Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery

Abstract

Background:

Acellular nerve allografts have been used successfully and with increasing frequency to reconstruct nerve injuries. As their use has been expanded to treat longer gap, larger diameter nerve injuries, some failed cases have been reported. We present the histomorphometry of 5 such cases illustrating these limitations and review the current literature of acellular nerve allografts.

Methods:

Between 2014 and 2019, 5 patients with iatrogenic nerve injuries to the median or ulnar nerve reconstructed with an AxoGen AVANCE nerve allograft at an outside hospital were treated in our center with allograft excision and alternative reconstruction. These patients had no clinical or electrophysiological evidence of recovery, and allograft specimens at the time of surgery were sent for histomorphological examination.

Results:

Three patients with a median and 2 with ulnar nerve injury were included. Histology demonstrated myelinated axons present in all proximal native nerve specimens. In 2 cases, axons failed to regenerate into the allograft and in 3 cases, axonal regeneration diminished or terminated within the allograft.

Conclusions:

The reported cases demonstrate the importance of evaluating the length and the function of nerves undergoing acellular nerve allograft repair. In long length, large-diameter nerves, the use of acellular nerve allografts should be carefully considered.

Keywords

nerve reconstruction nerve diagnosis nerve injury allograft basic science nerve regeneration autograft

Introduction

Nerve conduits were introduced in the late 1980s as an alternative to nerve autografts.^1,2 With expanded use, failures occurred, and in 2009, we reported 4 cases of nerve conduit failure and discussed length and diameter limitations with major nerve reconstructions.^3-5 Acellular nerve allografts (ANAs) were introduced in 2007, providing an extracellular matrix with experimental studies showing improved regeneration across ANAs as compared with conduits although not as robust as the “gold standard” autograft.^6,7

Acellular nerve allografts have since been used with increasing frequency and found an important role in the management of nerve injuries.^8-12 With successful sensory recovery across short gap, small-diameter injuries, indications for use have expanded to include longer gaps, larger diameters, and mixed or motor nerves.^8,13 Outcomes following nerve repair with ANAs have been diligently followed with the RANGER registry since 2008, with increasing numbers of mixed and motor nerve repairs being recorded.^9-12

As with any surgical innovation, with these expanding indications for use, limitations can be anticipated.¹⁴ Three recent reports demonstrate cases of failure of ANAs when used for long gap or large-diameter repairs of mixed or motor nerves.^13,15,16 These studies were the stimulus for this report of 5 cases where ANAs failed to support regeneration across median or ulnar nerve reconstructions. As we continue to expand the use of this important alternative to the “gold standard” nerve autograft, it is critical that we better understand the limitations being reported. In an effort to do so, we analyze the histomorphology of these failed cases. We also review the current clinical literature to explain why the currently available ANAs should have stricter limits of use than the “gold standard” nerve autograft when bridging a nerve gap of longer lengths and larger diameters.^17-22

Methods

Five patients with an iatrogenic injury to the median or ulnar nerve reconstructed with an AxoGen AVANCE nerve allograft at an outside institution presented to the senior author’s clinic from 2014 to 2019. These patients were treated with excision of the allografts allowing for histological evaluation of regeneration across the allografts. All patients included in this series had no clinical sensory or motor recovery and had significant neuropathic pain ranging from 8 to 10/10 on a visual analogue scale. Each patient demonstrated a prominent and nonadvancing Tinel sign at the proximal site of nerve repair. Nerve conduction studies demonstrated no recordable motor or sensory recovery. Electromyography revealed evidence of muscle denervation but no motor unit response.

At surgery, the nerve allograft including native proximal and distal nerve was harvested, stored in 3% glutaraldehyde, and postfixed in 1% osmium tetroxide and serially dehydrated in ethanol and toluene. The nerves were embedded in epoxy, sectioned on an ultramicrotome into 1-µm cross sections, and sections counterstained with 1% toluidine blue dye. Histomorphometric evaluation was performed at 1000× overall magnification using a Leitz Laborlux S microscope and custom image analysis software (Clemex Vision Professional, Clemex Technologies, Longueuil, Québec). Analyses were performed on proximal nerve, distal nerve, and allograft. The allograft itself was evaluated at proximal, middle, and distal sections.²³

Clinical Case Series

Details of this patient population are noted in Table 1 and specifics of each case discussed below.

