One central belief in the field of neuroscience is that the peripheral nervous system (PNS) regenerates whereas the central nervous system does not. However, clinicians are acutely aware that functional neural regeneration is limited following treatment of peripheral nerve injury. This is especially true with major nerve injuries, such as segmental nerve defects and brachial plexus injuries, which result in significant morbidity and debilitating functional deficits. The few available epidemiologic studies on civilian populations report that peripheral nerve injury occurs in 2.8% of multitrauma patients admitted to regional trauma facilities in North America each year, translating to >17,500 cases annually in the United States.1,2 Presentation of brachial plexus injury varies depending on etiology, including motor vehicle trauma, penetrating injury, and birth injury.3–5 A study of 1,019 patients with brachial plexus injury at a US medical center found that the most common types of lesion are stretch/contusion (50%), plexus tumors (16%), thoracic outlet syndrome (16%), gunshot wounds (12%), and lacerations (7%).6 Traumatic nerve injuries are also common in conjunction with blunt trauma-related fractures involving the extremities, pelvis, and acetabulum. Such injuries may be the result of traction caused by displaced fracture fragments or entrapment within the fracture itself.7–12 In rare instances, a nerve may be transected by a sharp fracture edge.13–15 Devastating nerve injuries may have lasting consequences despite appropriate fracture management.
Major nerve injuries have limited potential for spontaneous recovery. Advances in surgical treatment based on anatomic reconstruction have reached a plateau. At best, these efforts restore only partial function to the affected limb, and outcomes are inconsistent. Greater understanding of the molecular biology of peripheral nerve injury and repair is required to improve treatment of major nerve injuries.
Peripheral nerves are heterogeneous composite structures composed of neurons, glial cells (eg, Schwann cells), and connective tissue (Figures 1 and 2). The PNS uses nerves to relay information to and from the environment and the central nervous system. A neuron receives signals through its dendrites and processes them within the cell body. Subsequently, action potentials are formed and transmitted to targets via axons. In the PNS, Schwann cells ensheath axons in myelin and provide trophic support. Myelin enhances the speed of action potential propagation, as manifested by increased nerve conduction velocity. Direct damage to the axon, as in crush or transection injury, triggers a cascade of events that are collectively known as wallerian degeneration. Granular disintegration of the cytoskeleton is the hallmark of acute peripheral nerve injury.16 Following clearance of the myelin debris, a hollow tube composed of connective tissue scaffolding (ie, Büngner bands) provides a clear and guided path for the regenerating growth cone.17
Management of Major Nerve Injury
Established methods of managing major nerve injury involve anatomic reconstruction of the peripheral nerve. In acute transection injury, direct primary repair is performed via coaptation of the free ends of the injured nerve (Figure 3). If the lesion creates a segmental nerve defect and primary repair is not possible, the current standard of care involves reconnection of the free ends with nerve autograft, such as the sural nerve18 (Figure 4). Other modalities used to bridge nerve gaps include veins, muscle tissue, and artificial nerve tubes.19–21 In both direct and indirect nerve repair, surgical management involves manipulation and reconstruction of the neuronal connective tissue architecture and relies entirely on endogenous repair processes. The functional components of the nerve, such as the axons and Schwann cells, are not directly affected by these methods.
Traction injuries to the proximal brachial plexus frequently involve nerve root avulsion, and regenerating nerves must grow across considerable distances to achieve reinnervation of the target tissues. Restoration of biceps function in patients with superior trunk and upper spinal nerve root lesions at C5 and C6 is a priority in the presence of brachial plexus injury. This functional restoration improves morbidity considerably. In the Oberlin transfer, the ulnar nerve is used to reinnervate the biceps muscle.22 The nerve transfer technique takes advantage of neuroplasticity, and a functionally redundant nerve is used as a donor for another function.23 The free end of the donor nerve is connected near the terminal motor branches of the injured nerve. This effectively converts a proximal nerve lesion into a distal nerve lesion, leading to notable reduction in the time and distance required for regrowth. When nerve transfer is performed correctly, donor site deficits are minimal, and invaluable functions are regained in the affected limb.
