Taking into consideration the several different types

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1 J Neurosurg 119: , 2013 AANS, 2013 Limitations of nerve repair of segmental defects using acellular conduits Case report Yerko A. Berrocal, M.D., Vania W. Almeida, B.A., and Allan D. Levi, M.D., Ph.D. Department of Neurological Surgery and The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida The authors present the case of a 20-year-old man who, 3 months after his initial injury, underwent repair of a 1.7-cm defect of the ulnar nerve at the wrist; repair was performed with an acellular nerve allograft. Given the absence of clinical or electrophysiological recovery at 8 months postrepair, the patient underwent reexploration, excision of the regenerated cable, and rerepair of the ulnar nerve with sural nerve autografts. Histology of the cable demonstrated minimal axonal regeneration at the midpoint of the repair. At the 6- and 12-month follow-ups of the sural nerve graft repair, clinical and electrophysiological evidence of both sensory and motor reinnervation of the ulnar nerve and associated hand muscles was demonstrated. In this report, the authors describe a single case of failed acellular nerve allograft and correlate the results with basic science and human studies reporting length and diameter limitations in human nerve repair utilizing grafts or conduits devoid of viable Schwann cells. ( Key Words conduit nerve injury repair transplantation tube peripheral nerve Taking into consideration the several different types of PNI, the repair of completely transected large-diameter nerves, such as the ulnar and median nerves, arguably poses the greatest challenge for peripheral nerve surgeons. 36 For short-distance gaps (< 3 cm) in humans, entubulation technologies allow the creation of an artificial nerve to bridge the gap between the nerve stumps. 17,20,27 Synthetic and biological AGCs, such as silicone, PGA, and collagen conduits (NeuraGen, Integra LifeSciences Corp.), have become a viable alternative. More recently, peripheral nerve allografts devoid of Schwann cells and all antigenicity have been used (Avance, AxoGen Inc.). Advantages of AGCs as compared with nerve autografts include the avoidance of donor-site morbidity and possible painful neuromas. 2,3,9,10,25,28,35,41,44,46 A critical analysis of nerve gap lengths in which entubulation technology will no longer be successful has been performed in the laboratory. 12,13,17,20,29,32,45 More recently, it has been recognized that nerve diameter in addition to gap length may be a critical determinant in regeneration success, with largerdiameter nerves (for example, ulnar nerves) doing more poorly when compared with a small-diameter nerve (for example, digital nerve). 31 Case Report Abbreviations used in this paper: AGC = axon guidance channel; PGA = polyglycolic acid; PNI = peripheral nerve injury. J Neurosurg / Volume 119 / September 2013 History and Examination. A 20-year-old man sustained a complex left wrist fracture dislocation after a motocross accident requiring operative internal fixation (Fig. 1A and B). The patient noticed left hand tingling and numbness in the ulnar nerve distribution as well as severe grip weakness. An associated left ulnar nerve injury at the wrist level with complete loss of both sensory and motor function was diagnosed. First Nerve Repair. Three months after the injury, the patient underwent removal of the instrumentation, resection of a neuroma, and repair of the ulnar nerve (Fig. 1C) with a 1.7-cm Avance acellular nerve allograft. First Postoperative Course. At 8 months postrepair (11 months postinjury), there was no clinical or electrophysiological evidence of reinnervation in the distribution of the ulnar nerve. The patient complained of left hand tingling and numbness, grip weakness, and progressive clawing of the left hand. Physical examination revealed marked atrophy of the intrinsic muscles of his left hand as well as completely absent sensation on the hypothenar eminence and the medial aspect of the ring and small fingers. Second Nerve Repair. The patient underwent reexploration of the left ulnar nerve in the forearm where the previous Avance nerve graft had been placed at 11 months post initial injury. Numerous small 8-0 type sutures were identified at the area of repair. Scar tissue was dissected from around the nerve, and an area of thinning nerve was seen at the former site of the graft (Figs. 2 upper and 3). Intraoperative nerve action potentials did not reveal any conduction through the previous area of repair. The scar 733

