Original Article
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Biologic Strategies to Improve Nerve Regeneration after Peripheral Nerve Repair John R. Fowler, MD1
Mitra Lavasani, PhD2
Johnny Huard, PhD2
1 Department of Orthopaedics, University of Pittsburgh,
Pittsburgh, Pennsylvania 2 Stem Cell Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
Robert J. Goitz, MD1
Address for correspondence John R. Fowler, MD, Suite 1010, Kaufmann Bldg, 3471 Fifth Ave., Pittsburgh, PA 15213 (e-mail: [email protected]).
Abstract
Keywords
► Schwann cells ► stem cells ► nerve repair
Background Peripheral nerve injuries remain a challenging problem for microsurgeons. Direct repair is the gold standard, but often the surgeon is left with a gap that prevents tension-free repair. The use of empty tubes/conduits/allograft has resulted in regeneration of some sensory and motor function, but the results remain suboptimal compared with autograft. However, the use of nerve autograft has associated donor site morbidity and limited availability. Methods A review of the literature was performed to determine current biologic strategies to improve nerve regeneration after nerve repair. Results Nerve conduits, various neurotrophic factors, and stem cells are currently being studied as alternatives to the use of nerve autograft. Conclusions Sensory and motor recovery after peripheral nerve regeneration remains suboptimal, especially in cases where primary nerve repair is not possible. Current strategies to augment nerve regeneration have focused on modulating the presence and activity of Schwann cells, either through direct implantation or by stimulating stem cells to differentiate toward Schwann cells, and through the use of neurotrophic factors to enhance the speed and quality of axon growth. Clinical studies will be necessary to determine the benefit of these strategies.
Traumatic peripheral nerve injuries affect 350,000 patients per year,1 accounting for $150 billion in annual health care costs.2 Direct nerve repair is the gold standard, however, surgeons often find a gap that prevents a tension-free direct repair. Autograft appears to be the ideal choice for bridging these gaps, but it is associated with donor site morbidity and has limited availability.2 There have been multiple recent reviews detailing a variety of conduit and allograft options for reconstruction.3–9 Successful reconstruction of a nerve gap requires a scaffold, vascular ingrowth, fibroblasts, and Schwann cells.10 The ideal scaffold would have a microstructure to guide regenerating axons and secrete growth factors and local signaling factors. Nerve autograft allows revascularization within 48 to 72 hours because of existing vascular
networks, compared with greater than 7 days for conduits and allograft.11 Despite our best efforts, nerve repair has resulted in suboptimal clinical results. The purpose of this article is to review the current strategies for augmenting nerve repair, including the use of nerve conduits, neurotrophic factors, Schwann cells, and stem cell therapies.
received July 10, 2014 accepted after revision August 27, 2014 published online December 12, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Nerve Conduits (Tubulization) The donor site morbidity and limited availability of nerve autograft has led to the development or alternative methods to bridge nerve gaps that are unable to be directly repaired. Although early attempts at bridging nerve gaps were first
DOI http://dx.doi.org/ 10.1055/s-0034-1394091. ISSN 0743-684X.
