A Systematic Review and Meta-Analysis of Nerve Gap Repair: Comparative Effectiveness of Allografts, Autografts, and Conduits

Abstract

Background: 

Ideal nerve repair involves tensionless direct repair, which may not be possible after resection. Bridging materials include nerve autograft, allograft, or conduit. This study aimed to perform a systematic literature review and meta-analysis to compare the meaningful recovery (MR) rates and postoperative complications following autograft, allograft, and conduit repairs in nerve gaps greater than 5 mm and less than 70 mm. A secondary aim was to perform a comparison of procedure costs.

Methods: 

The search was conducted in MEDLINE from January of 1980 to March of 2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were included whether they reported nerve injury type, repair type, gap length, and outcomes for MR rates. Thirty-five studies with 1559 nerve repairs were identified.

Results: 

Overall MR for sensory and motor function was not significantly different between autograft (n = 670) and allograft (n = 711) across both short and long gaps. However, MR rates for autograft (81.6%) and allograft (87.1%) repairs were significantly higher compared with conduits (62.2%) (P < 0.05) in sensory short gap repairs. Complication rates were comparable for autograft and allograft but higher for conduit with regard to pain. Analysis of costs showed that total costs for allograft repair were less than autograft in the inpatient setting and were comparable in the outpatient setting.

Conclusions: 

Literature showed comparable rates of MR between autograft and allograft, regardless of gap length or nerve type. Furthermore, the rates of MR were lower in conduit repairs. In addition, the economic analysis performed demonstrates that allograft does not represent an increased economic burden compared with autograft.

Traumatic nerve injuries are common, where 1.5% of trauma and up to 15% of upper extremity and lower extremity trauma results in nerve injury.^1–5 Commonly affected nerves are the radial and digital nerves in the upper extremity and the peroneal nerve in the lower extremity, predominantly affecting men of working age.^4–6 These peripheral nerve injuries can have detrimental effects on quality of life and function.⁷

Following nerve transection, Wallerian degeneration occurs distally, as myelin is degraded by Schwann cells and macrophages⁸; proximally, degeneration may occur up to the first node of Ranvier.¹ This is followed by axonal regrowth, where exploratory fibers extend from the proximal nerve end and regenerate down endoneurial tubes toward the distal target.⁹ In the absence of structural support by endoneurial tubes, axons will regrow in a disorganized fashion forming a neuroma.¹⁰ However, restoration of function typically only occurs with proper nerve repair.

The ideal nerve repair involves tensionless direct repair of healthy fascicles, which may not be possible following resection of injured nerve ends and the resulting nerve gap. Thus, bridging a nerve gap with a nerve autograft, allograft, or conduit is necessary.^1,2 Although commercially available conduits come in lengths up to 30 mm, conduits are typically used for small gap repair. For gaps larger than 30 mm, autograft or allograft are the only options.¹¹

Despite increasing evidence on nerve repairs using autograft, allograft, or conduit, comparisons of outcomes remain sparse. Therefore, the primary aim of this study was to perform a systematic literature review and meta-analysis comparing the meaningful recovery (MR) rates following autograft, allograft, and conduit repairs in nerve gaps larger than 5 mm, in addition to postoperative complications. A secondary aim was to perform a procedure cost analysis if no difference was seen in MR rates.

PATIENTS AND METHODS

Literature Search

To identify relevant peer-reviewed studies, a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. The search was conducted in MEDLINE (by means of PubMed) from January of 1980 to March of 2020. Search terms included the following: “peripheral nerves” [Medical Subject Headings terms] OR peripheral nerve[tiab] OR “nerve injury”[tiab] AND (“nerve allograft”[tiab] OR “nerve conduit”[tiab] OR “nerve autograft”[tiab] OR “nerve repair”[tiab] OR “nerve graft”[tiab]). Inclusion criteria were established a priori and used to identify evaluable studies from the search results. Studies must have reported nerve injury type (sensory, mixed, or motor); nerve repair type [autograft, allograft (Avance Nerve Graft, Axogen Corp.), or conduit]; gap length where the nerve repair could be categorized as short gap (>5 to 30 mm; so only commercially available conduits would be evaluated) or long gap (>30 to 70 mm; so only commercially available allograft would be evaluated); and outcomes reported using static two-point discrimination (S2PD), Semmes-Weinstein monofilament (SWMF) testing, and/or Medical Research Council Classification (MRCC), such that MR rates (≥S3/M3) could be determined. Exclusion criteria included nonnerve graft repairs, previously published data, animal studies, non-English language, case reports with fewer than three subjects (to eliminate anecdotal evidence), nerve gaps less than 5 mm or greater than or equal to 110 mm, and vascularized autografts.

