HAND/PERIPHERAL NERVE Nerve Conduits for Peripheral Nerve Surgery Amit Pabari, M.R.C.S. Hawys Lloyd-Hughes, M.R.C.S. Alexander M. Seifalian, Ph.D. Ash Mosahebi, M.B.A., Ph.D., F.R.C.S.(Plast.) London, United Kingdom

cpt

Summary: Autologous nerve grafts are the current criterion standard for repair of peripheral nerve injuries when the transected nerve ends are not amenable to primary end-to-end tensionless neurorrhaphy. However, donor-site morbidities such as neuroma formation and permanent loss of function have led to tremendous interest in developing an alternative to this technique. Artificial nerve conduits have therefore emerged as an alternative to autologous nerve grafting for the repair of short peripheral nerve defects of less than 30 mm; however, they do not yet surpass autologous nerve grafts clinically. A thorough understanding of the complex biological reactions that take place during peripheral nerve regeneration will allow researchers to develop a nerve conduit with physical and biological properties similar to those of an autologous nerve graft that supports regeneration over long nerve gaps and in large-diameter nerves. In this article, the authors assess the currently available nerve conduits, summarize research in the field of developing these conduits, and establish areas within this field in which further research would prove most beneficial.  (Plast. Reconstr. Surg. 133: 1420, 2014.)

N

erve conduits have emerged as an alternative to autologous nerve grafts for repair of short peripheral nerve defects of less than 30 mm.1,2 Autologous nerve grafts are the current criterion standard for repair of peripheral nerve injuries when the transected nerve ends are not amenable to primary end-to-end tensionless neurorrhaphy.3,4 However, donor-site morbidities such as neuroma formation and permanent loss of function have led to tremendous interest in developing an alternative to this technique.5 Several synthetic nerve conduits have gained U.S. Food and Drug Administration and Conformit Europe approval for repair of peripheral and cranial nerves.6 Although manufactured from a diverse range of materials, each conduit is a permeable, hollow tube that yields results comparable to those of autologous grafts.1,7–11 The use of such conduits is currently limited to nerve defects smaller than 30 mm. With the advancement of ­tissue-engineering techniques, the quest for developing a conduit more successful than autologous nerve grafting is ongoing. A thorough understanding of the complex biological reactions that take place during peripheral nerve regeneration From the Department of Plastic Surgery, Royal Free Hampstead NHS Trust; and the Center for Nanotechnology, Biomaterials and Tissue Engineering, Division of Surgical and Interventional Sciences, University College London. Received for publication June 9, 2013; accepted November 11, 2013. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000226

1420

will allow researchers to develop a nerve conduit with physical and biological properties similar to those of an autologous nerve graft that supports regeneration over long nerve gaps and in large-diameter nerves. In this article, we assess ­ the currently available nerve conduits, summarize research in the field of developing these conduits, and establish the areas within this field in which further research would prove most beneficial.

CURRENT SOURCE OF MATERIAL FOR NERVE CONDUITS Currently, there are seven U.S. Food and Drug Administration/Conformit Europe–approved nerve conduits, produced primarily from biodegradable materials (Table 1). Such materials are advantageous in that they do not take up any space in the healed structure; however, it is imperative that degradation time is equivalent to the time taken for the nerve to heal. Nonbiodegradable materials have been known to cause compression and give rise to such issues as immunoreactivity and/or local inflammation.12 Although immune reactions may also be initiated by biodegradable materials, conduits can be engineered to be nontoxic or result in delayed toxicity, such that most of the material is degraded before initiating an immunologic response.13,14 Currently, just one U.S. Food and Drug Administration–approved nerve conduit is composed Disclosure: The authors have no financial interest in any of the products or devices mentioned in this article.

www.PRSJournal.com

Volume 133, Number 6 • Nerve Conduit Peripheral Nerve Repair Table 1.  U.S. Food and Drug Administration Conformit Europe–Approved Nerve Guide Conduits Company Synovis Micro Companies, Inc. Integra Life ­Sciences Corp. Collagen Matrix, Inc. Polyganics BV

Product

Composition

FDA Diameter Approval (mm)

Length (cm)

NeuroTube

Polyglycolic acid

1999

2.3–8

2–4

Neuragen

Type I collagen

2001

1.5–7

2–3

Type I collagen

2001

2–6

2.5

Poly-dl-lactidecaprolactone

2003

1.5–10

3

2003

1.5–7 mm

10

2010

2–10 mm

6.35

2012

Unavailable

NeuroMatrix and Neuroflex Neurolac

Cook Biotech Axoguard Nerve Porcine small intestine Products Connector submucosa SaluMedica, LLC SaluTunnel Nerve Salubria (PVA hydrogel) ­Protector Biom’Up SAS* Cova ­Ortho-Nerve Type I collagen

Treated Nerve Type in Humans Median, cranial, and facial Lingual and inferior alveolar Peripheral nerves of arm and hand; digital nerve of foot

Degradation Time 3 mo 3–4 yr 4–8 mo 16 mo

3 mo Does not degrade 3 mo

FDA, U.S. Food and Drug Administration; CE, Conformit Europe; PVA, polyvinyl alcohol. *U.S. Food and Drug Administration–approved but not commercially available as of May of 2013.

of nonbiodegradable material: the SaluTunnel Nerve Protector (SaluMedica, LLC, Atlanta, Ga.). This conduit is composed of a unique biomaterial, “Salubria,” a hydrogel made of a freeze-thawed organic polymer containing polyvinyl alcohol. Although the material is marketed as biocompatible and well tolerated even after long-term use, a lack of clinical data means that it is unknown whether the SaluTunnel conduit outperforms its biodegradable counterparts, or whether it suffers the same drawbacks as earlier nonbiodegradable conduits (such as silicone) in terms of nerve compression and immunogenicity.12 The NeuroTube (Synovis Life Technologies, Inc., St. Paul, Minn.) is composed of polyglycolic acid and gained U.S. Food and Drug Administration approval in 1999. Early studies suggested that conduits composed of polyglycolic acid gave results similar to those of autologous nerve grafts in defects up to 30 mm,15,16 and various reports favored the use of the NeuroTube over other available conduits17,18 based on its affordability and clinical outcomes. However, this may have been attributable to the relative abundance of clinical data regarding the NeuroTube compared with other conduits. Waitayawinyu et al. compared a polyglycolic acid to a collagen-based conduit and autologous nerve grafting in rats. Although they found that the collagen conduit provided results similar to those of autologous nerve grafts, the polyglycolic acid conduit resulted in less organized and less dense axonal sprouting, and less muscle contraction force.19 To date, there are few clinical data comparing the NeuroTube and collagen conduits in humans.

