Luminal fillers in nerve conduits for peripheral nerve repair

The use of nerve conduits as an alternative for nerve grafting has a long experimental and clinical history. Luminal fillers, factors introduced into these nerve conduits, were later developed to enhance the nerve regeneration through conduits. Though many luminal fillers have been reported to improve nerve regeneration, their use has not been subjected to systematic review. This review categorizes the types of fillers used, the conduits associated with fillers, and the reported performance of luminal fillers in conduits to present a preference list for the most effective fillers to use over specific distances of nerve defect.     

Use of nerve conduits in peripheral nerve repair

Studies on nerve conduits for peripheral nerve regeneration have concentrated on the manipulation of various conduit materials to avoid sacrificing native nerve in the clinical situation. With the proliferation of available nerve growth-stimulating factors, the focus is shifting experimentally toward molecular biologic manipulation, with the addition of these materials as substrates within the conduit. The clinical use of conduits has concentrated on the use of autogenous tissue, with a few examples of polyglactin (PGA) mesh and silicone. Ultimately, as yet, conduit material does not seem to have a profound effect on outcome. Substrate manipulation has not yet had clinical application. An important problem that remains, both experimentally and clinically, is overriding the size of the maximal gap that can be bridged successfully, as well as obtaining good functional sensory and motor recovery, compared with the use of nerve grafts. Advances in molecular biology may reveal further details about the nerve growth phenomenon, the precise sequencing of the substrate materials that are effective in promoting nerve growth, and when they should be applied. Advances in chemical engineering may provide additional biologically stable materials that have the ability to integrate growth-enhancing agents or factors into the lumen of the conduit.     

Use of motor nerve material in peripheral nerve repair with conduits

We have recently shown in experimental nerve injury models that nerve regeneration is enhanced across a motor nerve graft as compared with a sensory nerve graft. To test the hypothesis that nerve architecture may mediate the beneficial effect of motor nerve grafting, we developed a model of disrupted nerve architecture in which motor and sensory nerve fragments were introduced into silicone conduits. Lewis rats were randomized to 5 experimental groups: nerve repair with motor nerve fragments, sensory nerve fragments, mixed nerve fragments, saline-filled conduit (negative control), or nerve isograft (positive control). At 6, 9, or 12 weeks, animals were sacrificed and nerve tissues were analyzed by quantitative histomorphometry. No significant differences were observed between the motor, sensory, and mixed nerve fragment groups. These findings suggest that intact nerve architecture, regardless of neurotrophic or biochemical factors, is a prerequisite for the beneficial effect of motor nerve grafting.     

睫状神经营养因子涂层的聚羟基乙酸聚乳酸神经导管修复犬胫神经缺损

目的 探讨应用脉冲等离子体方法涂层睫状神经营养因子（CNTF）的聚羟基乙酸聚乳酸（PGLA）神经导管修复犬胫冲经缺损的疗效。方法 18只杂交犬．每只犬左后肢制成胫神经2．5cm缺损模型，随机分别应用三种方法修复。A组：应用脉冲等离子体方法涂层CNTF的PGLA神经导管；B组：单纯PGLA神经咩管；C组：自体神经。应用苏木精-伊红和Masson染色、S-100免疫组化染色、神经电生理及神经轴突计数方法评价神经再生效果。同时动态记录犬行走步态变化，实验观察期3个月。结果 神经导管血管化良好且大部分降解吸收，再生神经均已通过所有神经导管。A组与C组的神经传导速度和神经轴突计数差异无统计学意义（P〉0．05），而A组和C组的数据均优于B组（P〈0．05）。A组和C组的犬基本恢复正常行走步态，而B组犬仍有跛行。结论 脉冲等离子体方法涂层CNTF的PGLA神经导管能有效修复犬2．5cm胫神经缺损，取得与自体神经相近的效果。     

Nerve repair: experimental and clinical evaluation of neurotrophic factors in peripheral nerve regeneration

SUMMARY: Neurotrophic factors are a family of polypeptides required for survival of discrete neuronal populations. In the normal state such factors are mostly synthesised by target tissues and are used for the viability of the nerve-cell bodies. After nerve injury, neurotrophic factors (NFs) are synthesised by non-neuronal (Schwann cells and fibroblasts) in the nerve trunk, and act to support the outgrowth of axons. NFs can be classified into three major groups: (1) neurotrophins; (2) neurokines; and (3) the transforming growth factor beta (TGF)-beta superfamily.     