Table 1.

Clinical Case Series of 5 Patients With Failed AxoGen AVANCE Allograft Reconstructions of the Median or Ulnar Nerve.

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Age, y	56, male	68, female	45, female	57, male	17, male
Hand dominance	Right	Right	Right	Right	Right
Hand injured	Left	Left	Right	Right	Right
Nerve injured	Median	Median	Median	Ulnar	Ulnar
Iatrogenic injury	CTR	CTR	Endoscopic CTR	ORIF humerus	ORIF humerus
Allograft length, cm	N/A	4 × 3 cables	2	5	7
Allograft diameter, mm	N/A	N/A	N/A	N/A	4
Time from injury to ANA repair	11 y	3 y	1.5 y	8 mo	2 y
Time from ANA repair to excision, mo	16	24	17	9	14
Gap length, cm	8	7.5	6	N/A	11
Autograft source	MABC and TWFMN	MABC and PCBMN	Sural and Recurrent Motor	N/A	MABC
Adjunctive procedure	FDS opponensplasty	FDS opponensplasty	FDS opponensplasty	Proximal transposition of ulnar nerve under triceps Distal nerve and tendon transfers	Submuscular UNT

Note. CTR = carpal tunnel release; ORIF = open reduction internal fixation; N/A = not available; ANA = acellular nerve allograft; MABC = medial antebrachial cutaneous; TWFMN = third webspace fascicle of median nerve; PCBMN = palmar cutaneous branch of median nerve; FDS = flexor digitorum superficialis; UNT = ulnar nerve transposition.

Patient 1: A 56-year-old man had a complete median nerve injury following carpal tunnel release. This was reconstructed 11 years after the primary surgery with the use of an AxoGen AVANCE nerve allograft with no recovery. At exploration, a large neuroma involving the median nerve proximal to the nerve allograft was found, and the 8-cm nerve gap was reconstructed with a nerve autograft (Figure 1).

Patient 2: A 68-year-old woman suffered an injury to the median nerve following carpal tunnel release. A second surgeon explored her median nerve 10 months later, and a large neuroma in continuity was noted and reconstructed using an AxoGen AVANCE nerve allograft. She experienced no clinical recovery. At our surgery, a large neuroma proximal to the allograft was noted. In the mid-portion of the allograft reconstruction, there was very little tissue in continuity. Following excision of the allograft, the resulting 7.5-cm defect was reconstructed with a nerve autograft (Figure 2).

Patient 3: A 45-year-old woman suffered a median nerve injury following an endoscopic carpal tunnel release. Three months following this procedure, she underwent neuroma excision and reconstruction with an AxoGen AVANCE nerve allograft and a nerve wrap. We found a large neuroma of her median nerve proximal to the allograft; the area between the proximal and distal suture lines was noted to narrow significantly. Resection of the allograft resulted in a 6-cm gap which was reconstructed with a nerve autograft (Supplemental Figure S1).

Patient 4: A 57-year-old man suffered an ulnar nerve transection at the elbow following open reduction internal fixation of a distal humerus fracture. Five months later, he underwent reconstruction using an AxoGen AVANCE nerve allograft. He presented to us with severe neuropathic pain and no ulnar nerve function. We performed initial distal procedures to recover function with nerve and tendon transfers, followed by a second operation to address the marked neuropathic pain at the level of the allograft reconstruction. The allograft at the elbow was excised (Figure 3), and owing to the significant length of damage to the nerve and satisfaction with distal transfers for reconstruction, we elected to transpose the nerve proximally under the triceps muscle to control potential neuroma pain.²⁴

Patient 5: A 17-year-old individual suffered an ulnar nerve transection following open reduction internal fixation of a distal humerus fracture. This was reconstructed 8 months later using an AxoGen AVANCE nerve allograft. Several weeks later, he had an anterior interosseous to ulnar motor end-to-end nerve transfer. On presentation to our clinic, the patient had a good result from his distal nerve transfer. Surgery was recommended to manage neuropathic pain at the level of the elbow. On exploration of the ulnar nerve, a large neuroma in continuity was noted proximal to the allograft. The resulting 11-cm gap was reconstructed with a nerve autograft (Supplemental Figure S2).