The AxoGuard nerve connector (Cook Biotech, Inc., West Lafayette, Ind.) is derived from a porcine small intestine submucosa extracellular matrix and gained U.S. Food and Drug Administration approval in 2003. Small intestine submucosa–derived conduits appear to lack antigenicity11 and readily support the growth of Schwann cells.20 Although Kokkalis et al. were able to show that wrapped sciatic nerves of rabbits displayed normal myelination, density, and vascularity,21 there is a distinct lack of data regarding the effectiveness of porcine small intestine submucosa extracellular matrix as a nerve conduit, particularly in comparison with other materials. Two U.S. Food and Drug Administration– approved collagen-based nerve conduits are currently on the market [Nuragen by Integra LifeSciences (Plainsboro, N.J.) and NeuroMatrix and Neuroflex by Collagen Matrix, Inc. (Oakland, N.J.), both U.S. Food and Drug Administration approved in 2001], with another approved for production in 2012. Collagen has been relatively well studied within the field of nerve conduits,22,23 and has thus far proved to be a successful material for nerve conduit fabrication.9,19 Both currently available collagen-based conduits have shown positive outcomes in the repair of small-diameter nerves.14,24 Collagen nerve conduits are effective because of their biodegradation rate and promotion of Schwann cell proliferation,23 and a lack of antigenicity25 and enhanced neurovascularization.26 However, the currently available c­ollagen-based conduits do not surpass autologous nerve grafts in their efficacy, and perform poorly for nerve gaps of greater than 2 cm.23,25

1421

Plastic and Reconstructive Surgery • June 2014 The Neurolac nerve guide (Polyganics BV, Groningen, The Netherlands) is composed of poly-dl-lactide-caprolactone and gained U.S. Food and Drug Administration approval in 2005. The caprolactone conduit degrades more slowly than the polyglycolic acid NeuroTube conduit,27 a characteristic that Shin et al. translated into improved nerve recovery compared with polyglycolic acid conduits in terms of isometric muscle force, muscle weight, and axon counts.28 However, the longer degradation time of the Neurolac nerve guide may also be disadvantageous, as Meek and Jansen showed that fragments of the conduit remained in the surrounding tissue 2 years after implantation in rat sciatic nerves, accompanied by multinucleated giant cells and macrophages.29 It is possible that this results in granuloma formation in the longer term. Although the Neurolac nerve guide has been shown to be as effective as autologous nerve grafts for small nerve gaps,8 it once again does not surpass the criterion standard method. In addition, scaffolds that act as a guide for the regenerating nerves have also been developed lately. The Avance Nerve Graft (AxoGen, Inc., Alachua, Fla.) is a cadaveric graft from a donated peripheral nerve, which is decellularized to maintain an extracellular matrix with laminin and intact endoneural tubes. This scaffold provides a support for the growing axon without generating an immune response. These scaffolds provide a three-dimensional scaffolding to support the self-repair process of the damaged nerve. These scaffolds are eventually absorbed into the patient’s own tissue. A recent clinical trial evaluating the efficacy of Avance Nerve Grafts concluded that the Avance Nerve Graft was safe for reconstruction of nerve discontinuities, with 87.3 percent of the injuries achieving a meaningful recovery.30 Recovery was achieved in a majority of cases regardless of nerve type repaired (including mixed and motor), age of the patients, prolonged time to repair, or larger gap length (up to 50 mm) variables, which have been classically associated with poor axon regeneration and prognosis. A number of other materials have shown promising results for use in nerve conduits. Bian et al. evaluated the use of ­poly(3-hydroxybutyrate-co-3-hydroxyhexonate) in conduit design.31 The conduits were used in Sprague-Dawley rats to bridge gaps of up to 10 mm in the sciatic nerves. The authors observed very good mechanical properties when the conduits were manufactured with uniform and nonuniform porosity. Both were permeable to glucose, lysozyme, and bovine serum albumin. Combined with strong mechanical properties, good nerve regeneration

1422

ability, and nontoxicity of its degradation products, ­poly(3-hydroxybutyrate-co-3-hydroxyhexonate) nerve conduits hold great promise in conduit manufacture. Reid et al. developed a novel synthetic conduit composed of poly-ε-caprolactone that was used to bridge a 1-cm nerve gap in a rat sciatic nerve injury model. At 18 weeks after surgical repair, the poly-ε-caprolactone conduit was performing equally as well as the autograft control group in terms of the volume of regenerating axons, the number of myelinated axons, and reinnervation.32 Based on these data, poly-ε-caprolactone conduits also hold great promise for future clinical use.

TECHNIQUES OF PLACING NERVE CONDUITS To place a nerve conduit, an incision is made at the site of the nerve injury and the proximal and distal nerve segments are exposed by dissection of the area. The operating diameter of the nerve and the size of the gap between the nerve ends are measured. An appropriately sized conduit is selected and placed in the nerve gap, and each end of the nerve is sutured inside the conduit using microsurgical technique. Finally, the wound is irrigated and closed in layers.

FIBRIN GLUE SEALANTS Suture placement is believed to result in a hindrance to the sprouting axons and might also obstruct the blood supply. Inflammatory and fibrotic events following suture placement have also been reported and can result in serious damage to the regenerating nerve fibers. An obstructed blood supply can impair the regeneration process at the transected nerve ends after the placement of conduits.33 Moreover, formation of granulomas at the suture site causes a further obstruction in the regeneration of myelin and axons. Microsutures also make it difficult to control the nerve orientation, and the whole process involving sutures requires more time. Furthermore, in some clinical situations, microsutures are either difficult or impossible to apply. To overcome the negative aspects involved with the process of suturing nerve conduits, tissue sealants have been developed to repair the tissues after trauma. Several types of fibrin glues have been reported to date,34,35 in addition to cyanoacrylate and photochemical tissue bonding. Fibrin glue is the only natural material that has been used as a sealant, thereby avoiding the negative events associated with the placement of sutures. A study by Ornelas et al.36 comparing the repair of rat median nerve

Volume 133, Number 6 • Nerve Conduit Peripheral Nerve Repair using fibrin glue and microsutures found that the nerve repairs performed with fibrin sealants produced less inflammation, less fibrosis, better axonal regeneration, and better fiber alignment in comparison with the nerve repairs performed using the microsuture technique alone. In addition, working with fibrin sealants was reported to be easier and faster. Bozorg Grayeli et al.37 have also reported promising results with fibrin glue in the repair of facial nerve in humans. A recent systematic review on the use of fibrin glue for peripheral nerve repair in animal models has indicated that most studies on fibrin glue sealant have reported similar if not better outcomes using fibrin glue in comparison with microsutures.38

MECHANISM OF NERVE REGENERATION Injury to a peripheral nerve is followed by responses triggered by the axonal segments situated both proximal and distal to the area of injury and the surrounding neural and nonneural cells. Immediately after injury, the endogenous attempt to repair the injured nerve involves mechanisms such as an increase in the size of the neuronal cell body, dissolution of Nissl bodies, and peripheral migration of the nucleus.39 Debris clean-up is an important step for initiating the process of regeneration. Proinflammatory cytokines encourage the migration of macrophages that help in the degradation of myelin. The gap at the injury site is filled by a coordinated alignment of Schwann cells emerging from the distal stump to form columns of cells called the bands of Bungner. These columns act as guides and help the regenerating axons reach the end organ. Retrograde changes occur within the neuronal cell bodies at the proximal end, followed by the release of growth-promoting proteins, neurotrophins, and key transcription factors.40 Axonal sprouts emerging from the proximal stump grow toward the lesion site and enter the endoneurial tube. This process involves contact guidance between the growing axon tip and the Schwann cells lining the tube. Dedifferentiated Schwann cells up-regulate the expression of many ­regeneration-related genes and largely determine the regeneration ability following injury.