Overcoming short gaps in peripheral nerve repair: conduits and human acellular nerve allograft

Nerve conduits and acellular nerve allograft offer efficient and convenient tools for overcoming unexpected gaps during nerve repair. Both techniques offer guidance for migrating Schwann cells and axonal regeneration though utilizing very different scaffolds. The substantially greater amount of animal and clinical data published on nerve conduits is marked by wide discrepancies in results that may be partly explained by a still poorly defined critical repair gap and diameter size. The available information on acellular allografts appears more consistently positive though this tool is also hampered by a longer but also limited critical length. This article reviews the current relative literature and examines pertinent parameters for application of both acellular allograft and nerve conduits in overcoming short nerve gaps.     

Nerve conduits for nerve repair or reconstruction

Advances in treating peripheral nerve lesions have resulted from research in nerve regeneration and the use biomaterials as well as synthetic materials. When direct tensionless repair of peripheral nerve lesions is not possible, nerve conduits may be used to bridge digital sensory nerve gaps of ≤3 cm. Nerve autograft is the benchmark for larger, longer, mixed, or motor nerve defects. Biologic, autogenous conduits-typically veins or, rarely, arteries-have demonstrated their utility in nerve gaps <3 cm in length. Three types of bioabsorbable conduit have been approved by the US Food and Drug Administration, constructed of collagen, polyglycolic acid, or caprolactone. Caprolactone conduits have been found to be equivalent in results to autograft. Collagen conduits are next best, and polyglycolic acid conduits are functionally inferior. Further research and prospective, multicenter, large-scale trials are needed to help establish the role of synthetic, bioabsorbable conduits in peripheral nerve reconstruction.     

周围神经移植联合神经营养因子修复脊髓传导束的实验研究

目的探讨周围神经移植联合神经营养因子修复脊髓传导束的可行性并观察其再生的情况。方法121只Wistar雄性大鼠被随机分成5组,A组(实验组,n=25):在T9水平横行切断脊髓并切除5mm,植入肋间神经和含酸性成纤维因子(acidicfibroblastgrowthfactor,aFGF)纤维蛋白凝胶;B组(水平对照组1,n=25):同法制备脊髓横断模型,断端间由含aFGF的纤维蛋白凝胶填充;C组(水平对照组2,n=25):同法制备脊髓横断模型,断端间植入肋间神经和不含aFGF的纤维蛋白凝胶;D组(水平对照组3,n=25):同法制备脊髓横断模型,断端间旷置;E组(空白对照组,n=21):仅行椎板切除术。通过BDA顺行神经示踪、FG逆行神经示踪、运动诱发电位(MEP)和大鼠BBB后肢运动功能评分,观察脊髓传导束再生的情况。结果A组在损伤区有BDA标记的神经纤维通过,在颈髓背角和腹侧角、脑干中缝核和红核、网状结构、前庭侧核以及在大脑运动皮层的第V层均发现FG标记阳性的神经细胞数。A组大鼠MEP的平均潜伏期和波幅以及BBB功能评分明显提高,与B、C和D组比较差异有统计学意义(P<0.01)。结论周围神经移植联合神经营养因子能部分修复脊髓传导束。     

Silk fibroin conduits: a cellular and functional assessment of peripheral nerve repair

Silk fibroin conduits were designed with appropriate porosity for peripheral nerve repair. The aim of this work was to use these conduits to examine cell inflammatory responses and functional recovery in a sciatic nerve defect model. A total of 45 randomized Lewis rats were used 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 for 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 remyelination capacity for nerve repair.     

Schwann cells,neurotrophic factors,and peripheral nerve regeneration

The peripheral nervous system retains a considerable capacity for regeneration. However, functional recovery rarely returns to the preinjury level no matter how accurate the nerve repair is, and the more proximal the injury the worse the recovery. Among a variety of approaches being used to enhance peripheral nerve regeneration are the manipulation of Schwann cells and the use of neurotrophic factors. Such factors include, first, nerve growth factor (NGF) and the other recently identified members of the neurotrophin family, namely, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5); second, the neurokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF); and third, the transforming growth factors (TGFs)-β and their distant relative, glial cell line–derived neurotrophic factor (GDNF). In this review article we focus on the roles in peripheral nerve regeneration of Schwann cells and of the neurotrophin family, CNTF and GDNF, and the relationship between these. Finally, we discuss what remains to be understood about the possible clinical use of neurotrophic factors. © 1998 Wiley-Liss, Inc. MICROSURGERY 18:397–405, 1998     

生长因子载体局部控释技术在骨组织修复中的应用

生长因子载体局部控释成骨生长因子修复骨缺损具有作用时间长、效果稳定、成骨效果佳等优点,是当今极具开拓前景和实际应用价值的研究方向.该文回顾了这一技术在骨组织修复领域的发展历史和研究进展,并对影响成骨效果的重要因素如载体材料的选择和因子负载方式、因子释放模式、控释治疗常用因子种类及其负载剂量、目前较为前沿的多因子控释、靶向控释等新概念作了介绍.生长因子载体局部控释系统的设计及开发是一项涉及材料学、临床医学、组织细胞学和分子生物学等学科的系统工程,多学科通力合作是取得突破的必经之路.     