Limitations of Peripheral Nerve Regeneration
Existing treatments of peripheral nerve injuries offer limited capacity to effect true functional neural regeneration. Challenges with direct nerve repair include limited autograft material, poor or absent scaffolding, dense scar formation, misrouting of the growth cone, and end-organ atrophy. The use of autograft to repair segmental nerve defects induces donor site morbidity, and insufficient donor material may be available (Figure 5). Use of axonal guidance channels is an alternative to autograft. Currently, use of these channels is reserved for short segmental defects in sensory nerves.24 Studies on segmental nerve defects have revealed the existence of critical nerve gap length where the efficacy of tube conduits declines.25 Studies are under way to explore the use of various biomaterials within axonal guidance channels to improve peripheral nerve repair.26
Denervation atrophy of target tissues is one of the most significant issues associated with peripheral nerve repair. In adults, neural regeneration occurs at the rate of 1 to 3 mm per day.27 For proximal peripheral nerve lesions, the nerve must cover substantial distances, and adipose and fibrous changes in the denervated muscle are required for the nerve to reach its target.28 Prolonged target deprivation drastically reduces the ability of motor neurons to regenerate and causes Schwann cells associated with the target tissues to lose their growth-supportive phenotypes. 29–31 End-organ atrophy is addressed somewhat with nerve transfer. However, even the most successful nerve transfer leads to only partial restoration of muscle function, and preinjury strength is never fully recovered.32 Alternative treatment methods at the molecular and cellular levels have been proposed to improve peripheral nerve repair.
Molecular and Cell-based Therapy
Increasing the rate of neural regeneration is the goal with the most widely studied therapeutic strategies. Numerous studies have established the role of neurotrophic factors, such as nerve growth factor and glial cell line-derived neurotrophic factor, in the development and regrowth of peripheral nerves; failure to sustain their levels has been implicated in poor neural regeneration.33–35 Thus, neurotrophic factor supplementation of axonal guidance channels could promote and improve the rate of regeneration after peripheral nerve injury. One proposed method involves Schwann cells.36 Schwann cells are critical to regenerative processes, such as wallerian degeneration, and these cells produce and secrete neurotrophic factors. Adipose-derived, skin-derived, and mesenchymal stem cells have been successfully isolated, differentiated, and used as Schwann cell precursors in peripheral nerve repair.37–39 Stem cells provide prompt and abundant sources of Schwann cells without the complications of graft rejection and allograft immunosensitivity. Bone marrow stromal cells can also produce neurotrophic factors, but harvest of these cells involves a more invasive process.40–42
These attempts at improving on peripheral nerve regeneration have largely been experimental. Furthermore, increasing the rate of neural regeneration does not sufficiently address the crucial issue of end-organ atrophy.
Stabilization of the Neuromuscular Junction
The neuromuscular junction (NMJ) is the interface between the peripheral nerves and muscle at which critical actions occur. The NMJ is composed of three cellular constituents: the terminal branch of the motor axon, terminal Schwann cells (TSCs), and muscle fibers containing acetylcholine receptors (AChRs) at the motor end plates43 (Figure 6). Through this interface, nerves transmit signals for muscle contraction and provide trophic support to target tissues. Loss of this support during peripheral nerve injury induces end-organ changes through an underlying mechanism that is not fully understood. Stabilization of the NMJ may reduce the rate of end-organ atrophy after major nerve injury, resulting in better functional outcomes with peripheral nerve repair.
Major nerve injury induces distinct morphologic changes at the NMJ. Dispersion of AChR clusters is a key feature of acute peripheral nerve injury44 (Figure 7). Agrin has been identified as a critical regulator of AChR cluster maintenance and formation45 (Figure 6, A). Agrin is a glycoprotein that is synthesized and released by the distal nerve terminal.46 During synaptogenesis, agrin is responsible for the conversion of growth cones into presynaptic terminals by inducing tyrosine phosphorylation of its postsynaptic receptor, muscle-specific kinase.47 Decreased levels of agrin have been associated with poor AChR cluster formation, and the loss of agrin after nerve injury may significantly contribute to the dispersion of AChR clusters48 (Figure 7, B and C). Thus, increasing local levels of agrin can potentially preserve the integrity of AChR clusters and reduce end-organ changes following peripheral nerve injury.