Histology

Histological examination demonstrated either termination of axonal regeneration within the nerve allografts (3 of 5 cases) or failure of axons to regenerate into the allografts (2 of 5 cases). Specifically, the resected nerves revealed normal myelinated axons proximal to the neuroma at the junction of the native nerve and proximal ANA in all instances. However, all distal nerve specimens demonstrated a paucity of (1 of 5) or no axons (4 of 5) (Supplemental Table S1).

Discussion

Acellular nerve allografts were approved by the Food and Drug Administration in 2007 with the industry-sponsored RANGER registry tracking their clinical use since 2008, now containing more than 2000 nerve repairs.⁹ The early years of clinical application were predominantly for bridging small diameter, short gaps in sensory nerves with the literature providing evidence to indicate their use in these instances.^8,17,18 Recently, indications have expanded to include longer gaps in larger diameter mixed and motor nerves.

Currently there are 5 separate publications from the RANGER registry that provide documentation of the use of ANAs for the repair of mixed and motor nerves.^9-12,31 The first of these reports, in 2012, noted the functional outcomes following the use of ANAs for 76 nerve repairs (49 sensory, 18 mixed, and 9 motor nerves).⁹ “Meaningful recovery” (defined as greater than or equal to S3-M3) was seen in 13 (77%) of the mixed nerves and 7 (86%) of the motor nerves. Since this initial study, the majority of the publications demonstrating acceptable rates of sensory and motor recovery with the use of ANAs in mixed and motor nerves have come from the RANGER database (Supplemental Table S2). These studies have included nerve repairs with gaps as long as 7 cm, with conclusions suggesting that ANAs could be indicated for these complex reconstructive situations.^9-12,31

Recently, 3 reports discuss poor outcomes associated with ANAs when used to reconstruct long gap, large-diameter injuries of mixed and motor nerves (Supplemental Table S2).^13,15,16 Carlson et al reported on the use of ANAs in 3 mixed nerve injuries of the ulnar or radial nerve with a meaningful recovery (defined as M3 or better) observed in only 1 of the 3 patients.¹⁶ Nietosvaara et al published their experience with ANAs demonstrating no recovery in 2 cases of mixed or motor nerve reconstructions.¹⁵ A more recent study by Leckenby et al¹³ from Switzerland reported results from 171 ANAs used in 129 patients. In the 94 patients treated for acute nerve injuries, 72 of 94 (77%) achieved a sensory outcome of S3 or better. By contrast, ANAs were used in 25 patients to reconstruct gaps in mixed nerves with a mean diameter of 3.8 mm (range: 1-5 mm) and a mean length of 41 mm (range: 15-70 mm). Eleven of 25 grafts yielded a sensory recovery of S3 or better (44%) and 9 of 25 grafts yielded a motor recovery or M3 or better (36%). However, the most striking findings from the study were that an increase in both allograft length and allograft diameter yielded a significantly poorer outcome. In general, when allografts were grouped as those less than 30 mm and greater than 30 mm in length, the shorter group had significantly better results. Importantly, outcomes for motor recovery sharply diminished with increasing allograft length. For example, meaningful motor recovery decreased from 67% with gap lengths <3 cm to 38% with gap lengths between 3 and <5 cm with only 10% meaningful recovery with gap lengths greater than 5 cm (Table 2). Findings were similar regarding allograft diameter. The poorest outcomes were seen in large-diameter allografts, with greater than 3 mm in diameter appearing to inhibit axonal regeneration. Although the retrospective nature of this study weakens the findings, the relatively large number of patients included in the study raises concerns regarding their efficacy of bridging longer or larger diameter nerve gaps. In fact, a review on nerve gap substitutes by Rbia et al concluded that there is insufficient evidence for the use of ANAs in long gaps (>30 mm) in large-diameter nerves, and noted that there are no clinical studies that directly compare nerve allografts with cabled autograft.²² However, a recent large clinical series discussing nerve autografting in peroneal nerve injury confirmed the impact of nerve autograft length as a limiting factor. Good results (≥M4) were seen with autografts <6 cm in length (64%). This dramatically decreased to 29% with nerve autografts between 6 and 12 cm and 11% when graft length exceeded 12 cm.³² Thus, results with the “gold standard” autograft also decrease as graft length increases.