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documented in the late 1800s, contemporary bioabsorbable nerve conduits were first described in 1988.12,13 Nerve conduits of various absorbable materials (collagen, polyglycolic acid, silicone, and polycaprolactone) have been developed and studied clinically.13 Unfortunately, heterogeneous groups of patients, variable nerve gap size, and lack of standardized outcome measurements limits our ability to make definitive conclusions on their efficacy. An excellent recent review of the history and current use of conduits was performed by Konofaos and Ver Halen.13 A brief summary of current clinical studies using absorbable nerve conduits is provided later. Lohmeyer et al14 performed 55 nerve reconstructions using collagen conduits in 45 patients, with a mean nerve gap of 12 mm, and had 82% follow-up at 12 months. The authors noted that 51% of patients had two-point discrimination < 10 mm at 12 months and 77% had at least protective sensation. Boeckstyns et al 3 performed a prospective randomized trial comparing use of a collagen conduit with a nerve gap of < 6 mm to direct repair for mixed motor nerves (median and ulnar). A total of 23 patients received conduits and 21 underwent direct repair. The direct repair group showed a trend toward improved outcomes, but there was no statistical difference. Bushnell et al5 reported a series of 12 digital nerve gaps of 10 to 12 mm over a 2-year period. The authors reported that 44% had excellent results, 44% had good results, and 11% had fair results with an average DASH score of 10 points. Five patients had full sensory recovery, two patients had diminished sensory recovery, one patient had diminished protective sensation, and one patient had loss of sensation. In a prospective case series of 15 patients undergoing secondary nerve reconstructions of digital nerve gaps measuring approximately 17 mm with polyglycolic acid tubes, Mackinnon and Dellon15 found that 5 patients (33%) had excellent sensory recovery, 8 patients (53%) had good recovery, and 2 patients (14%) had poor or no recovery. Mackinnon and Dellon concluded that polyglycolic acid tubes could produce results equivalent to the classic nerve graft without donor site morbidity with gaps up to 3 cm. In a cohort study, Battiston et al16 examined the utility of polyglycolic acid tubes compared with biologically constructed muscle–vein conduits reporting equivalent results for digital nerve reconstruction. Muscle–vein combined conduits were used in 13 patients and polyglycolic acid conduits were used in 17 patients. The results showed no notable differences between the two groups with respect to evaluation testing used, although the polyglycolic acid group achieved S4 sensation (excellent sensibility) in 12% (2 of 17) compared with 38% (5 of 13) of the muscle–vein conduit group. Weber et al9 compared polyglycolic acid conduits with primary repair or autograft for digital nerve injuries. A total of 98 patients with 136 digital nerve repairs were prospectively randomized to either a group undergoing direct end-to-end repair or utilizing a nerve graft or a group undergoing repair with a polyglycolic acid conduit. The authors reported that conduits were superior in gaps of less than or equal to 4 mm and/or more than 8 mm. This study provided evidence that polyglycolic acid nerve conduits produce equivalent results to Journal of Reconstructive Microsurgery
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nerve repair or autologous grafts for short or moderate digital nerve gaps. Haug et al17 reviewed sensory outcomes in 45 digital nerve gaps up to 2.6 cm in size treated with conduits. The authors used a complicated scoring system and stated that 60% of the patients achieved good or excellent outcomes. Rinker and Liau18 performed a prospective randomized study comparing autogenous vein conduits with synthetic polyglycolic acid conduits for digital nerve gaps of 4 to 25 mm. Overall, 42 patients with 76 repairs were enrolled in the study, 36 with synthetic polyglycolic acid and 32 with vein conduits. The authors analyzed sensory recovery at 6 and 12 months after repair, the time and cost of repair, and the complication profile between the two treatment groups, and found equivalent results with similar cost profiles and sensory recovery outcomes.
Neurotrophic Factors Irreversible motor end-plate destruction occurs in the setting of chronic denervation. Therefore, there has been interest in ways to speed nerve regeneration through the use of immunosuppression and/or neurotrophic factors. FK506 is a drug used for immunosuppression after solid organ transplantation. Its immunosuppressive properties are due to inhibition of T-cell activation genes.19 Several authors have found that FK506 increases the rate of axonal regeneration after crush injury to a nerve20,21 and after nerve repair.22–24 Udina et al25 demonstrated that FK506 increased axonal regeneration and collateral sprouting in a mouse model. Lee et al compared the effects of cyclosporine to FK506 in a rat model21 and found that FK506 was superior to cyclosporine and control groups with respect to hindlimb function. Mohammadi et al26 bridged a 10-mm sciatic nerve defect in a rat model with a silicone tube filled with hepatocyte growth factor (HGF). The authors found an increased muscle mass in the HGF filled tube compared with an empty tube. The authors noted that HGF receptors are upregulated in the distal stump after sciatic nerve transection, possibly suggesting a need for HGF to improve nerve regeneration. Li et al27 found similar benefits using HGF in conjunction with acellular nerve allografts. Mohammadi et al, using the same sciatic nerve defect model with silicone tube graft, also found beneficial effects of adrenocortiotropic hormone (ACTH). ACTH is believed to exert its neurotrophic effects by mimicking and amplifying endogenous peptides.28 Vascular endothelial growth factor (VEGF) also demonstrated improved nerve regeneration over the controls. The improved outcomes were theorized to be due to the ability of VEGF to improve microcirculation, thus allowing the delivery of stem cells and the prevention of scarring.29 Celecoxib30 and dexamethasone31 exhibit neuroprotective effects through inhibition of the cyclooxygenase-2 (COX-2) pathway and the blockade of inflammatory cytokines. Compared with empty silicone tubes, addition of celecoxib and dexamethasone resulted in significantly improved nerve regeneration.