In addition to activating muscle-specific kinase, agrin maintains NMJ stability through critical interactions with components of motor end plate extracellular matrix, such as laminin and α-dystroglycan.49,50 Matrix metalloproteinase-3 (MMP-3) is a serine protease responsible for the degradation of agrin in the NMJ extracellular matrix. Levels of MMP-3 increase dramatically following peripheral nerve injury, leading to significantly reduced levels of agrin.51 Transgenic mice that lack MMP-3 have morphologically larger and more efficient end plates. Thus, pharmacologic inhibition of MMP-3 and increased levels of agrin could feasibly stabilize the NMJ and diminish end-organ atrophy subsequent to major nerve injury.
Change in AChR remodeling is also observed at the NMJ following acute peripheral nerve injury. The half-life of AChRs decreases from 10 days prior to denervation to 1 day after denervation; the mechanisms controlling AChR turnover are more directly dependent on the presence of the nerve than on the clustering of AChRs.52 The presence of the distal nerve stump can provide a therapeutic advantage by increasing AChR half-life and conserving AChR end plates.53 During acute nerve injury, the distal nerve stump immediately undergoes wallerian degeneration, but in slow wallerian degeneration mice, the process is delayed up to 2 weeks.54 This phenotype is attributed to a fusion protein product of ubiquitination factor E4B and nicotinamide mononucleotide adenylyltransferase-1; however, the mechanism of deferred wallerian degeneration is uncertain. Further study of these unique transgenic mice will provide insight into maintaining trophic support provided by the distal nerve stump and reducing changes in the denervated muscle.
Another potential therapeutic intervention makes use of TSCs and their role in the regenerative processes following peripheral nerve injury. TSCs are nonmyelinating glial cells associated with the distal nerve terminal and, as with their counterparts found outside the NMJ, TSCs provide trophic support to their environment. 55 TSCs modulate nerve growth throughout development and are actively involved in NMJ regeneration. 56 During nerve repair, TSCs extend processes and facilitate regrowth of motor axons to the muscles. 57 TSCs organize the NMJ for accepting and guiding the regenerating growth cone to sites of denervation. Much like Schwann cell supplementation of axonal guidance channels, Schwann cell precursors could also be differentiated into proregenerative TSCs and supplemented at the NMJ to promote successful reinnervation and peripheral nerve repair.
Major nerve injuries are severely debilitating, and no effective treatment option exists for functional neural regeneration. Surgical advancements in connective tissue reconstruction and nerve transfer have reached a plateau, and new treatments are required to improve outcomes. Attempts to increase the rate of nerve regrowth have been unsuccessful in resolving the limitations of peripheral nerve repair. A combination of multiple therapeutic approaches will be required to support successful neural regeneration.
Stabilization of the NMJ could potentially reduce end-organ atrophy following peripheral nerve injury. The NMJ is a dynamic structure, and the interactions between the terminal axon, TSCs, and motor end plate provide avenues for innovative therapeutic interventions. Other novel treatment strategies exist that involve targeting the NMJ, and further research is required into preservation of the NMJ as a method of treating patients with major nerve injury.
1. Midha R: Epidemiology of brachial plexus injuries in a multitrauma population. Neurosurgery
2. American College of Surgeons: National Trauma Data Bank Report 2009. Available at: http://www.facs.org/trauma/ntdb/docpub.html
. Accessed July 5, 2010.
