.

Two review authors (NN and SET) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by involving a third person (AH, MR, or PK). One review author (NN) will transfer data into the Cochrane authoring and statistical software, Review Manager 5 (RevMan 2014). A second review author (SET) will check the outcome data entries. The second review author (SET) will also spot‐check study characteristics for accuracy against the trial report.

When reports require translation, the translator will extract data directly using a data extraction form, or authors will extract data from the translation provided. Where possible, a review author will check numerical data in the translation against the study report.

Assessment of risk of bias in included studies

Two review authors (NN and SET) will independently assess risk of bias for each study using the criteria outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (AH, MR, or PK). We will assess the risk of bias according to the following domains.

• Random sequence generation.

• Allocation concealment.

• Blinding of participants and personnel.

• Blinding of outcome assessment.

• Incomplete outcome data.

• Selective outcome reporting.

• Other bias.

We will grade each potential source of bias as high, low, or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarise the 'Risk of bias' judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary (e.g. for non‐blinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a participant‐reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.

Measures of treatment effect

We will analyse dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs) and continuous data as mean difference (MD), or standardised mean difference (SMD) with 95% CIs, for results across studies with outcomes that are conceptually the same but measured in different ways. We will enter data presented as a scale with a consistent direction of effect.

We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense. Only studies with identical outcomes will be pooled in meta‐analysis.

We will narratively describe skewed data reported as medians and interquartile ranges.

Unit of analysis issues

Where there are three or more treatment groups in a single study with more than two eligible study groups, the sample size and event rate of the control group will be divided, so that the participants randomised to placebo or control intervention are not double counted.Only relevant intervention groups will be considered (section 16.5.2 Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011)).

Bilateral cases or situations with more than one graft are unlikely. Where more than one graft is present the possibility of co‐dependency exists. Where more than one graft is used and participants are randomised to the first graft and an alternative used for the second, we will take this into account. In such cases, we will extract outcomes taking into account the paired nature of the data by seeking information on paired statistics and estimate standard errors as described in Section 16.4.6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When a correlation coefficient is not provided to derive the appropriate adjusted estimate, we will employ a correlation of 0.5 for the standard analysis and we will use two other extreme values of 0.1 and 0.9 in a sensitivity analysis.

We do not anticipate inclusion of cluster‐randomised trials or cross‐over studies. We will not perform a multiple treatments meta‐analysis, which would be the subject of a further paper to formally compare interventions across studies if transitivity hypotheses were fulfilled.

We have specified six‐month, 12‐month and two‐year periods of follow‐up for inclusion in separate analyses to avoid errors arising from repeated observations.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is available as an abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in a sensitivity analysis.

Assessment of heterogeneity

We will evaluate the clinical heterogeneity of studies prior to performing any meta‐analysis, with attention to the distribution of individuals belonging to the groups defined in Subgroup analysis and investigation of heterogeneity between treatment arms.

We will use the I² statistic calculated by RevMan to measure statistical heterogeneity among the trials in each analysis (Higgins 2003). If we identify substantial unexplained heterogeneity, we will report it and explore possible causes by pre‐specified subgroup analysis.

Assessment of reporting biases

If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small‐study biases.

Data synthesis

If the review includes more than one comparison that cannot be included in the same analysis, we will report the results for each pair‐wise comparison separately (for example, conduit A versus gold standard, conduit B versus gold standard, wrap A versus gold standard, wrap B versus gold standard).

'Summary of findings' table

We will create a 'Summary of findings' table using the outcomes presented in the table. We will use the most clinically relevant and complete data set for presentation. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence (studies that contribute data for the prespecified outcomes). We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will use GRADEpro software (GRADEpro 2016). We will justify all decisions to downgrade or upgrade the quality of studies using footnotes, and we will make comments to aid readers' understanding of the review where necessary.

Outcomes for inclusion in the 'Summary of findings' table
BMRC Grading (sensory recovery)	Score S0 to S4 (S0 = no sensation, S4 = normal)
BMRC Grading (muscle strength)	Score 0 to 5 (0 = no movement, 5 = normal)
Rosén Model Instrument	Score <1 to 3 (0 = no demonstrable function, 3 = normal)
Semmes‐Weinstein Monofilament	Score 0 to 15 (0 = no sensory function, 5 = normal)
DASH PROM	Score 0 to 100 (0 = no disability, 100 = most severe disability)
Cost	Costs will be reported in GBP
Serious adverse events	Number of participants experiencing a serious adverse event per group

In order to maximally inform decision makers, we will select the time point of the summary of findings that presents the most clinically relevant and complete data‐set.

Subgroup analysis and investigation of heterogeneity

Ideally, subgroup analysis would be performed evaluating the role of the clinical factors detailed below on outcome. However, it is anticipated that this may be limited by heterogeneity within studies that meet the inclusion criteria.