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Insulin-like growth factor (IGF) has been found to be mitogenic to Schwann cells, thus increasing axon outgrowth. Mohammadi et al32 found improved nerve regeneration in silicone tubes filled with IGF, compared with empty silicone tubes on nerve healing. Emel et al33 compared IGF-1 to platelet-rich plasma (PRP) in a rat sciatic nerve crush model and found IGF-1 to be superior to PRP and saline controls. PRP is postulated to improve nerve regeneration because it contains many growth factors, including VEGF, IGF, and others. Lichtenfels et al compared PRP and platelet-rich fibrin to saline controls and found positive effects, but no significant improvement with histomorphometric analysis was found.34 Piskin et al35 echoed these results and did not find a beneficial effect of platelet gel when used with collagen conduits. In contrast, Sabongi et al compared outcomes in 30 rats, with an 8-mm sciatic nerve gap, randomized to one of three groups: nerve autograft, vein graft with PRP, and controls (no nerve injury).36 The authors examined functional outcomes during a walking track test, performed a morphologic and morphometric analysis of the sciatic nerve, and performed Fluoro-gold staining. The nerve autograft and PRP groups performed similarly on the walking track test and had similar findings with respect to the number and caliber of neurons on histologic analysis. Given these findings, the authors suggested that vein grafts filled with PRP may be an acceptable alternative to nerve autograft. Giannessi et al created a suturable PRP membrane and used it to supplement direct repair of sciatic nerve injuries in a rat model.37 The authors showed that sciatic nerves treated with the PRP membrane had improved electromyography characteristics compared with controls and found less epineural scarring in treated rats.
Schwann Cells Early research focused on the implantation of Schwann cells at the site of injury/repair. Schwann cells play an important role in peripheral nerve regeneration. After an injury, Wallerian degeneration occurs distally, removing debris. Schwann cells then proliferate and form Bungner bands to support and direct axon growth.38 Schwann cells synthesize cell adhesion molecules (CAMs) and release growth factors that optimize basement membranes for guidance and support of sprouting axons.39–41 Schwann cells and their basal lamina function as scaffolds, allowing regenerating axons to grow through the empty basal lamina.42 Schwann cells provide bioactive substrates on which axons migrate and have been shown to release factors that regulate axonal outgrowth.43,44 Weber and Mackinnon45 and Hudson et al46 suggested that Schwann cell implantation may improve peripheral nerve regeneration. Because of the importance of Schwann cells in peripheral nerve repair and regeneration, much research has been focused on modulating their presence and activity. There have been mixed results in animal models using various grafts/conduits seeded with harvested Schwann cells. Sun et al demonstrated that acellular nerve allografts seeded with Schwann cells harvested from the brachial plexus of
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young rats resulted in improved outcomes over acellular nerve allograft alone in a rat sciatic nerve gap model.47 Berrocal et al1 echoed these findings by bridging a sciatic nerve defect in a rat model with a collagen conduit filled with autologous Schwann cells. The Schwann cell–filled collagen conduits had superior results to serum-filled conduits and similar results to reversed autograft. In contrast, Aszmann et al48 harvested Schwann cells from the proximal neuroma stump and used these Schwann cells to seed an acellular nerve homograft. The authors found disappointing results with only sensory axons reaching their destination and noted that a reverse autograft control showed much better recovery. The authors theorized that Schwann cells likely secrete a variety of paracrine factors necessary for repair and these may not reach a high enough level during nerve repair/reconstruction to obtain complete nerve regeneration.48 Despite encouraging results in animal models, the clinical implantation of harvested Schwann cells has not been utilized for several reasons. First, Schwann cell harvest requires sacrifice of a healthy nerve.41,49 If it is necessary to sacrifice healthy nerve to obtain the Schwann cells, then the surgeon could elect to use nerve autograft instead with generally successful results. Second, Schwann cells are difficult to culture, requiring several weeks to obtain sufficient numbers of Schwann cells for implantation and cultures are often contaminated by other cells, making their use in acute peripheral nerve repair difficult.50 Third, Schwann cells that do not receive nerve contact lose their ability to stimulate nerve regeneration and can contribute to nerve scarring.51
