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1.  Alignment and composition of laminin–polycaprolactone nanofiber blends enhance peripheral nerve regeneration 
Peripheral nerve transection occurs commonly in traumatic injury, causing deficits distal to the injury site. Conduits for repair currently on the market are hollow tubes; however, they often fail due to slow regeneration over long gaps. To facilitate increased regeneration speed and functional recovery, the ideal conduit should provide biochemically relevant signals and physical guidance cues, thus playing an active role in regeneration. To that end, laminin and laminin–polycaprolactone (PCL) blend nanofibers were fabricated to mimic peripheral nerve basement membrane. In vitro assays established 10% (wt) laminin content is sufficient to retain neurite-promoting effects of laminin. In addition, modified collector plate design to introduce an insulating gap enabled the fabrication of aligned nanofibers. The effects of laminin content and fiber orientation were evaluated in rat tibial nerve defect model. The lumens of conduits were filled with nanofiber meshes of varying laminin content and alignment to assess changes in motor and sensory recovery. Retrograde nerve conduction speed at 6 weeks was significantly faster in animals receiving aligned nanofiber conduits than in those receiving random nanofiber conduits. Animals receiving nanofiber-filled conduits showed some conduction in both anterograde and retrograde directions, whereas in animals receiving hollow conduits, no impulse conduction was detected. Aligned PCL nanofibers significantly improved motor function; aligned laminin blend nanofibers yielded the best sensory function recovery. In both cases, nanofiber-filled conduits resulted in better functional recovery than hollow conduits. These studies provide a firm foundation for the use of natural–synthetic blend electrospun nanofibers to enhance existing hollow nerve guidance conduits.
PMCID: PMC3550006  PMID: 22106069
biomimetic material; ECM; laminin; nerve regeneration; nanotopography
2.  Allotransplanted Neurons Used to Repair Peripheral Nerve Injury Do Not Elicit Overt Immunogenicity 
PLoS ONE  2012;7(2):e31675.
A major problem hindering the development of autograft alternatives for repairing peripheral nerve injuries is immunogenicity. We have previously shown successful regeneration in transected rat sciatic nerves using conduits filled with allogeneic dorsal root ganglion (DRG) cells without any immunosuppression. In this study, we re-examined the immunogenicity of our DRG neuron implanted conduits as a potential strategy to overcome transplant rejection. A biodegradable NeuraGen® tube was infused with pure DRG neurons or Schwann cells cultured from a rat strain differing from the host rats and used to repair 8 mm gaps in the sciatic nerve. We observed enhanced regeneration with allogeneic cells compared to empty conduits 16 weeks post-surgery, but morphological analyses suggest recovery comparable to the healthy nerves was not achieved. The degree of regeneration was indistinguishable between DRG and Schwann cell allografts although immunogenicity assessments revealed substantially increased presence of Interferon gamma (IFN-γ) in Schwann cell allografts compared to the DRG allografts by two weeks post-surgery. Macrophage infiltration of the regenerated nerve graft in the DRG group 16 weeks post-surgery was below the level of the empty conduit (0.56 fold change from NG; p<0.05) while the Schwann cell group revealed significantly higher counts (1.29 fold change from NG; p<0.001). Major histocompatibility complex I (MHC I) molecules were present in significantly increased levels in the DRG and Schwann cell allograft groups compared to the hollow NG conduit and the Sham healthy nerve. Our results confirmed previous studies that have reported Schwann cells as being immunogenic, likely due to MHC I expression. Nerve gap injuries are difficult to repair; our data suggest that DRG neurons are superior medium to implant inside conduit tubes due to reduced immunogenicity and represent a potential treatment strategy that could be preferable to the current gold standard of autologous nerve transplant.
PMCID: PMC3276507  PMID: 22347502
3.  Guided regeneration with resorbable conduits in experimental peripheral nerve injuries 
International Orthopaedics  2000;24(3):121-125.
Guided tissue regeneration is a new approach in the reconstructive surgery of peripheral nerves. Artificial conduits can be constructed from biodegradable polymers. Lactic/caproic acid copolymers and polyphospazenes are biocompatible materials with a slow resorption rate. Conduits made from either poly-[l-lactide-co-6-caprolatone] or poly-[bis-(ethylalanate)-phosphazene] were assessed for use as guides for nerve regeneration in experimental animals. Under general anesthesia and by using a microsurgery technique both sciatic nerves were exposed in 2 groups of 9 Wistar rats. On the right side, a 10 mm segment of the nerve was removed, and the defect was then repaired using a conduit. On the left side, the same defect was bridged using as an autograft the nerve segment, which had been removed from the right sciatic nerve. Histological and electron microscopy investigations were performed after 30, 90 and 180 days and showed the gradual degradation of both types of conduits without any evidence of local toxicity. The regeneration of the nerve fibers in the lumen was not significantly different from that shown by the autologous grafts. Likewise, no differences were found at 180 days in the functional recovery of the nerve (evoked muscle action potential). Both conduits were found to be effective for guided nerve regeneration. Poly-[l-lactide-co-6-caprolactone] tubes were easier to insert, while polyphosphazene conduits allowed the use of neurite-promoting factors.
