Orthopedics

Feature Article 

The Present and Future for Peripheral Nerve Regeneration

Georgios N. Panagopoulos, MD; Panayiotis D. Megaloikonomos, MD; Andreas F. Mavrogenis, MD

Abstract

Peripheral nerve injury can have a potentially devastating impact on a patient's quality of life, resulting in severe disability with substantial social and personal cost. Refined microsurgical techniques, advances in peripheral nerve topography, and a better understanding of the pathophysiology and molecular basis of nerve injury have all led to a decisive leap forward in the field of translational neurophysiology. Nerve repair, nerve grafting, and nerve transfers have improved significantly with consistently better functional outcomes. Direct nerve repair with epineural microsutures is still the surgical treatment of choice when a tension-free coaptation in a well-vascularized bed can be achieved. In the presence of a significant gap (>2–3 cm) between the proximal and distal nerve stumps, primary end-to-end nerve repair often is not possible; in these cases, nerve grafting is the treatment of choice. Indications for nerve transfer include brachial plexus injuries, especially avulsion type, with long distance from target motor end plates, delayed presentation, segmental loss of nerve function, and broad zone of injury with dense scarring. Current experimental research in peripheral nerve regeneration aims to accelerate the process of regeneration using pharmacologic agents, bioengineering of sophisticated nerve conduits, pluripotent stem cells, and gene therapy. Several small molecules, peptides, hormones, neurotoxins, and growth factors have been studied to improve and accelerate nerve repair and regeneration by reducing neuronal death and promoting axonal outgrowth. Targeting specific steps in molecular pathways also allows for purposeful pharmacologic intervention, potentially leading to a better functional recovery after nerve injury. This article summarizes the principles of nerve repair and the current concepts of peripheral nerve regeneration research, as well as future perspectives. [Orthopedics. 2017; 40(1):e141–e156.]

Abstract

Peripheral nerve injury can have a potentially devastating impact on a patient's quality of life, resulting in severe disability with substantial social and personal cost. Refined microsurgical techniques, advances in peripheral nerve topography, and a better understanding of the pathophysiology and molecular basis of nerve injury have all led to a decisive leap forward in the field of translational neurophysiology. Nerve repair, nerve grafting, and nerve transfers have improved significantly with consistently better functional outcomes. Direct nerve repair with epineural microsutures is still the surgical treatment of choice when a tension-free coaptation in a well-vascularized bed can be achieved. In the presence of a significant gap (>2–3 cm) between the proximal and distal nerve stumps, primary end-to-end nerve repair often is not possible; in these cases, nerve grafting is the treatment of choice. Indications for nerve transfer include brachial plexus injuries, especially avulsion type, with long distance from target motor end plates, delayed presentation, segmental loss of nerve function, and broad zone of injury with dense scarring. Current experimental research in peripheral nerve regeneration aims to accelerate the process of regeneration using pharmacologic agents, bioengineering of sophisticated nerve conduits, pluripotent stem cells, and gene therapy. Several small molecules, peptides, hormones, neurotoxins, and growth factors have been studied to improve and accelerate nerve repair and regeneration by reducing neuronal death and promoting axonal outgrowth. Targeting specific steps in molecular pathways also allows for purposeful pharmacologic intervention, potentially leading to a better functional recovery after nerve injury. This article summarizes the principles of nerve repair and the current concepts of peripheral nerve regeneration research, as well as future perspectives. [Orthopedics. 2017; 40(1):e141–e156.]

Peripheral nerve injury is a substantial clinical problem with potentially devastating consequences for patients. Peripheral nerve surgery is performed annually in 100,000 patients in the United States and Europe alone.1 In the United States, approximately $150 billion is spent annually as a result of nerve injury, with the costs for injuries to a median and an ulnar nerve estimated at roughly $70,000 and $45,000, respectively; 87% of these costs are the result of lost production.2

Traumatic etiologies for peripheral nerve injury include penetrating trauma, traction and compression, ischemia, electrocution, and vibration injuries.3 Traction-related injury secondary to a motor vehicle accident and lacerations by sharp objects or long bone fractures are the most frequent mechanisms implicated in the civilian setting4; blast injuries from explosives or gunshot wounds are the main causes of nerve injury seen in warfare or a hostile setting.5 Many patients treated for peripheral nerve injury continue to exhibit incomplete recovery in the long term, often with partial or total loss of motor, sensory, and autonomic function, as well as intractable neuropathic pain.6

In recent years, peripheral nerve surgery has progressed substantially. Advances in microsurgical techniques and refinements in clinical management protocols, experimental research using versatile in vitro and animal models, better understanding of the pathophysiology of nerve injury, deeper knowledge of the internal topography of peripheral nerves and molecular basis of neuronal growth, and development of reproducible methods of peripheral nerve regeneration evaluation have improved functional outcomes.6–8

The surgical treatment strategy depends on the type and level of injury (Figure 1). Primary direct end-to-end microsurgical epineural nerve repair remains the gold standard for surgical treatment (Figure 2), and the ideal setting for direct nerve repair is an injury zone with good blood supply and soft tissue coverage.7,9 Primary microsurgical nerve repair involves a tension-free, end-to-end coaptation of nerve ends after adequate mobilization of the proximal and distal stumps. However, primary repair is usually possible only in cases of clean-cut nerve transection with minimal gap and neuronal tissue loss.


Peripheral nerve repair treatment algorithm. Abbreviations: I–V, degrees of nerve injury according to Sunderland; NCS, nerve conduction studies; OT, occupational therapy.

Figure 1:

Peripheral nerve repair treatment algorithm. Abbreviations: I–V, degrees of nerve injury according to Sunderland; NCS, nerve conduction studies; OT, occupational therapy.


Intraoperative photograph showing direct end-to-end repair of a superficial radial nerve in the dorsum of the palm.

Figure 2:

Intraoperative photograph showing direct end-to-end repair of a superficial radial nerve in the dorsum of the palm.

When tension-free primary nerve repair is not possible, autogenous nerve grafting is considered the gold standard for bridging repair of the nerve gaps. The use of biological or artificial nerve conduits, or the application of nerve transfers are further viable alternatives (Table 1).7,8 Following nerve repair, nerve regeneration is the goal. Current research aims to accelerate nerve regeneration using pharmacologic agents and growth factors, stem cell-based therapies (stem cell-derived Schwann cells), and bioengineered nerve conduits.4,10 This article summarizes the principles of nerve repair and the current concepts of peripheral nerve regeneration research, as well as future perspectives.