Stem Cells Because of the difficulties with Schwann cell harvest and culture, stem cell–based therapies have emerged as a possible solution through differentiation into tissue-specific cell types and subsequent signaling and release of neurotrophic growth factors.50,52–54 Bone marrow–derived stem cells (BMDSC) can be induced to differentiate into nonmesencymal cells, such as Schwann cells. These cells have been shown to improve myelin formation and nerve regeneration after transplant into peripheral nerve injury models.55–57 Mesenchymal stem cells have been studied as a potential cell line for augmenting nerve regeneration as they have been shown to differentiate into multiple cell lineages, including astrocytes, oligodendrocytes, microglia, neurons, and Schwann cell–like cells.38 Ladak et al harvested mesenchymal stem cells from the bone marrow of young rats and induced them to differentiate into Schwann cell–like cells. The authors found that > 50% of the mesenchymal cells differentiated toward a Schwann cell phenotype in a rat sciatic nerve gap model. Walsh et al50 used skin-derived Schwann cells combined with freezethawed nerve graft in a 12-mm rat sciatic nerve model. The authors found viable skin-derived Schwann cells in the regenerating axons and that levels of neurotrophin production were increased over controls. Stem-cell derived Schwann cells have shown promise over conduits alone. Adipose-derived stem cells (ADSC) induced to differentiate into Schwann cells were compared with primary Journal of Reconstructive Microsurgery
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adult Schwann cells in a fibrin conduit rat model.41 The authors found similar results between the ADSC and primary adult Schwann cell groups, both better than fibrin conduit alone. di Summa et al seeded fibrin conduits with primary Schwann cells, Schwann cell–like differentiated BMDSC, and Schwann cell–like differentiated ADSC.10 The authors compared these groups to empty conduit and autograft. The seeded conduit groups demonstrated less muscle atrophy and improvement in axon myelination compared with empty conduits. The ADSC cells were the most effective cell population. Oliveira et al58 seeded polycaprolactone conduits with mesenchymal stem cells and found improved myelination and functional performance compared with empty conduits. Orbay et al59 used collagen conduits in a rat model and suspended ADSC in a collagen gel. The authors found improved results over controls and similar results to nerve autograft. Muscle-derived stem cells have been shown to stimulate the regeneration of skeletal and cardiac muscle, bone, cartilage, and bone marrow.60–63 Depending on environmental cues, human muscle progenitor cells can differentiate into neuronal and glial cells.64 Implantation of human muscle progenitor cells into a rat sciatic nerve defect resulted in an enhanced rate of nerve regeneration and reduced the amount of muscle atrophy.64 Multilineage progenitor cells have been found in the walls of blood vessels, notably in skeletal muscle. Venous grafts have been used with success to bridge nerve grafts and venous wraps have been used to augment nerve repair, suggesting an endothelial origin of these progenitor cells.65 Studies using irradiation to prevent cell migration have demonstrated that nerve regeneration with the use of vein wrapping is minimal without functional endothelial cell involvement.65 Muscle-derived progenitor cells not only provide donor cells, but also secrete local neurotrophic factors that contribute to axonal growth.64
review article, no actual patient data were used. Therefore, no informed consent was obtained.
Acknowledgments None.
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Summary Sensory and motor recovery after peripheral nerve regeneration remains suboptimal, especially in cases where primary nerve repair is not possible. Current strategies to augment nerve regeneration have focused on modulating the presence and activity of Schwann cells, either through direct implantation or by stimulating stem cells to differentiate toward Schwann cells, and through the use of neurotrophic factors to enhance the speed and quality of axon growth. Clinical studies will be necessary to determine the benefit of these strategies.
Conflicts of Interest J. R. F., M. L., J. H., and R. J. G. declare no conflicts of interest.