PMCID: PMC3619877  PMID: 10990379
4.  Enhanced Femoral Nerve Regeneration After Tubulization with a Tyrosine-Derived Polycarbonate Terpolymer: Effects of Protein Adsorption and Independence of Conduit Porosity 
Tissue Engineering. Part A  2013;20(3-4):518-528.
Following complete nerve transection, entubulation of the nerve stumps helps guide axons to reconnect distally. In this study, a biodegradable and noncytotoxic tyrosine-derived polycarbonate terpolymer composed of 89.5 mol% desaminotyrosyl tyrosine ethyl ester (DTE), 10 mol% desaminotyrosyl tyrosine (DT), and 0.5 mol% poly(ethylene glycol) (PEG, molecular weight [Mw]=1 kDa) [designated as E10-0.5(1K)] was used to fabricate conduits for peripheral nerve regeneration. These conduits were evaluated against commercially available nonporous polyethylene (PE) tubes. The two materials are characterized in vitro for differences in surface properties, and the conduits are then evaluated in vivo in a critical-sized nerve defect in the mouse femoral nerve model. Conduits were fabricated from E10-0.5(1K) in both porous [P-E10-0.5(1K)] and nonporous [NP-E10-0.5(1K)] configurations. The results illustrate that adsorption of laminin, fibronectin, and collagen type I was enhanced on E10-0.5(1K) compared to PE. In addition, in vivo the E10-0.5(1K) conduits improved functional recovery over PE conduits, producing regenerated nerves with a fivefold increase in the number of axons, and an eightfold increase in the percentage of myelinated axons. These increases were observed for both P-E10-0.5(1K) and NP-E10-0.5(1K) after 15 weeks. When conduits were removed at 7 or 14 days following implantation, an increase in Schwann cell proteins and fibrin matrix formation was observed in E10-0.5(1K) conduits over PE conduits. These results indicate that E10-0.5(1K) is a pro-regenerative material for peripheral nerves and that the porosity of P-E10-0.5(1K) conduits was inconsequential in this model of nerve injury.
PMCID: PMC3926162  PMID: 24011026
5.  Sciatic nerve regeneration in rats by a promising electrospun collagen/poly(ε-caprolactone) nerve conduit with tailored degradation rate 
BMC Neuroscience  2011;12:68.
To cope with the limitations faced by autograft acquisitions particularly for multiple nerve injuries, artificial nerve conduit has been introduced by researchers as a substitute for autologous nerve graft for the easy specification and availability for mass production. In order to best mimic the structures and components of autologous nerve, great efforts have been made to improve the designation of nerve conduits either from materials or fabrication techniques. Electrospinning is an easy and versatile technique that has recently been used to fabricate fibrous tissue-engineered scaffolds which have great similarity to the extracellular matrix on fiber structure.
In this study we fabricated a collagen/poly(ε-caprolactone) (collagen/PCL) fibrous scaffold by electrospinning and explored its application as nerve guide substrate or conduit in vitro and in vivo. Material characterizations showed this electrospun composite material which was made of submicron fibers possessed good hydrophilicity and flexibility. In vitro study indicated electrospun collagen/PCL fibrous meshes promoted Schwann cell adhesion, elongation and proliferation. In vivo test showed electrospun collagen/PCL porous nerve conduits successfully supported nerve regeneration through an 8 mm sciatic nerve gap in adult rats, achieving similar electrophysiological and muscle reinnervation results as autografts. Although regenerated nerve fibers were still in a pre-mature stage 4 months postoperatively, the implanted collagen/PCL nerve conduits facilitated more axons regenerating through the conduit lumen and gradually degraded which well matched the nerve regeneration rate.
All the results demonstrated this collagen/PCL nerve conduit with tailored degradation rate fabricated by electrospinning could be an efficient alternative to autograft for peripheral nerve regeneration research. Due to its advantage of high surface area for cell attachment, it is believed that this electrospun nerve conduit could find more application in cell therapy for nerve regeneration in future, to further improve functional regeneration outcome especially for longer nerve defect restoration.
PMCID: PMC3148572  PMID: 21756368
6.  Use new PLGL-RGD-NGF nerve conduits for promoting peripheral nerve regeneration 
Nerve conduits provide a promising strategy for peripheral nerve injury repair. However, the efficiency of nerve conduits to enhance nerve regeneration and functional recovery is often inferior to that of autografts. Nerve conduits require additional factors such as cell adhesion molecules and neurotrophic factors to provide a more conducive microenvironment for nerve regeneration.
In the present study, poly{(lactic acid)-co-[(glycolic acid)-alt-(L-lysine)]} (PLGL) was modified by grafting Gly-Arg-Gly-Asp-Gly (RGD peptide) and nerve growth factor (NGF) for fabricating new PLGL-RGD-NGF nerve conduits to promote nerve regeneration and functional recovery. PLGL-RGD-NGF nerve conduits were tested in the rat sciatic nerve transection model. Rat sciatic nerves were cut off to form a 10 mm defect and repaired with the nerve conduits. All of the 32 Wistar rats were randomly divided into 4 groups: group PLGL-RGD-NGF, group PLGL-RGD, group PLGL and group autograft. At 3 months after surgery, the regenerated rat sciatic nerve was evaluated by footprint analysis, electrophysiology, and histologic assessment. Experimental data were processed using the statistical software SPSS 10.0.