NERVE REGENERATION INSIDE A CONDUIT To mimic the functioning of a natural nerve, ideally, an effective nerve conduit requires a combination of three primary components: a scaffold to

support the growth of the damaged tissue, cells to promote the regeneration process, and appropriate signaling molecules. Generally, an ­open-lumen nerve conduit is used to constrain axon growth to the distal stump and prevent the formation of neuroma and the infiltration of fibrous tissue. After transection, the axoplasm is lost from the nerve, neurotrophic factors are secreted by fibroblasts, and Schwann cells secrete several neurotrophic factors.41 It is thought that the nerve conduits help in the migration of Schwann cells and accumulation of neurotropic factors. Inside the conduits, the wound healing response results in the formation of a fibrin matrix in the lumen and across short lengths.42 This fibrin matrix accommodates Schwann cells, fibroblasts, and macrophages.43,44 Most importantly, conduits must be degradable to avoid the formation of a scar, which would result in compression of the damaged nerve.

PHYSICAL PROPERTIES OF CONDUITS Permeability, flexibility, strength, fabrication design, lumen diameter, and an internal framework all influence the quality of synthetic nerve conduits. The permeability of the conduit allows supportive cells to access nutrients and oxygen. Different techniques such as cutting holes in the walls,45 fiber spinning,46 rolling of meshes,47 and adding sugar48 or salt crystals49 have been used to make conduits permeable. Engineering to produce conduits with permeability to different molecules has been attempted. Wang et al. evaluated the use of porous fiber–reinforced chitosan material conduits fabricated to be permeable to molecules between 180 (glucose) and 66,200 Da (bovine serum albumin).50 The authors reported good porosity of the material without sacrificing tensile strength and without any toxicity by means of in vitro assays. Because the nerve gap may not be in one plane, bending of the conduit may be required for nerve regeneration. However, flexibility and strength must be balanced judiciously so that the material is strong enough to hold the nerve in place. Therefore, in addition to the type of material used, other parameters influencing flexibility such as material thickness, design, lumen diameter, and internal framework must be carefully evaluated.51,52 In an attempt to specifically address these issues, Collagen Matrix developed the Neuroflex nerve conduit, the only specifically labeled flexible type I collagen nerve conduit on the market. Although the kinkresistant properties of this conduit may prove

1423

Plastic and Reconstructive Surgery • June 2014 beneficial in some circumstances, weakness of this conduit means that it can be used to bridge only short nerve gaps.53 However, it is possible that designing conduits with varying properties is an effective way of accommodating for a range of peripheral nerve injuries.

INTERNAL PROPERTIES OF CONDUITS To date, several internal modifications of conduits have been tested for their ability to enhance nerve regeneration. Modifications include adding an internal microarchitecture, transplanting in supportive cells (e.g., Schwann cells), supplying growth factors, and using conductive polymers. Most of these modifications have successfully increased the length of the gap that could be repaired.54 Adding an intrinsic framework to the lumen of the conduit, such as polymeric fibers,55 longitudinally oriented channels,56 or collagen sponges,57 assists in the stabilization of the fibrin matrix that naturally forms across the injury gap, or will act as an artificial matrix in the event that it is unable to form. The properties of the gel substance should be examined carefully to minimize bioreactivity and toxicity. Recently, laminin-derived oligopeptides have proven beneficial.58 An intrinsic framework also acts in the release of growth factors,59 and provides a greater surface area for migrating nonneuronal cells, which act to enhance the regeneration process.60 The incorporation of an intrinsic framework modifies the physical properties of the conduit and highlights the importance of ongoing in vitro studies into the effects of various intrinsic frameworks.

SUPPORTIVE CELLS FOR NERVE GROWTH The incorporation of Schwann cells has been vastly beneficial for nerve regeneration. The

subject has been investigated in detail, and the advantages of using these cells are obvious.61–63 When incorporating supportive cells inside the hollow lumen, porosity must be maintained to allow the diffusion of growth factors, other nutrients, and oxygen. A number of different methods of delivering supportive cells into the nerve conduit have been evaluated (Table 2).64–72 Although the necessity of Schwann cells for successful nerve repair has been well established, the importance of other cell types has been less studied. One area is that of stretch-grown axons. Pfister et al. showed that mature axon tracts experience rapid growth when mechanically stretched at the central portion of the axon cylinder.64 The axons reached an impressive growth rate of 1 cm/day, and 5-cm axon tracts were generated in 8 days. The cells could be inserted into a synthetic conduit before surgery, or growth could be induced directly on a surgical membrane suitable for transplantation. Further development of this field could prove beneficial to the success of artificial nerve conduits in peripheral nerve repair. The use of olfactory ensheathing cells also requires further evaluation. Olfactory ensheathing cells are similar to Schwann cells in that they up-regulate the production of neurotrophic factors following injury, albeit to a lesser extent.73,74 You et al. showed that using olfactory ensheathing cells in combination with Schwann cells in a polyglycolic acid conduit provided better axonal regeneration and muscle restoration than using either cell type individually in an adult rat sciatic nerve model.68 Combined with the ability of olfactory ensheathing cells to remyelinate damaged axons,75 this finding suggests that these cells could prove useful when used synergistically with Schwann cells in nerve conduits. The addition of stem cells to the nerve conduit and their differentiation into both neurons and glia

Table 2.  Supportive Cells Used in Nerve Conduits and Their Delivery Methods Cell Type BMSC EMSC Fibroblast OEC Schwann cell Schwann cell Schwann cell Stem cell (adipose derived) Stretch grown axons

Delivery Method

Conduit Composition

Animal Model

Reference

Gelatine/PCL matrix Gelatine/PCL N/A Collagen matrix PLGA Rat sciatic nerve Collagen matrix Silicone Rat sciatic nerve Direct culture onto conduit wall PGA Rat sciatic nerve Gel matrix Collagen Mouse sciatic nerve Keratin matrix Silicone Mouse tibial nerve Direct culture onto conduit wall Poly-3-hydroxybutyrate Rat sciatic nerve Direct culture onto conduit wall Fibrin Rat sciatic nerve

Zhang et al., 200565 Nie et al., 200766 Phillips et al., 200567 You et al., 201168 Udina et al., 200469 Apel et al., 200870 Kalbermatten et al., 200871 di Summa et al., 201072

Direct culture onto conduit wall

Pfister et al., 200664

Type I collagen

N/A

BMSC, bone marrow–derived stromal cell; EMSC, ectomesenchymal stem cell; OEC, olfactory ensheathing cell; PCL, poly-ε-caprolactone; PLGA, poly(lactic-co-glycolic acid); N/A, not applicable.