Table 2.

Percent Meaningful Sensory and Motor Recovery Decreases in Mixed Nerve Injuries Repaired With Increasing AxoGen AVANCE Allograft Length.⁷

Gap length bridged with allograft, mm	Meaningful sensory recovery, % (n)	Meaningful motor recovery, % (n)
5-14	90.0 (20)	N/A (0)
15-29	81.3 (43)	66.7 (5)
30-49	74.5 (39)	37.5 (8)
≥50	52.9 (7)	10.0 (10)

Note. Meaningful recovery is defined as S3 or better for sensory recovery and M3 or better for motor recovery. N/A = no patients.

Basic science nerve laboratory work is used to inform clinical practice. Beyond the discussed clinical literature, basic science studies provide strong evidence and context as to why currently available ANAs have these limits compared with nerve autograft. Acellular nerve allografts share an extracellular matrix similar to nerve autografts, but are initially by definition, completely acellular providing only the scaffold for cell migration, angiogenesis, and nerve regeneration (Figure 4). Therefore, to facilitate regeneration, monocytes/macrophages infiltrate the allografts recruiting endothelial cells via angiogenic signaling (ie, vascular endothelial growth factor expression) to promote angiogenesis.²⁵ Driven by these new vessels, T cells accumulate within this environment to promote proregenerative signaling,^21,33 and Schwann cells repopulate this region guided by these new vessels.²⁵ Only then will axon growth finally occur.^26,34,35,36 Conversely, the nerve autograft provides a similar scaffold for regenerating nerve, but also a diverse cell population, including Schwann cells and a vascular network. Therefore, in small-diameter nerve autografts, functional blood flow is rapidly restored within 2 to 3 days via inosculation at the proximal and distal nerve ends with the autograft.³⁵ Overall, the autograft is capable of almost immediately facilitating axon regeneration into the graft, whereas at least 2 weeks are needed to provide the proper cellular environment for axon growth to enter the ANAs.²¹ Revascularization of the ANAs was not assessed in this clinical study.

Finally, animal studies directly demonstrate the superiority of nerve autograft compared to allograft. Whitlock et al, in a rat sciatic nerve model, demonstrated that nerve regeneration across gaps of 14 and 28 mm using AxoGen allografts was inferior to autografts both in regards to nerve fiber counts and functional analysis.⁷ Guisti et al assessed the return of motor function in rats with a 10 mm sciatic nerve defect treated with autograft or ANAs. They demonstrated that ANAs were inferior to autografts in the restoration of motor function.⁶ Using green florescent-protein (GFP) transgenic rats, we showed the challenge of graft length. ANAs failed to support axonal regeneration as graft lengths increase, whereas autografts facilitate adequate axon regeneration across these longer grafts.^19,20

Understanding the limits of both autografts and ANAs will ensure more consistent results with nerve reconstruction. Owing to the ease of use of these off the shelf products and the avoidance of a secondary donor site for nerve autograft harvest, the use of ANAs for the reconstruction of larger diameter long gap nerve injuries is very appealing. However, mixed nerves of the upper extremity, such as the median and ulnar nerves, provide critical function. The result of the reconstruction should not be potentially compromised in an effort to avoid a donor site for nerve autograft harvest if autograft is the best option to ensure adequate axonal regeneration. Fortunately, probably only 30% of nerve fibers are needed to obtain normal function.^29,30,37 But, the longer the nerve graft (whether autograft or allograft), the lesser the chance of reaching this threshold of 30%.^32,37 Using nerve autograft in critical nerve repairs, however, allows for a larger “buffer” regarding the number of nerve fibers reaching target. As ANAs are substituted for nerve autograft, there is a higher chance that the critical 30% will not be reached and functional results will not be obtained (Figure 5).