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Statement of Human and Animal Rights This article does not contain any studies with human or animal subjects. Statement of Informed Consent This article does not contain any identifiable patient information or any other identifying details. As this is a Journal of Reconstructive Microsurgery
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Biologic Strategies to Improve Nerve Regeneration after Peripheral Nerve Repair John R. Fowler, MD1
Mitra Lavasani, PhD2
Johnny Huard, PhD2
1 Department of Orthopaedics, University of Pittsburgh,
Pittsburgh, Pennsylvania 2 Stem Cell Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
Robert J. Goitz, MD1
Address for correspondence John R. Fowler, MD, Suite 1010, Kaufmann Bldg, 3471 Fifth Ave., Pittsburgh, PA 15213 (e-mail: [email protected]).
Abstract
Keywords
► Schwann cells ► stem cells ► nerve repair
Background Peripheral nerve injuries remain a challenging problem for microsurgeons. Direct repair is the gold standard, but often the surgeon is left with a gap that prevents tension-free repair. The use of empty tubes/conduits/allograft has resulted in regeneration of some sensory and motor function, but the results remain suboptimal compared with autograft. However, the use of nerve autograft has associated donor site morbidity and limited availability. Methods A review of the literature was performed to determine current biologic strategies to improve nerve regeneration after nerve repair. Results Nerve conduits, various neurotrophic factors, and stem cells are currently being studied as alternatives to the use of nerve autograft. Conclusions Sensory and motor recovery after peripheral nerve regeneration remains suboptimal, especially in cases where primary nerve repair is not possible. Current strategies to augment nerve regeneration have focused on modulating the presence and activity of Schwann cells, either through direct implantation or by stimulating stem cells to differentiate toward Schwann cells, and through the use of neurotrophic factors to enhance the speed and quality of axon growth. Clinical studies will be necessary to determine the benefit of these strategies.
Traumatic peripheral nerve injuries affect 350,000 patients per year,1 accounting for $150 billion in annual health care costs.2 Direct nerve repair is the gold standard, however, surgeons often find a gap that prevents a tension-free direct repair. Autograft appears to be the ideal choice for bridging these gaps, but it is associated with donor site morbidity and has limited availability.2 There have been multiple recent reviews detailing a variety of conduit and allograft options for reconstruction.3–9 Successful reconstruction of a nerve gap requires a scaffold, vascular ingrowth, fibroblasts, and Schwann cells.10 The ideal scaffold would have a microstructure to guide regenerating axons and secrete growth factors and local signaling factors. Nerve autograft allows revascularization within 48 to 72 hours because of existing vascular
networks, compared with greater than 7 days for conduits and allograft.11 Despite our best efforts, nerve repair has resulted in suboptimal clinical results. The purpose of this article is to review the current strategies for augmenting nerve repair, including the use of nerve conduits, neurotrophic factors, Schwann cells, and stem cell therapies.
received July 10, 2014 accepted after revision August 27, 2014 published online December 12, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
Nerve Conduits (Tubulization) The donor site morbidity and limited availability of nerve autograft has led to the development or alternative methods to bridge nerve gaps that are unable to be directly repaired. Although early attempts at bridging nerve gaps were first
DOI http://dx.doi.org/ 10.1055/s-0034-1394091. ISSN 0743-684X.