2 Y. A. Berrocal, V. W. Almeida, and A. D. Levi Fig. 1. A: Photograph of the patient s swollen left wrist immediately after injury. B: Radiograph of the wrist fracture showing internal fixation with a metal plate and screws. C: Intraoperative photograph of the ulnar nerve with a neuroma in continuity 3 months after the injury and just prior to neuroma resection and repair with a 1.7-cm Avance decellularized allograft. was resected proximally and distally to areas within the ulnar nerve in which normal fascicular anatomy could be identified, creating a 4-cm gap in the nerve. An 18-cm segment of the left sural nerve was harvested from the patient and served as an autograft, whereupon 4 4 cm sural nerve grafts were then sutured with 8-0 nylon to bridge the gap supplemented with fibrin glue (Fig. 2 lower). A detailed histological analysis (Fig. 3) of the regenerated nerve cable 8 months after repair with the decellularized nerve allograft demonstrated poor regeneration at the midpoint of the cable with approximate ly 6% (approximately 1000/16,000) myelinated axons as com pared with the number at the normal ulnar nerve at the wrist.35 Second Postoperative Course. Six months after the sural nerve autograft repair, the patient demonstrated significant improvement with recovery of protective sensation in his palm. At 12 months, there was further sensory recovery, less clawing of the hand, and new movement of the abductor digiti minimi muscle of the hand. Nerve conduction studies (Fig. 4 upper) of the left ulnar nerve stimulated at the wrist as well as below and above the elbow demonstrated an amplitude response of 4.5 mv from the hypothenar muscles. The ulnar sensory nerve action potential was not obtainable. Electromyography analysis of the left upper extremity revealed evidence of reinnervation in the first dorsal interosseous and abductor digiti minimi muscles. Motor units of increased amplitude and duration and a decreased number of fast firing units were seen in both muscles. Ultrasound revealed continuity of the graft with the ulnar nerve, fascicular anatomy, and the absence of neuroma formation (Fig. 4 lower). Discussion Fig. 2. Upper: Intraoperative view of the nerve with a tapered middle section 8 months after a repair utilizing a 1.7-cm Avance allograft. Lower: Intraoperative view after nerve repair with sural nerve autografts. 734 Even though the peripheral nervous system is a permissive environment for regeneration, many challenges must be overcome to restore motor and sensory function in the target area after PNI.37 The field of PNI repair has come a long way since Glück s first attempt in 1880 to restore a nerve deficit with a decalcified bone segment, and the development of new materials for the tubular repair of nerve injuries has advanced significantly in the last decade.2 In the last 17 years, the FDA has approved 11 biological and synthetic conduits for use in the treatment of PNIs.16 DeJ Neurosurg / Volume 119 / September 2013

3 Limitations of human peripheral nerve repair Fig. 3. Upper: Excised left ulnar nerve graft 8 months after repair with a processed nerve allograft (Avance). Dashed lines specify the 3 areas (proximal stump, midpoint, and distal stump) that were embedded and cut for histological analysis. Center: Axial histological semithin cut sections (1 mm) stained with toluidine blue and imaged at 10, corresponding to each of the 3 areas depicted by the dashed lines. Total number of myelinated axons (n) is shown for each section (midpoint, 1056 axons). Normal myelinated axon count of ulnar nerve: approximately 16, Lower: High-power view with detailed profiles of myelinated figures (oil immersion 63). spite Sunderland s pessimistic statement in 1978 that the use of nonbiologic materials is of no value in the bridging of gaps in nerves, silicone tubes started being used in the 1980s as an effective alternative to end-to-end nerve coaptation in short segmental nerve loss.8,19,30,34,42 However, the