The sciatic function index value of groups PLGL-RGD-NGF and autograft was significantly higher than those of groups PLGL-RGD and PLGL. The nerve conduction velocities of groups PLGL-RGD-NGF and autograft were significantly faster than those of groups PLGL-RGD and PLGL. The regenerated nerves of groups PLGL-RGD-NGF and autograft were more mature than those of groups PLGL-RGD and PLGL. There was no significant difference between groups PLGL-RGD-NGF and autograft.
PLGL-RGD-NGF nerve conduits are more effective in regenerating nerves than both PLGL-RGD nerve conduits and PLGL nerve conduits. The effect is as good as that of an autograft. This work established the platform for further development of the use of PLGL-RGD-NGF nerve conduits for clinical nerve repair.
PMCID: PMC3465232  PMID: 22776032
RGD peptide; Nerve growth factor; Peripheral nerve; Nerve conduits; Nerve regeneration
7.  Photo-Crosslinked Poly(ε-caprolactone fumarate) Networks for Peripheral Nerve Regeneration: Physical Properties and Preliminary Biological Evaluations 
Acta biomaterialia  2009;5(5):1531-1542.
In an effort of achieving suitable biomaterials for peripheral nerve regeneration, we present a material design strategy of combining a crystallite-based physical network and a crosslink-based chemical network. Biodegradable polymer disks and conduits have been fabricated by photo-crosslinking three poly(ε-caprolactone fumarate)s (PCLF530, PCLF1250, and PCLF2000), which were synthesized from the precursor poly(ε-caprolactone) (PCL) diols with nominal molecular weights of 530, 1250, and 2000 g.mol−1, respectively. Thermal properties such as glass transition temperature (Tg), melting temperature (Tm), and crystallinity of photo-crosslinked PCLFs were examined and correlated with their rheological and mechanical properties. Furthermore, in vitro degradation of uncrosslinked and crosslinked PCLFs in PBS crosslinked PCLFs in 1 N NaOH aqueous solution at 37 °C was studied. In vitro cytocompatibility, attachment, and proliferation of Schwann cell precursor line SPL201 cells on three PCLF networks were investigated. Crosslinked PCLF2000 with the highest crystallinity and mechanical properties was found to best support cell attachment and proliferation. Using a new photo-crosslinking method, single-lumen crosslinked PCLF nerve conduits without defects were fabricated in a glass mold. Crosslinked PCLF2000 nerve conduits were selected for evaluation in a 1-cm gap rat sciatic nerve model. Histological evaluation demonstrated that the material was biocompatible with sufficient strength to hold sutures in place after 6 and 17 weeks of implantation. Nerve cable with myelinated axons was found in the crosslinked PCLF2000 nerve conduit.
PMCID: PMC2869216  PMID: 19171506
Poly(ε-caprolactone fumarate); Photo-crosslinking; Peripheral nerve regeneration; Cell responses
8.  Utilization of Adipose-Derived Stem Cells to Fabricate Scaffold-less Tissue Engineered Neural Conduits In Vitro 
Neuroscience  2011;201:349-356.
Peripheral nerve injuries resulting from trauma or disease often necessitate surgical intervention. While the gold standard for such repairs utilizes nerve autografts, alternatives that do not require invasive harvesting of autologous nerve tissues are currently being designed and evaluated. We previously established the use of scaffold-less engineered neural conduits fabricated from primary cells as one such alternative in sciatic nerve repair in rats (Baltich, 2010; Adams 2011). The present study establishes protocols for fabricating neural conduits from adipose-derived stem cells (ASCs) differentiated to either a fibroblast or neural lineage and co-cultured into a three-dimensional scaffold-less tissue engineered neural conduit. Addition of ascorbic acid-2-phosphate and fibroblast growth factor FGF-2 to the medium induced and differentiated ASCs to a fibroblast lineage in over 90% of the cell population, as confirmed by collagen I expression. ASC-differentiated fibroblasts formed monolayers, delaminated and formed 3-D conduits. Neurospheres were formed by culturing ASCs on non-adherent surfaces in serum-free neurobasal medium with the addition of epidermal growth factor EGF and FGF-2. The addition of 10 ng EGF and 10 ng FGF-2 produced larger and more numerous neurospheres than treatments of lower EGF and FGF-2 concentrations. Subsequent differentiation to glial-like cells was confirmed by the expression of S100. ASC-derived fibroblast monolayers and neurospheres were co-cultured to fabricate a three-dimensional scaffold-less tissue engineered neural conduit. Their nerve-like structure and incorporation of glial-like cells which would associate with regenerating axons may make these novel, stem cell derived neural conduits an efficacious technology for repairing critical gaps following peripheral nerve injury.