Current Treatment Options When Primary Tensionless End-to-End Neurorrhaphy Is Unfeasible

Table 1:

Current Treatment Options When Primary Tensionless End-to-End Neurorrhaphy Is Unfeasible

Nerve Repair

Direct nerve repair with epineural microsutures is still the surgical treatment of choice when a tension-free coaptation in a well-vascularized bed can be achieved. This entails gross fascicular matching between the proximal and distal nerve ends by lining up both the internal nerve fascicles and the surface epineural blood vessel patterns. Nerve suture should be performed using an atraumatic microsurgical technique and surgical loupes or an operating microscope for magnification. A range of sutures is used; 6-0 and 7-0 nylon on an 8-mm vascular needle is useful for epineurial suture. Finer sutures of 8-0, 9-0, and 10-0 are used for perineurial suturing, nerve transfer, and grafting.

The appropriate needle holders, fine forceps, and scissors for work under the microscope should be available. Fine skin hooks, plastic slings, light clips, and malleable retractors are necessary. All tissues must be treated gently. Tender tissue handling and accurate hemostasis are more important than antibiotics for infection prevention. Bipolar diathermy is essential. The operating field should be maintained as free of blood as possible but kept moist by regular saline irrigation. Tourniquet use should be kept to the bare minimum.

Other techniques for nerve repair include fascicular and grouped fascicular repair, requiring intraneural dissection and direct matching and suturing of fascicular groups. This approach attempts a more accurate approximation of regenerating axons but requires more dissection and potential soft-tissue disruption. Thus, the advantage of a better fascicle alignment comes with the cost of more surgical trauma and scarring. Although outcomes are controversial, this technique often is used in nerves with straightforward and consistent motor and sensory topography.9,11 Visual clues, such as surface vessels, electrical stimulation in the awake patient, and histologic staining with acetylcholine esterase and carbonic anhydrase, have been used to achieve better matching.12

An alternative repair technique is the use of tissue adhesives such as fibrin glue to either supplement or replace sutures. This approach creates a gel-like clot that can be applied as an adhesive cylinder around the approximated nerve ends. This repair strategy is efficient and easy to use, minimizes trauma to the nerve ends, and possibly creates a barrier to invading scar tissue. Material intervening between nerve ends does not seem to block nerve regeneration. The main disadvantage of this technique is inferior holding strength.13

Nerve Grafts

In the presence of a significant gap (>2–3 cm) between the proximal and distal nerve stumps, primary end-to-end nerve repair often is not possible. Such gaps can occur in severe neurotmesis lesions such as high-velocity gunshot wounds or in axonotmesis stretch injuries in which long regions of the nerve may be damaged in the setting of a lesion-in-continuity.14 In these cases, nerve grafting is the treatment of choice; this implies that a piece of nerve harvested from another nerve is sutured between the proximal and distal stumps of the injured nerve (Figure 3).


Intraoperative photograph showing repair of a median nerve laceration in the distal forearm with an autogenous nerve graft (sural nerve graft).

Figure 3:

Intraoperative photograph showing repair of a median nerve laceration in the distal forearm with an autogenous nerve graft (sural nerve graft).

The proximal and distal nerve stumps are trimmed of scar tissue (bread-loafing) until normal fascicular structure is revealed for the nerve fascicles to be properly realigned. The trimmed nerve stumps should be inspected for mushrooming, which stands for slight protrusion of the nerve fascicles with concurrent retraction of the epineurium; reaching such tissue after debridement signifies that these particular nerve ends are suitable for suturing or graft interposition.6 Motor and sensory fascicles also should be properly realigned.8

Next, the nerve graft is interpositioned; it is essential to leave some redundancy in the repair in proximity to the sutured proximal and distal sites. It is difficult to give a general rule for how much tension is acceptable in each individual case, but if flexion of a joint is necessary to shorten the distance between the nerve ends, the resulting tension usually will be too great, and further dissection or a longer graft should be considered. Because the graft may shrink slightly, it should be approximately 15% longer than the maximum gap.

Nerve grafting may include autografts and allografts. Nerve autografts are considered the gold standard in nerve repair of irreducible nerve gaps.8 Autografts provide appropriate neurotrophic factors and viable Schwann cells, both essential for axonal regeneration. Many factors may affect the choice of an autogenous nerve graft, including the size of the nerve gap, location of proposed nerve repair, and associated donor-site morbidity.8 Nerve grafts can be single, cable, trunk, interfascicular, or vascularized.15,16 The grafts are either sutured to the epineurium of single nerves or more commonly to the perineurium of individual fascicles, depending on nerve caliber, type, and location.

Debridement of nerve stumps must continue until an orderly and recognizable architecture of bundles is displayed. The current authors favor a grouped fascicular repair, as the creating of multiple “fascicular fingers” may provide a better match and alignment. Sutures should be as few as possible, but as many as necessary to ensure a persistently correct orientation. Intact nerve tissue should be manipulated as little as possible to avoid potential fibrotic reactions. Fibrin glue is an adjunct to reduce the total number of sutures, thus reducing the likelihood of suture-induced fibrosis.15,16

Nerve autografts usually are harvested from expendable sensory nerve sites. The sural nerve is the workhorse graft; it allows 30 cm to 40 cm of graft to be obtained from each leg. Alternative nerve donor sites are the medial and lateral cutaneous nerves of the forearm, the dorsal cutaneous branch of the ulnar nerve, the superficial sensory branch of the radial nerve, the superficial and deep peroneal nerves, the intercostal nerves, and the posterior and lateral cutaneous nerves of the thigh (Table 2).17 Ray and Mackinnon8 suggest the anterior branch of the medial antebrachial cutaneous nerve is the ideal donor for upper extremity reconstruction; they also propose using a noncritical portion of a proximally injured nerve as an autograft. Such examples include the third web space fascicle of the median nerve or the dorsal cutaneous branch of the ulnar nerve.18


Common Nerves Used as Nerve Autografts

Table 2:

Common Nerves Used as Nerve Autografts

Nerve harvesting can be performed through a single long longitudinal incision, multiple stair-step incisions, or endoscopic methods. The proximal end of the cut nerve should be transposed proximally and buried deep to the fascia or fat tissue to prevent neuroma formation and pain. Long-lasting anesthesia also can be injected directly into the nerve to minimize discomfort. The harvested nerve should be handled gently, denuded of excess mesoneurial tissue, and laid between saline-soaked swabs until used.

