周围神经损伤的修复技术和生物材料汇总
周围神经损伤是一个世界性的临床问题，它可能导致中枢神经系统（CNS）与周围器官之间的感觉神经和运动神经失去神经联系，影响患者的生活质量。治疗完全性病变的首要要求是无张力、端到端的修复。
当端到端修复为不可能时，可使用周围神经移植物或神经导管。自体移植有一定局限性，以及同种异体和异种移植有一定的缺点，如免疫反应，这迫使研究人员研究和开发替代的方法，主要是神经导管。本文介绍了各种类型的导管材料（由生物和合成聚合物制成）和设计（管状、纤维状和基质型）的信息。
介绍
周围神经损伤是影响患者生活质量的一个世界性的临床问题，中枢神经系统（CNS）由大脑和脊髓组成。另一方面，周围神经系统位于中枢神经系统之外，包括颅神经、脊神经和外周神经，这些神经传导来自中枢神经系统的脉冲。
周围神经损伤可导致中枢神经系统与周围器官之间沿感觉神经和运动神经的神经元通讯丧失。外周神经损伤通常会导致运动和感觉功能减退导致疼痛性神经病变，这对患者来说可能是灾难性的，严重影响他们的日常活动。
周围神经由神经纤维束和周围结缔组织鞘（包括血管）组成。每个单独的神经纤维和支持施万细胞的周围都有一个松散的结缔组织，即神经内膜。在结缔组织中，一束神经纤维被胶原纤维固定，形成束，束周围有一个称为神经束膜的致密结缔组织。神经干内的整个神经束完全被一种叫做神经外膜的致密不规则的结缔组织包裹，它是结缔组织鞘的最外层。
一般来说，周围神经损伤是由机械性、热性、化学性或缺血性损伤引起的，主要是由创伤性事故或一些退行性疾病引起的。损伤的严重程度决定了功能结果。周围神经损伤通常根据Seddon和sanderland分类进行评估。Seddon将损伤的严重程度分为神经失用、轴索中断和神经断裂。1951年，sanderland将其归为1-5度伤。
一级损伤，相当于神经失能，轴突解剖上完整无缺，Wallerian氏变性不存在，但有部分脱髓鞘，脉冲无法传递。这些损伤在几个月内通过治疗痊愈。
二级损伤中，相当于Seddon分类中的神经轴索中断，神经内膜和施万细胞完整，但轴突被切断。这些损伤可以在完整的神经内膜的帮助下再生。
三级损伤，即使神经束和神经束的排列被保留，神经束内神经也被破坏。在这些情况下，纤维束内会发生纤维化，运动和感觉功能的恢复会明显延迟。
四级损伤，轴突、神经内膜和神经束膜被破坏，而只有最外层的神经外膜完整。退变程度明显高于轻度损伤；因此，可能需要切除疤痕组织和手术修复神经以实现再生。
五级损伤，相当于神经损伤，整个神经干被完全切断，形成疤痕。结果，神经瘤和Wallerian氏变性分别在近端和远端形成。在这种严重的损伤中，需要手术修复。
周围神经末梢的髓鞘损伤和轴突破坏等是引起末梢神经损伤的原因。远端与神经体断开，发生Wallerian氏（顺行）变性。轴突细胞骨架成分被分解，轴突碎裂。这些事件导致髓鞘破裂。
另一方面，受损神经元胞体发生一系列细胞和分子改变、逆行反应和染色质溶解，并与近端神经残端的逆行轴突变性有关。施万细胞和浸润性巨噬细胞被用于清除轴突、髓鞘和组织碎片。此外，施万细胞增殖并沿外板排列形成Büngner带，引导再生轴突芽，再生轴突起源于轴突的近端。新的轴突芽经历髓鞘化，这些再生轴突达到其目标，以达到功能恢复。轴突近端再生的理想进程为1mm/天。然而，如果轴突芽不能穿过损伤部位，就会导致神经瘤的形成，失去神经支配的肌肉纤维萎缩。
神经损伤的治疗策略
虽然周围神经在损伤后有再生的能力，但这种自发的神经修复可能不足以实现适当的功能恢复。神经间隙的长度、损伤与修复之间的时间以及患者的年龄是周围神经损伤修复中需要考虑的重要参数。完全性病变的主要治疗方法是通过神经外膜缝合术或神经组束缝合术，对神经残端进行无张力的端到端的修复。如果出现明显的神经间隙形成，无法进行端到端修复，则需要周围神经移植物或神经导管作为穿过神经残端之间的桥梁，并支持轴突再生。
周围神经移植
自体移植
最广泛使用的神经修复策略，被认为是“黄金标准”，用于弥补神经间隙的神经，取自病人自己身体的其他地方。自体神经移植已被广泛研究，并已报道其优于张力下神经外膜缝合。
