Detergent‐based decellularized peripheral nerve allografts: An in vivo preclinical study in the rat sciatic nerve injury model

Nerve autograft is the gold standard technique to repair critical nerve defects, but efficient alternatives are needed. The present study evaluated the suitability of our novel Roosens‐based (RSN) decellularized peripheral nerve allografts (DPNAs) in the repair of 10‐mm sciatic nerve defect in rats at the functional and histological levels after 12 weeks. These DPNAs were compared with the autograft technique (AUTO) and Sondell (SD) or Hudson (HD) based DPNAs. Clinical and functional assessments demonstrated a partial regeneration in all operated animals. RSN‐based DPNAs results were comparable with SD and HD groups and closely comparable with the AUTO group without significant differences (p > .05). Overall hematological studies confirmed the biocompatibility of grafted DPNAs. In addition, biochemistry revealed some signs of muscle affection in all operated animals. These results were confirmed by the loss of weight and volume of the muscle and by muscle histology, especially in DPNAs. Histology of repaired nerves confirmed an active nerve tissue regeneration and partial myelination along with the implanted grafts, being the results obtained with HD and RSN‐based DPNAs comparable with the AUTO group. Finally, this in vivo study suggests that our novel RSN‐based DPNAs supported a comparable tissue regeneration, along the 10‐mm nerve gap, after 12‐week follow‐up to HD DPNAs, and both were superior to SD group and closely comparable with autograft technique. However, further improvements are needed to overcome the efficacy of the nerve autograft technique.     

Delivery of chondroitinase ABC and glial cell line‐derived neurotrophic factor from silk fibroin conduits enhances peripheral nerve regeneration

Nerve conduits are a proven strategy for guiding axon regrowth following injury. This study compares degradable silk–trehalose films containing chondroitinase ABC (ChABC) and/or glial cell line‐derived neurotrophic factor (GDNF) loaded within a silk fibroin‐based nerve conduit in a rat sciatic nerve defect model. Four groups of silk conduits were prepared, with the following silk–trehalose films inserted into the conduit: (a) empty; (b) 1 µg GDNF; (3) 2 U ChABC; and (4) 1 µg GDNF/2 U ChABC. Drug release studies demonstrated 20% recovery of GDNF and ChABC at 6 weeks and 24 h, respectively. Six conduits of each type were implanted into 15 mm sciatic nerve defects in Lewis rats; conduits were explanted for histological analysis at 6 weeks. Tissues stained with Schwann cell S‐100 antibody demonstrated an increased density of cells in both GDNF‐ and ChABC‐treated groups compared to empty control conduits (p < 0.05). Conduits loaded with GDNF and ChABC also demonstrated higher levels of neuron‐specific PGP 9.5 protein when compared to controls (p < 0.05). In this study we demonstrated a method to enhance Schwann cell migration and proliferation and also foster axonal regeneration when repairing peripheral nerve gap defects. Silk fibroin‐based nerve conduits possess favourable mechanical and degradative properties and are further enhanced when loaded with ChABC and GDNF. Copyright © 2014 John Wiley & Sons, Ltd.     

Cell‐free artificial implants of electrospun fibres in a three‐dimensional gelatin matrix support sciatic nerve regeneration in vivo

Surgical repair of larger peripheral nerve lesions requires the use of autologous nerve grafts. At present, clinical alternatives to avoid nerve transplantation consist of empty tubes, which are only suitable for the repair over short distances and have limited success. We developed a cell‐free, three‐dimensional scaffold for axonal guidance in long‐distance nerve repair. Sub‐micron scale fibres of biodegradable poly‐ε‐caprolactone (PCL) and collagen/PCL (c/PCL) blends were incorporated in a gelatin matrix and inserted in collagen tubes. The conduits were tested by replacing 15‐mm‐long segments of rat sciatic nerves in vivo. Biocompatibility of the implants and nerve regeneration were assessed histologically, with electromyography and with behavioural tests for motor functions. Functional repair was achieved in all animals with autologous transplants, in 12 of 13 rats that received artificial implants with an internal structure and in half of the animals with empty nerve conduits. In rats with implants containing c/PCL fibres, the extent of recovery (compound muscle action potentials, motor functions of the hind limbs) was superior to animals that had received empty implants, but not as good as with autologous nerve transplantation. Schwann cell migration and axonal regeneration were observed in all artificial implants, and muscular atrophy was reduced in comparison with animals that had received no implants. The present design represents a significant step towards cell‐free, artificial nerve bridges that can replace autologous nerve transplants in the clinic. Copyright © 2017 John Wiley & Sons, Ltd.     