Understanding the nerve gap lengths and diameters that are problematic regarding the currently available ANAs should be a stimulus to focus on ways to minimize donor site morbidity with nerve autografting. With modern nerve autografting techniques, there are ways to prevent painful neuroma formation and to recover sensation back into the donor site distribution. Neuroma formation can be prevented by managing the proximal stump of the donor nerve. Available techniques included crush, transposition, and capping to blunt or dwindle regeneration or alternatively newer techniques such as targeted muscle reinnervation or regenerative peripheral nerve interface.^24,38,39 Sensation can be restored to the donor nerve distribution by an end-to-side transfer of the distal end of the donor nerve to an intact nearby sensory nerve.⁴⁰ Special consideration should also be given to the choice of donor site for the nerve autograft. While the sural nerve is the “workhorse,” in most cases, there are nerve autografts available from the same upper extremity as the nerve injury or from noncritical portions of the damaged nerves.⁴⁰ Examples of upper extremity nerve autografts include the medial antebrachial cutaneous and lateral antebrachial cutaneous nerves.⁴⁰ In the case of median nerve injury, the third webspace fascicle can be used as a nerve autograft. Sensation can be restored to the third webspace by transferring the distal end of the third webspace fascicle end-to-side into the second or fourth webspace fascicle. In the case of ulnar nerve injury, the dorsal cutaneous branch of the ulnar nerve (DCU) can be used as nerve autograft.⁴⁰ Sensation can be restored into the distal DCU territory by transferring the distal end of the DCU end-to-side into the ulnar sensory nerve or with an end-to-end transfer to the palmar cutaneous branch of the median nerve.⁴⁰

This is a small series of patients referred to a tertiary referral center for complex nerve injuries, and owing to the nature of our practice, we are not referred patients with successful ANA reconstructions. All 5 patients in this study demonstrated neuromas proximal to the nerve allograft. Although there was an abundance of healthy myelinated axons seen proximal to the nerve allograft, it is possible that there was a confounding presence of technical error at the time of the original operation. As these allograft reconstructions were performed at an outside institution, limited information was available regarding the initial surgery. In theory, it is possible that the neuromas seen were not “new” and the original surgeon did not adequately trim back the proximal nerve stump at the time of initial allograft reconstruction. However, the findings in this report share many similarities to basic science observations, and thus serve as stimulus to continue research to further understand regenerative mechanisms involved when utilizing ANAs, and to improve ANAs to the level of or better than autograft. While we define the nerve autograft as the “gold standard,” it is better considered as silver or bronze as it also has similar limits as do ANAs, just at longer lengths. Continuing basic science research regarding limitations of ANAs will provide information needed to improve recovery of function for nerve injuries/patients, regardless of the technique of reconstruction.

Supplemental Material

sj-docx-1-han-10.1177_15589447211003175 – Supplemental material for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery

Supplemental material, sj-docx-1-han-10.1177_15589447211003175 for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery by Blair R. Peters, Matthew D. Wood, Daniel A. Hunter and Susan E. Mackinnon in HAND

Supplemental Material

sj-jpg-1-han-10.1177_15589447211003175 – Supplemental material for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery

Supplemental material, sj-jpg-1-han-10.1177_15589447211003175 for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery by Blair R. Peters, Matthew D. Wood, Daniel A. Hunter and Susan E. Mackinnon in HAND

Supplemental Material

sj-jpg-2-han-10.1177_15589447211003175 – Supplemental material for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery

Supplemental material, sj-jpg-2-han-10.1177_15589447211003175 for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery by Blair R. Peters, Matthew D. Wood, Daniel A. Hunter and Susan E. Mackinnon in HAND

Supplemental Material

sj-pdf-1-han-10.1177_15589447211003175 – Supplemental material for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery

Supplemental material, sj-pdf-1-han-10.1177_15589447211003175 for Acellular Nerve Allografts in Major Peripheral Nerve Repairs: An Analysis of Cases Presenting With Limited Recovery by Blair R. Peters, Matthew D. Wood, Daniel A. Hunter and Susan E. Mackinnon in HAND

Footnotes

Ethical Approval

This study was approved by our institutional review board.