PMCID: PMC3258380  PMID: 22119639
Adipose-derived stem cells (ASC); peripheral nerve repair; nerve conduit; tissue engineering
9.  Sustained Growth Factor Delivery Promotes Axonal Regeneration in Long Gap Peripheral Nerve Repair 
Tissue Engineering. Part A  2011;17(9-10):1263-1275.
The aim of this study was to evaluate the long-term effect of localized growth factor delivery on sciatic nerve regeneration in a critical-size (>1 cm) peripheral nerve defect. Previous work has demonstrated that bioactive proteins can be encapsulated within double-walled, poly(lactic-co-glycolic acid)/poly(lactide) microspheres and embedded within walls of biodegradable polymer nerve guides composed of poly(caprolactone). Within this study, nerve guides containing glial cell line-derived neurotrophic factor (GDNF) were used to bridge a 1.5-cm defect in the male Lewis rat for a 16-week period. Nerve repair was evaluated through functional assessment of joint angle range of motion using video gait kinematics, gastrocnemius twitch force, and gastrocnemius wet weight. Histological evaluation of nerve repair included assessment of Schwann cell and neurofilament location with immunohistochemistry, evaluation of tissue integration and organization throughout the lumen of the regenerated nerve with Masson's trichrome stain, and quantification of axon fiber density and g-ratio. Results from this study showed that the measured gastrocnemius twitch force in animals treated with GDNF was significantly higher than negative controls and was not significantly different from the isograft-positive control group. Histological assessment of explanted conduits after 16 weeks showed improved tissue integration within GDNF releasing nerve guides compared to negative controls. Nerve fibers were present across the entire length of GDNF releasing guides, whereas nerve fibers were not detectable beyond the middle region of negative control guides. Therefore, our results support the use of GDNF for improved functional recovery above negative controls following large axonal defects in the peripheral nervous system.
PMCID: PMC3079170  PMID: 21189072
10.  Engineering Bi-Layer Nanofibrous Conduits for Peripheral Nerve Regeneration 
Trauma injuries often cause peripheral nerve damage and disability. A goal in neural tissue engineering is to develop synthetic nerve conduits for peripheral nerve regeneration having therapeutic efficacy comparable to that of autografts. Nanofibrous conduits with aligned nanofibers have been shown to promote nerve regeneration, but current fabrication methods rely on rolling a fibrous sheet into the shape of a conduit, which results in a graft with inconsistent size and a discontinuous joint or seam. In addition, the long-term effects of nanofibrous nerve conduits, in comparison with autografts, are still unknown. Here we developed a novel one-step electrospinning process and, for the first time, fabricated a seamless bi-layer nanofibrous nerve conduit: the luminal layer having longitudinally aligned nanofibers to promote nerve regeneration, and the outer layer having randomly organized nanofibers for mechanical support. Long-term in vivo studies demonstrated that bi-layer aligned nanofibrous nerve conduits were superior to random nanofibrous conduits and had comparable therapeutic effects to autografts for nerve regeneration. In summary, we showed that the engineered nanostructure had a significant impact on neural tissue regeneration in situ. The results from this study will also lead to the scalable fabrication of engineered nanofibrous nerve conduits with designed nanostructure. This technology platform can be combined with drug delivery and cell therapies for tissue engineering.
PMCID: PMC3124110  PMID: 21501089
11.  Neurotrophin releasing single and multiple lumen nerve conduits 
Tissue engineering strategies for nerve repair employ polymer conduits termed guidance channels and bridges to promote regeneration for peripheral nerve injury and spinal cord injury, respectively. An approach for fabrication of nerve conduits with single and multiple lumens capable of controlled release of neurotrophic factors was developed. These conduits were fabricated from a mixture of poly(lactide-co-glycolide) (PLG) microspheres and porogen (NaCl) that was loaded into a mold and processed by gas foaming. The porosity and mechanical properties of the constructs were regulated by the ratio of porogen to polymer microsphere. The neurotrophin, nerve growth factor (NGF), was incorporated into the conduit by either mixing the protein with microspheres or encapsulating the protein within microspheres prior to gas foaming. A sustained release was observed for at least 42 days, with the release rate controlled by method of incorporation and polymer molecular weight. Released NGF retained its bioactivity, as demonstrated by its ability to stimulate neurite outgrowth from primary dorsal root ganglion (DRG). In vivo results indicate that conduits retain their original architecture, and allow for cellular infiltration into the channels. Polymer conduits with controllable lumen diameters and protein release may enhance nerve regeneration by guiding and stimulating neurite outgrowth.
PMCID: PMC2648409  PMID: 15911044
Guidance channel; NGF; Nerve regeneration; Drug delivery
12.  Electrospun micro- and nanofiber tubes for functional nervous regeneration in sciatic nerve transections 
BMC Biotechnology  2008;8:39.
Although many nerve prostheses have been proposed in recent years, in the case of consistent loss of nervous tissue peripheral nerve injury is still a traumatic pathology that may impair patient's movements by interrupting his motor-sensory pathways. In the last few decades tissue engineering has opened the door to new approaches;: however most of them make use of rigid channel guides that may cause cell loss due to the lack of physiological local stresses exerted over the nervous tissue during patient's movement. Electrospinning technique makes it possible to spin microfiber and nanofiber flexible tubular scaffolds composed of a number of natural and synthetic components, showing high porosity and remarkable surface/volume ratio.