1424

Volume 133, Number 6 • Nerve Conduit Peripheral Nerve Repair has also been investigated.76,77 As Schwann cells can be slow to culture and difficult to isolate, stem cells with the ability to differentiate into Schwann-like cells offer a potential shortcut. Specifically, adipose or bone marrow–derived mesenchymal stem cells can be induced to differentiate into Schwann-like cells.78,79 Mesenchymal stem cells are advantageous in that they produce inflammatory cytokines and neurotrophic factors.80 Furthermore, mesenchymal stem cells proliferate rapidly in culture, survive well in vivo, and integrate successfully with the injured nerve.78,81 Ribeiro-Resende et al.82 treated transected rat sciatic nerves with bone marrow–derived mesenchymal stem cells and reported reduced cell death, improved neuronal growth, and an increase in glial cell populations compared with control animals. Additional studies into the use of stem cells in nerve conduits in vivo are warranted to establish whether positive clinical outcomes result.

GROWTH FACTORS FOR NERVE GROWTH As is the case for supportive cells, growth factors are essential for peripheral nerve regeneration.41,83 The delivery of growth factors must be highly precise and sustained at the appropriate concentration throughout the regeneration period.84,85 As with supportive cells, the delivery of growth factors into the conduit lumen can be approached in many different ways, including the use of matrices, cross-linking to the nerve conduit wall, or using microspheres to deliver the growth factors. Various

growth factors have been added to single-lumen nerve tubes using these methods, with the inclusion of these factors leading to improved neuronal growth rates (Table 3).85–98 Relevant in vitro assays should be performed to identify further factors responsible for nerve growth. Identification of factors specifically for differential growth of motor and sensory neurons may allow tailoring of the construct according to the type of injury.

CONDUCTIVE POLYMERS Fabricating nerve conduits from materials with electrical activity, such as polypyrrole or electrically poled (piezoelectric) poly(vinylidene fluoride), accelerates axonal extension.99,100 In addition, it has been shown that low-frequency electrical stimulation to the proximal nerve stump following transection accelerates axonal outgrowth.101,102 Huang et al. constructed a conductive scaffold to bridge a 15-mm sciatic nerve defect in rats. Axonal regeneration and remyelination were significantly enhanced when electrical stimulation was applied to the scaffold.103 Furthermore, motor and sensory recovery was enhanced, muscle atrophy partially reversed, and the production of certain neurotrophic factors up-regulated. Currently, nerve conduits do not use conductive polymers, likely because of the nonbiodegradable nature of such polymers. However, with the development of novel polymers, this is certainly an avenue deserving of further experimentation.

Table 3.  Growth Factors Used in Peripheral Nerve Repair Using Nerve Conduits and Their Delivery Methods Factor

Delivery Method

Conduit Composition

Animal Model

Collagen matrix Calcium alginate microspheres Cross-linking to conduit wall PLGA microspheres Collagen matrix Heparin/alginate/ethylenediamine matrix GDNF Overexpressed in Schwann cells GDNF Cross-linking to conduit wall GGF Alginate matrix

PHEMA-MMA Biodegradable capsule Type I collagen Chitosan/chitin PHEMA-MMA Alginate gel

Rat sciatic nerve Rat sciatic nerve Rat sciatic nerve N/A Rat sciatic nerve Rat sciatic nerve

Midha et al., 200386 Vögelin et al., 200687 Ho et al., 199888 Goraltchouk et al., 200689 Midha et al., 200386 Ohta et al., 200490

PLGA Type I collagen PHB

Zhou et al., 200891 Madduri et al., 201085 Mohanna et al., 200592

IGF-I LIF NGF NGF NT-3 PDGF PDGF VEGF

Acellular muscle PHB Silicone Polysulfone PHEMA-MMA Type I collagen Silastic Silicone

Rat facial nerve Chick DRG Rabbit peroneal nerve Rat sciatic nerve Rat sciatic nerve Rat sciatic nerve Rat sciatic nerve Rat sciatic nerve Rat sciatic nerve Rat sciatic nerve Rat sciatic nerve

BDNF BDNF CNTF EGF FGF-1 FGF-2

Osmotic pumps Calcium alginate matrix Microinjection ports Agarose matrix Collagen matrix Cross-linking to conduit wall Methylcellulose matrix Gel matrix

Reference

Fansa et al., 200293 McKay Hart et al., 200394 Kemp et al., 200795 Dodla and Bellamkonda, 200896 Midha et al., 200386 Ho et al., 199888 Wells et al., 199797 Hobson, 200298

BDNF, brain-derived neurotrophic factor; PHEMA-MMA, poly(2-hydroxyethyl methacrylate-co-methyl methacrylate); FGF, fibroblast growth factor; CNTF, ciliary neurotrophic factor; EGF, endothelial growth factor; PLGA, poly(lactide-co-glycolide); GDNF, glial-derived neurotrophic factor; GGF, glial growth factor; PHB, poly-3-hydroxybutyrate; IGF-I, insulin-like growth factor I; LIF, leukemia inhibitory factor; NGF, nerve growth factor; NT-3, neurotrophin-3; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor.

1425

Plastic and Reconstructive Surgery • June 2014 DIAMETER OF THE CONDUIT LUMEN AND THE NERVE Another largely ignored variable is the diameter of the conduit lumen and the damaged nerve. In one report,44 the authors state that ­large-diameter conduits may not be as effective as their smaller counterparts, and that conduits should not be used in the repair of large-diameter nerves (e.g., median, radial, or ulnar nerve). As conduit volume is increased, the neurotrophic and progenerative factors produced by the distal and proximal injured nerve are diluted and overall recovery is diminished. Conduit lumen diameter should be given due consideration to ensure that the concentration of neurotrophic substances is sufficient for nerve growth. In addition, this study noted that the diameters of even the largest nerves used in animal models are smaller than human nerves, such that human physiologic conditions are never mimicked in animal models. Therefore, when extrapolating the results of animal studies to humans, the diameter of the animal nerve and the relative diameter of nerve and conduit should be considered carefully, as both will affect the concentration of the neurotrophic factors necessary for nerve regeneration.