Statement of Human and Animal Rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

Statement of Informed Consent

Informed consent was obtained from all individual participants in the study.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Blair R. Peters

Matthew D. Wood

Susan E. Mackinnon

Supplemental material is available in the online version of the article.

References

Dellon

Mackinnon

SE.

An alternative to the classical nerve graft for the management of the short nerve gap. Plast Reconstr Surg. 1988;82(5):849-856.

Mackinnon

SE.

Surgical management of the peripheral nerve gap. Clin Plast Surg. 1989;16(3):587-603.

Meek

Coert

JH.

Clinical use of nerve conduits in peripheral nerve repair: review of the literature. J Reconstr Microsurg. 2002;18(2):97-109.

Strauch

Use of nerve conduits in peripheral nerve repair. Hand Clin. 2000;16(1):123-130.

Moore

Kasukurthi

Magill

, et al. Limitations of conduits in peripheral nerve repairs. Hand (N Y). 2009;4(2): 180-186.

Giusti

Willems

Kremer

, et al. Return of motor function after segmental nerve loss in a rat model: comparison of autogenous nerve graft, collagen conduit, and processed allograft (AxoGen). J Bone Joint Surg Am. 2012;94:410-417.

Whitlock

Tuffaha

Luciano

, et al. Processed allografts and type I collagen conduits for repair of peripheral nerve gaps. Muscle Nerve. 2009;39(6):787-799.

Rinker

Zoldos

Weber

, et al. Use of processed nerve allografts to repair nerve injuries greater than 25 mm in the hand. Ann Plast Surg. 2017;78(6S suppl 5):S292-S295.

Brooks

Weber

Chao

, et al. Processed nerve allografts for peripheral nerve reconstruction: a multicenter study of utilization and outcomes in sensory, mixed, and motor nerve reconstructions. Microsurgery. 2012;32(1):1-14.

10.

Isaacs

Safa

A preliminary assessment of the utility of large-caliber processed nerve allografts for the repair of upper extremity nerve injuries. Hand (N Y). 2017;12(1):55-59.

11.

Safa

Jain

Desai

, et al. Peripheral nerve repair throughout the body with processed nerve allografts: results from a large multicenter study. Microsurgery. 2020;40:527-537. doi:10.1002/micr.30574.

12.

Safa

Shores

Ingari

, et al. Recovery of motor function after mixed and motor nerve repair with processed nerve allograft. Plast Reconstr Surg Glob Open. 2019;7(3):e2163.

13.

Leckenby

Furrer

Haug

, et al. A retrospective case series reporting the outcomes of Avance nerve allografts in the treatment of peripheral nerve injuries. Plast Reconstr Surg. 2020;145(2):368e-381e.

14.

Hoben

Schellhardt

, et al. Increasing nerve autograft length increases senescence and reduces regeneration. Plast Reconstr Surg. 2018;142(4):952-961.

15.

Nietosvaara

Grahn

Sommarhem

Failed peripheral nerve reconstruction with processed nerve allografts in three patients. J Hand Surg Eur Vol. 2019;44(3):318-320.

16.

Carlson

Wallace

Konofaos

Cadaveric nerve allograft: single center’s experience in a variety of peripheral nerve injuries. Ann Plast Surg. 2018;80(6S suppl 6):S328-S332.

17.

Ray

Mackinnon

SE.

Management of nerve gaps: autografts, allografts, nerve transfers, and end-to-side neurorrhaphy. Exp Neurol. 2010;223(1):77-85.

18.

Lin

Manzano

Gupta

Nerve allografts and conduits in peripheral nerve repair. Hand Clin. 2013;29:331-348.

19.

Saheb-Al-Zamani

Yan

Farber

, et al. Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence. Exp Neurol. 2013;247:165-177.

20.