In this study we used electrospun tubes made of biodegradable polymers (a blend of PLGA/PCL) to regenerate a 10-mm nerve gap in a rat sciatic nerve in vivo. Experimental groups comprise lesioned animals (control group) and lesioned animals subjected to guide conduits implantated at the severed nerve stumps, where the tubular scaffolds are filled with saline solution. Four months after surgery, sciatic nerves failed to reconnect the two stumps of transected nerves in the control animal group. In most of the treated animals the electrospun tubes induced nervous regeneration and functional reconnection of the two severed sciatic nerve tracts. Myelination and collagen IV deposition have been detected in concurrence with regenerated fibers. No significant inflammatory response has been found. Neural tracers revealed the re-establishment of functional neuronal connections and evoked potential results showed the reinnervation of the target muscles in the majority of the treated animals.
Corroborating previous works, this study indicates that electrospun tubes, with no additional biological coating or drug loading treatment, are promising scaffolds for functional nervous regeneration. They can be knitted in meshes and various frames depending on the cytoarchitecture of the tissue to be regenerated. The versatility of this technique gives room for further scaffold improvements, like tuning the mechanical properties of the tubular structure or providing biomimetic functionalization. Moreover, these guidance conduits can be loaded with various fillers like collagen, fibrin, or self-assembling peptide gels or loaded with neurotrophic factors and seeded with cells. Electrospun scaffolds can also be synthesized in different micro-architectures to regenerate lesions in other tissues like skin and bone.
PMCID: PMC2358889  PMID: 18405347
13.  Use of nerve conduits for peripheral nerve injury repair: A Web of Science-based literature analysis★ 
Neural Regeneration Research  2012;7(35):2826-2833.
To identify global research trends in the use of nerve conduits for peripheral nerve injury repair.
Numerous basic and clinical studies on nerve conduits for peripheral nerve injury repair were performed between 2002–2011. We performed a bibliometric analysis of the institutions, authors, and hot topics in the field, from the Web of Science, using the key words peripheral nerve and conduit or tube.
Inclusion criteria: peer-reviewed published articles on nerve conduits for peripheral nerve injury repair, indexed in the Web of Science; original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items. Exclusion criteria: articles requiring manual searching or telephone access; documents not published in the public domain; and several corrected papers.
(a) Annual publication output; (b) publication type; (c) publication by research field; (d) publication by journal; (e) publication by funding agency; (f) publication by author; (g) publication by country and institution; (h) publications by institution in China; (i) most-cited papers.
A total of 793 publications on the use of nerve conduits for peripheral nerve injury repair were retrieved from the Web of Science between 2002–2011. The number of publications gradually increased over the 10-year study period. Articles constituted the main type of publication. The most prolific journals were Biomaterials, Microsurgery, and Journal of Biomedical Materials Research Part A. The National Natural Science Foundation of China supported 27 papers, more than any other funding agency. Of the 793 publications, almost half came from American and Chinese authors and institutions.
Nerve conduits have been studied extensively for peripheral nerve regeneration; however, many problems remain in this field, which are difficult for researchers to reach a consensus.
PMCID: PMC4190865  PMID: 25317133
nerve conduit; biomaterial; axon; neurotrophic factor; stem cell; extracellular matrix; peripheral nerve injury; peripheral nerve repair; degradation; biocompatibility; neural regeneration
14.  In vivo application of poly-3-hydroxyoctanoate as peripheral nerve graft 
Objective: This study aims to investigate the degree of biocompatibility and neuroregeneration of a polymer tube, poly-3-hydroxyoctanoate (PHO) in nerve gap repair. Methods: Forty Wistar Albino male rats were randomized into two groups: autologous nerve gap repair group and PHO tube repair group. In each group, a 10-mm right sciatic nerve defect was created and reconstructed accordingly. Neuroregeneration was studied by sciatic function index (SFI), electromyography, and immunohistochemical studies on Days 7, 21, 45 and 60 of implantation. Biocompatibility was analyzed by the capsule formation around the conduit. Biodegradation was analyzed by the molecular weight loss in vivo. Results: Electrophysiological and histomorphometric assessments demonstrated neuroregeneration in both groups over time. In the experimental group, a straight alignment of the Schwann cells parallel to the axons was detected. However, autologous nerve graft seems to have a superior neuroregeneration compared to PHO grafts. Minor biodegradation was observed in PHO conduit at the end of 60 d. Conclusions: Although neuroregeneration is detected in PHO grafts with minor degradation in 60 d, autologous nerve graft is found to be superior in axonal regeneration compared to PHO nerve tube grafts. PHO conduits were found to create minor inflammatory reaction in vivo, resulting in good soft tissue response.