LENGTH OF THE DAMAGED NERVE Currently, the length of the nerve under repair is a key limiting factor in using nerve conduits for peripheral nerve repair, with most studies to date recommending conduit use for a maximum gap of 30 mm.1,2 In a nonhuman primate study, median nerve defects of 5, 20, and 50 mm in length were repaired with nerve conduits.104 Adequate functional outcomes were attained in the 5-mm and 20-mm groups, but not in the 50-mm group. The authors suggested that any mechanism aimed to shorten the time to reinnervation would improve the final level of recovery, strengthening the cause for research into conductive polymers and electrical stimulation. Another study comparing Neuragen (Integra LifeSciences) type I collagen conduit to decellularized allografts (AxoGen, Inc.) and autograft controls found that the Neuragen conduit and allografts were not equivalent to the autografts.25 In a short nerve gap (14 mm) in a rat sciatic nerve model, it was observed that at 6 weeks the conduit (1.5-mm diameter) showed significantly less nerve regeneration than the processed allografts. When the nerve gap was doubled (28 mm), the conduit and the allografts did not show any axonal regeneration distally in any of the animals at the 6-week

1426

time point. However, this does not necessarily imply the absence of axonal regeneration at later time points. There have been reports indicating successful regeneration at nerve gaps greater than 28 mm in human and animal models.16,19

ANIMAL MODELS FOR RESEARCH ON NERVE CONDUITS Research into the use of nerve conduits has been performed predominantly in rodents. Although convenient, rodents demonstrate superior neuroregenerative capacity compared with higher mammals and humans.44 In rodents, late–time point observations may show positive and negative groups to be equivalent because of the superior regenerative capacity of the rodent nervous system masking differences between these groups.105 These late evaluations are critical in our understanding of the long-term effects of nerve conduits on peripheral nerve repair. Animal models should be used with caution and with these differences in mind when results are compared with human outcomes.

CONCLUDING REMARKS A number of factors need to be considered carefully when nerve conduits are designed. First and foremost is the material used in the fabrication of the conduit. Although significant progress has been made in this field, further research should focus on establishing a balance between the rates of nutrient filtration and material biodegradation to achieve faster nerve regeneration without significant immunoreactivity. This, along with exploring the use of conductive polymers and electrical stimulation, would result in faster nerve regeneration, an important factor in ­long-term outcome. The selection of a conduit material should be based on its physical properties with respect to porosity, facilitation of supportive cells, degradation time, and rate of nerve regeneration. Internal modifications to the conduit such as the addition of microarchitecture, the use of Schwann and other supporting cells, and the inclusion of growth factors have all led to improved nerve regeneration. Further research should focus on the use of additional cell types, such as olfactory ensheathing cells and stem cells, which may act synergistically with Schwann cells to enhance peripheral nerve regeneration. Extensive study of growth factors could result in the replacement of the use of supportive cells, which would increase the practicality of nerve conduits by eliminating the need for tissue culture facilities.

Volume 133, Number 6 • Nerve Conduit Peripheral Nerve Repair In brief, although there are currently several nerve conduits available for clinical use, none surpasses the criterion standard technique of autologous nerve grafting. However, an integrated research approach into combinations of the factors discussed above may result in improved performance of nerve conduits, including faster nerve repair and the ability to repair longer nerve defects, currently a critical limiting factor in the clinical use of nerve conduits for peripheral nerve repair.

cpt

CODING PERSPECTIVE

This information provided by Dr. Raymund Janevicius is intended to provide coding guidance.

64910 N  erve repair; with synthetic conduit or vein allograft (e.g., nerve tube), each nerve • Code 64910 is used for nerve conduits that are synthetic or allogeneic. A nerve conduit using the autogenous vein is reported with code 64911. • Code 64910 is used for all synthetic ­products. It is a global code that includes the following: °  N  erve preparation (e.g., dissection, neurolysis, débridement) °  S  ecuring proximal and distal ends of the nerve to the conduit, whether by ­suturing or with tissue glue °  Use of the operating microscope °  Uncomplicated wound closure °  Application of splint • When more than one nerve is repaired with a synthetic conduit, code 64910 is reported for each nerve repair. Thus, if both digital nerves of a finger are repaired with a synthetic conduit, the procedures are reported as follows:



64910   Radial digital nerve repair with    ­synthetic conduit 64910-59 U  lnar digital nerve repair with   ­synthetic conduit • Use of the operating microscope is included in the global code 64910. Do not report 69990 in addition. This is in contrast to autogenous nerve grafts as well as direct nerve repairs (64831 to 64870), where code 69990 is reported in addition to the neurorrhaphy codes.

Amit Pabari, M.R.C.S. Royal Free Hampstead NHS Trust London, United Kingdom [email protected]

REFERENCES 1. Schlosshauer B, Dreesmann L, Schaller HE, Sinis N. Synthetic nerve guide implants in humans: A comprehensive survey. Neurosurgery 2006;59:740–747; discussion 747. 2. Deal DN, Griffin JW, Hogan MV. Nerve conduits for nerve repair or reconstruction. J Am Acad Orthop Surg. 2012;20:63–68. 3. Millesi H. Nerve grafting. Clin Plast Surg. 1984;11:105–113. 4. Siemionow M, Brzezicki G. Chapter 8: Current techniques and concepts in peripheral nerve repair. Int Rev Neurobiol. 2009;87:141–172. 5. Panseri S, Cunha C, Lowery J, et al. Electrospun micro- and nanofiber tubes for functional nervous regeneration in sciatic nerve transections. BMC Biotechnol. 2008;8:39. 6. Kehoe S, Zhang XF, Boyd D. FDA approved guidance conduits and wraps for peripheral nerve injury: A review of materials and efficacy. Injury 2012;43:553–572. 7. Lohmeyer JA, Siemers F, Machens HG, Mailänder P. The clinical use of artificial nerve conduits for digital nerve repair: A prospective cohort study and literature review. J Reconstr Microsurg. 2009;25:55–61. 8. Bertleff MJ, Meek MF, Nicolai JP. A prospective clinical evaluation of biodegradable neurolac nerve guides for sensory nerve repair in the hand. J Hand Surg Am. 2005;30:513–518. 9. Bushnell BD, McWilliams AD, Whitener GB, Messer TM. Early clinical experience with collagen nerve tubes in digital nerve repair. J Hand Surg Am. 2008;33:1081–1087. 10. Rosson GD, Williams EH, Dellon AL. Motor nerve regeneration across a conduit. Microsurgery 2009;29:107–114. 11. Smith RM, Wiedl C, Chubb P, Greene CH. Role of small intestine submucosa (SIS) as a nerve conduit: Preliminary report. J Invest Surg. 2004;17:339–344. 12. Merle M, Dellon AL, Campbell JN, Chang PS. Complications from silicon-polymer intubulation of nerves. Microsurgery 1989;10:130–133. 13. Meek MF, Coert JH. Clinical use of nerve conduits in peripheral-nerve repair: Review of the literature. J Reconstr Microsurg. 2002;18:97–109. 14. Taras JS, Nanavati V, Steelman P. Nerve conduits. J Hand Ther. 2005;18:191–197. 15. Mackinnon SE, Dellon AL. Clinical nerve reconstruction with a bioabsorbable polyglycolic acid tube. Plast Reconstr Surg. 1990;85:419–424. 16. 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. 2000;106:1036–1045; discussion 1046. 17. Meek MF, Coert JH. US Food and Drug Administration/ Conformit Europe-approved absorbable nerve conduits for clinical repair of peripheral and cranial nerves. Ann Plast Surg. 2008;60:466–472. 18. Wolford LM, Stevao EL. Considerations in nerve repair. Proc (Bayl Univ Med Cent.) 2003;16:152–156. 19. Waitayawinyu T, Parisi DM, Miller B, et al. A comparison of polyglycolic acid versus type 1 collagen bioabsorbable nerve conduits in a rat model: An alternative to autografting. J Hand Surg Am. 2007;32:1521–1529. 20. Hadlock TA, Sundback CA, Hunter DA, Vacanti JP, Cheney ML. A new artificial nerve graft containing rolled Schwann cell monolayers. Microsurgery 2001;21:96–101.