Two independent reviewers (J.L. and J.F.S.) evaluated each study for inclusion and exclusion criteria. Data extraction from evaluable studies followed, which was validated independently by both reviewers.

Data Extraction

The following data were extracted using standardized forms and recorded: study design, nerve location (digit, arm, face, lower extremity), nerve type (motor, sensory or mixed), gap length (in millimeters, mean, standard deviation, and range), age (mean, standard deviation, and range), mean follow-up, the number of nerves repaired, donor nerve for autograft, MRCC data, number of patients with MRCC greater than or equal to S3/M3, number of patients with MRCC greater than or equal to S3+/M4, S2PD data, SWMF test data, and complications. The MRCC data were directly extracted as reported or derived from the SWMF data or the S2PD data, as reported previously (Table 1).^12–14 All data were verified by secondary clinical reviewers, and inconsistencies were resolved by discussion. The independent reviewers also assessed the quality of the included studies using the Methodological Index for Nonrandomized Studies criteria, and discrepancies were resolved by discussion.¹⁵

Table 1. - Conversion of SMWF and 2PDS to MRCC MR

SMWF		MRCC	2PDS
Force (g)	Monofilament No.	—	—
100–300	6.10–6.65	S0	Loss of protective sensation
10–60	5.07–5.88	S1
4–8	4.56–4.93	S2
0.6–2	3.84–4.31	S3	>15 mm with recovery of pain and touch sensibility
0.16–0.4	3.22–3.61	S3+	7–15 mm
<0.7	1.62–2.83	S4	≤6 mm

Nerve Injury Categorization

Nerve injury type was defined as (1) sensory, if only a sensory nerve was repaired; (2) motor, if only a motor nerve was repaired; and (3) mixed, if a mixed motor nerve and a sensory nerve were repaired. Outcomes for mixed nerve repairs were reported in the sensory and/or motor outcomes and were counted separately if both types of outcomes were reported. Nerve repairs were grouped as “short gap” (>5 to ≤30 mm) or “long gap” (>30 to ≤70 mm). This categorization grouping was determined by the average gap length of the study population; when these data were unavailable, the midpoint (median) of the gap length range was used to categorize the nerve repairs as short gap or long gap. When the gap length range was used to determine the gap length categorization, in short gaps, the upper limit of the range could not exceed 70 mm; and for long gaps, the upper limit of the range could not exceed 110 mm. This minimized the exclusion of relevant data that included longer gaps but where the median gap was representative of the short or long gap range. Nerve injuries were categorized as (1) short gap, sensory; (2) long gap, sensory; (3) short gap, motor; and (4) long gap, motor.

Outcomes

The primary outcome was MR, defined as greater than or equal to S3 and greater than or equal to M3 based on MRCC sensory scales and muscle strength grading (Table 2).^16–19 In addition, higher-level MR was assessed and defined as greater than or equal to S3+ and greater than or equal to M4. Outcomes also included complications, consisting of revision surgery, symptomatic neuroma, pain, infection, or altered sensibility (paresthesia, cold intolerance, hyperesthesia). Donor-site complications (symptomatic neuroma or donor-site pain) were also evaluated in studies assessing autograft nerve repairs.