Nerve lengthening and subsequent end‐to‐end repair yield more favourable outcomes compared with autograft repair of rat sciatic nerve defects

Outcomes of end‐to‐end nerve repairs are more successful compared with outcomes of repairs bridged by nerve grafts. However, end‐to‐end repairs are not always possible for large nerve gaps, as excessive tension may cause catastrophic failure. In this study, we built on previous nerve‐lengthening studies to test the hypotheses that gradual lengthening of the proximal stump across a large nerve gap enables an end‐to‐end repair and such a repair results in more favourable regenerative outcomes than autografts, which represent the gold standard in bridging nerve gaps. To test these, we compared structural and functional outcomes in Lewis rats after repair of sciatic nerve gaps using either autografts or a novel compact internal fixator device, which was used to lengthen proximal nerve stumps towards the distal stump over 2 weeks, prior to end‐to‐end repair. Twelve weeks after the initial injury, outcomes following nerve lengthening/end‐to‐end repair were either comparable or superior in every measure compared with repair by autografting. The sciatic functional index was not significantly different between groups at 12 weeks. However, we observed a reduced rate of contracture and corresponding significant increase in paw length in the lengthening group. This functional improvement was consistent with structural regeneration; axonal growth distal to the injury was denser and more evenly distributed compared with the autograft group, suggesting substantial regeneration into both tibial and peroneal branches of the sciatic nerve. Our findings show that end‐to‐end repairs following nerve lengthening are possible for large gaps and that this strategy may be superior to graft‐based repairs.     

Application of marrow mesenchymal stem cell‐derived extracellular matrix in peripheral nerve tissue engineering

To advance molecular and cellular therapy into the clinic for peripheral nerve injury, modification of neural scaffolds with the extracellular matrix (ECM) of peripheral nerves has been established as a promising alternative to direct inclusion of support cells and/or growth factors within a neural scaffold, while cell‐derived ECM proves to be superior to tissue‐derived ECM in the modification of neural scaffolds. Based on the fact that bone marrow mesenchymal stem cells (BMSCs), just like Schwann cells, are adopted as support cells within a neural scaffold, in this study we used BMSCs as parent cells to generate ECM for application in peripheral nerve tissue engineering. A chitosan nerve guidance conduit (NGC) and silk fibroin filamentous fillers were respectively prepared for co‐culture with purified BMSCs, followed by decellularization to stimulate ECM deposition. The ECM‐modified NGC and lumen fillers were then assembled into a chitosan–silk fibroin‐based, BMSC‐derived, ECM‐modified neural scaffold, which was implanted into rats to bridge a 10 mm‐long sciatic nerve gap. Histological and functional assessments after implantation showed that regenerative outcomes achieved by our engineered neural scaffold were better than those achieved by a plain chitosan–silk fibroin scaffold, and suggested the benefits of BMSC‐derived ECM for peripheral nerve repair. Copyright © 2016 John Wiley & Sons, Ltd.     