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documented in the late 1800s, contemporary bioabsorbable nerve conduits were first described in 1988.12,13 Nerve conduits of various absorbable materials (collagen, polyglycolic acid, silicone, and polycaprolactone) have been developed and studied clinically.13 Unfortunately, heterogeneous groups of patients, variable nerve gap size, and lack of standardized outcome measurements limits our ability to make definitive conclusions on their efficacy. An excellent recent review of the history and current use of conduits was performed by Konofaos and Ver Halen.13 A brief summary of current clinical studies using absorbable nerve conduits is provided later. Lohmeyer et al14 performed 55 nerve reconstructions using collagen conduits in 45 patients, with a mean nerve gap of 12 mm, and had 82% follow-up at 12 months. The authors noted that 51% of patients had two-point discrimination < 10 mm at 12 months and 77% had at least protective sensation. Boeckstyns et al 3 performed a prospective randomized trial comparing use of a collagen conduit with a nerve gap of < 6 mm to direct repair for mixed motor nerves (median and ulnar). A total of 23 patients received conduits and 21 underwent direct repair. The direct repair group showed a trend toward improved outcomes, but there was no statistical difference. Bushnell et al5 reported a series of 12 digital nerve gaps of 10 to 12 mm over a 2-year period. The authors reported that 44% had excellent results, 44% had good results, and 11% had fair results with an average DASH score of 10 points. Five patients had full sensory recovery, two patients had diminished sensory recovery, one patient had diminished protective sensation, and one patient had loss of sensation. In a prospective case series of 15 patients undergoing secondary nerve reconstructions of digital nerve gaps measuring approximately 17 mm with polyglycolic acid tubes, Mackinnon and Dellon15 found that 5 patients (33%) had excellent sensory recovery, 8 patients (53%) had good recovery, and 2 patients (14%) had poor or no recovery. Mackinnon and Dellon concluded that polyglycolic acid tubes could produce results equivalent to the classic nerve graft without donor site morbidity with gaps up to 3 cm. In a cohort study, Battiston et al16 examined the utility of polyglycolic acid tubes compared with biologically constructed muscle–vein conduits reporting equivalent results for digital nerve reconstruction. Muscle–vein combined conduits were used in 13 patients and polyglycolic acid conduits were used in 17 patients. The results showed no notable differences between the two groups with respect to evaluation testing used, although the polyglycolic acid group achieved S4 sensation (excellent sensibility) in 12% (2 of 17) compared with 38% (5 of 13) of the muscle–vein conduit group. Weber et al9 compared polyglycolic acid conduits with primary repair or autograft for digital nerve injuries. A total of 98 patients with 136 digital nerve repairs were prospectively randomized to either a group undergoing direct end-to-end repair or utilizing a nerve graft or a group undergoing repair with a polyglycolic acid conduit. The authors reported that conduits were superior in gaps of less than or equal to 4 mm and/or more than 8 mm. This study provided evidence that polyglycolic acid nerve conduits produce equivalent results to Journal of Reconstructive Microsurgery
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nerve repair or autologous grafts for short or moderate digital nerve gaps. Haug et al17 reviewed sensory outcomes in 45 digital nerve gaps up to 2.6 cm in size treated with conduits. The authors used a complicated scoring system and stated that 60% of the patients achieved good or excellent outcomes. Rinker and Liau18 performed a prospective randomized study comparing autogenous vein conduits with synthetic polyglycolic acid conduits for digital nerve gaps of 4 to 25 mm. Overall, 42 patients with 76 repairs were enrolled in the study, 36 with synthetic polyglycolic acid and 32 with vein conduits. The authors analyzed sensory recovery at 6 and 12 months after repair, the time and cost of repair, and the complication profile between the two treatment groups, and found equivalent results with similar cost profiles and sensory recovery outcomes.
Neurotrophic Factors Irreversible motor end-plate destruction occurs in the setting of chronic denervation. Therefore, there has been interest in ways to speed nerve regeneration through the use of immunosuppression and/or neurotrophic factors. FK506 is a drug used for immunosuppression after solid organ transplantation. Its immunosuppressive properties are due to inhibition of T-cell activation genes.19 Several authors have found that FK506 increases the rate of axonal regeneration after crush injury to a nerve20,21 and after nerve repair.22–24 Udina et al25 demonstrated that FK506 increased axonal regeneration and collateral sprouting in a mouse model. Lee et al compared the effects of cyclosporine to FK506 in a rat model21 and found that FK506 was superior to cyclosporine and control groups with respect to hindlimb function. Mohammadi et al26 bridged a 10-mm sciatic nerve defect in a rat model with a silicone tube filled with hepatocyte growth factor (HGF). The authors found an increased muscle mass in the HGF filled tube compared with an empty tube. The authors noted that HGF receptors are upregulated in the distal stump after sciatic nerve transection, possibly suggesting a need for HGF to improve nerve regeneration. Li et al27 found similar benefits using HGF in conjunction with acellular nerve allografts. Mohammadi et al, using the same sciatic nerve defect model with silicone tube graft, also found beneficial effects of adrenocortiotropic hormone (ACTH). ACTH is believed to exert its neurotrophic effects by mimicking and amplifying endogenous peptides.28 Vascular endothelial growth factor (VEGF) also demonstrated improved nerve regeneration over the controls. The improved outcomes were theorized to be due to the ability of VEGF to improve microcirculation, thus allowing the delivery of stem cells and the prevention of scarring.29 Celecoxib30 and dexamethasone31 exhibit neuroprotective effects through inhibition of the cyclooxygenase-2 (COX-2) pathway and the blockade of inflammatory cytokines. Compared with empty silicone tubes, addition of celecoxib and dexamethasone resulted in significantly improved nerve regeneration.