1427

Plastic and Reconstructive Surgery • June 2014 21. Kokkalis ZT, Pu C, Small GA, Weiser RW, Venouziou AI, Sotereanos DG. Assessment of processed porcine extracellular matrix as a protective barrier in a rabbit nerve wrap model. J Reconstr Microsurg. 2011;27:19–28. 22. Stang F, Fansa H, Wolf G, Keilhoff G. Collagen nerve conduits: Assessment of biocompatibility and axonal regeneration. Biomed Mater Eng. 2005;15:3–12. 23. Keilhoff G, Stang F, Wolf G, Fansa H. Bio-compatibility of type I/III collagen matrix for peripheral nerve reconstruction. Biomaterials 2003;24:2779–2787. 24. Farole A, Jamal BT. A bioabsorbable collagen nerve cuff (NeuraGen) for repair of lingual and inferior alveolar nerve injuries: A case series. J Oral Maxillofac Surg. 2008;66:2058–2062. 25. Whitlock EL, Tuffaha SH, Luciano JP, et al. Processed allografts and type I collagen conduits for repair of peripheral nerve gaps. Muscle Nerve 2009;39:787–799. 26. Kim DH, Connolly SE, Zhao S, Beuerman RW, Voorhies RM, Kline DG. Comparison of macropore, semipermeable, and nonpermeable collagen conduits in nerve repair. J Reconstr Microsurg. 1993;9:415–420. 27. Luis AL, Rodrigues JM, Lobato JV, et al. Evaluation of two biodegradable nerve guides for the reconstruction of the rat sciatic nerve. Biomed Mater Eng. 2007;17:39–52. 28. Shin RH, Friedrich PF, Crum BA, Bishop AT, Shin AY. Treatment of a segmental nerve defect in the rat with use of bioabsorbable synthetic nerve conduits: A comparison of commercially available conduits. J Bone Joint Surg Am. 2009;91:2194–2204. 29. Meek MF, Jansen K. Two years after in vivo implantation of poly(DL-lactide-epsilon-caprolactone) nerve guides: Has the material finally resorbed? J Biomed Mater Res A 2009;89:734–738. 30. Brooks DN, Weber RV, Chao JD, et al. Processed nerve allografts for peripheral nerve reconstruction: A multicenter study of utilization and outcomes in sensory, mixed, and motor nerve reconstructions. Microsurgery 2012;32:1–14. 31. Bian YZ, Wang Y, Aibaidoula G, Chen GQ, Wu Q. Evaluation of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) conduits for peripheral nerve regeneration. Biomaterials 2009;30:217–225. 32. Reid AJ, de Luca AC, Faroni A, et al. Long term peripheral nerve regeneration using a novel PCL nerve conduit. Neurosci Lett. 2013;544:125–130. 33. Smahel J, Meyer VE, Bachem U. Glueing of peripheral nerves with fibrin: Experimental studies. J Reconstr Microsurg. 1987;3:211–220. 34. Martins RS, Siqueira MG, Da Silva CF, Plese JP. Overall assessment of regeneration in peripheral nerve lesion repair using fibrin glue, suture, or a combination of the 2 techniques in a rat model: Which is the ideal choice? Surg Neurol. 2005;64(Suppl 1):S1:10–16; discussion S1:16. 35. Ornelas L, Padilla L, Di Silvio M, et al. Fibrin glue: An alternative technique for nerve coaptation—Part I. Wave amplitude, conduction velocity, and plantar-length factors. J Reconstr Microsurg. 2006;22:119–122. 36. Ornelas L, Padilla L, Di Silvio M, et al. Fibrin glue: An alternative technique for nerve coaptation—Part II. Nerve regeneration and histomorphometric assessment. J Reconstr Microsurg. 2006;22:123–128. 37. Bozorg Grayeli A, Mosnier I, Julien N, El Garem H, Bouccara D, Sterkers O. Long-term functional outcome in facial nerve graft by fibrin glue in the temporal bone and cerebellopontine angle. Eur Arch Otorhinolaryngol. 2005;262:404–407. 38. Sameem M, Wood TJ, Bain JR. A systematic review on the use of fibrin glue for peripheral nerve repair. Plast Reconstr Surg. 2011;127:2381–2390.