The drawbacks of nerve autografting include sacrificing a functioning but otherwise expendable nerve (usually sensory) for a more important injured nerve (usually motor) and donor-site morbidity including sensory loss and scarring at the donor site as well as the potential for neuroma formation and pain.19 The harvested autogenous nerve graft undergoes Wallerian degeneration and thus merely provides mechanical guidance, creating a supportive structure for the ingrowing axons.20 In addition, at the repair site, there is unavoidable size and fascicle mismatch, scarring, and fibrosis from sutures, as well as damage from tissue handling. All of these factors, jointly with the injury itself, may lead to poor regeneration.21

An alternative to autogenous nerve grafting is the use of nerve allografts. Nerve allografts are readily accessible, offer an unlimited supply of neuronal tissue, and are not associated with donor-site morbidity. However, nerve allografts require systemic immunosuppression; this fact, as well as the increased cost of allografts, represent potential drawbacks to nerve repair with nerve allografts.22 Several techniques have been used to reduce allograft antigenicity, such as cold preservation, irradiation, and lyophilization.22 Furthermore, it has been observed that once adequate host Schwann cell migration has occurred into the nerve allograft at approximately 24 months after nerve repair, systemic immunosuppression can be withdrawn.8 Also, despite the morbidity of immunosuppressive therapy, a commonly used immunosuppressive agent (FK506, tacrolimus [Prograf]; Astellas Pharma US Inc, Northbrook, Illinois) has been demonstrated to further enhance peripheral nerve regeneration.19,23,24

To avoid immunosuppression, nerve allografts are decellularized by a process of chemical detergent, enzyme degradation, and irradiation, resulting in an acellular nerve scaffold. The advantage of decellular nerve allografts compared with hollow nerve conduits is that the internal nerve structure including endoneurial tubes, basal lamina, and laminin remain intact, maintaining a structural environment ideal for axonal regeneration.11 Currently, there is only 1 commercially available decellular nerve allograft (Avance Nerve Graft; AxoGen Inc, Alachua, Florida). Although many believe that these nerve allografts may have a longer “critical gap depth,” research currently supports their use for small diameters (1–2 mm) and short gap lengths (up to 30 mm).25

Nerve Transfers

The concept of nerve transfer is not new, but it recently has been revived and has gained significant momentum. A nerve transfer is the surgical coaptation of a healthy nerve donor to an injured nerve.26 The concept of nerve transfer is similar to that of tendon transfer, with an essential distal function being recovered at the expense of a secondary function. Similarly, a nerve transfer converts a proximal injury into a distal one by transferring a nearby redundant nerve function to a distal denervated nerve close to the target.8 Indications for nerve transfer include brachial plexus injuries, especially avulsion type with long distance from target motor end plates, delayed presentation, segmental loss of nerve function, and a broad zone of injury with dense scarring.27

Among the most popular goals for reinnervation via nerve transfer are elbow flexion, shoulder abduction, scapular stabilization, elbow extension, and distal motor transfers (Table 3).26 Elbow flexion can be restored with a double fascicular transfer of ulnar or median nerve fascicles to the biceps. For shoulder abduction, the spinal accessory nerve can be transferred to the suprascapular nerve. Scapular stabilization can be achieved by transferring the thoracodorsal nerve to the long thoracic nerve. Transfer of the distal anterior interosseous nerve to the ulnar nerve can restore some intrinsic muscle function of the hand.26,27


Common Nerve Transfers

Table 3:

Common Nerve Transfers

The benefits of nerve transfers are well established8,27,28: nerve transfers avoid autografts and associated donor-site morbidity; proximity of donor nerves to target motor end plates provides earlier reinnervation; in most cases, there is only 1 neurorrhaphy site instead of 2, as in nerve grafts; neurorrhaphy and dissection are performed in uninjured and unscarred tissue beds; original muscle biomechanics remain unaltered; and more rapid nerve recovery and motor reeducation usually is possible. Disadvantages include possible loss of function in the donor nerve site, as well as the fact that the donor muscle is no longer an acceptable donor for muscle transfer.8,27,28

A reemerging concept similar to nerve transfer is end-to-side coaptation or neurorrhaphy.8,29 This technique, described as early as 1873, subsequently was abandoned and revived in the early 1990s after the successful report of Viterbo et al.30 End-to-side neurorrhaphy is indicated when the proximal stump of the injured nerve is not available or is inaccessible; instead of nerve repair or grafting, which is not applicable, the distal stump of the injured nerve is coaptated to the side of an uninjured donor nerve. The rationale is that collateral axonal sprouting from a healthy nerve can invade the stump of an injured nerve, when the 2 are sutured together in an end-to-side fashion.31

Although no randomized clinical trials have been performed, current literature includes a number of case reports and small case series on different clinical applications, including sensory nerve lesions, brachial plexus lesions, facial nerve injuries, mixed nerve lesions, and painful neuromas.32 The results have been controversial; current evidence shows that collateral sprouting occurs more consistently in sensory fibers, with or without development of a perineural window. In contrast, motor sprouting following end-to-side neurorrhaphy requires axonotomy to be done to the donor nerve.33 Therefore, pending further refinement of end-to-side neurorrhaphy, this procedure should not substitute for standard techniques in most cases. Instead, it can be considered a valid therapeutic option in selected situations, such as for reconstruction of noncritical sensory deficits, in combination with other strategies in cases of failure of other previous attempts of nerve repair, or whenever other approaches are not feasible.8,29

Terzis and Tzafetta34 first described the reverse end-to-side neurorrhaphy named the “babysitter procedure” in 1984. They dissected a normal motor fascicle from the hypoglossal nerve and transferred it to the side of an injured, in-continuity facial nerve to gain some reinnervation of the facial musculature while awaiting cross facial nerve grafting. Davidge et al35 referred to this procedure as a supercharged, end-to-side neurorrhaphy and reported encouraging results in both laboratory and clinical studies.