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Insulin-like growth factor (IGF) has been found to be mitogenic to Schwann cells, thus increasing axon outgrowth. Mohammadi et al32 found improved nerve regeneration in silicone tubes filled with IGF, compared with empty silicone tubes on nerve healing. Emel et al33 compared IGF-1 to platelet-rich plasma (PRP) in a rat sciatic nerve crush model and found IGF-1 to be superior to PRP and saline controls. PRP is postulated to improve nerve regeneration because it contains many growth factors, including VEGF, IGF, and others. Lichtenfels et al compared PRP and platelet-rich fibrin to saline controls and found positive effects, but no significant improvement with histomorphometric analysis was found.34 Piskin et al35 echoed these results and did not find a beneficial effect of platelet gel when used with collagen conduits. In contrast, Sabongi et al compared outcomes in 30 rats, with an 8-mm sciatic nerve gap, randomized to one of three groups: nerve autograft, vein graft with PRP, and controls (no nerve injury).36 The authors examined functional outcomes during a walking track test, performed a morphologic and morphometric analysis of the sciatic nerve, and performed Fluoro-gold staining. The nerve autograft and PRP groups performed similarly on the walking track test and had similar findings with respect to the number and caliber of neurons on histologic analysis. Given these findings, the authors suggested that vein grafts filled with PRP may be an acceptable alternative to nerve autograft. Giannessi et al created a suturable PRP membrane and used it to supplement direct repair of sciatic nerve injuries in a rat model.37 The authors showed that sciatic nerves treated with the PRP membrane had improved electromyography characteristics compared with controls and found less epineural scarring in treated rats.
Schwann Cells Early research focused on the implantation of Schwann cells at the site of injury/repair. Schwann cells play an important role in peripheral nerve regeneration. After an injury, Wallerian degeneration occurs distally, removing debris. Schwann cells then proliferate and form Bungner bands to support and direct axon growth.38 Schwann cells synthesize cell adhesion molecules (CAMs) and release growth factors that optimize basement membranes for guidance and support of sprouting axons.39–41 Schwann cells and their basal lamina function as scaffolds, allowing regenerating axons to grow through the empty basal lamina.42 Schwann cells provide bioactive substrates on which axons migrate and have been shown to release factors that regulate axonal outgrowth.43,44 Weber and Mackinnon45 and Hudson et al46 suggested that Schwann cell implantation may improve peripheral nerve regeneration. Because of the importance of Schwann cells in peripheral nerve repair and regeneration, much research has been focused on modulating their presence and activity. There have been mixed results in animal models using various grafts/conduits seeded with harvested Schwann cells. Sun et al demonstrated that acellular nerve allografts seeded with Schwann cells harvested from the brachial plexus of
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young rats resulted in improved outcomes over acellular nerve allograft alone in a rat sciatic nerve gap model.47 Berrocal et al1 echoed these findings by bridging a sciatic nerve defect in a rat model with a collagen conduit filled with autologous Schwann cells. The Schwann cell–filled collagen conduits had superior results to serum-filled conduits and similar results to reversed autograft. In contrast, Aszmann et al48 harvested Schwann cells from the proximal neuroma stump and used these Schwann cells to seed an acellular nerve homograft. The authors found disappointing results with only sensory axons reaching their destination and noted that a reverse autograft control showed much better recovery. The authors theorized that Schwann cells likely secrete a variety of paracrine factors necessary for repair and these may not reach a high enough level during nerve repair/reconstruction to obtain complete nerve regeneration.48 Despite encouraging results in animal models, the clinical implantation of harvested Schwann cells has not been utilized for several reasons. First, Schwann cell harvest requires sacrifice of a healthy nerve.41,49 If it is necessary to sacrifice healthy nerve to obtain the Schwann cells, then the surgeon could elect to use nerve autograft instead with generally successful results. Second, Schwann cells are difficult to culture, requiring several weeks to obtain sufficient numbers of Schwann cells for implantation and cultures are often contaminated by other cells, making their use in acute peripheral nerve repair difficult.50 Third, Schwann cells that do not receive nerve contact lose their ability to stimulate nerve regeneration and can contribute to nerve scarring.51