longer the nerve gap (range 2 5 cm), the poorer the functional recovery of sensory and motor skills in patients with either ulnar or median nerve transections repaired with silicone tubes, as reported by Braga-Silva.6 The use of a tubular approach to repair peripheral nerve deficits in humans was based on findings from animal models, which showed that the lumen of a conduit formed an ideal biological environment for axonal growth.20,21 Axon guidance channels provide an enclosed chamber for the diffusion of neurotrophic factors released by the nerve stumps and for the influx of endogenous Schwann cells especially in the first 2 weeks of the regenerative process.3,9 Furthermore, the internal milieu of the conduits can also be modified with the addition of several substrates such as extracellular matrix proteins and trophic support to further stimulate axonal regeneration.2,3,18,44 This approach to incorporate bioactive components into the lumen of AGCs has been shown to be especially beneficial when conduits have been used to bridge long nerve gaps in animals.4,37,43 The addij Neurosurg / Volume 119 / September 2013 tion of autologous Schwann cells within a collagen tube can significantly improve long-distance regeneration in the rat but is not as effective as a reversed nerve autograft.4 Yet another advantage to tubular repair is that AGCs provide a linear structure in which a fibrin matrix scaffold can form. Studies have shown that the formation of this matrix is essential for axons to regenerate successfully since it helps align them as well as guide their growth longitudinally from the proximal to the distal stump.10,22,37 The architectural properties of AGCs reduce the likelihood of aberrant axonal growth and neuroma formation by providing a structure that directs the regenerating fibers toward the entry to their appropriate target, namely the endoneurial tube of the distal nerve stump.1,9,11 The biological conduit used to repair the ulnar nerve injury in the patient in our case was a nerve allograft. The patient did not need to be submitted to a systemic immunosuppression regimen.16,34 The manufacturer AxoGen describes Avance as a decellularized and cleansed extracellular matrix from donated human peripheral nerve, which does not require the use of immunosuppressives. This acellular nerve allograft was approved for clinical use in 2007, and it is supplied in lengths of between 15 and 70 mm and in internal diameters of between 1 and 5 735

4 Y. A. Berrocal, V. W. Almeida, and A. D. Levi Fig. 4. Upper: Traces from electromyography analysis and motor nerve conduction studies of the ulnar nerve 12 months after repair. MS = milliseconds; MA = milliamps; MV = millivolts. The numbers 1, 2, and 3 indicate the beginning, middle, and end of a wave. Lower: Sagittal ultrasound image of the left ulnar nerve repaired with sural nerve grafts 12 months postrepair demonstrating fascicular profiles and the absence of a neuroma. Single arrow indicates skin; double arrows, distal ulnar/ sural nerve graft interface. mm. 7 Although the tissue goes through an intricate process to remove donor allogeneic cells and decrease immunogenicity, it still retains the multifascicular structure characteristic of a peripheral nerve, which serves as a temporary scaffold for nerve regeneration until the allograft is completely absorbed and replaced with host components. 11 Recent literature has shown that the microtopography of the scaffolding that forms in the lumen of a conduit plays an important role not only in the initial axonal growth but also in the overall restoration of nerve function. 38,39 In 2009, Karabekmez and colleagues described successful outcomes when using Avance to repair sensory nerve gaps up to 3 cm in the hands and fingers of 7 patients. 15 In 2012, results from the first and most comprehensive multicenter trial on the Avance processed allograft were published by Brooks et al. 7 The study findings were based on data collected during the course of 3 years from 59 patients with 76 peripheral nerve injuries with a gap. Of these nerve injuries, 49 were sensory, 18 were mixed, and 9 were motor nerves. The average gap length was 22 ± 11 mm (range 5 50 mm), and the authors reported an 87% meaningful sensory and motor recovery based on the Mackinnon modification of the Medical Research Council grading system. Surgical reconstruction of long, large-diameter peripheral nerve gaps (range cm) with cadaveric nerve allografts and immunosuppression is a viable alternative when no other options exist. 