We will evaluate the clinical heterogeneity of studies prior to performing any meta‐analysis, with attention to the distribution of individuals belonging to the above subgroups between treatment arms. We will assess statistical heterogeneity using the I² statistic (value > 50% represents substantial heterogeneity) and X² test (significance level 0.1). In the case of low level of heterogeneity (I²< 50% or P > 0.1), we will perform a meta‐analysis. In the case of significant heterogeneity among included trials, we will provide a systematic narrative synthesis instead.

We selected the following subgroup analyses as predicted and proven factors influencing nerve healing (Hart 2011; Birch 2015; Camara 2015; Hundepool 2015).

• Length of nerve gap (none, < 3 cm, > 3 cm) (Grinsell 2014).

• Nerve type (sensory, motor, or mixed) (Lundborg 1986).

• Delay from time of injury until repair (< 48 hours, 48 hours to two weeks, two weeks to two months, over two months) (British Orthopaedic Association) (Hart 2008).

• Participant age in years (< 12, 12 to 25, 26 to 40, > 40). Younger age confers increased regenerative capacity and younger individuals may be less able to comply with assessment; therefore, where possible we will perform subgroup analysis to consider those under the age of 12 and over the age of 40.

• Smoking status at time of surgery (smoker versus non‐smoker) (Hundepool 2015).

• Biological versus synthetic scaffold for wrap or conduit (Hart 2011.

We will use the outcomes selected for inclusion in the 'Summary of findings' table in subgroup analyses.

We will use the formal test for subgroup interactions in Review Manager (RevMan 2014).

Sensitivity analysis

We plan to carry out the following sensitivity analyses to ensure results are robust and meaningful.

• Repeat the analysis excluding any unpublished studies.

• Repeat the analysis excluding studies at high risk of bias (non‐blinded trials, questionable randomisation methods, significant difference between treatment groups, non gold‐standard management in control group).

• Repeat the analysis excluding any large studies to establish how much they dominate the results.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will suggest priorities for future research and outline remaining uncertainties in the area.

Appendices

Appendix 1. Types of Outcome Measurement

Outcome measurements that currently prevail in the literature are British Medical Research Council (BMRC) motor and sensory grading system, Semmes Weinstein Monofilament (SWM) test and static or moving two‐point discrimination (s/m2PD). Neurophysiological and magnetic resonance imaging (MRI) assessment modalities are not routinely employed in the postoperative period at present. The Rosén Model Instrument is becoming increasingly recognised as a comprehensive assessment tool of integrated function, but is yet to be adopted throughout the literature. Ideally, following peripheral nerve surgery a holistic evaluation of outcome would be made. This would be performed at regular and defined postoperative periods and comprise of an objective, sensitive analysis of integrative function (e.g. The Model Instrument, Rosén 2000), accurate biodynamic outcome analysis (Pruszynski 2014) or vibrotactile perception (Dahlin 2015). Combined with participant‐reported outcome measurements investigating the individual’s perception of performance over a series of tasks, this would allow more detailed evaluation. Currently resource limitations and clinical practicalities necessitate the pragmatic use of less rigorous measurements of outcome in most studies.

The BMRC Motor Grade assesses motor function on a six‐point scale, with ability to overcome gravity and comparison to the contralateral limb providing important benchmarks.

BMRC Motor Grade	Muscle Strength
M0	No movement is observed
M1	Trace or flicker of movement or fasciculations seen
M2	Muscle can exert movement when gravity is eliminated
M3	Muscle can exert movement against gravity
M4	Muscle strength is reduced but some movement against resistance
M5	Normal movement

The BMRC sensory grade (Zachary 1954), assesses sensory recovery on a seven‐point scale, where S0 is absence of any sensory recovery and S4 is recovery of sensibility and two‐point discrimination of 3 mm to 6mm (S2 and S3 are further subdivided into S2+ and S3+). Weighted pins (e.g. 5 g to10g) may be used for testing pressure and pain, Von Frey's hairs are used to assess tactile sensation; these are available in various calibres, and a two‐point discrimination is assessed with a fine calliper. The sensory scale will be interpreted critically and detailed methodology provided.

BMRC Sensory Grade	Sensory Recovery
S0	Absence of sensibility in the autonomous area
S1	Recovery of deep cutaneous pain sensibility
S2	Return of some degree of some degree of superficial cutaneous pain and tactile sensibility within the autonomous area of the nerve
S3	Return of some degree of some degree of superficial cutaneous pain and tactile sensibility within the autonomous area of the nerve with disappearance of any previous over reactivity
S3+	Return of sensibility as in Stage 3 with the addition that there is recovery of two‐point discrimination within the autonomous area
S4	Complete recovery

The Model Instrument is one of the most well recognised and widely applied composite assessment tools for assessment of peripheral nerve function following repair at the distal forearm and wrist (Rosén 2000). This standardised tool correlates well with the Disability of the Arm Shoulder and Hand (DASH), a validated participant‐reported outcome measurement of perceived ability to carry out activities of daily living (Beaton 2001; Gummesson 2003). A detailed protocol of the components of the test has been published, allowing inter‐operator standardisation. Briefly, a quantitative assessment of:

‐ Motor recovery ‐ manual muscle testing and Jamar® dynamometer to test motor innervation and grip strength)

‐ Sensory recovery ‐ Semmes Weinstein Monofilaments (SWM) are used to assess touch/pressure thresholds, two‐point discrimination (2PD)

‐ Tactile gnosis and dexterity ‐ shape texture identification (STI) to assess as well as three selected tasks from the Sollerman grip test (Sollerman 1995)

‐Pain/discomfort ‐ four‐point scale questionnaire focusing on cold sensitivity, hyperaesthesia and allodynia is performed.