Poppler

Schellhardt

, et al. Axonal growth arrests after an increased accumulation of Schwann cells expressing senescence markers and stromal cells in acellular nerve allografts. Tissue Eng Part A. 2016;22(13-14):949-961.

21.

Pan

Hunter

Schellhardt

, et al. The accumulation of T cells within acellular nerve allografts is length-dependent and critical for nerve regeneration. Exp Neurol. 2019;318:216-231.

22.

Rbia

Shin

AY.

The role of nerve graft substitutes in motor and mixed motor/sensory peripheral nerve injuries. J Hand Surg Am. 2017;42(5):367-377.

23.

Hunter

Moradzadeh

Whitlock

, et al. Binary imaging analysis for comprehensive quantitative histomorphometry of peripheral nerve. J Neurosci Methods. 2007;166(1):116-124.

24.

Domeshek

Krauss

Snyder-Warwick

, et al. Surgical treatment of neuromas improves patient-reported pain, depression and quality of life. Plast Reconstr Surg. 2017;139(2):407-418.

25.

Pan

Acevedo-Cintron

Sayanagi

, et al. The CCL2/CCR2 axis is critical to recruiting macrophages into acellular nerve allograft bridging a nerve gap to promote angiogenesis and regeneration. Exp Neurol. 2020;331:113363. doi:10.1016/j.expneurol.2020.113363.

26.

Cattin

Burden

Van Emmenis

, et al. Macrophage-induced blood vessels guide Schwann cell-mediated regeneration of peripheral nerves. Cell. 2015;162(5):1127-1139.

27.

Parrinello

Napoli

Ribiero

, et al. EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting. Cell. 2010;143(1):145-155.

28.

Pan

Mackinnon

Wood

MD.

Advances in the repair of segmental nerve injuries and trends in reconstruction. Muscle Nerve. 2020;61:726-739. doi:10.1002/mus.26797.

29.

Gordon

Yang

Ayer

, et al. Recovery potential of muscle after partial denervation: a comparison between rats and humans. Brain Res Bull. 1993;30(3-4):477-482.

30.

Gordon

Tyreman

Sprouting capacity of lumbar motoneurons in normal and hemisected spinal cords of the rat. J Physiol. 2010;588(pt 15):2745-2768.

31.

Cho

Rinker

Weber

, et al. Functional outcome following nerve repair in the upper extremity using processed nerve allograft. J Hand Surg Am. 2012;37(11):2340-2349.

32.

George

Boyce

DE.

An evidence-based structured review to assess the results of common peroneal nerve repair. Plast Reconstr Surg. 2014;134(2):302e-311e.

33.

Pan

Hunter

Schellhardt

, et al. T cells modulate IL-4 expression by eosinophil recruitment within decellularized scaffolds to repair nerve defects. Acta Biomater. 2020;112:149-163. doi:10.1016/j.actbio.2020.05.009.

34.

Best

Mackinnon

Midha

, et al. Revascularization of peripheral nerve autografts and allografts. Plast Reconstr Surg. 1999;104:152-160.

35.

Farber

Hoben

Hunter

, et al. Vascularization is delayed in long nerve constructs compared with nerve grafts. Muscle Nerve. 2016;54(2):319-321.

36.

Best

Mackinnon

Evans

, et al. Peripheral nerve revascularization: histomorphometric study of small- and large-caliber grafts. J Reconstr Microsurg. 1999;15(3):183-190.

37.

Power

Sharma

El-Haj

, et al. Compound muscle action potential amplitude predicts the severity of cubital tunnel syndrome. J Bone Joint Surg Am. 2019;101(8):730-738.

38.

Hong

Wood

Hunter

, et al. Neuroma management: capping nerve injuries with an acellular nerve allograft can limit axon regeneration [published online ahead of print May 29, 2020]. Hand (N Y). doi:10.1177/1558944719849115.

39.

Panucci

Mykatyn

Mackinnon

, et al. End-to-side nerve repair: review of the literature. Restor Neurol Neurosci. 2007;25:45-63.

40.

Poppler

Davidge

, et al. Alternatives to sural nerve grafts in the upper extremity. Hand (N Y). 2015;10(1):68-75.

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