1428

39. Chaudhry V, Glass JD, Griffin JW. Wallerian degeneration in peripheral nerve disease. Neurol Clin. 1992;10:613–627. 40. Fenrich K, Gordon T. Canadian Association of Neuroscience review: Axonal regeneration in the peripheral and central nervous systems. Current issues and advances. Can J Neurol Sci. 2004;31:142–156. 41. Fu SY, Gordon T. The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol. 1997;14:67–116. 42. Belkas JS, Shoichet MS, Midha R. Peripheral nerve regeneration through guidance tubes. Neurol Res. 2004;26:151–160. 43. Evans GR. Peripheral nerve injury: A review and approach to tissue engineered constructs. Anat Rec. 2001;263:396–404. 44. Moore AM, Kasukurthi R, Magill CK, Farhadi HF, Borschel GH, Mackinnon SE. Limitations of conduits in peripheral nerve repairs. Hand (NY) 2009;4:180–186. 45. Jenq CB, Coggeshall RE. Nerve regeneration through holey silicone tubes. Brain Res. 1985;361:233–241. 46. Aebischer P, Guénard V, Valentini RF. The morphology of regenerating peripheral nerves is modulated by the surface microgeometry of polymeric guidance channels. Brain Res. 1990;531:211–218. 47. Dellon AL, Mackinnon SE. An alternative to the classical nerve graft for the management of the short nerve gap. Plast Reconstr Surg. 1988;82:849–856. 48. Rodríguez FJ, Gómez N, Perego G, Navarro X. Highly permeable polylactide-caprolactone nerve guides enhance peripheral nerve regeneration through long gaps. Biomaterials 1999;20:1489–1500. 49. Widmer MS, Gupta PK, Lu L, et al. Manufacture of porous biodegradable polymer conduits by an extrusion process for guided tissue regeneration. Biomaterials 1998;19:1945–1955. 50. Wang A, Ao Q, Wei Y, et al. Physical properties and biocompatibility of a porous chitosan-based fiber-reinforced conduit for nerve regeneration. Biotechnol Lett. 2007;29:1697–1702. 51. Belkas JS, Munro CA, Shoichet MS, Johnston M, Midha R. Long-term in vivo biomechanical properties and biocompatibility of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) nerve conduits. Biomaterials 2005;26:1741–1749. 52. Meek MF, Jansen K, Steendam R, van Oeveren W, van Wachem PB, van Luyn MJ. In vitro degradation and biocompatibility of poly(DL-lactide-epsilon-caprolactone) nerve guides. J Biomed Mater Res A 2004;68:43–51. 53. Uebersax L, Mattotti M, Papaloïzos M, Merkle HP, Gander B, Meinel L. Silk fibroin matrices for the controlled release of nerve growth factor (NGF). Biomaterials 2007;28:4449–4460. 54. Wang S, Cai L. Polymers for fabricating nerve conduits. Int J Polym Sci. 2010. 55. Chew SY, Mi R, Hoke A, Leong KW. Aligned p ­ rotein-polymer composite fibers enhance nerve regeneration: A potential tissue-engineering platform. Adv Funct Mater. 2007;17:1288–1296. 56. Bozkurt A, Deumens R, Beckmann C, et al. In vitro cell alignment obtained with a Schwann cell enriched microstructured nerve guide with longitudinal guidance channels. Biomaterials 2009;30:169–179. 57. Hisasue S, Kato R, Sato Y, Suetomi T, Tabata Y, Tsukamoto T. Cavernous nerve reconstruction with a biodegradable conduit graft and collagen sponge in the rat. J Urol. 2005;173:286–291. 58. Yu TT, Shoichet MS. Guided cell adhesion and outgrowth in peptide-modified channels for neural tissue engineering. Biomaterials 2005;26:1507–1514. 59. Nakamura T, Inada Y, Fukuda S, et al. Experimental study on the regeneration of peripheral nerve gaps through a polyglycolic acid-collagen (PGA-collagen) tube. Brain Res. 2004;1027:18–29.

Volume 133, Number 6 • Nerve Conduit Peripheral Nerve Repair 60. Hadlock T, Sundback C, Hunter D, Cheney M, Vacanti JP. A polymer foam conduit seeded with Schwann cells promotes guided peripheral nerve regeneration. Tissue Eng. 2000;6:119–127. 61. Ansselin AD, Fink T, Davey DF. Peripheral nerve regeneration through nerve guides seeded with adult Schwann cells. Neuropathol Appl Neurobiol. 1997;23:387–398. 62. Evans GR, Brandt K, Katz S, et al. Bioactive poly(L-lactic acid) conduits seeded with Schwann cells for peripheral nerve regeneration. Biomaterials 2002;23:841–848. 63. Sinis N, Schaller HE, Schulte-Eversum C, et al. Nerve regeneration across a 2-cm gap in the rat median nerve using a resorbable nerve conduit filled with Schwann cells. J Neurosurg. 2005;103:1067–1076. 64. Pfister BJ, Iwata A, Taylor AG, Wolf JA, Meaney DF, Smith DH. Development of transplantable nervous tissue constructs comprised of stretch-grown axons. J Neurosci Methods 2006;153:95–103. 65. Zhang Y, Ouyang H, Lim CT, Ramakrishna S, Huang ZM. Electrospinning of gelatin fibers and gelatin/PCL composite fibrous scaffolds. J Biomed Mater Res B Appl Biomater. 2005;72:156–165. 66. Nie X, Zhang YJ, Tian WD, et al. Improvement of peripheral nerve regeneration by a tissue-engineered nerve filled with ectomesenchymal stem cells. Int J Oral Maxillofac Surg. 2007;36:32–38. 67. Phillips JB, Bunting SC, Hall SM, Brown RA. Neural tissue engineering: A self-organizing collagen guidance conduit. Tissue Eng. 2005;11:1611–1617. 68. You H, Wei L, Liu Y, et al. Olfactory ensheathing cells enhance Schwann cell-mediated anatomical and functional repair after sciatic nerve injury in adult rats. Exp Neurol. 2011;229:158–167. 69. Udina E, Rodríguez FJ, Verdú E, Espejo M, Gold BG, Navarro X. FK506 enhances regeneration of axons across long peripheral nerve gaps repaired with collagen guides seeded with allogeneic Schwann cells. Glia 2004;47:120–129. 70. Apel PJ, Garrett JP, Sierpinski P, et al. Peripheral nerve regeneration using a keratin-based scaffold: Long-term functional and histological outcomes in a mouse model. J Hand Surg Am. 2008;33:1541–1547. 71. Kalbermatten DF, Erba P, Mahay D, Wiberg M, Pierer G, Terenghi G. Schwann cell strip for peripheral nerve repair. J Hand Surg Eur Vol. 2008;33:587–594. 72. di Summa PG, Kingham PJ, Raffoul W, Wiberg M, Terenghi G, Kalbermatten DF. Adipose-derived stem cells enhance peripheral nerve regeneration. J Plast Reconstr Aesthet Surg. 2010;63:1544–1552. 73. Ruitenberg MJ, Vukovic J, Sarich J, Busfield SJ, Plant GW. Olfactory ensheathing cells: Characteristics, genetic engineering, and therapeutic potential. J Neurotrauma 2006;23:468–478. 74. Byrnes KR, Wu X, Waynant RW, Ilev IK, Anders JJ. Low power laser irradiation alters gene expression of olfactory ensheathing cells in vitro. Lasers Surg Med. 2005;37:161–171. 75. Akiyama Y, Lankford K, Radtke C, Greer CA, Kocsis JD. Remyelination of spinal cord axons by olfactory ensheathing cells and Schwann cells derived from a transgenic rat expressing alkaline phosphatase marker gene. Neuron Glia Biol. 2004;1:47–55. 76. Pabari A, Yang SY, Seifalian AM, Mosahebi A. Modern surgical management of peripheral nerve gap. J Plast Reconstr Aesthet Surg. 2010;63:1941–1948. 77. Amoh Y, Kanoh M, Niiyama S, et al. Human hair follicle pluripotent stem (hfPS) cells promote regeneration of