5,14,15,26,34,35 Large-caliber nerves that have been successfully repaired include the sciatic, posterior tibial, median, ulnar, and radial nerves. The use of multiple, small-diameter nerve allografts improves revascularization of the construct. The addition of immunosuppression permits survival of the donor Schwann cells until axons can reach their target. Immunosuppression has been administered prior to surgery and continued until 6 months after sensory and motor function returned in the most distal targets. 26,35 Only 1 patient demonstrated rejection of the allograft 4 months after surgery. The 6 remaining patients showed motor recovery and the return of sensation in the affected limbs. Lundborg and colleagues published results from a clinical study in 1997, which showed no difference between the use of a silicone tube and microsurgical coaptation repair of complete short-gap transections in the median and ulnar nerves. 22 In 2004, the same group published a 5-year follow-up of 30 patients with complete median or ulnar nerve injuries. 23 The report showed no significant difference in functional recovery among patients whose short nerve defects (range 3 5 mm) were treated with either a silicone tube or nerve coaptation. The use of inert materials in tubular repair can also lead to nerve compression and hinder axonal conduction. 8,19,30 These problems can be circumvented with the use of bioabsorbable compounds, since permeability has been shown to play a major role in the efficacy of tubular repair of peripheral nerve discontinuities. 3,10 Two prominent types of AGCs with such resorption properties are PGA and collagen tubes. 25,44 The former has a faster absorption time (range 3 4 months), and thus is applicable mostly for use in short nerve gaps, whereas the latter has a much slower rate of absorption (range 3 4 years). 16,33,40,44 As stated by de Ruiter and colleagues in 2009, the ideal nerve tube should remain intact for the time axons need to regenerate across the nerve gap and then degrade gradually with minimal swelling and foreign body reaction. 10 Polyglycolic acid tubes have been extensively studied in several animal models, ranging from rodents to nonhuman primates, before being used in a clinical setting. Mackinnon and Dellon reported that patients with 0.5- to 3-cm-long digital nerve gaps repaired with a PGA tube showed functional recovery similar to that in patients whose nerve deficits were reconstructed with nerve autografts. 25 Besides the aforementioned limitations imposed by the length of a neurotmetic injury, the diameter of the nerve to be repaired also plays an important role in the decision of whether to use a tubular approach to bridge a nerve defect. 9,31 Although more reports have featured large-caliber nerves repaired with AGCs in recent years, the clinical data are still limited and most cases involve short nerve gaps. Furthermore, animal models are impractical to explore this question since few nerves, even those in nonhuman primates, have diameters equivalent to the large-caliber nerves in humans. In 2009, Moore and colleagues described 4 cases of large-caliber nerve injuries unsuccessfully repaired with AGCs. 31 Three of the 4 largediameter nerve defects were bridged with a NeuraGen 736 J Neurosurg / Volume 119 / September 2013

5 Limitations of human peripheral nerve repair conduit, and 1 was reconstructed with a PGA tube, but all patients showed poor functional outcomes. Increasing nerve diameter may negatively influence regeneration by diluting neurotrophic factors in the relatively large chamber as well as reduce opportunities for vascularization. Conclusions Thus, taken together, the conclusions from the basic science data, case report(s), and the clinical data reviewed here suggest that a PNI requiring direct repair of a long segmental gap and/or large diameter is best treated with nerve autografting techniques. 4,31,35 Processed donor nerve allografts and artificial conduits in PNI repair can be used, but their application should be restricted to the bridging of small-diameter, short nerve defects. 