Pharmacologic Agents

Currently, there are no clinically available pharmacologic methods to enhance nerve regeneration. Nevertheless, several small molecules, peptides, hormones, neurotoxins, and growth factors have been studied and suggested as potential candidates to improve and accelerate nerve repair and regeneration by reducing neuronal death and promoting axonal outgrowth.36 Recent advances in molecular biology have indicated that targeting specific steps in molecular pathways may allow for purposeful pharmacologic intervention, potentially leading to a better functional recovery after nerve injury.36

Experimental studies have shown that major molecular pathways implicated in neuron survival and neurite outgrowth include PI3K (phosphatidylinositol-3 kinase)/Akt (protein kinase B) signaling cascade, Ras-ERK (rat sarcoma-extracellular signal-regulated kinase) pathway, the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), and Rho–ROK signaling.36 Various molecules, otherwise frequently used in a totally different clinical setting, have been studied for their potential influence in the nerve regeneration process; among these are erythropoietin (EPO),37 tacrolimus (FK506),38 acetyl-L-carnitine (ALCAR),39 N-acetylcysteine (NAC),40 ibuprofen,41 melatonin,42 and transthyretin43 (Table 4).44–48


Pharmacologic Agents Shown to Enhance Nerve Regeneration

Table 4:

Pharmacologic Agents Shown to Enhance Nerve Regeneration

The PI3K/Akt signaling cascade provides trophic support for neurons, blocks apoptosis, and mediates growth, differentiation, and directional signaling.49 The Ras-ERK pathway is a key promoter of neurite outgrowth and also has been found to enhance axonal survival.49 The cAMP/PKA pathway has been implicated in neuronal outgrowth and survival, differentiation, and guidance, both in vitro and in vivo.50 Agents acting on this pathway used in nerve regeneration research include rolipram and testosterone.36 In the Rho–ROK signaling pathway, Rho GTPases mediate the response of growth cones to extracellular ligands and serve to link them to the actin cytoskeleton, either positively or negatively modulating neurite outgrowth.51 Agents acting on this signaling pathway include fasudil, ibuprofen, and proteoglycan digesting enzyme chondroitinase ABC.36

A striking example of how a substance, normally used in another clinical setting, can actually have a substantial effect on peripheral nerve regeneration is represented by the immunosuppressant agent tacrolimus (FK506). FK506 is a macrocyclic lactone produced by the bacterium Streptomyces tsukubaensis, isolated in 1984 from a soil sample in Tsukuba, Japan.52 Currently, FK506 is an FDA-approved immunosuppressant used in prevention of allograft reject after liver, kidney, and other solid organ transplantation. It has been found to have a 10 to 100 times stronger immunosuppressant effect than cyclosporine-A, with fewer side effects.53

Interestingly, FK506 was found to enhance nerve regeneration by increasing axonal outgrowth and inducing Schwann cell proliferation (Figure 4).54 The exact mechanism of its neuroregenerative effect remains unclear; many suggest that binding to FKBP-12 and inhibiting calcineurin, as well as increasing expression of growth associated protein 43 (GAP-43) and transforming growth factor beta 1 (TGF ß-1), may be some of the implicated mechanisms.24 Other studies have examined the ideal dosing, timing, and route of administration of FK506,24 aiming to bioengineer a local release delivery system that would avoid potential systemic side effects related to immunosuppression.55


Intraoperative photographs showing complete transection of the left sciatic nerve in a rat (A), nerve repair with a 1-cm nerve gap using a collagen-based nerve conduit (B), and injection of FK506 into the nerve gap for acceleration of nerve repair (C).

Figure 4:

Intraoperative photographs showing complete transection of the left sciatic nerve in a rat (A), nerve repair with a 1-cm nerve gap using a collagen-based nerve conduit (B), and injection of FK506 into the nerve gap for acceleration of nerve repair (C).

As most of the aforementioned pharmacologic agents have been tested only in cell culture or animal models, this field is still in its infancy. As researchers gain insight to new molecular pathways, new potential molecular targets and novel therapeutic options will emerge for patients with nerve injury.

Nerve Conduits

Autograft scarcity, donor-site morbidity, potential for donor-site neuroma formation, and suboptimal outcomes have driven increasing efforts to seek viable alternatives to autologous nerve grafts during the past few decades.56 A way to circumvent these issues is the use of biological or synthetic nerve guidance channels, or simply nerve conduits. A nerve conduit is a tubular structure designed to bridge the gap of a sectioned nerve that is not amenable to primary end-to-end neurorrhaphy, to protect the nerve from the surrounding tissue and scar formation, and to guide the regenerating axons into the distal nerve stump (Figure 5).56 Currently, several nerve conduits are available (Table 5), with diameters ranging from 1.5 to 10 mm. Clinical use presently is limited to the repair of relatively small nerve defects (<3 cm) in small-caliber digital nerves and as a nerve repair wrapping material.57


Intraoperative photograph showing direct end-to-end repair with placement of a nerve conduit protector for a median nerve laceration in the wrist.

Figure 5:

Intraoperative photograph showing direct end-to-end repair with placement of a nerve conduit protector for a median nerve laceration in the wrist.