自体神经移植为轴突从近端到远端的轴突进展提供了结构上的指导。腓肠神经、浅表皮神经、前臂外侧和内侧皮神经等功能不太重要的神经作为自体神经组织的供体。然而，自体神经移植的应用有很大的局限性，例如造成第二个手术部位从供区获取组织，导致供区发病和功能丧失。神经的可用性和长度是有限的，目前自体移植的使用仅限于近5厘米长的关键神经间隙。供体神经大小的不匹配和自体神经与受体近端和远端残端的分支不一致是自体神经移植应用的主要限制因素。
事实上，选择的自体神经移植类型，如感觉神经、运动神经或混合神经，对于成功的结果也很重要，因为轴突大小、分布和排列的不匹配限制了自体神经移植的再生能力。Nichols等人报道了自体运动神经或混合神经移植轴突再生优于感觉神经移植。自体神经移植的另一个重要缺点是潜在的感染和疼痛性神经瘤的形成。此外，由于需要二次手术，病人的恢复时间较长。
自体移植的局限性迫使研究人员研究和开发替代方法，例如制造用于周围神经损伤的新型神经导管。
同种移植
同种异体神经移植是一种将周围神经损伤与来自同一物种不同个体的组织桥接的技术。
同种异体神经组织可作为引导的支持物和来源，供者来源的施万细胞可促进近端和远端轴突的连接，从而实现靶组织或器官的再神经化。然而，同种异体移植物的使用存在局限性，特别是免疫排斥反应、交叉感染的风险、继发感染和供应有限。因此，同种异体移植的应用需要全身免疫抑制治疗，但长期免疫抑制由于感染风险增加，导致治愈率降低，偶尔会导致肿瘤形成等全身效应而不是理想的治疗方法。
为了克服这些局限性，神经移植物可以通过反复的冻融循环、照射和用清洁剂去细胞化来处理。
异种移植
异种神经移植是从受体以外的物种中获得的。
1997年，Hebebrand等人将从金色叙利亚仓鼠处获得的2cm的异种坐骨神经移植到Lewis大鼠坐骨神经0.5cm的缝隙中。通过步行轨迹分析、测量体感诱发电位和对异种神经进行组织学检查来评估移植手术的性能。用RS-61443和FK-506对实验模型进行免疫抑制，以非免疫抑制动物为对照。实验动物的功能恢复不如对照同种移植物。另一方面，Jia等人，采用脱细胞异种神经移植，并植入骨髓基质细胞（BMSCs）。异种移植材料取自Sprague-Dawley大鼠和新西兰兔，植入1cm大鼠坐骨神经间隙。
将同种异体移植物和异种移植物与电生理学研究进行比较，发现异种移植物在再生神经元方面与同种异体移植物一样有效。然而，异种移植会考虑到跨物种疾病传播的风险。
神经导管
去细胞神经外膜导管
同种异体和异种移植物有可能在宿主组织中引起免疫原性反应。为了抑制免疫原性反应，移植物与免疫抑制剂联合使用。然而，使用这些药物可能会导致更易感染和肿瘤的形成。因此，为了消除引起免疫原性反应的细胞成分，保留已知能增强再生能力的天然细胞外基质（ECM），人们开发了“去细胞化方法”。
保存细胞外基质（ECM）与同种异体或异种移植物的基底膜一起保存，为再生轴突提供了一种机械引导手段。脱细胞过程包括各种物理和化学方法以及酶法。广泛使用的物理方法有冻干、直接加压、超声和搅拌。
冷冻神经组织导致细胞膜破裂，导致细胞溶解。在冷冻步骤中，应避免因快速冷冻产生冰晶而导致ECM中断。
直接加压法是另一种用于移植物去细胞的方法。
机械搅拌和超声处理与化学处理一起用来破坏细胞膜。
使用或不使用物理处理的化学方法包括使用碱性和酸性溶液的工艺，非离子、离子和zwitter离子洗涤剂，低张和高渗溶液。用酸性或碱性溶液处理会溶解细胞成分并破坏核酸。离子洗涤剂如十二烷基硫酸钠和Triton X-200也能溶解细胞成分和变性蛋白质。
低张和高渗溶液如乙二胺四乙酸（EDTA）溶液会导致渗透性休克并导致细胞溶解。像EDTA这样的溶液通常与涉及酶（如核酸外切酶、核酸内切酶和胰蛋白酶）的治疗结合使用。移植物中残留的组织需要去细胞，这可能是由于移植物体内残留的化学物质造成的。胰蛋白酶蛋白水解作为一种酶降解方法已被广泛应用于真皮或心脏瓣膜的去细胞化，但其稳定性可能受到胰蛋白酶处理后胶原含量变化的限制。