3. Songcharoen P: Brachial plexus injury in Thailand: A report of 520 cases. Microsurgery
4. Secer HI, Solmaz I, Anik I, et al: Surgical outcomes of the brachial plexus lesions caused by gunshot wounds in adults. J Brachial Plex Peripher Nerve Inj
5. Terzis JK, Kokkalis ZT: Pediatric brachial plexus reconstruction. Plast Reconstr Surg
6. Kim DH, Cho YJ, Tiel RL, Kline DG: Outcomes of surgery in 1019 brachial plexus lesions treated at Louisiana State University Health Sciences Center. J Neurosurg
7. Barrick EF: Entrapment of the obturator nerve in association with a fracture of the pelvic ring: A case report. J Bone Joint Surg Am
8. Holstein A, Lewis GM: Fractures of the humerus with radial-nerve paralysis. J Bone Joint Surg Am
9. Morris AH: Irreducible Monteggia lesion with radial-nerve entrapment: A case report. J Bone Joint Surg Am
10. Nunley JA, Urbaniak JR: Partial bony entrapment of the median nerve in a greenstick fracture of the ulna. J Hand Surg Am
11. Wiss DA, Doyle BS: Irreducible open intertrochanteric hip fracture secondary to entrapment of the sciatic nerve in a child. J Orthop Trauma
12. Dunbar RP Jr, Gardner MJ, Cunningham B, Routt ML Jr: Sciatic nerve entrapment in associated both-column acetabular fractures: A report of 2 cases and review of the literature. J Orthop Trauma
13. Banskota A, Volz RG: Traumatic laceration of the radial nerve following supracondylar fracture of the elbow: A case report. Clin Orthop Relat Res
14. Foster RJ, Swiontkowski MF, Bach AW, Sack JT: Radial nerve palsy caused by open humeral shaft fractures. J Hand Surg Am
15. Torpey BM, Pess GM, Kircher MT, Faierman E, Absatz MG: Ulnar nerve laceration in a closed both bone forearm fracture. J Orthop Trauma
16. George R, Griffin JW: The proximodistal spread of axonal degeneration in the dorsal columns of the rat. J Neurocytol
17. Weinberg HJ, Spencer PS: The fate of Schwann cells isolated from axonal contact. J Neurocytol
18. Berger A, Millesi H: Nerve grafting. Clin Orthop Relat Res
19. Flores LP: The use of autogenous veins for microsurgical repair of the sural nerve after nerve biopsy. Neurosurgery
2010;66(6 suppl operative):238-243.
20. Meek MF, Varejão AS, Geuna S: Use of skeletal muscle tissue in peripheral nerve repair: Review of the literature. Tissue Eng
21. Agnew SP, Dumanian GA: Technical use of synthetic conduits for nerve repair. J Hand Surg Am
22. Oberlin C, Ameur NE, Teboul F, Beaulieu JY, Vacher C: Restoration of elbow flexion in brachial plexus injury by transfer of ulnar nerve fascicles to the nerve to the biceps muscle. Tech Hand Up Extrem Surg
23. Brown JM, Shah MN, Mackinnon SE: Distal nerve transfers: A biology-based rationale. Neurosurg Focus
24. Strauch B: Use of nerve conduits in peripheral nerve repair. Hand Clin
25. Lundborg G, Dahlin LB, Danielsen N, et al: Nerve regeneration across an extended gap: A neurobiological view of nerve repair and the possible involvement of neuronotrophic factors. J Hand Surg Am
26. Kemp SW, Walsh SK, Midha R: Growth factor and stem cell enhanced conduits in peripheral nerve regeneration and repair. Neurol Res
27. Sunderland S: Rate of regeneration in human peripheral nerves: Analysis of the interval between injury and onset of recovery. Arch Neurol Psychiatry
28. Sunderland S: Capacity of reinnervated muscles to function efficiently after prolonged denervation. AMA Arch Neurol Psychiatry
29. You S, Petrov T, Chung PH, Gordon T: The expression of the low affinity nerve growth factor receptor in long-term denervated Schwann cells. Glia
30. Furey MJ, Midha R, Xu QG, Belkas J, Gordon T: Prolonged target deprivation reduces the capacity of injured motoneurons to regenerate. Neurosurgery
31. Fu SY, Gordon T: Contributing factors to poor functional recovery after delayed nerve repair: Prolonged axotomy. J Neurosci
1995;15(5 pt 2):3876-3885.