Commercially Available FDA-Approved Nerve Conduits

Table 5:

Commercially Available FDA-Approved Nerve Conduits

The key concept behind the use of nerve conduits is that guidance to nerve regeneration is provided not only by a mechanical effect (conduit lumen and wall), but also by a chemical effect (accumulation of neurotropic and neurotrophic factors), thus favorably conditioning the nerve injury microenvironment.56 This process ultimately permits the formation of new extracellular matrix over which fibroblasts, blood vessels, and Schwann cells can migrate and provide the circumstances for successful nerve regeneration.56

Although materials vary considerably, the technique of nerve conduit preparation and positioning is generally the same. The chosen conduit, slightly larger than the nerve in question, usually is soaked in normal or heparinized saline prior to use. Then, the conduit is stabilized to the surrounding soft tissues by means of 2 or 3 anchoring interrupted sutures to facilitate nerve stump insertion. Next, the conduit is sewn in a U-shaped fashion on itself to create the desirable lumen. Finally, both nerve stumps are inserted 2 mm into the conduit and fixed via 2 or 3 epineural sutures (8-0 or 9-0 nylon). Saline is injected into the conduit to prevent clot formation and lumen blockage.56

Nerve conduits can be biological (autogenous and nonautogenous) and synthetically fabricated (absorbable and nonabsorbable).56 Biological autogenous nerve conduits include arteries, veins, muscle, tendon, and epineural sheath. Although experimental use and small case studies have yielded occasionally promising results, their clinical use is not currently recommended.56,58 Biological nonautogenous nerve conduits include type I collagen such as NeuraGen (Integra LifeSciences Co, Plainsboro, New Jersey) or NeuroFlex (Collagen Matrix Inc, Oakland, New Jersey), gelatin (a protein deriving from collagen), silk fibroin, and polysaccharides such as chitosan, alginate, and agarose hydrogel-based conduits.59–61

Collagen is advantageous as it is abundant, easily isolated and purified, shows adhesiveness for different cell types, and has been demonstrated to be effective both in vitro and clinically. A key limitation is the variable time needed for complete biodegradation, ranging from 8 months (NeuroFlex) to 48 months (NeuraGen), potentially leading to nerve compression.62 Synthetic absorbable nerve conduits include aliphatic polyesters and copolyester-based conduits such as polyglycolic acid, polylactic acid, poly(epsilon-caprolactone-co-lactide), polycaprolactone, and polyvinyl alcohol.4,63 Synthetic nonabsorbable nerve conduits include silicone and expanded polytetrafluoroethylene (ePTFE, Gore-Tex; W. L. Gore & Associates, Inc, Newark, Delaware) conduits.64,65

In an attempt to enhance nerve conduit efficacy and to extend operational distance in nerve regeneration, the concept of introducing luminal additives into conduits also has been explored.66 Cellular components (Schwann cells, bone stromal cells, and fibroblasts), structural components (fibrin, laminin, and collagen), and neurotrophic factors (fibroblast growth factor, nerve growth factor [NGF], glial growth factor, ciliary neurotrophic factor, vascular endothelial growth factor, glial cell-line derived neurotrophic factor, and neurotrophin-3) have been thoroughly investigated in vitro with encouraging results (Table 6).67–83


Luminal Additives in Nerve Conduits for Nerve Repair

Table 6:

Luminal Additives in Nerve Conduits for Nerve Repair

Currently, nerve conduits represent a viable alternative to autologous nerve grafting only in selected clinical situations. In the near future, tissue-engineered conduits enriched with neurotrophic factor-delivery systems and cellular components, alone or in combination, are expected to be introduced in clinical practice. Developing nerve conduits for ever-longer gaps is another challenge to overcome.

Stem Cells

Stem cells have been shown to have the potential to help regenerate lost neurons, increase glial support cells and make the microenvironment around the nerve injury site more favorable.84,85 As autologous Schwann cell culture is impractical, stem cells differentiated into a Schwann cell-like phenotype can aid with axonal guidance and remyelination, enhanced growth factor, and extracellular matrix production.85 The selection of the ideal stem cells has been long debated in the field of regenerative medicine; stem cells should be easily accessible, expand rapidly in culture, be able to survive in vitro and integrate into host tissue, and be amenable to transfection and expression of exogenous genes.86

Stem cell differentiation for nerve regeneration is an argument. Stem cells may be transplanted at the injury site as they are in their undifferentiated state, or they can undergo a short period of in vitro differentiation into Schwann cell-like cells. The latter can be achieved with stem cell exposure to ß-mercaptoethanol, all-trans retinoic acid, fetal bovine serum, forskolin, recombinant human basic fibroblast growth factor, recombinant human platelet-derived growth factor-A, and heregulin ß-1.87 However, the necessity of stem cell differentiation currently is debated. Some authors maintain that it only incurs an unnecessary delay, as neuronal differentiation partially reverts in vivo to the original phenotype.88 In addition, undifferentiated stem cells seem to demonstrate equally good results and also may undergo in vivo differentiation in response to local stimuli.67

Stem cell preferred tissue harvest is another argument. Since their discovery, stem cells have been harvested from a variety of tissues including embryonic, fetal, neural, bone marrow, adipose tissue, skin, hair follicles, and dental pulp (Table 7).85,86,89–105 Reprogramming of somatic cells to induced pluripotent stem cells following ectopic co-expression of transcription factors also has been described.106 Embryonic stem cells were first isolated from human blastocysts in 1998.107 They can form derivatives of all 3 embryonic germ layers and have great differentiation potential and long-term proliferation capacity.85 However, their neural differentiation is challenging. Furthermore, possible immunogenicity and tumorigenicity, as well as potential ethical controversy, represent disadvantages hindering their clinical applications.85


Types of Stem Cells Studied for Acceleration of Nerve Regeneration

Table 7:

Types of Stem Cells Studied for Acceleration of Nerve Regeneration

Fetal stem cells can be harvested from amniotic membrane and fluid, umbilical cord cells and blood, and Wharton's jelly. As these tissues are commonly discarded after birth, they are abundant in supply. However, the use of autogenous cells after injury is impractical; on the other hand, allogeneic cells may demonstrate clinically relevant immunoreactivity. Widespread banking of fetal products may obviate this obstacle.85

The same lack of autogenous supply also is valid in the case of stem cells derived from hair follicles and dental pulp, still restricting their use in the experimental setting.85 Skin-derived precursors reside in the dermis, are easily accessible and expandable in culture, and demonstrate a behavior similar to pluripotent neural crest cells. They also have been shown to have positive effects on nerve regeneration.98

Nerve stem cells were first isolated from adult murine brain in the early 1990s.108 They naturally differentiate into neurons and glial cells, but this occurs almost exclusively during embryogenesis or in limited locations in the central nervous system after injury.109 Even though initially promising, their use has been limited due to harvesting difficulties and high rates of neuroblastoma tumorigenesis.85

Stem cells derived from bone marrow are readily accessible, have no potential ethical concerns, and are more clinically applicable than embryonic stem cells and neural stem cells. However, harvesting is invasive and painful, and their proliferation capacity and differentiation potential are inferior.85