Regenerative effect of adipose tissue‐derived stem cells transplantation using nerve conduit therapy on sciatic nerve injury in rats

This study proposed a biodegradable GGT nerve conduit containing genipin crosslinked gelatin annexed with tricalcium phosphate (TCP) ceramic particles for the regeneration of peripheral nerves. Cytotoxicity tests revealed that GGT‐extracts were non‐toxic and promoted proliferation and neuronal differentiation in the induction of stem cells (i‐ASCs) derived from adipose tissue. Furthermore, the study confirmed the effectiveness of a GGT/i‐ASCs nerve conduit as a guidance channel in the repair of a 10‐mm gap in the sciatic nerve of rats. At eight weeks post‐implantation, walking track analysis showed a significantly higher sciatic function index (SFI) (P < 0.05) in the GGT/i‐ASC group than in the autograft group. Furthermore, the mean recovery index of compound muscle action potential (CMAP) differed significantly between GGT/i‐ASCs and autograft groups (P < 0.05), both of which were significantly superior to the GGT group (P < 0.05). No severe inflammatory reaction in the peripheral nerve tissue at the site of implantation was observed in either group. Histological observation and immunohistochemistry revealed that the morphology and distribution patterns of nerve fibers in the GGT/i‐ASCs nerve conduits were similar to those of the autografts. These promising results achieved through a combination of regenerative cells and GGT nerve conduits suggest the potential value in the future development of clinical applications for the treatment of peripheral nerve injury. Copyright © 2012 John Wiley & Sons, Ltd.     

Human nail bed‐derived decellularized scaffold regulates mesenchymal stem cells for nail plate regeneration

Among hand trauma, nail bed is the most involved tissue in hospital emergency departments, resulting in the loss of nail plate, which leads to a disturbance of hand grasp function, long‐lasting digit tip pain, hyperpathia, and disesthesia. Treatment of nail bed defects is a significant clinical challenge due to the lack of uniform nail bed thickness and distinct regenerative ability. In this study, it is shown that the extracellular matrix of decellularized nail bed scaffolds can play an important role in inducing bone mesenchymal stem cells to differentiate into nail epithelial cells. Using decellularized nail bed scaffolds combined with bone mesenchymal stem cells, it is revealed that the engineered nail bed can promote nude mouse nail plate regeneration ectopically. The natural extracellular matrix of decellularized nail bed scaffolds can serve as a 3D structural template for bone mesenchymal stem cell differentiation into nail‐associated cells, initiating the nail plate regeneration. These results not only provide a proof‐of‐principle for the generation of transplantable nail grafts based on decellularized nail bed scaffolds derived from clinically wasted amputated fingers but also provide important considerations for clinical treatment for digit tip trauma.     

Safety and efficacy evaluation of a human acellular nerve graft as a digital nerve scaffold: a prospective,multicentre controlled clinical trial

This study developed a human acellular nerve graft (hANG) as an alternative to autogenous nerve and reports on its safety and efficacy. There were two groups comprised of 72 patients that received digital nerve repair with hANG (test) and 81 that received conventional direct tension‐free suture repair of the nerve defect (control). The efficacy of the treatment was evaluated by static 2‐point discrimination (s2PD) and Semmes‐Weinstein monofilament testing. Safety was evaluated by local wound response and laboratory testing. Mean age of patients in the test group was 33.0 ± 11.1 years (range 18‐61 years) and in the control group 36.9 ± 13.4 years (range 15‐77 years) (p = 0.0470). Mean time from injury to repair in the test group was 23.7 ± 52 days (range 0‐200 days) and in the control group 1.5 ± 10.4 days (range 0‐91 days) (p = 0.0005). Mean length of nerve graft was 1.80 ± 0.82 cm (range 1‐5 cm). All surgeries were performed successfully and without complications. The excellent and good rate of s2PD in the test group was 65.28% and 95% CI was 51.98‐78.93%. s2PD in the test group improved over time and average distance was 12.81 ± 5.99 mm at 6 months postoperatively. No serious adverse or product‐related events were reported. These results indicate that hANG is a safe and effective for the repair of nerve defects of 1‐5 cm in size. © 2015 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons, Ltd.     