The score for each subtest is normalised by dividing by a “normal” result – this may be pre‐determined or obtained by testing the uninjured, contralateral arm. The mean score is calculated for each domain and the sum of these three scores generates the overall score which is plotted against 'average results' and over time. This allows recording of functional recovery and a prediction of recovery, by comparison to values generated in participants with similar injuries ('average results'). As the Rosén method encompasses a spectrum of tests it requires availability of assessment tools, experienced staff and protected time periods to conduct. This ideally would form part of ongoing routine assessment by a dedicated and experienced hand surgery team, unfortunately this limits its use in some settings. As such, although desirable, lack of this reporting outcome will not be used as exclusion criteria.

Appendix 2. MEDLINE (OvidSP) draft search strategy

Database: Ovid MEDLINE(R) <1946 to February Week 2 2016> Search Strategy: ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 randomised controlled trial.pt. (406217) 2 controlled clinical trial.pt. (90055) 3 randomized.ab. (303442) 4 placebo.ab. (155007) 5 clinical trials as topic.sh. (174864) 6 randomly.ab. (214885) 7 trial.ti. (131755) 8 exp Cohort Studies/ (1493921) 9 cohort*1.tw. (297767) 10 or/1‐9 (2349178) 11 exp animals/ not humans.sh. (4187037) 12 10 not 11 (2248669) 13 (nerve adj2 (wrap* or cuff* or repair* or graft* or allograft* or autograft*)).mp. (5629) 14 13 or conduit*1.mp. (21783) 15 (upper limb* or arm*1 or upper extremit*).mp. (175831) 16 exp upper extremity/ (142589) 17 15 or 16 (276373) 18 Peripheral Nerve Injuries/ (5016) 19 12 and 14 and 17 and 18 (61) 20 remove duplicates from 19 (61)

Contributions of authors

SET, MR, AH, and PK conceived the review.

SET drafted the protocol, and MR, AH, PK, LD, and MW revised the draft.

All authors developed the search strategy with assistance from Cochrane team.

All authors have approved publication of the protocol.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Medical Research Council, UK.

  Clinical Research Training Fellowship (SET)

Declarations of interest

SET: is currently undertaking a PhD clinical research training fellowship (MRC ‐ 70085) This three years of funding is to support PhD consumables and salary and not a perceived conflict of interest.

NYBN: None known.

MOR: was previously supported by 3b's, but their work has no relation to the review, and there is no ongoing connection. The funded work supports and supported the work in the group towards the development of future conduit, where the outcome is not yet defined. There is no current or developing commercial interest to impact or bias the review process.

PJK: None known.

LBD was previously in receipt of a consulting fee from Axogen Inc, Fl, US during 2009/2010, and there are no ongoing connection. LBD is currently a member of an EU consortium, financially supported by an EU grant, in which Medovent AG (manufacturer of chitosan nerve guides) is also a member. He has received no financial support from this company. Medovent Inc provides chitosan conduits in the Project. He has an active research collaboration with Vibrosense Inc concerning evaluation of vibrotactile sense (Dahlin 2015), which is supported by the foundation VINNOVA, Sweden. He has received no financial support from the company. He has been consultant for AxoGen Inc, Gainsville, FL, USA 2003‐2004. AxoGen Inc produce Avance (R) Nerve Graft, Axoguard((R) Nerve Connector, and Axoguard(R) Nerve Protector. LBD is also a board member of Scania Hand Center AB.

MW was previously in receipt of an AstraTech research funding for the investigation of PHB as a material for use in peripheral nerve repair from 1992‐2008 and received AstraTech funding for a prospective randomised clinical controlled trial of the use of PHB material for wraparound repair of peripheral nerve injuries. The research has been concluded.

AMH previously served on a multicentre wraparound nerve trial design group funded by AstraTech (manufacturer of poly‐3‐hydroxybutyrate sheets for nerve repair), and has been in receipt of a 20,000 GBP nerve research grant from the same company ‐ the grant has been concluded (2007) and there is no existing link. He has worked with NHS Blood & Transplant (NHSBT) in relation to the development of future nerve repair products. He is involved in preparation of a multicentre research project that if successful will involve partnership with NHSBT in application for independent grant funding. At present no financial links have been established, and there has been no joint research output.

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