Stem Cells Because of the difficulties with Schwann cell harvest and culture, stem cell–based therapies have emerged as a possible solution through differentiation into tissue-specific cell types and subsequent signaling and release of neurotrophic growth factors.50,52–54 Bone marrow–derived stem cells (BMDSC) can be induced to differentiate into nonmesencymal cells, such as Schwann cells. These cells have been shown to improve myelin formation and nerve regeneration after transplant into peripheral nerve injury models.55–57 Mesenchymal stem cells have been studied as a potential cell line for augmenting nerve regeneration as they have been shown to differentiate into multiple cell lineages, including astrocytes, oligodendrocytes, microglia, neurons, and Schwann cell–like cells.38 Ladak et al harvested mesenchymal stem cells from the bone marrow of young rats and induced them to differentiate into Schwann cell–like cells. The authors found that > 50% of the mesenchymal cells differentiated toward a Schwann cell phenotype in a rat sciatic nerve gap model. Walsh et al50 used skin-derived Schwann cells combined with freezethawed nerve graft in a 12-mm rat sciatic nerve model. The authors found viable skin-derived Schwann cells in the regenerating axons and that levels of neurotrophin production were increased over controls. Stem-cell derived Schwann cells have shown promise over conduits alone. Adipose-derived stem cells (ADSC) induced to differentiate into Schwann cells were compared with primary Journal of Reconstructive Microsurgery
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adult Schwann cells in a fibrin conduit rat model.41 The authors found similar results between the ADSC and primary adult Schwann cell groups, both better than fibrin conduit alone. di Summa et al seeded fibrin conduits with primary Schwann cells, Schwann cell–like differentiated BMDSC, and Schwann cell–like differentiated ADSC.10 The authors compared these groups to empty conduit and autograft. The seeded conduit groups demonstrated less muscle atrophy and improvement in axon myelination compared with empty conduits. The ADSC cells were the most effective cell population. Oliveira et al58 seeded polycaprolactone conduits with mesenchymal stem cells and found improved myelination and functional performance compared with empty conduits. Orbay et al59 used collagen conduits in a rat model and suspended ADSC in a collagen gel. The authors found improved results over controls and similar results to nerve autograft. Muscle-derived stem cells have been shown to stimulate the regeneration of skeletal and cardiac muscle, bone, cartilage, and bone marrow.60–63 Depending on environmental cues, human muscle progenitor cells can differentiate into neuronal and glial cells.64 Implantation of human muscle progenitor cells into a rat sciatic nerve defect resulted in an enhanced rate of nerve regeneration and reduced the amount of muscle atrophy.64 Multilineage progenitor cells have been found in the walls of blood vessels, notably in skeletal muscle. Venous grafts have been used with success to bridge nerve grafts and venous wraps have been used to augment nerve repair, suggesting an endothelial origin of these progenitor cells.65 Studies using irradiation to prevent cell migration have demonstrated that nerve regeneration with the use of vein wrapping is minimal without functional endothelial cell involvement.65 Muscle-derived progenitor cells not only provide donor cells, but also secrete local neurotrophic factors that contribute to axonal growth.64
review article, no actual patient data were used. Therefore, no informed consent was obtained.
Acknowledgments None.
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Summary Sensory and motor recovery after peripheral nerve regeneration remains suboptimal, especially in cases where primary nerve repair is not possible. Current strategies to augment nerve regeneration have focused on modulating the presence and activity of Schwann cells, either through direct implantation or by stimulating stem cells to differentiate toward Schwann cells, and through the use of neurotrophic factors to enhance the speed and quality of axon growth. Clinical studies will be necessary to determine the benefit of these strategies.
Conflicts of Interest J. R. F., M. L., J. H., and R. J. G. declare no conflicts of interest.
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Statement of Human and Animal Rights This article does not contain any studies with human or animal subjects. Statement of Informed Consent This article does not contain any identifiable patient information or any other identifying details. As this is a Journal of Reconstructive Microsurgery
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