Repairing peripheral nerve defects with revascularized tissue‐engineered nerve based on a vascular endothelial growth factor‐heparin sustained release system

To enhance the angiogenic capacity of tissue‐engineered peripheral nerves, we have constructed revascularized tissue‐engineered nerves based on a vascular endothelial growth factor (VEGF)‐heparin sustained release system. However, the effects of the repair of large peripheral nerve defects are not known. In this study, we used the above revascularized tissue‐engineered nerve to repair large nerve defects in rats. The repair effects were observed through general observation, functional evaluation of nerve regeneration, ultrasound examination, neural electrophysiology, wet weight ratio of bilateral gastrocnemius muscle, histological evaluation, and quantitative real‐time polymerase chain reaction (PCR) analysis. The results showed that the tissue‐engineered peripheral nerve based on a VEGF‐heparin sustained release system can achieve early vascularization and restore blood supply in the nerve graft area. The realization of early vascularization in the area of the nerve defect greatly promotes the speed of nerve regeneration and reconstruction in the area of the nerve defect, which greatly advances the process of nerve repair and reconstruction and accelerates the restoration of the normal morphological structure and function of peripheral nerves.     

Low‐intensity pulsed ultrasound combination with induced pluripotent stem cells‐derived neural crest stem cells and growth differentiation factor 5 promotes sciatic nerve regeneration and functional recovery

The treatment of lengthy peripheral nerve defect is challenging in the field of nerve regeneration. Our previous studies have shown that low‐intensity pulsed ultrasound (LIPUS) could promote the proliferation, cell viability, and neural differentiation of induced pluripotent stem cells‐derived neural crest stem cells (iPSCs‐NCSCs) and improve the regeneration of damaged peripheral nerve. In this study, the mechanical signal transduction pathway of LIPUS promoting iPSCs‐NCSCs proliferation and differentiation was further explored, and the effects of LIPUS combined with iPSCs‐NCSCs, perfluorotributylamine (PFTBA), and growth differentiation factor 5 (GDF5) on the repair of peripheral nerve injury were evaluated. Results showed LIPUS may regulate the proliferation and differentiation of iPSCs‐NCSCs through FAK‐ERK1/2 signal pathway. PFTBA could supply sufficient oxygen to promote the viability of iPSCs‐NCSCs under 5% hypoxia culture condition and provide a favourable microenvironment for nerve regeneration. The addition of GDF5 could promote the neural differentiation of iPSCs‐NCSCs in vitro. LIPUS treatment of allogeneic decellularized nerve conduit containing iPSCs‐NCSCs, PFTBA, and GDF5 has very good effect on the repair of sciatic nerve injury. Taken together, these results provide functional evidence that LIPUS might be a useful tool to explore alternative approaches in the field of nerve regeneration.     

合成材料神经导管与自体神经移植修复周围神经缺损的比较

背景：生物可降解材料制成的神经导管可在体内降解,避免出现的神经卡压等问题,因而受到越来越多的关注. 目的：比较自体神经移植与3种合成可生物降解材料神经导管在修复周围神经损伤的效果差异. 方法：通过电生理学检测,形态学观察等神经恢复效果评价方法,对比分析近年来常用的胶原神经导管、DL-乳酸-ε-己内酯神经导管、聚乙醇酸神经导管与自体神经移植修复周围神经缺损的效果. 结果与结论：虽然神经导管与自体神经移植相比在理论上有其优势的一面,但不同合成材料的神经导管之间在神经功能恢复中存在明显差异性,DL-乳酸-ε-己内酯神经导管修复效果与自体神经移植无明显差异,是较为理想的神经导管材料,聚乙醇酸神经导管因自身的因素影响其降解性能,在3种神经导管中的修复周围神经损伤效果最差,胶原神经导管需要交联剂改善其机械性能,其修复周围神经损伤效果居于前两者之间,因此,这3种神经导管在神经功能再生方面还有潜在的缺陷,不能完全替代自体神经移植,而且3者之间的性价比,还缺少足够的大样本长期随机对照实验结果来验证,还需要进一步的实验观察.     