Particular attention has been given to adipose-derived stem cells. Adipose tissue contains a stromal population known as the stromal vascular fraction, which can be isolated by centrifugation of collagenase-digested adipose tissue.110 It has been shown that cultured stromal vascular fraction can give rise to multipotent precursor cells.111 In addition, adipose tissue is easily harvested, and donor age and harvesting site do not seem to influence the therapeutic effect of the derived stem cells.112 In light of their easier harvest, superior stem cell fraction, differentiation potential, and proliferation capacity, adipose-derived stem cells have supplanted stem cells derived from bone marrow and are considered the preferred option for preclinical studies.85

Stem cell method of delivery is another concern in stem cell research. Stem cells may be injected directly around nerve stumps or a bridging nerve graft, injected into the lumen of a nerve conduit, suspended in a scaffold, injected into a neuromuscular junction, or administered systemically. Future research likely will focus on stem cells injected systemically with the ability to specifically target and support the injury site.85

Gene Therapy

Gene therapy can be defined as the introduction of a foreign therapeutic gene into living cells to treat a disease.113 This foreign gene is termed a transgene, whose expression is driven by a so-called promoter. The most efficient way to insert a transgene into a cell is with the use of a viral vector. This is a specially modified virus that has lost its capacity to replicate but maintains the ability to attach to and enter into cells, delivering a transgene to the cell nucleus.113

Studied potential vectors include herpes simplex, adenovirus, lentivirus, and adeno-associated viral vectors.114 Of these, adeno-associated viral vectors have been shown to be the most reliable as a gene delivery platform.115 The main targets for gene therapy in peripheral nerve injury are Schwann cells, fibroblasts, and denervated muscle. The aim of gene therapy is to obtain a sort of transcriptional reprogramming so that more neurotrophic factors, cell adhesion or extracellular matrix molecules, and transcription factors are produced. As gene delivery technology approaches a state of clinical readiness, the time when gene therapy will become an integral part of the armory of nerve surgeons is fast approaching.

Other Research Areas

Low-intensity electrical stimulation has been shown to improve nerve regeneration, probably due to an increased production of brain-derived neurotrophic factor (BDNF) and NGF, and a subsequent enhancement of myelin production.116 Low-power laser phototherapy also has been studied extensively both in vitro and in vivo.117 Finally, the future potential of olfactory ensheathing cells as an adjunct to peripheral nerve regeneration is promising. Olfactory ensheathing cells are specialized glial cells, which support axons that leave the olfactory epithelium and project through the olfactory nerve system into the olfactory bulb of the central nervous system. They are pluripotent, displaying Schwann cell and astrocyte-like properties. They possess the ability to phagocytose degenerating axons, create channels to guide new axon regeneration and produce a variety of neurotrophic factors, including NGF, BDNF, platelet-derived growth factor, and neuropeptide Y, enhancing injured axon survival.118

Overview of Clinical Outcomes

The past few decades have seen a shift from nerve repair or grafting in proximal injuries toward nerve transfer. In distal nerve injuries, however, nerve repair and grafting generally are more appropriate. Patient outcome and recovery are correlated to the method and timing of nerve repair. Comparing clinical outcomes in peripheral nerve surgery is problematic. The multitude of treatments available, the multitude of injured nerves, the different degrees of nerve injury, and the often inconsistent timing of repair are factors that make the construction of a well-conducted and reproducible study a difficult endeavor, hence, the relative lack of meaningful comparative studies or randomized trials. Most outcome studies report the application of a given technique in a variable number of patients. More numerous well-constructed and well-executed studies should be performed in the near future to obtain meaningful results that would have a strong impact on clinical practice.

In a recently published case series, Karabeg et al119 reported the clinical outcomes of ulnar nerve grafting in 48 patients with a mean age of 32.4 years. The graft length, level of injury, and denervation time significantly influenced the functional outcome in both motor and sensory recovery. Better results were obtained in patients with an autograft length of up to 5 cm, those who underwent surgery within 6 months after injury, and those with distal lesions. Ozmen et al120 reported the clinical outcomes of facial nerve grafting in 155 patients; preoperative deficit duration was the only significant factor that affected prognosis. Okazaki et al121 reported the outcomes of axillary nerve injury treated with nerve grafting in 36 patients. They concluded that nerve grafting to the axillary nerve is a reliable method of regaining deltoid function when the lesion is distal to its origin from the posterior cord.

Clinical outcomes with conduits overwhelmingly regard small nerves. Weber et al122 performed a prospective randomized trial of polyglycolic acid conduits in digital nerve repair compared with standard repair in 98 patients with 136 nerve lacerations. After 1 year of follow-up in 77 nerves, the authors reported that in nerve gaps of 4 mm or less and in nerve gaps of 8 mm or greater, the conduits performed better than standard repair techniques. Haug et al123 studied 45 digital nerve defects in 35 patients with 1-year follow-up using collagen tubes. Outcomes were reported as a cumulative score of sensory functions with the following results: very good in 4 cases, good in 21 cases, mediocre in 14 cases, and bad in 3 cases. A prospective randomized study evaluating poly (dl-lactide-epsilon-caprolactone) (Neurolac; Polyganics, Groningen, The Netherlands) tubes concluded that regeneration was equivalent in digital nerve repairs with Neurolac versus standard repair techniques in nerve gaps of up to 20 mm.124

There are also a few clinical studies available on AxoGen's decellularized allograft. Karabekmez et al125 at the Mayo Clinic reported on 10 sensory nerve reconstructions in 7 patients. Mean follow-up time was 9 months, with an average gap of 2.23 cm. They achieved an average of 4.4-mm moving and 5.5-mm static 2-point discrimination. Despite the lack of a con trol group, their study validated the role for acellular allografts in defects up to 3 cm in length and showed reasonably good results. Brooks et al126 reviewed the use of acellular allografts with data from 25 surgeons at 12 centers reporting on 132 nerve injuries, with complete data for 76 of the repairs. These repairs included 49 sensory, 18 mixed, and 9 motor nerves with nerve gaps up to 50 mm; findings indicated meaningful recovery was accomplished in 87% of these cases.

