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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.  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
4.  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
5.  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
6.  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
7.  Recent Advances and Developments in Neural Repair and Regeneration for Hand Surgery 
End-to-end suture of nerves and autologous nerve grafts are the ‘gold standard’ for repair and reconstruction of peripheral nerves. However, techniques such as sutureless nerve repair with tissue glues, end-to-side nerve repair and allografts exist as alternatives. Biological and synthetic nerve conduits have had some success in early clinical studies on reconstruction of nerve defects in the hand. The effectiveness of nerve regeneration could potentially be increased by using these nerve conduits as scaffolds for delivery of Schwann cells, stem cells, neurotrophic and neurotropic factors or extracellular matrix proteins. There has been extensive in vitro and in vivo research conducted on these techniques. The clinical applicability and efficacy of these techniques needs to be investigated fully.
PMCID: PMC3293168  PMID: 22431954
Conduits; Grafts; Repair; Neurotrophic factors; Schwann cells.
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Custom prefabrication of silicone tubes from urinary catheters for experimental peripheral nerve surgery 
The entubulation principle represents a neurobiological approach to nerve surgery in which the role of the surgeon is limited and intrinsic healing capabilities of the nerve play the primary role. Herein, a technique for fabricating custom-made silicone tubes from a silicone urinary catheter is described. Silicone tubes with varying size and dimensions can be tailored depending on the diameter of the silicone urinary catheter (14 F to 18 F). Tubes crafted from silicone urinary catheters were used either as a nerve conduit to facilitate regeneration or as compressive nerve banding to simulate compressive neuropathy in the rat sciatic nerve. Custom-made silicone tubes have similar pros and cons to the commercially available silicone tubes regarding the capsule and foreign body reaction. It can be concluded that these cost effective tubes can be easily cut and used in experimental peripheral nerve surgery in developing countries where the cost of such materials becomes an important issue for the researchers.
PMCID: PMC3792762  PMID: 24115867
Nerve conduit; Peripheral nerve surgery; Silicone tube; Urinary catheter
14.  Sciatic nerve repair with tissue engineered nerve: Olfactory ensheathing cells seeded poly(lactic-co-glygolic acid) conduit in an animal model 
Indian Journal of Orthopaedics  2013;47(6):547-552.
Background and Aim:
Synthetic nerve conduits have been sought for repair of nerve defects as the autologous nerve grafts causes donor site morbidity and possess other drawbacks. Many strategies have been investigated to improve nerve regeneration through synthetic nerve guided conduits. Olfactory ensheathing cells (OECs) that share both Schwann cell and astrocytic characteristics have been shown to promote axonal regeneration after transplantation. The present study was driven by the hypothesis that tissue-engineered poly(lactic-co-glycolic acid) (PLGA) seeded with OECs would improve peripheral nerve regeneration in a long sciatic nerve defect.
Materials and Methods:
Sciatic nerve gap of 15 mm was created in six adult female Sprague-Dawley rats and implanted with PLGA seeded with OECs. The nerve regeneration was assessed electrophysiologically at 2, 4 and 6 weeks following implantation. Histopathological examination, scanning electron microscopic (SEM) examination and immunohistochemical analysis were performed at the end of the study.
Nerve conduction studies revealed a significant improvement of nerve conduction velocities whereby the mean nerve conduction velocity increases from 4.2 ΁ 0.4 m/s at week 2 to 27.3 ΁ 5.7 m/s at week 6 post-implantation (P < 0.0001). Histological analysis revealed presence of spindle-shaped cells. Immunohistochemical analysis further demonstrated the expression of S100 protein in both cell nucleus and the cytoplasm in these cells, hence confirming their Schwann-cell-like property. Under SEM, these cells were found to be actively secreting extracellular matrix.
Tissue-engineered PLGA conduit seeded with OECs provided a permissive environment to facilitate nerve regeneration in a small animal model.
PMCID: PMC3868134  PMID: 24379458
Olfactory ensheathing cells; poly(lactic-co-glycolic acid); sciatic nerve defect; tissue engineering
15.  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
16.  Long-Term Regeneration and Functional Recovery of a 15 mm Critical Nerve Gap Bridged by Tremella fuciformis Polysaccharide-Immobilized Polylactide Conduits 
Novel peripheral nerve conduits containing the negatively charged Tremella fuciformis polysaccharide (TF) were prepared, and their efficacy in bridging a critical nerve gap was evaluated. The conduits were made of poly(D,L-lactide) (PLA) with asymmetric microporous structure. TF was immobilized on the lumen surface of the nerve conduits after open air plasma activation. The TF-modified surface was characterized by the attenuated total reflection Fourier-transformed infrared spectroscopy and the scanning electron microscopy. TF modification was found to enhance the neurotrophic gene expression of C6 glioma cells in vitro. TF-modified PLA nerve conduits were tested for their ability to bridge a 15 mm gap of rat sciatic nerve. Nerve regeneration was monitored by the magnetic resonance imaging. Results showed that TF immobilization promoted the nerve connection in 6 weeks. The functional recovery in animals receiving TF-immobilized conduits was greater than in those receiving the bare conduits during an 8-month period. The degree of functional recovery reached ~90% after 8 months in the group of TF-immobilized conduits.