PMCID: PMC3829648  PMID: 24190445
Axonal spurting; Biodegradable polymer; Neuroregeneration; Nerve grafting
15.  Biomaterials for the Development of Peripheral Nerve Guidance Conduits 
Currently, surgical treatments for peripheral nerve injury are less than satisfactory. The gold standard of treatment for peripheral nerve gaps >5 mm is the autologous nerve graft; however, this treatment is associated with a variety of clinical complications, such as donor site morbidity, limited availability, nerve site mismatch, and the formation of neuromas. Despite many recent advances in the field, clinical studies implementing the use of artificial nerve guides have yielded results that are yet to surpass those of autografts. Thus, the development of a nerve guidance conduit, which could match the effectiveness of the autologous nerve graft, would be beneficial to the field of peripheral nerve surgery. Design strategies to improve surgical outcomes have included the development of biopolymers and synthetic polymers as primary scaffolds with tailored mechanical and physical properties, luminal “fillers” such as laminin and fibronectin as secondary internal scaffolds, surface micropatterning, stem cell inclusion, and controlled release of neurotrophic factors. The current article highlights approaches to peripheral nerve repair through a channel or conduit, implementing chemical and physical growth and guidance cues to direct that repair process.
PMCID: PMC3262974  PMID: 21812591
16.  Preclinical evaluations of acellular biological conduits for peripheral nerve regeneration 
Journal of Tissue Engineering  2013;4:2041731413481036.
Various types of natural biological conduits have been investigated as alternatives to the current surgical standard approach for peripheral nerve injuries. Autologous nerve graft, the current gold standard for peripheral nerve damage, is limited by clinical challenges such as donor-site morbidity and limited availability. The purpose of this study was to evaluate the efficacy of using acellular xenographic conduits (nerve, artery, and dermis) for the repair of a 1.2 cm critical size defect of peripheral nerve in a rodent model. Four months post surgery, the animal group receiving acellular artery as a nerve conduit showed excellent physiological outcome in terms of the prevention of muscle atrophy and foot ulcer. Histological assessment of the bridged site revealed excellent axon regeneration, as opposed to the nonrepaired control group or the group receiving dermal conduit. Finally, the study evaluated the potential improvement via the addition of undifferentiated mesenchymal stem cells into the artery conduit during the bridging procedure. The mesenchymal stem cell–dosed artery conduit group resulted in significantly higher concentration of regenerated axons over artery conduit alone, and exhibited accelerated muscle atrophy rescue. Our results demonstrated that xenographic artery conduits promoted excellent axonal regeneration with highly promising clinical relevance.
PMCID: PMC3604911  PMID: 23532671
Peripheral nerve regeneration; decellularized tissue; nerve guide; mesenchymal stem cells; regenerative medicine
17.  Extracellular matrix components in peripheral nerve repair: how to affect neural cellular response and nerve regeneration? 
Neural Regeneration Research  2014;9(22):1943-1948.
Peripheral nerve injury is a serious problem affecting significantly patients’ life. Autografts are the “gold standard” used to repair the injury gap, however, only 50% of patients fully recover from the trauma. Artificial conduits are a valid alternative to repairing peripheral nerve. They aim at confining the nerve environment throughout the regeneration process, and providing guidance to axon outgrowth. Biocompatible materials have been carefully designed to reduce inflammation and scar tissue formation, but modifications of the inner lumen are still required in order to optimise the scaffolds. Biomicking the native neural tissue with extracellular matrix fillers or coatings showed great promises in repairing longer gaps and extending cell survival. In addition, extracellular matrix molecules provide a platform to further bind growth factors that can be released in the system over time. Alternatively, conduit fillers can be used for cell transplantation at the injury site, reducing the lag time required for endogenous Schwann cells to proliferate and take part in the regeneration process. This review provides an overview on the importance of extracellular matrix molecules in peripheral nerve repair.
PMCID: PMC4283273  PMID: 25598773
peripheral nerve repair; extracellular matrix; nerve conduits; surface modification; fillers; growth factors
18.  Novel use of biodegradable casein conduits for guided peripheral nerve regeneration 
Recent advances in nerve repair technology have focused on finding more biocompatible, non-toxic materials to imitate natural peripheral nerve components. In this study, casein protein cross-linked with naturally occurring genipin (genipin-cross-linked casein (GCC)) was used for the first time to make a biodegradable conduit for peripheral nerve repair. The GCC conduit was dark blue in appearance with a concentric and round lumen. Water uptake, contact angle and mechanical tests indicated that the conduit had a high stability in water and did not collapse and cramped with a sufficiently high level of mechanical properties. Cytotoxic testing and terminal deoxynucleotidyl transferase dUTP nick-end labelling assay showed that the GCC was non-toxic and non-apoptotic, which could maintain the survival and outgrowth of Schwann cells. Non-invasive real-time nuclear factor-κB bioluminescence imaging accompanied by histochemical assessment showed that the GCC was highly biocompatible after subcutaneous implantation in transgenic mice. Effectiveness of the GCC conduit as a guidance channel was examined as it was used to repair a 10 mm gap in the rat sciatic nerve. Electrophysiology, labelling of calcitonin gene-related peptide in the lumbar spinal cord, and histology analysis all showed a rapid morphological and functional recovery for the disrupted nerves. Therefore, we conclude that the GCC can offer great nerve regeneration characteristics and can be a promising material for the successful repair of peripheral nerve defects.