32. Noaman HH, Shiha AE, Bahm J: Oberlin's ulnar nerve transfer to the biceps motor nerve in obstetric brachial plexus palsy: Indications, and good and bad results. Microsurgery
33. Gordon T: The physiology of neural injury and regeneration: The role of neurotrophic factors. J Commun Disord
34. Boyd JG, Gordon T: Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury. Mol Neurobiol
35. Nguyen QT, Parsadanian AS, Snider WD, Lichtman JW: Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle. Science
36. Radtke C, Vogt PM: Peripheral nerve regeneration: A current perspective. Eplasty
37. Brohlin M, Mahay D, Novikov LN, et al: Characterisation of human mesenchymal stem cells following differentiation into Schwann cell-like cells. Neurosci Res
38. Kingham PJ, Kalbermatten DF, Mahay D, Armstrong SJ, Wiberg M, Terenghi G: Adipose-derived stem cells differentiate into a Schwann cell phenotype and promote neurite outgrowth in vitro. Exp Neurol
39. Walsh S, Biernaskie J, Kemp SW, Midha R: Supplementation of acellular nerve grafts with skin derived precursor cells promotes peripheral nerve regeneration. Neuroscience
40. García R, Aguiar J, Alberti E, de la Cuétara K, Pavón N: Bone marrow stromal cells produce nerve growth factor and glial cell line-derived neurotrophic factors. Biochem Biophys Res Commun
41. Auffray I, Chevalier S, Froger J, et al: Nerve growth factor is involved in the supportive effect by bone marrow—derived stromal cells of the factor-dependent human cell line UT-7. Blood
42. Wang D, Liu XL, Zhu JK, et al: Bridging small-gap peripheral nerve defects using acellular nerve allograft implanted with autologous bone marrow stromal cells in primates. Brain Res
43. Hughes BW, Kusner LL, Kaminski HJ: Molecular architecture of the neuromuscular junction. Muscle Nerve
44. Burden SJ, Sargent PB, McMahan UJ: Acetylcholine receptors in regenerating muscle accumulate at original synaptic sites in the absence of the nerve. J Cell Biol
45. McMahan UJ: The agrin hypothesis. Cold Spring Harb Symp Quant Biol
46. Reist NE, Werle MJ, McMahan UJ: Agrin released by motor neurons induces the aggregation of acetylcholine receptors at neuromuscular junctions. Neuron
47. Glass DJ, Bowen DC, Stitt TN, et al: Agrin acts via a MuSK receptor complex. Cell
48. Gautam M, Noakes PG, Moscoso L, et al: Defective neuromuscular synaptogenesis in agrin-deficient mutant mice. Cell
49. Nishimune H, Valdez G, Jarad G, et al: Laminins promote postsynaptic maturation by an autocrine mechanism at the neuromuscular junction. J Cell Biol
50. Grady RM, Zhou H, Cunningham JM, Henry MD, Campbell KP, Sanes JR: Maturation and maintenance of the neuromuscular synapse: Genetic evidence for roles of the dystrophin-glycoprotein complex. Neuron
51. Werle MJ: Cell-to-cell signaling at the neuromuscular junction: The dynamic role of the extracellular matrix. Ann N Y Acad Sci
52. Shyng SL, Salpeter MM: Degradation rate of acetylcholine receptors inserted into denervated vertebrate neuromuscular junctions. J Cell Biol
53. Fu SY, Gordon T: The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol
54. Conforti L, Tarlton A, Mack TG, et al: A Ufd2/D4Cole1e chimeric protein and overexpression of Rbp7 in the slow Wallerian degeneration (WldS) mouse. Proc Natl Acad Sci U S A
55. Rochon D, Rousse I, Robitaille R: Synapse-glia interactions at the mammalian neuromuscular junction. J Neurosci
56. Son YJ, Trachtenberg JT, Thompson WJ: Schwann cells induce and guide sprouting and reinnervation of neuromuscular junctions. Trends Neurosci
57. Reynolds ML, Woolf CJ: Terminal Schwann cells elaborate extensive processes following denervation of the motor endplate. J Neurocytol