PMCID: PMC3763589  PMID: 24027599
17.  Salicylic acid-derived poly(anhydride-ester) electrospun fibers designed for regenerating the peripheral nervous system 
Continuous biomaterial advances and the regenerating potential of the adult human peripheral nervous system offer great promise for restoring full function to innervated tissue following traumatic injury via synthetic nerve guidance conduits. To most effectively facilitate nerve regeneration, a tissue engineering scaffold within a conduit must be similar to the linear microenvironment of the healthy nerve. To mimic the native nerve structure, aligned poly(lactic-co-glycolic acid)/bioactive polyanhydride fibrous substrates were fabricated through optimized electrospinning parameters with diameters of 600 ± 200 nm. Scanning electron microscopy images show fibers with a high degree of alignment. Schwann cells and dissociated rat dorsal root ganglia demonstrated elongated and healthy proliferation in a direction parallel to orientated electrospun fibers with significantly longer Schwann cell process length and neurite outgrowth when compared to randomly orientated fibers. Results suggest that an aligned polyanhydride fiber mat holds tremendous promise as a supplement scaffold for the interior of a degradable polymer nerve guidance conduit. Bioactive salicylic acid based polyanhydride fibers are not limited to nerve regeneration and offer exciting promise for a wide variety of biomedical applications.
PMCID: PMC3096072  PMID: 21442724
Nerve regeneration; electrospinning; fibers; polyanhydride; salicylic acid
18.  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
19.  Biodegradable Conduit Small Gap Tubulization for Peripheral Nerve Mutilation: A Substitute for Traditional Epineurial Neurorrhaphy 
Nerve regeneration and re-innervation are usually difficult after peripheral nerve injury. Epineurium neurorrhaphy to recover the nerve continuity is the traditional choice of peripheral nerve mutilation without nerve defects, whereas the functional recovery remains quite unsatisfactory. Based on previous research in SD rats and Rhesus Monkeys, a multiple centers clinical trial about biodegradable conduit small gap tubulization for peripheral nerve mutilation to substitute traditional epineurial neurorrhaphy was carried out. Herein, the authors reviewed the literature that focused on peripheral nerve injury and possible clinical application, and confirmed the clinical possibilities of biodegradable conduit small gap tubulization to substitute traditional epineurial neurorrhaphy for peripheral nerve mutilation. The biodegradable conduit small gap tubulization to substitute traditional epineurial neurorrhaphy for peripheral nerve mutilation may be a revolutionary innovation in peripheral nerve injury and repair field.
PMCID: PMC3547215  PMID: 23329889
Biodegradable Conduit; Epineurial Neurorrhaphy; Peripheral Nerve Mutilation; Small Gap; 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.  Ferulic Acid Enhances Peripheral Nerve Regeneration across Long Gaps 
This study investigated the effect of ferulic acid (FA) on peripheral nerve injury. In the in vitro test, the effect of FA on viability of Schwann cells was studied. In the in vivo test, right sciatic nerves of the rats were transected, and a 15 mm nerve defect was created. A nerve conduit made of silicone rubber tube filled with FA (5 and 25 μg/mL), or saline (control), was implanted into the nerve defect. Results show that the number of proliferating Schwann cells increased significantly in the FA-treated group at 25 μg/mL compared to that in the control group. After 8 weeks, the FA-treated group at 25 μg/mL had a higher rate of successful regeneration across the wide gap, a significantly calcitonin gene-related peptide (CGRP) staining of the lamina I-II regions in the dorsal horn ipsilateral to the injury, a significantly diminished number of macrophages recruited, and a significantly shortening of the latency and an acceleration of the nerve conductive velocity (NCV) of the evoked muscle action potentials (MAPs) compared with the controls. In summary, the FA may be useful in the development of future strategies for the treatment of peripheral nerve injury.
PMCID: PMC3652149  PMID: 23690861
22.  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
23.  Types of neural guides and using nanotechnology for peripheral nerve reconstruction 
Peripheral nerve injuries can lead to lifetime loss of function and permanent disfigurement. Different methods, such as conventional allograft procedures and use of biologic tubes present problems when used for damaged peripheral nerve reconstruction. Designed scaffolds comprised of natural and synthetic materials are now widely used in the reconstruction of damaged tissues. Utilization of absorbable and nonabsorbable synthetic and natural polymers with unique characteristics can be an appropriate solution to repair damaged nerve tissues. Polymeric nanofibrous scaffolds with properties similar to neural structures can be more effective in the reconstruction process. Better cell adhesion and migration, more guiding of axons, and structural features, such as porosity, provide a clearer role for nanofibers in the restoration of neural tissues. In this paper, basic concepts of peripheral nerve injury, types of artificial and natural guides, and methods to improve the performance of tubes, such as orientation, nanotechnology applications for nerve reconstruction, fibers and nanofibers, electrospinning methods, and their application in peripheral nerve reconstruction are reviewed.
PMCID: PMC2963930  PMID: 21042546
peripheral nerve injuries; nerve reconstruction; neural guide; nanofibers
24.  Silk Fibroin Conduits: A Cellular and Functional Assessment of Peripheral Nerve Repair 
Annals of plastic surgery  2011;66(3):273-279.
Novel silk fibroin conduits were designed with appropriate porosity for peripheral nerve repair. The aim of this work was to utilize these conduits to examine cell inflammatory responses and functional recovery in a sciatic nerve defect model.
45 randomized Lewis rats were utilized to create an 8-mm defect bridged by a silk guide, commercial collagen guide, or an autograft. After 1, 4 and 8 weeks, macrophage recruitment, percentage of newly formed collagen, number of myelinated axons, and gastrocnemius muscle mass were evaluated. Following 8 weeks, ED1+ cells in autograft and silk conduits decreased to < 1% and 17% of week 1 values, respectively. Collagen formation revealed no difference all measured time points, suggesting a similar foreign body response. Myelinated axon counts within the silk guide revealed a greater number of proximal spouts and distal connections than collagen guides. Gastrocnemius weights demonstrated a 27% decrease between silk and autografts after 8 weeks.
This study demonstrates that, in addition to tailorable degradation rates, our silk conduits possess a favorable immunogenicity and re-myelination capacity for nerve repair.
PMCID: PMC3090669  PMID: 21263296
25.  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

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