NGF／PLGA复合神经导管修复大鼠周围神经缺损的实验研究

目的：应用神经生长因子（NGV）、聚乳酸和聚羟基乙酸的共聚物（PLGA）和牛血清白蛋白（BSA）制成NGF／PLGA复合神经导管。检测其综合性能和了解其修复大鼠周围神经缺损的可能性。方法：体外模拟体内环境，检测它的降解时间及用ELISA的方法来检测NGF的释放情况；手术造成大鼠坐骨神经约10mm的缺损，分别采用自体神经移植（A组）、NGF／PLGA复合神经导管桥接（B组）和单纯PLGA导管（C组）桥接，术后4、8、12周进行大体观察、神经电生理测定、HE染色、变色酸2R一亮绿髓鞘染色、电镜观察和图像分析对比。结果：在体外NGF／PLGA复合神经导管能在体外释放NGF约18天，约在14周左右导管降解完毕。NGF／PLGA神经导管组在促进坐骨神经再生、再生神经纤维排列规律化、提高再生神经髓鞘化、加速再生神经功能重建等方面均优于单纯PLGA导管组。比自体神经移植组略差。结论：NGF，PLGA复合神经导管具有良好的组织相容性，对大鼠坐骨神经缺损具有良好的桥梁作用和促神经生长的作用，效果接近自体神经移植。     

GDNF-chitosan blended nerve guides: a functional study

Nerve guides are currently being fabricated by blending a variety of biomaterials with different proteins. Adding proteins, which can support nerve repair and regeneration, optimizes the biological properties of a nerve guide. In our study we have blended glial cell line-derived nerve growth factor (GDNF) and laminin with chitosan to fabricate GDNF-laminin blended chitosan (GLC) nerve guides. As GDNF is known to provide trophic support to motor neurons, the main objective of this study was assess the functional restoration of an injured sciatic nerve treated with GLC. Functional nerve recovery was evaluated using a video gait-analysis technique. Gastrocnemius muscle weight measurements and sensitivity testing were correlated to functional nerve recovery. Our results indicate an increase in the functional recovery of the GLC group when compared to the unblended chitosan nerve guides. At the end of 12 weeks, GLC nerve guides had comparable functional values to the Laminin-I blended chitosan nerve guides (LC) and autograft groups, which were both significantly higher at the terminal stance phase angle as compared to the unblended chitosan nerve guides. Muscle weights for the GLC group indicated decreased atrophy and restoration of functional strength, compared to the unblended chitosan groups. In addition, behavioural testing demonstrated that the GLC group regained sensation while the control groups displayed no restoration. Thus, the addition of GDNF and laminin to the chitosan nerve guides enhanced both functional and sensory recovery.     

Bioengineered lungs generated from human iPSCs‐derived epithelial cells on native extracellular matrix

The development of an alternative source for donor lungs would change the paradigm of lung transplantation. Recent studies have demonstrated the potential feasibility of using decellularized lungs as scaffolds for lung tissue regeneration and subsequent implantation. However, finding a reliable cell source and the ability to scale up for recellularization of the lung scaffold still remain significant challenges. To explore the possibility of regeneration of human lung tissue from stem cells in vitro, populations of lung progenitor cells were generated from human iPSCs. To explore the feasibility of producing engineered lungs from stem cells, we repopulated decellularized human lung and rat lungs with iPSC‐derived epithelial progenitor cells. The iPSCs‐derived epithelial progenitor cells lined the decellularized human lung and expressed most of the epithelial markers when were cultured in a lung bioreactor system. In decellularized rat lungs, these human‐derived cells attach and proliferate in a manner similar to what was observed in the decellularized human lung. Our results suggest that repopulation of lung matrix with iPSC‐derived lung epithelial cells may be a viable strategy for human lung regeneration and represents an important early step toward translation of this technology.     