PMCID: PMC3177610  PMID: 21525148
casein; nerve conduit; nerve regeneration; nerve injury
19.  Enhanced peripheral nerve regeneration by the combination of a polycaprolactone tubular prosthesis and a scaffold of collagen with supramolecular organization 
Brain and Behavior  2013;3(4):417-430.
The purpose of this study was to investigate the influence of implanting collagen with a supramolecular organization on peripheral nerve regeneration, using the sciatic nerve tubulization technique. For this purpose, adult female Sprague Dawley rats were divided into five groups: (1) TP – sciatic nerve repaired with empty polyethylene tubular prothesis (n = 10), (2) TPCL – nerve repair with empty polycaprolactone (PCL) tubing (n = 8), (3) TPCLF – repair with PCL tubing filled with an implant of collagen with a supramolecular organization (n = 10), (4) AG – animals that received a peripheral nerve autograft (n = 8), and (5) Normal nerves (n = 8). The results were assessed by quantification of the regenerated fibers, nerve morphometry, and transmission electron microscopy, 60 days after surgery. Immunohistochemistry and polarization microscopy were also used to analyze the regenerated nerve structure and cellular elements. The results showed that the AG group presented a larger number of regenerated axons. However, the TPCL and TPCLF groups presented more compact regenerated fibers with a morphometric profile closer to normal, both at the tube midpoint and 2 mm distal to the prosthesis. These findings were reinforced by polarization microscopy, which indicated a better collagen/axons suprastructural organization in the TPCLF derived samples. In addition, the immunohistochemical results obtained using the antibody anti-p75NTR as a Schwann cell reactivity marker demonstrated that the Schwann cells were more reactive during the regenerative process in the TPCLF group as compared to the TPCL group and the normal sciatic nerve. Altogether, the results of this study indicated that the implant of collagen with a supramolecular organization positively influenced and stimulated the regeneration process through the nerve gap, resulting in the formation of a better morphologically arranged tissue.
PMCID: PMC3869682  PMID: 24381812
Biomaterials; collagen; nerve regeneration; polarization microscopy; tubulization
20.  Rat Sciatic Nerve Reconstruction Across a 30 mm Defect Bridged by an Oriented Porous PHBV Tube With Schwann Cell as Artificial Nerve Graft 
Asaio Journal  2014;60(2):224-233.
An oriented poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit has been used to evaluate its efficiency based on the promotion of peripheral nerve regeneration in rats. The oriented porous micropatterned artificial nerve conduit was designed onto the micropatterned silicon wafers, and then their surfaces were modified with oxygen plasma to increase cell adhesion. The designed conduits were investigated by cell culture analyses with Schwann cells (SCs). The conduits were implanted into a 30 mm gap in sciatic nerves of rats. Four months after surgery, the regenerated nerves were monitored and evaluated by macroscopic assessments and histology and behavioral analyses. Results of cellular analyses showed suitable properties of designed conduit for nerve regeneration. The results demonstrated that in the polymeric graft with SCs, the rat sciatic nerve trunk had been reconstructed with restoration of nerve continuity and formatted nerve fibers with myelination. Histological results demonstrated the presence of Schwann and glial cells in regenerated nerves. Functional recovery such as walking, swimming, and recovery of nociceptive function was illustrated for all the grafts especially conduits with SCs. This study proves the feasibility of the artificial nerve graft filled with SCs for peripheral nerve regeneration by bridging a longer defect in an animal model.
PMCID: PMC3942346  PMID: 24399063
sciatic regeneration; Schwann cell; artificial conduit; oriented PHBV; histological and behavioral assessments
21.  Comparison of divided sciatic nerve growth within dermis, venous and nerve graft conduit in rat 
Considering the common origin of skin and peripheral nervous system, a tube of dermal layer of skin hypothetically can be an ideal conduit for nerve reconstruction. An experimental study performed to evaluate the nerve regeneration of efficacy into a dermal tube.
Sixty male Wistar rats were used. A 10 mm gap was produced in right sciatic nerves. In group A the autogenous nerve grafts were used to bridge the defects. In group B vein conduit were use to reconstruct the gaps. In group C dermal tube were used to bridge the defects. Morphologic studies were carried out after 3 month.
The density of nerve fibers was significantly higher in autogenous nerve graft group. The efficacy of nerve growth into the dermal tube group was significantly poor in comparison to other groups.
In the present study, dermis was used as the nerve conduit for the first time. This study indicates that the dermal tube is not a suitable conduit for nerve regeneration till further studies to resolve the problems before clinical application.