Table 2. - MRCC Sensory and Motor Function Scale^a

Level of Recovery	Sensory		Motor
Not meaningful recovery	S0	Absence of sensibility in the autonomous area	M0	No contraction
Not meaningful recovery	S1	Recovery of deep cutaneous pain sensibility within the autonomous area of the nerve	M1	Flicker/trace contraction
Not meaningful recovery	S2	Return of some degree of superficial cutaneous pain and tactile sensibility within the autonomous area of the nerve	M2	Active movement with gravity eliminated
Meaningful recovery	S3	Return of superficial cutaneous pain and tactile sensibility throughout the autonomous area, with disappearance of any pervious over response	M3	Active movement against gravity
Higher level meaningful recovery	S3+	Return of sensibility as in S3; in addition, there is some recovery of two-point discrimination within the autonomous area (7–15 mm)	M4	Moderate movement against resistance
Higher level meaningful recovery	S4	Complete recovery (two-point discrimination, 2–6 mm)	M5	Normal/full power

^aThe British Medical Research Council muscular function grading system includes M4-, slight movement against resistance; M4, moderate movement against resistance; and M4+, strong movement against resistance.

Statistical Analysis

Continuous variables were reported as averages and standard deviations, and categorical variables were reported as frequencies and percentages. Descriptive statistics with weighted averages were calculated for each cohort. The MR rate was compared between the nerve repair techniques along with comparison for each nerve injury category, using bootstrap methods.

A bootstrap using Monte Carlo methodology was performed to generate the distribution under the null hypothesis (MR outcomes of the two compared nerve repair techniques have the same distribution). This avoided type I error inflation attributable to underestimated standard error of the difference between studies.^20,21 The P values between pooled data for repair techniques were obtained from comparison of the test statistic: the observed difference in MR rate reported per pooled data by nerve repair technique, with the distribution of the difference under the null hypothesis. A value of P < 0.05 was set as statistically significant for all tests. Forest plots for each repair modality (autograft, allograft, and conduit) were provided for each nerve type (sensory or motor) to demonstrate the mean MRCC, weight, and 95% confidence interval for each study and the pooled average for the study groups. Interstudy heterogeneity was qualified using the Q and I² statistics, where less than 50% was considered low heterogeneity, 50% to 75% was considered moderate heterogeneity, greater than 75% was considered high heterogeneity, and Cochran Q test was applied for assessing the statistical significance. Statistical analyses were conducted using R version 3.5.2 (The R Foundation for Statistical Computing, Vienna, Austria).

Procedure Cost Analysis

The cost analysis was conducted for nerve graft repair using national Medicare hospital claims data for 2018, as reported in the Standard Analytic File. Autograft and allograft inpatient and outpatient nerve repairs were identified by International Classification of Diseases, 10th Revision, and CPT procedures codes, respectively. Hospital facility cost information was computed separately for inpatient and outpatient nerve repair cases across all gap lengths by applying national cost-to-charge ratios for hospital department charges calculated by the Centers for Medicare and Medicaid Services.

RESULTS

Included Studies

A total of 4143 studies were screened, and 115 studies were identified for review (Fig. 1). Thirty-five studies with a total of 1559 results (mixed nerve repairs had results for sensory and motor outcomes counted separately) were identified that reported MR, gap length, and type of nerve repaired. The analysis included 21 studies with 670 autograft repairs,^22–42 nine studies with 711 allograft repairs,^43–51 and seven studies with 178 conduit repairs^{43,44,52–56} (two studies evaluated more than one technique)^43,44 (Table 3). Sixteen of these studies^{26,28–30,37,43,44,46–51,53,54,56} reported postoperative complications (Table 4). All studies reporting the full range of MRCC scores for subjects were presented in forest plots. [See Figure, Supplemental Digital Content 1, which shows forest plots displaying averaged MRCC score results for each clinical study captured in the analysis. Data are divided into five repair types. (Above) Autograft repair of sensory nerve gaps of 5 to 70 mm, (second from above) autograft repair of motor nerve gaps of 5 to 70 mm, (center) allograft repair of sensory nerve gaps of 5 to 70 mm, (second from below) allograft repair of motor nerve gaps of 5 to 70 mm, and (below) conduit-assisted repair of sensory nerve gaps of 5 to 30 mm. Diamonds represent averaged MRCC score subtotal for the five repair types. Edges of diamond represent 95% confidence interval for data. Squares are located at the mean MRCC score of each study. Sizes of squares are proportional to weight of clinical study, which is the number of patients, with the exception of the Ranger Registry clinical study in the allograft sensory plot, where the sample size was so large for this study that the weight was adjusted to fit on plot. For this study, the sample size was divided by 10. **Because of limited accessibility of data in the Leckenby 2019 clinical study, only MRCC scores for mixed or motor nerve injuries in lower limbs were considered in these plots, https://links.lww.com/PRS/F780.] The forest plots provide an overall representation of the data heterogeneity, the pooled mean, and 95% confidence interval.