Genipin‐crosslinked decellularized annulus fibrosus hydrogels induces tissue‐specific differentiation of bone mesenchymal stem cells and intervertebral disc regeneration

Biomaterial‐based therapy that can restore annulus fibrosus (AF) function in early stage and promote endogenous repair of AF tissues is a promising approach for AF tissue repair. In this study, we established a genipin‐crosslinked decellularized AF hydrogels (g‐DAF‐G) that are injectable and could manifest better in situ formability than noncrosslinked decellularized AF hydrogel, while preserving the capacity of directing differentiation of human bone mesenchymal stem cells (hBMSCs) towards AF cells. Hematoxylin and eosin staining, 4',6‐diamidino‐2‐phenylindole staining, and so forth showed that the majority of cellular components were removed, whereas extracellular matrix and microstructure were largely preserved. The storage modulus increased from 465.5 ± 9.4 Pa to 3.29 ± 0.24 MPa after 0.02% genipin crosslinking of decellularized AF hydrogels (DAF‐G) to form g‐DAF‐G. AF‐specific genes (COL1A1, COL5A1, TNMD, IBSP, FBLN1) were significantly higher in DAF‐G and g‐DAF‐G groups than that in control group after 21 days of culturing. g‐DAF‐G significantly restored nucleus pulposus water content and preserved intervertebral structure in vivo. Summarily, we produced a novel AF regeneration biomaterial, g‐DAF‐G, which exhibited well biocompatibility, great bioactivity, and much higher mechanical strength than DAF‐G. This study will provide an easy and fast therapeutic alternative to repair AF injuries or tears.     

GDNF 基因诱导大鼠骨髓间充质干细胞促周围神经再生的实验研究

目的：探讨胶质细胞源性神经营养因子（GDNF）诱导骨髓间充质干细胞（BMSCs）促周围神经再生。方法建立大鼠坐骨神经损伤模型,实验分为2组：对照组为未经诱导 BMSCs 组,实验组为 GDNF 基因诱导后 BMSCs组。每组20只 SD 大鼠。①术后4周和8周观察坐骨神经指数和腓肠肌湿质量恢复率。②术后8周测量再生神经纤维轴突直径、髓鞘厚度及有髓神经纤维计数。③术后4周腓肠肌肌细胞行 DAPI 染色。④术后8周坐骨神经扫面电镜观察神经丝再生交联情况。结果经 GDNF 基因诱导 BMSCs 组各方面检测指标均较对照组为好,其中诱导后实验组扫描电镜下观察周围神经再生更加明显。结论GDNF 基因诱导的间充质干细胞对周围神经再生有着显著的疗效。     

Poly‐3‐hydroxybutyrate strips seeded with regenerative cells are effective promoters of peripheral nerve repair

Peripheral nerve injuries are often associated with loss of nerve tissue and require a graft to bridge the gap. Autologous nerve grafts are still the 'gold standard' in reconstructive surgery but have several disadvantages, such as sacrifice of a functional nerve, neuroma formation and loss of sensation at the donor site. Bioengineered grafts represent a promising approach to address this problem. In this study, poly‐3‐hydroxybutyrate (PHB) strips were used to bridge a 10 mm rat sciatic nerve gap and their effects on long‐term (12 weeks) nerve regeneration were compared. PHB strips were seeded with different cell types, either primary Schwann cells (SCs) or SC‐like differentiated adipose‐derived stem cells (dASCs) suspended in a fibrin glue matrix. The control group was PHB and fibrin matrix without cells. Functional and morphological properties of the regenerated nerve were assessed using walking track analysis, EMGs, muscle weight ratios and muscle and nerve histology. The animals treated with PHB strips seeded with SCs or dASCs showed significantly better functional ability than the control group. This correlated with less muscle atrophy and greater axon myelination in the cell groups. These findings suggest that the PHB strip seeded with cells provides a beneficial environment for nerve regeneration. Furthermore, dASCs, which are abundant and easily accessible, constitute an attractive cell source for future applications of cell therapy for the clinical repair of traumatic nerve injuries. Copyright © 2015 John Wiley & Sons, Ltd.     