The data on nerve transfers in brachial plexus reconstruction for shoulder and elbow function have shown outcomes to be reliably equal or better than traditional proximal graft reconstruction and with faster reinnervation in many cases. Ray et al127 studied the use of double fascicular nerve transfer to the biceps and brachialis muscles after brachial plexus injury in 29 patients; postoperatively, 97% of the patients could achieve elbow flexion. Novak and Mackinnon128 reported their results of terminal anterior interosseous nerve-to-deep motor branch of the ulnar nerve transfer in the setting of high ulnar palsy with mean follow-up of 18 months in 8 patients. All patients had reinnervation of the ulnar nerve intrinsic hand muscles, with improved pinch and grip strength.

Conclusion

This review summarized the current concepts of peripheral nerve injury repair and regeneration to inform physicians on current and future perspectives unfolding in the ever-growing field of nerve regeneration research. It is evident that today's advances in translational research and biotechnology, together with a greater understanding of the mechanisms underlying the neurobiology of nerve regeneration, can make yesterday's chimera tomorrow's reality.

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Current Treatment Options When Primary Tensionless End-to-End Neurorrhaphy Is Unfeasible

OptionIndicationsProsCons
Nerve autograftsGold standard for bridging irreducible nerve gapsBridge nerve gap, nonimmunogenic, variety of donor nerves availableSensory loss, scarring, neuroma formation, second incision, limited supply, inferior to tension-free primary repair
Nerve allograftsReserved for devastating or segmental injuryReadily accessible, unlimited supply, bridge nerve gap, avoid donor-site morbidityPotential side effects of host immunosuppression
Nerve transfersProximal upper limb injury, brachial plexus reconstruction, segmental nerve injuryAvoid donor-site morbidity, potential earlier reinnervation due to proximity of donor nerves to target motor end platesPossible loss of function from donor nerve site, donor muscle no longer an acceptable donor for muscle transfer
End-to-side coaptationProximal nerve stump unavailable or inaccessibleLow-morbidity technique when used for sensory defectsMotor nerve recovery only seen after donor nerve axotomy
Nerve conduitsShort nerve defects (up to 3 cm)Readily available, avoid donor-site morbidity, bridge nerve gap, barrier to scar tissue infiltration, local neurotrophic factor accumulationVariable outcomes, lack of laminin scaffold and Schwann cells, use limited to short nerve gaps

Common Nerves Used as Nerve Autografts

Donor NerveLength, cmSensory Defect
Sural nerve30–40Dorsal aspect of lower leg and lateral foot
Medial antebrachial cutaneous nerve10–12a8–10bMedial forearm
Lateral antebrachial cutaneous nerve10–12Lateral forearm
Superficial sensory branch of the radial nerve25Radial dorsal hand

Common Nerve Transfers

Injured NerveMissing FunctionDonor NerveRecipient Nerve
Motor
  SuprascapularShoulder abduction, external rotationDistal spinal accessorySuprascapular
  Long thoracicScapular stabilization, forward abductionMedial pectoral, thoracodorsal, intercostalLong thoracic
  AxillaryShoulder abductionTriceps branch of radial nerve, medial pectoralAxillary
  MusculocutaneousElbow flexionUlnar nerve fascicle to FCU; median nerve fascicle to FCR, FDSBrachialis branch; biceps branch
  Spinal accessoryShoulder elevation and abductionMedial pectoral, C7 redundant fascicleSpinal accessory
  UlnarIntrinsic handTerminal AIN (branch to pronator quadratus)Ulnar nerve fascicles to deep motor branch
  MedianThumb oppositionTerminal AIN (branch to pronator quadratus)Median (recurrent) motor
Finger flexionFCU, brachialisAIN
PronationECRB, FCU, FDSPronator branch
  RadialElbow, wrist, and finger extensionFCR, FDS±PLECRB and PIN
Sensory
  Median sensoryThumb-index key pinch area sensationUlnar common sensory branch to 4th web spaceMedian common sensory branch to 1st web space
Dorsal sensory branch of the ulnar nerveMedian common sensory branch to 1st web space
  Ulnar sensoryRing and small finger sensationMedian common sensory branch to the 3rd web spaceUlnar common sensory branch to the 4th web space; ulnar digital nerve to the small finger
Lateral antebrachial cutaneousDorsal sensory branch of the ulnar nerve

Pharmacologic Agents Shown to Enhance Nerve Regeneration

Agent/Key ReferenceClinical Use/PropertiesMechanism of ActionObserved Effects
Erythropoietin37Anemia in CRFCGRP increased; activation of PI3K/Akt, JAK–STAT, and NFκB signaling pathwaysSensory axonal density and caliber increased; improved motor axonal outgrowth; downregulation of injury markers in central perikarya
Tacrolimus (FK506)38Prevention of organ rejection after transplantActivation of ERK via FKBP-52 and Hsp-90 binding; calcineurin inhibition; activation of GAP-43 and TGF-ß1; induces SC proliferation and myelin debris removalNumber of myelinated axons, myelin thickness, and axon sprouting increased; neuroprotection; rate of axon regeneration increased
Geldanamycin44Originally developed as a chemotherapeutic agentBinds Hsp-90, activating ERK and GAP-43Rate of axon regeneration increased; functional recovery increased
Acetyl-L-carnitine39Natural antioxidantNeurotrophins increased, TKA and ERK 1/2; apoptotic proteins (eg, caspase-3) decreasedEnhanced survival; myelin thickness and axon number and diameter increased
N-acetylcysteine40Mucolytic, acetaminophen antidote, prevents contrast toxicityActivates Ras–ERK and JAK–STAT; upregulates Bcl-2 mRNA; downregulates Bax and caspase-3 mRNANeuronal death decreased; promoted sensory nerve regeneration
Rolipram45N/APDE-5 inhibitionPrevents cAMP decrease; myelination and neuron number across repair site increased
Testosterone46HormoneGFAP and HSP decreased, BDNF expression increased; upregulates RAGs (ßII-tubulin and GAP-43)Axon regeneration rate increased
Fasudil47SAH treatment in JapanPrevents collapse of growth conesNerve fiber number, density, and width increased; number of large myelinated axons increased; improved sensory neurite outgrowth
Chondroitinase ABC48Enzyme that degrades proteoglycansDegrades chondroitin sulfate proteoglycans, inactivates RhoARegeneration of motor and sensory neurons across the repair site increased
Ibuprofen41NSAIDInhibits RhoA cascadeArea and thickness of myelinated axons increased
Melatonin42Hormone; regulates circadian rhythmTGF-ß1 and bFGF decreased; SOD increasedCollagen production and neuroma formation, antioxidant properties decreased
Transthyretin43Serum carrier of thyroxine and retinol; called prealbuminUnknownNeurite number and length increased