Table 3. - Characteristics per Nerve Repair Technique

	Total (%)	Nerve Autograft (%)	Nerve Allograft (%)	Nerve Conduit (%)
Total no. of repairsa	1559	670	711	178
Nerve injury type
Sensory	1216 (78.0)	411 (61.3)	627 (88.2)	178 (100.0)
Short gap	835 (53.6)	245 (36.6)	412 (57.9)	178 (100.0)
Long gap	381 (24.4)	166 (24.8)	215 (30.2)	—
Motor	343 (22.0)	259 (38.7)	84 (11.8)	—
Short gap	100 (6.4)	73 (10.9)	27 (3.8)	—
Long gap	243 (15.6)	186 (27.8)	57 (8.0)	—
Location nerve repair
Digital	834 (53.5)	271 (40.4)	397 (55.8)	166 (93.3)
Arm	342 (21.9)	209 (31.2)	121 (17.0)	12 (6.7)
Hand/arm combined	176 (11.3)	176 (26.3)	—	—
Digit/hand/arm/leg combined	156 (10.0)	—	156 (21.9)	—
Head and neck	31 (2.0)	—	31 (4.4)	—
Lower extremity	20 (1.3)	14 (2.1)	6 (0.8)	—
No. of studies	35b	21	9	7

^aSensory and motor results for mixed nerves counted as separate nerves.

^bTwo studies evaluated more than one nerve technique. Not all mixed nerves reported motor and/or sensory data.

Table 4. - Complications Noted in Reviewed Literature

Complication	Autograft		Allograft		Conduit
	%	No. of Studies/Total No.	%	No. of Studies/Total No.	%	No. of Studies/Total No.
Revision surgery	NR	NR/NR	5.96	3/498	6.16	5/146
Symptomatic neuroma	NR	NR/NR	3.00	1/475	NR	NR/NR
Pain	20.59	2/34	19.44	2/36	37.50	2/40
Infection	3.57	1/28	0.94	7/666	4.55	4/88
Altered sensibility	13.33	1/15	33.33	1/18	25.88	3/85
Donor-site neuroma	14.29	1/28	NA	NA/NA	NA	NA/NA
Donor-site pain	14.29	1/7	NA	NA/NA	NA	NA/NA

NR, not reported; NA, not applicable.

Fig. 1.: Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram demonstrating the study screening and selection process.

Nerve Autograft

Twenty-one studies reported on nerve recovery following autograft nerve repair including four comparative studies^23,26,30,33 and 17 case series^{22,24,25,27–29,31,32,34–42} (Table 5). Of the autograft repairs, 271 (40.4%) were in the digit, 209 (31.2%) were in the forearm/arm, 176 (26.3%) were in the hand/arm, and 14 (2.1%) were in the lower extremity (Table 3). The mechanisms of these injuries included, but were not limited to, laceration, blunt trauma, power tool injury, gunshot, and explosive blast. The donor nerves included the sural nerve, anterior/posterior interosseous nerve, lateral/medial antebrachial cutaneous nerve, or digital nerve. Postoperative complications noted in the autograft studies included pain in 20.59% of patients (two studies), infection in 3.57% of patients (one study), and altered sensibility in 13.33% of patients (one study). Revision and symptomatic neuroma rates were not reported in any of the autograft studies. Donor-site complications included donor-site neuromas in 14.29% of patients (one study) and donor-site pain in 14.29% of patients (one study) (Table 4). Patients in the autograft studies were predominantly men (77%), and the mean age was 31.5 years (range, 1 to 79 years). Overall MR for autograft was 71.8% for sensory function and 56% for motor function.