5,14,15,26,34,35 In a 2011 letter, Mackinnon stated, acellularized nerve allografts have largely replaced conduits in my practice, but I still restrict their use to noncritical, small-diameter sensory nerves with gaps less than 4 cm. 24 In the future, the use of autologous cultured Schwann cells may increase the potential for nerve repair using acellular nerve grafts/ conduits without the use of immunosuppression. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: all authors. Ac quisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: all authors. Critically revising the ar ticle: all authors. Reviewed submitted version of manuscript: all au thors. Approved the final version of the manuscript on behalf of all authors: Levi. Acknowledgments The authors acknowledge Dr. Marina Dididze for the acquisition of electromyography reports and ultrasound images and Mr. Roberto Suazo for his assistance with the figures. References 1. Babu P, Behl A, Chakravarty B, Bhandari PS, Bhatti TS, Maurya S: Entubulation techniques in peripheral nerve repair. 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6 Y. A. Berrocal, V. W. Almeida, and A. D. Levi al-nerve repair: review of the literature. J Reconstr Microsurg 18:97 109, Meek MF, Fresow R, Hawinkels H: Reconstruction of a 4-cm human median nerve gap by including an autogenous nerve slice in a bioabsorbable nerve conduit: case report. J Hand Surg Am 33: , 2008 (Letter) 30. Merle M, Dellon AL, Campbell JN, Chang PS: Complications from silicon-polymer intubulation of nerves. Microsurgery 10: , Moore AM, Kasukurthi R, Magill CK, Farhadi HF, Borschel GH, Mackinnon SE: Limitations of conduits in peripheral nerve repairs. Hand (NY) 4: , Nagao RJ, Lundy S, Khaing ZZ, Schmidt CE: Functional characterization of optimized acellular peripheral nerve graft in a rat sciatic nerve injury model. Neurol Res 33: , Nectow AR, Marra KG, Kaplan DL: Biomaterials for the development of peripheral nerve guidance conduits. Tissue Eng Part B Rev 18:40 50, Pabari A, Yang SY, Seifalian AM, Mosahebi A: Modern surgical management of peripheral nerve gap. J Plast Reconstr Aesthet Surg 63: , Ray WZ, Mackinnon SE: Management of nerve gaps: autografts, allografts, nerve transfers, and end-to-side neurorrhaphy. Exp Neurol 223:77 85, Ruijs AC, Jaquet JB, Kalmijn S, Giele H, Hovius SER: Median and ulnar nerve injuries: a meta-analysis of predictors of motor and sensory recovery after modern microsurgical nerve repair. Plast Reconstr Surg 116: , Schlosshauer B, Dreesmann L, Schaller HE, Sinis N: Synthetic nerve guide implants in humans: a comprehensive survey. Neurosurgery 59: , Shanti RM, Ziccardi VB: Use of decellularized nerve allograft for inferior alveolar nerve reconstruction: a case report. J Oral Maxillofac Surg 69: , Spivey EC, Khaing ZZ, Shear JB, Schmidt CE: The fundamental role of subcellular topography in peripheral nerve repair therapies. Biomaterials 33: , Stanec S, Stanec Z: Ulnar nerve reconstruction with an expanded polytetrafluoroethylene conduit. Br J Plast Surg 51: , Staniforth P, Fisher TR: The effects of sural nerve excision in autogenous nerve grafting. Hand 10: , Sunderland S: Nerves and Nerve Injuries, ed 2. London: Churchill Livingstone, Wang PH, Tseng IL, Hsu SH: Review: bioengineering approaches for guided peripheral nerve regeneration. Med Biol Eng Comput 31: , Weber RA, Breidenbach WC, Brown RE, Jabaley ME, Mass DP: A randomized prospective study of polyglycolic acid conduits for digital nerve reconstruction in humans. Plast Reconstr Surg 106: , Williams LR, Danielsen N, Müller H, Varon S: Exogenous matrix precursors promote functional nerve regeneration across a 15-mm gap within a silicone chamber in the rat. J Comp Neurol 264: , Wolford LM, Stevao ELL: Considerations in nerve repair. Proc (Bayl Univ Med Cent) 16: , 2003 Manuscript submitted October 12, Accepted April 22, Please include this information when citing this paper: published online June 7, 2013; DOI: / JNS Address correspondence to: Allan D. Levi, M.D., Ph.D., University of Miami Miller School of Medicine, Department of Neurological Surgery, Lois Pope Life Center, 1095 NW 14th Terrace (D4-6), Miami, FL ALevi@med.miami.edu. 738 J Neurosurg / Volume 119 / September 2013