各种研究表明，在大鼠坐骨模型中，去细胞化的移植物能够促进超过1-2厘米长的缺损的再生。一项研究表明，在没有软骨素酶等其他成分的支持下，去细胞神经外膜导管用于治疗超过1-2厘米的缺损时，轴突并不总是到达远端。
在研究中发现4cm长的冻干去细胞异体神经和软骨素酶可以支持整个长度的再生。在一个大鼠模型上研究了含有自体、转分化脂肪干细胞（dADSCs）的去细胞同种异体动脉导管对8 mm长面神经分支损伤的影响。术后8周，进行振动功能评价和电生理评价，面神经运动神经元逆行标记，再生神经形态分析。
脱细胞异体动脉导管与自体dADSCs联合应用对神经再生和功能恢复有明显的效果。通过在纤维蛋白中补充骨髓基质干细胞来实现去细胞神经移植的神经再生。在这项研究中，间充质干细胞（MSCs）注射在移植物周围有助于改善周围神经损伤的神经再生和功能恢复，这是通过功能分析和组织学确定的。
人工神经导管
圆柱形神经移植早在1879年就被用于神经修复，第一次应用骨管作为神经导管。然而，由于疤痕的形成，实验失败了。神经移植的优点是：1）有限的肌成纤维细胞浸润，2）减少瘢痕形成，3）引导神经再生。由于其局限性，如可能导致供体部位发病，研究人员已开始设计人工神经导管，使用合成和生物聚合物作为替代治疗。理想的神经导管需要具有生物相容性、生物降解性、柔韧性、高孔隙率、顺应性、神经诱导性、具有适当表面的神经传导性和机械性能。神经导管可采用不同的设计方法；它们可以是具有内部通道或基质的圆柱形管，多孔壁，或细胞合并，设计可能包括生物活性剂。
具有适当性质的高分子材料已被研究并用作周围神经再生的神经导管。
生物神经导管
生物聚合物在组织工程和其他植入物中的生物活性使得细胞与支架之间的相互作用更好，从而促进细胞的增殖和组织的再生。尽管生物聚合物的高生物相容性使其成为神经导管的良好候选材料，但它们也有一些局限性，如批次间的差异。
在神经再生研究中常用的生物聚合物有聚酯（聚3-羟基丁酸酯）[P3HB]和共聚酯（β-羟基丁酸与β-羟基戊酸））、蛋白质（丝素蛋白、胶原、明胶、纤维蛋白原、弹性蛋白和角蛋白）和多糖（透明质酸、壳聚糖和海藻酸钠）占大多数。
聚酯
各种生物聚酯是从微生物中获得的。
P3HB（聚-3-羟基丁酸酯）
P3HB型用作细菌储存产品，可作为可吸收片材、颗粒和薄膜在商业上获得，它已被用于周围神经再生研究二十多年。
PHBV
3-羟基丁酸酯和3-羟基戊酸盐共聚物是应用最广泛的PHBV聚合物，因为我们能够根据我们的需要和它们的加工性能来调整它们的物理特性，这些特性使得这些聚合物非常适合用于神经再生研究以及其他组织工程应用。
蛋白质
由ECM蛋白（胶原、纤维蛋白、纤维粘连蛋白和透明质酸）和神经营养因子构建的支架已被广泛研究用于周围神经再生。
胶原蛋白
胶原蛋白是一个由26个蛋白质组成的家族，具有三重螺旋结构，以一个延伸的棒状结构，是细胞外基质的主要成分。
明胶
明胶是一种变性的胶原蛋白，与多种化学物质交联后被广泛应用于组织工程。
纤维连接蛋白
纤维连接蛋白（Fibronectin）是一种二硫键连接的糖蛋白。它在细胞粘附、形态、迁移和分化中起重要作用，并与胶原、肝素、纤维蛋白和细胞表面受体相互作用。
丝素蛋白
蚕丝是由蜘蛛纲成员合成的纤维蛋白和螨类、蝴蝶和蛾子的腺体中排列的特殊上皮细胞合成的。丝素蛋白是由重复的蛋白质序列组成的。蜘蛛丝蛋白也被推荐用于神经再生，因为它们支持细胞增殖和再生。
角蛋白
角蛋白是角质形成细胞产生的一种蛋白质。半胱氨酸在结构上富含硫，它对头发的黏结起作用。角蛋白支架能够支持神经再生。
多糖
多糖是一类由单糖或双糖组成的生物大分子，在细胞膜和细胞内通讯中起作用；它们在存储方面也有作用，它们具有高度的生物相容性，这使得它们在组织工程应用中非常有用。神经再生结构中最常用的一些糖类如下所示。
甲壳素和壳聚糖
甲壳素是昆虫外骨骼和甲壳类动物外骨骼细胞骨架的组成部分，是壳聚糖的主要来源，是地球上含量仅次于淀粉的多糖。壳聚糖基支架具有形成相互连接的多孔结构（海绵）的能力、阳离子性质和合理的力学性能，因此在组织工程应用中具有吸引力。