Table 5. - Autograft Clinical Studies

Reference	Study Design	No. of Results	Nerve Location	Nerve Types Included	Gap Category	Gap Length (mm)	MINORS Score
Saeki et al., 2018 22 a	Retrospective case series	37	Digit	Sensory	Short	18.7	15
Ahmad et al., 2017 23	Randomized comparative study	9	Arm	Motor	Short	27.4	12
Sallam et al., 2017 24	Retrospective case series	28 (56) sensory and motor MR results)	Arm	Mixed	Long	30–50b	17
Unal et al., 2017 25	Case series	13	Digit	Sensory	Short	18.5	12
Flores, 2015 26	Retrospective comparative study	20	Arm	Motor	Long	57	17
Manoli et al., 2014 27	Retrospective case series	14	Digit	Sensory	Short	10–20b	10
					Long	43.3
Chevrollier et al., 2014 28	Retrospective chart review	16	Digit	Sensory	Long	38	13
Pilanci et al., 2014 29	Case series	15	Digit	Sensory	Short	18.1	12
Stang et al., 2013 30	Retrospective comparative study	28	Digit	Sensory	Short	22	12
Bertelli et al., 2011 31	Prospective case series	5 (10 sensory and motor MR results)	Arm	Mixed	Short	25	13
					Long	40
Seidel et al., 2008 32	Retrospective case series	14	Lower extremity	Mixed	Short	25	8
					Long	55.8
Roganovic et al., 2007 33	Prospective comparative study	23	Arm	Motor	Long	37	11
Amillo and Moro, 1999 34	Retrospective case series	6	Arm	Motor	Short	25	11
					Long	68
Wang et al., 1996 35 a	Case series	11	Digit	Sensory	Short	24	11
Vastamaki et al., 1993 36	Retrospective case series	42	Hand, arm	Mixed	Short	<35b	12
					Long	35–75b
Kallio et al., 1993 37	Retrospective case series	77	Digit	Sensory	Short	10–29b	12
					Long	30–49b
Kallio et al., 1993 38	Prospective case series	67 (134 sensory and motor MR results)	Hand, arm	Mixed	Short	20–39b	9
					Long	40–69b
Doi et al., 1992 39	Randomized case series	18 (25 sensory and motor MR results)	Arm	Mixed	Long	62.5	12
			Digit	Sensory	Long	56.7
Barrios et al., 1990 40	Case series	33 (66 sensory and motor MR results)	Arm	Mixed	Short	27.5	8
					Long	51.8
Nunley et al., 1989 41	Retrospective case series	18	Digit	Sensory	Short	20.5	11
					Long	33.6
Tenny and Lewis, 1984 42	Prospective case series	36	Digit	Sensory	Short	11.9	8
					Long	36.3

MINORS, Methodological Index for Nonrandomized Studies.

^aStudies not included in forest plots because of missing MRCC scores.

^bGap length range; average gap length unavailable.

Nerve Allograft

The allograft repair studies included one randomized controlled trial⁴³; a prospective case-control study⁴⁷; six case series^{44,45,48–51}; and an ambispective, multicenter registry study⁴⁶ (Table 6). Of the allograft repairs, 397 (55.8%) were in the digit, 121 (17.0%) were in the forearm/arm, 156 (21.9%) were in the digit/hand/arm/lower extremities, 31 (4.4%) were in the head/neck, and six (0.8%) were in the lower extremity (Table 3). The mechanisms of these injuries included, but were not limited to, laceration, blunt trauma, power tool injury, amputation, avulsion, gunshot, shrapnel, explosive blast, neuroma resection, surgical transection, and oncologic resection. Postoperative complications noted in the allograft studies included revision surgery in 5.96% of patients (three studies), symptomatic neuromas in 3.0% of patients (one study), pain in 19.44% of patients (two studies), infection in 0.94% of patients (seven studies) infection, and altered sensibility in 33.33% of patients (one study) (Table 4). Patients in the allograft studies were predominantly men (78.2%) with a mean age of 41.5 years (range, 6 to 83 years). Overall MR rate for allograft was 81.9% for sensory function and 58.3% for motor function.