PMCID: PMC3082818  PMID: 21526083
Nerve Injury; Nerve Gap; Nerve Conduit; Dermal Tube; Autogenous Nerve Graft
22.  A biomaterials approach to peripheral nerve regeneration: bridging the peripheral nerve gap and enhancing functional recovery 
Microsurgical techniques for the treatment of large peripheral nerve injuries (such as the gold standard autograft) and its main clinically approved alternative—hollow nerve guidance conduits (NGCs)—have a number of limitations that need to be addressed. NGCs, in particular, are limited to treating a relatively short nerve gap (4 cm in length) and are often associated with poor functional recovery. Recent advances in biomaterials and tissue engineering approaches are seeking to overcome the limitations associated with these treatment methods. This review critically discusses the advances in biomaterial-based NGCs, their limitations and where future improvements may be required. Recent developments include the incorporation of topographical guidance features and/or intraluminal structures, which attempt to guide Schwann cell (SC) migration and axonal regrowth towards their distal targets. The use of such strategies requires consideration of the size and distribution of these topographical features, as well as a suitable surface for cell–material interactions. Likewise, cellular and molecular-based therapies are being considered for the creation of a more conductive nerve microenvironment. For example, hurdles associated with the short half-lives and low stability of molecular therapies are being surmounted through the use of controlled delivery systems. Similarly, cells (SCs, stem cells and genetically modified cells) are being delivered with biomaterial matrices in attempts to control their dispersion and to facilitate their incorporation within the host regeneration process. Despite recent advances in peripheral nerve repair, there are a number of key factors that need to be considered in order for these new technologies to reach the clinic.
PMCID: PMC3243399  PMID: 22090283
peripheral nerve conduit; topographical guidance; molecular therapy; Schwann cells; stem cells; neurotrophic factors
23.  Nanofibrous nerve conduits for repair of 30-mm-long sciatic nerve defects 
Neural Regeneration Research  2013;8(24):2266-2274.
It has been confirmed that nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit can promote peripheral nerve regeneration in rats. However, its efficiency in repair of over 30-mm-long sciatic nerve defects needs to be assessed. In this study, we used a nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit to bridge a 30-mm-long gap in the rat sciatic nerve. At 4 months after nerve conduit implantation, regenerated nerves were cally observed and histologically assessed. In the nanofibrous graft, the rat sciatic nerve trunk had been reconstructed by restoration of nerve continuity and formation of myelinated nerve fiber. There were Schwann cells and glial cells in the regenerated nerves. Masson's trichrome staining showed that there were no pathological changes in the size and structure of gastrocnemius muscle cells on the operated side of rats. These findings suggest that nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit is suitable for repair of long-segment sciatic nerve defects.
PMCID: PMC4146035  PMID: 25206536
neural regeneration; peripheral nerve injury; sciatic nerve; artificial conduit; nanofiber; poly(3-hydroxybutyrate-co-3-hydroxyvalerate); macroscopic observation; histology; grants-supported paper; neuroregeneration
24.  Peripheral nerve morphogenesis induced by scaffold micropatterning 
Biomaterials  2014;35(13):4035-4045.
Several bioengineering approaches have been proposed for peripheral nervous system repair, with limited results and still open questions about the underlying molecular mechanisms. We assessed the biological processes that occur after the implantation of collagen scaffold with a peculiar porous microstructure of the wall in a rat sciatic nerve transection model compared to commercial collagen conduits and nerve crush injury using functional, histological and genome wide analyses. We demonstrated that within 60 days, our conduit had been completely substituted by a normal nerve. Gene expression analysis documented a precise sequential regulation of known genes involved in angiogenesis, Schwann cells/axons interactions and myelination, together with a selective modulation of key biological pathways for nerve morphogenesis induced by porous matrices. These data suggest that the scaffold’s microstructure profoundly influences cell behaviors and creates an instructive micro-environment to enhance nerve morphogenesis that can be exploited to improve recovery and understand the molecular differences between repair and regeneration.
PMCID: PMC4061729  PMID: 24559639
Biomaterials; Peripheral nervous system; Nerve regeneration; Medical device
25.  Role of lumbricus extract in the nerve amplification effect during peripheral nerve regeneration 
Among the methods of the peripheral nerve repair, artificial conduit bridging surgery is superior to epineurium and perineurium neurorrhaphy because of supplying enough space for nerve regeneration. Artificial conduit provides important microenvironment for peripheral nerve regeneration, especially for nerve amplification effect. Amplification phenomenon has been demonstrated in many studies using artificial conduit. When a finer nerve is used as a donor to connect to a distal nerve after injury, the donor nerve regenerates more lateral buds than its own fibers, which grow into distal endoneurial tubes and finally dominate the target organs. In this study, we used artificial conduit to investigate the amplification phenomenon in rats treated with Lumbricus extract as adjuvant treatment. The rats were divided into three groups at random. In the surgical groups, the proximal common peroneal nerve was used as a donor nerve to connect the distal tibial nerve. Rats in the normal group were not performed surgery. Postoperatively, the treatment group was administered Lumbricus extract as adjuvant treatment, while the model group and normal group were not given treatment. The results showed that the nerve conduction velocity, the morphometric measurements, the histological analysis and the amplification ratio in the treatment group were better than in the model group.
PMCID: PMC4297355  PMID: 25628798
Traditional Chinese medicine; lumbricus extract; amplification effect; lateral bud; peripheral nerve regeneration; nerve conduction velocity

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