­ eripheral-nerve injury: An advantageous alternative to ES p and iPS cells. J Cell Biochem. 2009;107:1016–1020. 78. Keilhoff G, Goihl A, Langnäse K, Fansa H, Wolf G. Transdifferentiation of mesenchymal stem cells into Schwann cell-like myelinating cells. Eur J Cell Biol. 2006;85:11–24. 79. Caddick J, Kingham PJ, Gardiner NJ, Wiberg M, Terenghi G. Phenotypic and functional characteristics of mesenchymal stem cells differentiated along a Schwann cell lineage. Glia 2006;54:840–849. 80. Wang J, Ding F, Gu Y, Liu J, Gu X. Bone marrow mesenchymal stem cells promote cell proliferation and neurotrophic function of Schwann cells in vitro and in vivo. Brain Res. 2009;1262:7–15. 81. Tohill M, Mantovani C, Wiberg M, Terenghi G. Rat bone marrow mesenchymal stem cells express glial markers and stimulate nerve regeneration. Neurosci Lett. 2004;362:200–203. 82. Ribeiro-Resende VT, Carrier-Ruiz A, Lemes RM, Reis RA, Mendez-Otero R. Bone marrow-derived fibroblast growth factor-2 induces glial cell proliferation in the regenerating peripheral nervous system. Mol Neurodegener. 2012;7:34. 83. Raivich G, Kreutzberg GW. Peripheral nerve regeneration: Role of growth factors and their receptors. Int J Dev Neurosci. 1993;11:311–324. 84. Pfister LA, Papaloïzos M, Merkle HP, Gander B. Nerve conduits and growth factor delivery in peripheral nerve repair. J Peripher Nerv Syst. 2007;12:65–82. 85. Madduri S, Feldman K, Tervoort T, Papaloïzos M, Gander B. Collagen nerve conduits releasing the neurotrophic factors GDNF and NGF. J Control Release 2010;143:168–174. 86. Midha R, Munro CA, Dalton PD, Tator CH, Shoichet MS. Growth factor enhancement of peripheral nerve regeneration through a novel synthetic hydrogel tube. J Neurosurg. 2003;99:555–565. 87. Vögelin E, Baker JM, Gates J, Dixit V, Constantinescu MA, Jones NF. Effects of local continuous release of brain derived neurotrophic factor (BDNF) on peripheral nerve regeneration in a rat model. Exp Neurol. 2006;199:348–353. 88. Ho PR, Coan GM, Cheng ET, et al. Repair with collagen tubules linked with brain-derived neurotrophic factor and ciliary neurotrophic factor in a rat sciatic nerve injury model. Arch Otolaryngol Head Neck Surg. 1998;124:761–766. 89. Goraltchouk A, Scanga V, Morshead CM, Shoichet MS. Incorporation of protein-eluting microspheres into biodegradable nerve guidance channels for controlled release. J Control Release 2006;110:400–407. 90. Ohta M, Suzuki Y, Chou H, et al. Novel heparin/alginate gel combined with basic fibroblast growth factor promotes nerve regeneration in rat sciatic nerve. J Biomed Mater Res A 2004;71:661–668. 91. Zhou L, Du HD, Tian HB, Li C, Tian J, Jiang JJ. Experimental study on repair of the facial nerve with Schwann cells transfected with GDNF genes and PLGA conduits. Acta Otolaryngol. 2008;128:1266–1272. 92. Mohanna PN, Terenghi G, Wiberg M. Composite PHB-GGF conduit for long nerve gap repair: A long-term evaluation. Scand J Plast Reconstr Surg Hand Surg. 2005;39:129–137. 93. Fansa H, Schneider W, Wolf G, Keilhoff G. Influence of insulin-like growth factor-I (IGF-I) on nerve autografts and tissue-engineered nerve grafts. Muscle Nerve 2002;26:87–93. 94. McKay Hart A, Wiberg M, Terenghi G. Exogenous leukaemia inhibitory factor enhances nerve regeneration after late secondary repair using a bioartificial nerve conduit. Br J Plast Surg. 2003;56:444–450. 95. Kemp SW, Walsh SK, Zochodne DW, Midha R. A novel method for establishing daily in vivo concentration gradients of soluble nerve growth factor (NGF). J Neurosci Methods 2007;165:83–88.

1429

Plastic and Reconstructive Surgery • June 2014 96. Dodla MC, Bellamkonda RV. Differences between the effect of anisotropic and isotropic laminin and nerve growth factor presenting scaffolds on nerve regeneration across long peripheral nerve gaps. Biomaterials 2008;29:33–46. 97. Wells MR, Kraus K, Batter DK, et al. Gel matrix vehicles for growth factor application in nerve gap injuries repaired with tubes: A comparison of biomatrix, collagen, and methylcellulose. Exp Neurol. 1997;146:395–402. 98.  Hobson MI. Increased vascularisation enhances axonal regeneration within an acellular nerve conduit. Ann R Coll Surg Engl. 2002;84:47–53. 99. Aebischer P, Valentini RF, Dario P, Domenici C, Galletti PM. Piezoelectric guidance channels enhance regeneration in the mouse sciatic nerve after axotomy. Brain Res. 1987;436:165–168. 100. Schmidt CE, Shastri VR, Vacanti JP, Langer R. Stimulation of neurite outgrowth using an electrically conducting polymer. Proc Natl Acad Sci USA 1997;94:8948–8953.

101. de Ruiter GC, Malessy MJ, Yaszemski MJ, Windebank AJ, Spinner RJ. Designing ideal conduits for peripheral nerve repair. Neurosurg Focus 2009;26:E5. 102. Al-Majed AA, Neumann CM, Brushart TM, Gordon T. Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J Neurosci. 2000;20:2602–2608. 103. Huang J, Lu L, Zhang J, et al. Electrical stimulation to conductive scaffold promotes axonal regeneration and remyelination in a rat model of large nerve defect. PLoS One 2012;7:e39526. 104. Krarup C, Archibald SJ, Madison RD. Factors that influence peripheral nerve regeneration: An electrophysiological study of the monkey median nerve. Ann Neurol. 2002;51:69–81. 105. Brenner MJ, Moradzadeh A, Myckatyn TM, et al. Role of timing in assessment of nerve regeneration. Microsurgery 2008;28:265–272.

Contribute to Plastic Surgery History The Journal seeks to publish historical photographs that pertain to plastic and reconstructive surgery. We are interested in the following subject areas: • Departmental photographs • Key historical people • Meetings/gatherings of plastic surgeons • Photographs of operations/early surgical procedures • Early surgical instruments and devices Please send your high-resolution photographs, along with a brief picture caption, via email to the Journal Editorial Office ([email protected]). Photographs will be chosen and published at the Editor-inChief’s discretion.

1430

Nerve conduits for peripheral nerve surgery.

Autologous nerve grafts are the current criterion standard for repair of peripheral nerve injuries when the transected nerve ends are not amenable to ...
368KB Sizes 4 Downloads 4 Views