Table 6. - Allograft Clinical Studies

Reference	Study Design	No. of Nerve Repairs	Nerve Location	Nerve Types Included	Gap Category	Gap Length (mm)	MINORS Score
Leckenby et al., 2020 45	Retrospective case series	156	Digit, hand, arm	Sensory (n = 132)	Short	15.1	11
				Motor (n = 24)	Long	36.3
Safa et al., 2020 50	Ambispective, multicenter	475	Digit, arm, face, lower	Motor	Long	45.5	13
			Digit, arm, face, lower	Motor	Short	19.1
			Digit, arm, face	Sensory	Long	38.4
			Digit, arm, Face	Sensory	Short	14.
Rbia et al., 2019 44	Single-institution case reports and retrospective case series	18	Digit	Sensory	Short	18.4	17
Zuniga et al., 2017 47	Prospective, case-controlled, multisite study	18	Face	Sensory	Long	62.7	13
Means et al., 2016 43	Prospective, multicenter, randomized, double-blinded	6	Digit	Sensory	Short	12.8	20
Salomon et al., 2016 48	Retrospective, cohort	7	Face	Sensory	Long	50–70a	11
Guo et al., 2013 49	Retrospective case series	5	Digit	Sensory	Short	23	13
Taras et al., 2013 50	Prospective case series	18	Digit	Sensory	Short	11	12
Karabeckmez et al., 2009 51	Retrospective case series	8	Digit	Sensory	Short	22.3	14

MINORS, Methodological Index for Nonrandomized Studies.

^aGap length range, average gap length unavailable.

Nerve Conduit

The seven studies on nerve conduit repairs included one randomized controlled trial⁴³ and six case series^44,52–56 (Table 7). Because commercially available conduits are indicated for use only in gaps up to 30 mm, all of the nerve injuries that were included in these studies were short gap, with 166 (93.3%) being repairs in the digit and 12 (6.7%) being in the arm (Table 3). Postoperative complications noted in the conduit studies included revision surgery in 6.16% of patients (five studies), pain in 37.5% of patients (two studies), infection in 4.55% of patients (four studies), and altered sensibility in 25.88% of patients (three studies) (Table 4). Symptomatic neuromas were not reported in any of the conduit studies. Patients in the conduit studies were also predominantly men (78.6%), and the mean age was 41.2 years (range, 11 to 83 years). Overall MR for the conduit group was 62.2% for sensory function. No studies reported on mixed or motor nerve repairs with conduits.

Table 7. - Conduit Clinical Studies

Reference	Study Design	No. of Nerve Repairs	Nerve Location	Nerve Types Included	Gap Category	Gap Length (mm)	MINORS Score
Rbia et al., 2019 44	Single-institution case reports and retrospective case series	19	Digit	Sensory	Short	14	17
Means et al., 2016 43	Prospective, multicenter, randomized, double-blinded	12	Digit	Sensory	Short	12.2	20
Lohmeyer et al., 2014 52 a	Prospective cohort study	40	Digit	Sensory	Short	12.3	11
Haug et al., 2013 53 a	Case series	45	Digit	Sensory	Short	12	12
Chiriac et al., 2012 54	Case series	28	Digit	Sensory	Short	10.8	13
			Arm	Sensory	Short	11.3	13
Taras et al., 2011 55	Prospective case series	22	Digit	Sensory	Short	12	13
Lohmeyer et al., 2009 56	Prospective cohort study	12	Digit	Sensory	Short	12.7	11

MINORS, Methodological Index for Nonrandomized Studies.

^aStudies not included in forest plots because of missing MRCC scores.

Meaningful Recovery Comparisons by Gap Size and Nerve Type

Overall MR for both sensory and motor function was not significantly different between autograft (n = 670) and allograft (n = 711) (sensory, 71.8% versus 81.9%, P = 0.186; motor, 56.0% versus 58.3%, P = 0.500). However, meaningful sensory recovery rates for both autograft and allograft were significantly better than for conduit, which had a meaningful sensory recovery rate of 62.2% (n = 178; P = 0.031 and P = 0.033, respectively) (Fig. 2). In addition, MR rates for autograft and allograft remained comparable across short and long gaps for sensory and motor function [short gap sensory autograft (n = 245) versus allograft (n = 412), 81.6% versus 87.1%, P = 0.186; long gap sensory autograft (n = 166) versus allograft (n = 215), 57.2% versus 72.6%, P = 0.055; short gap motor autograft (n = 73) versus allograft (n = 27), 69.9% versus 70.4%, P = 0.500; long gap motor autograft (n = 186) versus allograft (n = 57), 50.5% versus 52.6%, P = 0.425] (Fig. 3).