碳纳米管增强型天然复合材料神经导管修复大鼠副神经缺损

背景:近年来,纳米技术在组织重建领域的应用研究十分活跃.碳纳米材料应用于骨组织修复的相关报道较多,但应用于周围神经系统修复的报道较少.目的:应用功能性修饰的碳纳米管作为增强成分改善几丁糖/胶原复合材料神经导管的理化和生物性能,探讨以功能性修饰的碳纳米管增强型复合材料神经导管修复周围神经缺损的疗效.设计、时间及地点:同体自身对照动物实验,于2005-02/2006-11在上海交通大学医学院El腔组织工程实验室(上海市口腔重点实验室)和上海交通大学薄膜与微细技术实验室(教育部重点实验室)完成.材料:将碳纳米管与2%的酸溶性几丁糖溶液及胶原按一定比例充分混合,涂覆在模具上,经红外加热成型并达到预期厚度后,干燥脱模制备碳纳米管增强型复合材料导管.以不含碳纳米管的几丁糖,胶原复合材料导管为对照材料.方法:成年健康雄性Sprague-Dawley大鼠80只,制备4 mm副神经缺损,实验材料组和对照材料组分别应用相应神经导管进行修复.自体神经移植组将切除的神经原位吻接于断端,空白对照组则仅将神经切除掉2 mm,不做处理.左侧为实验侧,右侧为正常对照侧.主要观察指标:通过神经电生理学、肌肉功能及组织学检测手段对其修复效果进行评价.结果:应用碳纳米管增强型复合材料神经导管可有效地重建副神经缺损大鼠斜方肌的运动功能.术后再生神经电生理与组织学指标检测结果与白体神经移植的疗效相当,部分指标结果超过自体神经移植.结论:碳纳米管增强型复合材料神经导管是桥接修复周围神经的理想材料.     

Recent advances in artificial nerve conduit design: Strategies for the delivery of luminal fillers

Artificial nerve conduits offer an attractive alternative to nerve autografts for the repair of peripheral nerve injuries and several commercially-available conduits are currently on the market. However, at present, utilization of these conduits is limited to the repair of nerve gaps less than 3 cm in length. Thus, current research is focused on how best to design artificial conduits with improved nerve regeneration potential over longer distances. Successful nerve regeneration necessitates that the cells, extracellular matrix components, and growth factors involved interact in a highly specific manner that is tightly coordinated. Combinatorial approaches that take into account these interactions and conduits that utilize supportive factors, such as neurotrophins and stem cells, may be key components of the next generation of artificial conduits. Additionally, design strategies that combine physical cues for contact guidance and biochemical signals to enhance cellular function have shown promise. This review highlights recent advances in artificial nerve conduit design, focusing on the use of luminal fillers, with special focus on the various techniques for accessory cell and/or growth factor delivery into artificial nerve conduits.     

Functional collagen conduits combined with human mesenchymal stem cells promote regeneration after sciatic nerve transection in dogs

Numerous studies have focused on the development of novel and innovative approaches for the treatment of peripheral nerve injury using artificial nerve guide conduits. In this study, we attempted to bridge 3.5‐cm defects of the sciatic nerve with a longitudinally oriented collagen conduit (LOCC) loaded with human umbilical cord mesenchymal stem cells (hUC‐MSCs). The LOCC contains a bundle of longitudinally aligned collagenous fibres enclosed in a hollow collagen tube. Our previous studies showed that an LOCC combined with neurotrophic factors enhances peripheral nerve regeneration. However, it remained unknown whether an LOCC seeded with hUC‐MSCs could also promote regeneration. In this study, using various histological and electrophysiological analyses, we found that an LOCC provides mechanical support to newly growing nerves and functions as a structural scaffold for cells, thereby stimulating sciatic nerve regeneration. The LOCC and hUC‐MSCs synergistically promoted regeneration and improved the functional recovery in a dog model of sciatic nerve injury. Therefore, the combined use of an LOCC and hUC‐MSCs might have therapeutic potential for the treatment of peripheral nerve injury.