Commercially Available FDA-Approved Nerve Conduits

Product NameMaterialStructureManufacturerFDA ClearanceLength, cmNerve Repair
NeuraGenCollagen type ISemipermeable, fibrillar collagen structureIntegra LifeSciences Co (http://www.integra-ls.com)June 20012–3Digital nerves; lingual and inferior alveolar nerves; brachial plexus birth palsy; median, ulnar, radial, posterior interosseous, common digital, and superficial radial nerves
NeuroFlexCollagen type IFlexible, semipermeable tubular collagen matrixCollagen Matrix Inc (http://www.collagenmatrix.com)September 20012.5
NeuroMatrixCollagen type ISemipermeable tubular collagen matrixCollagen Matrix IncSeptember 20012.5
NeuraWrapCollagen type ILongitudinal slit in a tubular wall structureIntegra LifeSciences CoJuly 20042–4
NeuroMendCollagen type ISemipermeable collagen wrap that unrolls and self-curlsCollagen Matrix IncJuly 20062.5–5
NeurotubePGAAbsorbable woven PGA mesh tubeSynovis Micro Companies (http://www.synovismicro.com)March 1995/19992–4Spinal accessory, median, ulnar, facial, and digital nerves
NeurolacPLCLTubular structurePolyganics (http://www.polyganics.com)October 2003/20053Digital nerves
SalutunnelPVATubular structureSalumedica LCCAugust 20106.35

Luminal Additives in Nerve Conduits for Nerve Repair

Category/Key ReferencesAdditivesConduitsAnimal ModelGap Length, mm
Cellular66–69SC (syngeneic)PLGARat sciatic20
SCAVNCRabbit tibial40
SC (autologous)SiliconeRat sciatic10
SC (allogeneic)PLARat sciatic12
SC (lacZ transduced)PHBRat sciatic10
SC (syngeneic)CollagenRat sciatic20
EMSCAutologous muscleRat sciatic20
Fibroblast-like MSCSiliconeRat sciatic15
NSCChitosan-coated PDMSRat sciatic10
Structural70–75Fibrin gelBioabsorbable polymerRat sciatic10
LamininPGACanine peroneal80
LamininPolysulfoneRat sciatic10
CollagenSiliconeRat sciatic5
FibronectinPHBRat sciatic10
Spider silk fibersVeinRat sciatic20
Bioglass 45S5SilasticRat sciatic5
Neurotrophic76–80NGFSilicone or PPERat sciatic10
NT-3PHEMA-MMA hydrogelRat sciatic10
GDNFSiliconeRat sciatic13
aFGFPHEMA-MMA hydrogelRat sciatic10
bFGFHeparin/alginate hydrogelRat sciatic10
CNTFSiliconeRat sciatic10
VEGFSiliconeRat sciatic10
IGF-1Autologous nerve grafts or acellular ECMRat sciatic20
PDGFSiliconeRat sciatic8
Combined81,82Laminin and NGFPolysulfoneRat sciatic10
Laminin and NGFPolysulfoneRat sciatic20
Fibrin, SC, and dMSCPHBRat sciatic10

Types of Stem Cells Studied for Acceleration of Nerve Regeneration

Stem Cell Source/Key ReferencesAnimal ModelScaffoldDelivery SystemDifferentiationOutcomes
Embryonic89–91Rat sciaticCulture mediumEpineurium natural conduitYesDifferentiated into SC after 3 months
Mouse sciaticMatrigelDirect microsphere injectionNoBetter SFI, CMAP, and histology
Rat sciaticPBSDirect injection into gastrocnemius muscleYesNew NMJ observed in treated muscle; benefit lost after 21 days
Fetal92–94Rat sciaticFibrin glueDirect injection in situNoMyelination and motor recovery better if used with G-CSF
Rat sciaticMatrigelDirect injection in situNoBetter results when GDNF modified
Rat sciaticCulture mediumSeeded onto PCL wrapYesIncreased myelin thickness and better functional recovery
Neural95–97Rabbit facialCollagen spongeChitosan conduitNoNSC+NGF group superior to NGF alone; comparable to autograft
Pig nervis cruralisNeurosphereAutologous veinNoNSC group had superior EMG results
Rat sciaticCulture mediumDirect injectionNo12 of 45 rodents developed neuroblastomas
Skin98,99Mouse sciaticCulture mediumInjection in situBothSKP induced into SKP-SC
Rat sciaticPBSCollagen conduitYesSFI and CMAP better in conduits filled with SDSC
Hair follicle100Mouse sciaticCulture mediumInjection in situNoHFSC differentiated into SC-like cells; gastrocnemius contraction improved
Dental pulp101Rat DRG in vitroCulture mediumCollagen gelYeshDPSC differentiated to SC-like cells; able to support DRG neurite outgrowth
Bone marrow102,103Rat facialMatrigelSilicone conduitBothBetter histologic and functional outcomes than controls
Rat sciaticFibrin glueANANoSurvival of BMSC within fibrin glue
Adipose86,104Rat sciaticCulture mediumFibrin glueYesGreater axon and fiber diameter; comparable to autograft
Rat facialMatrigelDecellularized allogeneic arteryYesResults inferior to autograft
Induced pluripotent105Mouse sciaticMicrosphere into conduitPLA/PCL conduitYesResults inferior to autograft
Authors

The authors are from the First Department of Orthopaedics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

The authors have no relevant financial relationships to disclose.

Correspondence should be addressed to: Andreas F. Mavrogenis, MD, First Department of Orthopaedics, National and Kapodistrian University of Athens, School of Medicine, 41 Ventouri St, 15562 Holargos, Athens, Greece ( afm@otenet.gr).

Received: April 15, 2016
Accepted: August 23, 2016
Posted Online: October 27, 2016

10.3928/01477447-20161019-01

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