Fig. 2.: Overall meaningful sensory recovery by repair type. Overall meaningful sensory recovery, defined as MRCC greater than or equal to S3, was not significantly different between autograft and allograft. However, both autograft and allograft meaningful sensory recovery were significantly better than that for conduit (P = 0.031 and P = 0.033, respectively).

Fig. 3.: MR by gap size and nerve type. There were no significant differences in MR between autograft and allograft across both short and long gaps for both sensory and motor function.

Although greater than or equal to S3/M3 on the MRCC scale has historically been the threshold recognized as clinically meaningful, rates of a higher threshold of recovery (defined as ≥S3+/M4 on the MRCC scale) were also assessed. Overall MR rates at the higher threshold for autograft were 52.6% for sensory and 36.3% for motor. For allograft, overall rates were 66.7% for sensory and 36.7% for motor. When evaluated by gap length and nerve type, the autograft and allograft groups were again comparable (short gap sensory, 67.8% versus 75.0%, P = 0.284; long gap sensory, 30.1% versus 47.7%, P = 0.117; short gap motor, 39.7% versus 42.9%, P = 0.400; and long gap motor, 34.9% versus 33.3%, P = 0.542) (Fig. 4).

Fig. 4.: Higher threshold MR by gap size and nerve type. There were no significant differences in higher threshold MR between autograft and allograft across both short and long gaps for both sensory and motor function.

MR rates were also analyzed by publication date, because 43% of the autograft studies were published before 2000 and 89% of the allograft studies were published after 2010 (Fig. 5, above). The MR rates for autograft by decade were consistent (68.2% versus 70.3% versus 71.4%, respectively) (Fig. 5, below), indicating that surgical technique advancements likely did not have an impact on autograft MR rates, and therefore did not affect the comparison of autograft to allograft in this analysis.

Fig. 5.: Historical analysis of publications. (Above) Number of studies published per decade by repair type. Forty-three percent of included autograft studies were published before 2000 and 0% of allograft or conduit studies were published then. (Below) MR per decade by repair type. MR for autograft is consistent over the decades, indicating that evolution of technique over this time period did not impact MR rates.

Cost Analysis

As there were no significant differences in the MR rates between autograft and allograft, a cost analysis to determine whether there were cost differences by repair type was performed. Conduits were not included in this analysis because conduit delivered significantly lower MR than autograft and allograft in short gap sensory nerve injuries and were not applicable in the other injury types. Evaluation of the data from the 2018 Standard Analytic File reported 340 hospital nerve graft repair claims, where 293 were outpatient and 47 were inpatient. A total of 25 inpatient autograft, 22 inpatient allograft, 95 outpatient autograft, and 198 outpatient allograft procedures were evaluated. Total inpatient costs for allograft repair were less than autograft, $25,751 and $29,560, respectively (Fig. 6, left). Total outpatient costs were similar for allograft and autograft, $13,143 and $12,635, respectively (Fig. 6, right). The higher inpatient costs for autograft appear to be attributable to operating room costs ($13,227 versus $9742 for allograft). In the outpatient setting, the operating room costs are also higher for autograft ($5352 versus $3717), but this is offset by the higher implant cost for allograft ($5623 versus $2187 for autograft).

Fig. 6.: Economic analysis for autograft and allograft. Evaluation of the 2018 Standard Analytic File showed that total costs for allograft repair were less than costs for autograft in the inpatient setting (left) and were similar for allograft and autograft in the outpatient setting (right).