透明质酸
透明质酸是一种普遍存在于人体内的免疫中性多糖，临床应用已有30多年，透明质酸可以加工成许多物理形式，如粘弹性溶液、水凝胶、电纺纤维、无纺布网、大孔和纤维海绵、柔性薄板和纳米颗粒。
合成神经导管
生物可降解合成聚合物具有以下优点：1）一些可生物降解的合成聚合物具有生物相容性，不会引发任何免疫反应，是一种很有吸引力的替代品，2）在不改变聚合物本体特性的前提下，通过改变工艺条件和组分可以控制其力学性能和降解速率；3）可以以多种形式加工，以增强组织的生长。随着时间的推移，神经导管的材料选择转向使用更具生物相容性的合成聚合物。可生物降解聚酯，如聚乳酸（PLA）、聚乙醇酸（PGA）、聚（乳酸-乙醇酸）（PLGA）、己内酯（ε-己内酯）（PCL）、聚氨酯（PUs）、碳酸三甲酯-ε-己内酯、聚（D，L-丙交酯-co-ε-己内酯）和非生物降解聚合物，如甲基丙烯酸盐水凝胶、聚苯乙烯、有机硅，以聚四氟乙烯为神经导管材料。
聚酯
聚酯在主链上有一个酯官能团。聚乳酸、聚乳酸（PLLA）、PGA、PLGA和PCL是神经导管制造中最常用的聚酯。
PLA
聚乳酸可由玉米、甜菜或小麦中提取的乳酸制成，具有生物相容性. 在许多研究中，聚乳酸被用作神经导管材料。与自体移植相比，在微图案化表面添加神经干细胞进一步提高了导管的疗效。
PLLA
PLLA是PLA的一种立体规则的高度结晶形式。它也被广泛应用于组织工程应用。
PGA
PGA是另一种可生物降解、刚性、热塑性和高结晶性聚酯，具有很高的拉伸模量，在有机溶剂中的溶解度很低。PGA通常也与天然聚合物如胶原蛋白结合在一起。
PLGA
作为一种低反应性神经材料，FDA已经广泛地将其作为一种低炎症反应材料。与其他导管相比，PCLF管能显著改善神经再生和恢复。
PCL
PCL另一种聚酯，在有机溶剂中具有高溶解度，熔点低（55°C–60°C）和玻璃化转变温度(−60°C）
聚（D，L-丙交酯-co-ε-己内酯）
聚（D，L-丙交酯-co-ε-己内酯）是乳酸和己内酯单体的共聚物。
聚氨酯
聚氨酯是一种主链含有氨基甲酸酯键的聚合物，用于制造许多生物医学设备，包括神经导管，聚氨酯神经导管具有更好的再生性能，可与自体神经移植相媲美。
多元醇
聚乙烯醇（PVA）是一种水溶性、不可降解的合成聚合物，除了在生物医学领域的许多其他用途外，还被用作神经导管材料。聚乙烯醇会与壳聚糖复合。
混合神经导管
神经导管的表面特性和电荷密度对细胞粘附有重要影响。
大多数用于此目的的合成材料都是疏水性的，它们不太适合细胞粘附。因此，研究人员开始在导管表面涂上ECM蛋白或设计具有不同结构的混合神经导管来克服这个问题。近年来，由于天然聚合物和合成聚合物的结合使其性能得到改善，因此，在神经导向器生产中使用这种杂交种的情况有所增加。
合成生物材料聚酯
像PHBV这样的生物聚酯可以与合成聚合物结合。体外研究表明，细胞能够在三维组织工程化神经管中存活并保持排列整齐。
合成生物材料多糖
像壳聚糖这样的多糖被广泛地与合成聚合物结合来制备神经导管。将含壳聚糖的支架材料与PC12神经细胞接触进行体外细胞培养，发现在PVA支架中加入壳聚糖可提高神经细胞的活性和增殖能力。
含合成生物材料的蛋白质
蛋白质是天然聚合物，因此，它们与合成聚合物的共混物可视为杂化结构。杂交制剂中最常用的蛋白质是胶原蛋白。与自体移植相比，这种PGA胶原神经导管具有更好的功能恢复。
未来展望和结论
神经引导领域正朝着多种方向发展，如选择不同类型的神经和支持细胞（施万细胞），利用纤维或通道进行引导，利用生物活性剂（主要是生长因子）增强种子细胞或缺陷部位附近细胞的反应，并选择聚合物作为引导材料。所取得的进展是重大的，从商业上可买到的神经导管的数量可以看出，导管限制于我们可以使用的精密材料和设计处理的长度缺陷（不超过2厘米）。
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