几丁糖复合聚乙烯醇神经导管修复大鼠坐骨神经损

目的 径较粗,达到正常神经的直径。肌肉湿重和肌细胞截面积：A组和C组比较,差异无统计学意义(P＞0.05);A、C组明显优于B组,差异有统计学意义(P＜0.05)。组织学观察：A组和C组神经纤维数日多、大小均匀、成熟良好,B组神经纤维数目少、不均匀、髓鞘发育较差。神经示踪观察结果显示：A、B、C三组在L4～L6节段脊髓前角和背根节均可见到真蓝标记的神经元细胞,其中A组脊髓前角真蓝标记的神经元数目和C组相似,差异无统计学意义(P＞0.05),但明显优于B组,差异有统计学意义(P＜0.05)。 结论 几丁糖复合聚乙烯醇神经导管具有促进神经轴突再生的作用,有望成为自体神经的替代材料,应用于周围神经缺损的修复。     

Repair of lacerated peripheral nerves with nerve conduits

Peripheral nerve lesions are relatively common injuries encountered by hand surgeons. These injuries are notorious for causing significant and potentially long-standing impairment to hand function. Numerous surgical techniques with varying degrees of success have been described to treat this injury. The evolution of peripheral nerve repair has led to the development of the nerve conduit, a surgical technique that functionally bridges the gap between transected nerves. We discuss a brief history and evolution of nerve conduits and offer our preferred technique for peripheral nerve repair with a collagen nerve conduit. In addition, we offer case studies and postoperative rehabilitation goals and present early results associated with this type of repair.     

Invited review: Different conduits in peripheral nerve surgery

A considerable amount of research is being undertaken regarding the possibility of bridging loss of nerve substance with different guiding tubes, in order to improve functional outcome, reduce the surgical time, and reduce damage at donor nerve sites. A review of the literature and personal research allows us to state that: for short gaps, biological tubes (autologous veins) may give good results and also allow chemotactic attraction with selective arrangements of motor and sensory axons. Gaps longer than 1 cm do not allow tropism and are associated with failure to support axonal regrowth. Artificial biodegradable conduits still show results that are controversial; they may give good results provided that the material of which they are made is perfectly tolerated. Empty tubes, longer than 8-10 mm, besides being deprived of the chemotactic attraction, may collapse or be partially reabsorbed and replaced by scar. Probably in the near future biological or biodegradable tubes, containing lamininlike substances or muscle scaffold, will allow us to bridge increasingly large defects in nerves.     

The influence of nerve conduits diameter in motor nerve recovery after segmental nerve repair

Many conduits have demonstrated potential to substitute nerve autografts; however, the influence of conduit inner diameter (ID) has never been studied as a separate parameter. This experimental study compared motor recovery after segmental nerve repair with two different ID collagen conduits: 1.5 and 2.0 mm. In addition, the conduits were analyzed in vitro to determine the variations of ID before and after hydration. Thirty rats were divided into three groups: 2.0 mm ID, 1.5 mm ID, and a control group autograft. After 12 weeks, the 1.5 mm ID group demonstrated significant increase in force (P < 0.0001) and weight (P < 0.0001) of the tibialis anterior muscle and better histomorphometry results of the peroneal nerve (P < 0.05) compared to 2.0 mm ID group; nevertheless, autograft results outperformed both conduits (P < 0.0001). Conduits ID were somewhat smaller than advertised, measuring 1.59 ± 0.03 mm and 1.25 ± 0.0 mm. Only the larger conduit showed a 6% increase in ID after hydration, changing to 1.69 ± 0.02 mm. Although autografts perform best, an improvement in motor recovery can be achieved with collagen conduits when a better size match conduit is being used. Minimal changes in collagen conduits ID can be expected after implantation. © 2014 Wiley Periodicals, Inc. Microsurgery 34:646–652, 2014.     

Engineering strategies for peripheral nerve repair

Tissue engineering in the peripheral nervous system unites efforts by physicians, engineers, and biologists to create either natural or synthetic tubular nerve guidance channels as alternatives to nerve autografts for the repair of peripheral nerve defects. Guidance channels help direct axons sprouting from the regenerating nerve end, provide a conduit for diffusion of neurotropic and neurotrophic factors secreted by the damaged nerve stumps, and minimize infiltration of fibrous tissue. In addition to efforts to control these physical characteristics of nerve guidance channels, researchers are optimizing the incorporation of biologic factors and engineering interactive biomaterial that can specifically stimulate the regeneration process. Current and future research will ultimately result in biologically active and interactive nerve guidance channels that can support and enhance peripheral nerve regeneration over longer, more clinically relevant defect lengths.