DISCUSSION

This systematic literature review of 35 studies reporting 1559 nerve repair outcomes included 670 autograft repairs, 711 allograft repairs, and 178 conduit repairs. This analysis showed that the MR rates for autograft and allograft repairs of sensory, motor, or mixed motor nerve repairs showed no significant differences. The similarities noted between the motor and mixed motor nerve repairs were unexpected, as historically the standard of care for bridging nerve defects is autograft. Autografts have been considered the standard for bridging nerve gaps because they offer an axonal guidance scaffold through intact endoneurial tubes and are nonimmunogenic.⁵⁷ However, recent literature suggests that in mixed and motor nerve repairs, autograft and allograft repairs were comparable.^46,58 Furthermore, results also showed that autograft and allograft repairs had significantly higher MR rates as compared with conduit repairs. These comparisons were analyzed in short gap (>5 to ≤30 mm) sensory nerve injuries, which was the only category where conduit data were available (81.6% and 87.1%, respectively, versus 62.2%). These results were expected and comparable to a nerve allograft versus conduit study performed by Means et al., which showed that patients with digital nerve gaps repaired with nerve allografts showed more consistent functional sensory outcomes compared with conduits.⁴³ Furthermore, the reported pain rates for conduit as compared with autograft and allograft was 37.5% versus 20.59% and 19.44%, respectively, suggesting that repair with autograft or allograft may improve outcomes with lower complication rates compared with conduit in short gap sensory nerve repairs.

Before the advent of alternative peripheral nerve gap treatments, the historical standard for repair of nerve gap injuries where a tension-free coaptation was not possible was autograft. This study suggests that autograft and allograft results showed comparable outcomes regardless of gap length or nerve type (sensory, 71.8% versus 81.9%; motor, 56.0% versus 58.3%). Furthermore, the complication rates for autograft and allograft were comparable, and with regard to infection, both were in line with the expected surgical rate. Therefore, the tradeoffs between autograft and allograft repairs are worth further consideration.

When evaluating these tradeoffs, it is important to consider autograft donor-site complications and the index procedure costs. Allograft has been noted to eliminate donor-site complications and have reduced operating time.^59,60 One study in this analysis reported that 14.3% of patients experienced donor-site neuroma and associated pain.³⁰ Although these data are limited, symptomatic neuromas reduce patient quality of life, increase the risk of developing an opioid misuse disorder, may lead to multiple additional operations, and lead to donor-site allodynia and other complications such as infection.^59,61–67 Finally, the procedure cost analysis demonstrated that overall allograft costs are lower than autograft costs in the inpatient setting and comparable in the outpatient setting. This suggests that allograft repair may achieve similar outcomes at similar or lower costs as compared with autograft repair.

Systematic reviews by their nature have some limitations. This analysis included data from studies with various injury types, study designs, populations, study n values, gap lengths, nerve locations, patient follow-up, and disclosed industry funding. Furthermore, studies including mixed motor nerves typically showed limited n values. In addition, no studies compared all reconstructive techniques using a randomized study design. Therefore, a pooled analysis was performed, which did not account for study population differences. In addition, generalization was difficult, as repair techniques offered variable repair numbers and nature of injury. In addition, all surgical treatment groups were not applicable across all gaps and nerve types, as analysis of conduit repairs were limited to only short gap sensory nerve injuries and it is unknown whether follow-up was adequate in the studies, as the distance from the injury to the distal target was not assessed. Lastly, as expected, authors reported industry grant funding of their research in four of nine allograft repair studies^43,46,48,50 and in one of seven nerve conduit studies.⁵⁵ Although the variability introduced because of these limitations should be considered, it is important to note that this analysis offers valuable insight into autograft, allograft, and conduit repair outcomes, complications, and costs that could not be analyzed by limiting this analysis to a specific nerve injury type, gap length, or study design.

CONCLUSIONS

Autograft and allograft have MR rates that do not differ significantly regardless of gap length or nerve type and are significantly better than the MR rates reported for conduits in short gap sensory nerves, the only modality in which conduits were used. In addition, the cost analysis performed demonstrates that allograft does not represent an increased economic burden compared with autograft. Further direct comparative clinical studies would be beneficial to confirm these findings and offer additional support.

DISCLOSURE

Drs. Eberlin, Evans, Mercer, Greenberg, and Styron are paid consultants of Axogen Corporation, a producer of peripheral nerve repair technologies discussed in this review. However, the authors of the article had complete and final control of the data collection, analysis, and manuscript composition. Dr. Lans has no financial interests to declare.

ACKNOWLEDGMENT

This research was financially supported by a grant from Axogen Corporation.