人工韧带在前交叉韧带重建中的应用研究进展——从生物相容性到生物活性

张昊智 ,  陈鑫 ,  王添欣 ,  雷蕾 ,  郑力真 ,  代冰洋 ,  童文学 ,  傅世铨 ,  许建坤 ,  容树恒 ,  秦岭

工程（英文） ›› 2025, Vol. 46 ›› Issue (3) : 50 -64.

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工程（英文） ›› 2025, Vol. 46 ›› Issue (3) : 50 -64. DOI: 10.1016/j.eng.2024.10.018
研究论文

人工韧带在前交叉韧带重建中的应用研究进展——从生物相容性到生物活性

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Current Advances of Artificial Ligaments for Anterior Cruciate Ligament Reconstruction: From Biocompatibility to Bioactivity

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摘要

前交叉韧带（ACL）损伤常见于运动损伤和创伤。对于韧带完全断裂的病例，前交叉韧带重建（ACLR）术是恢复韧带完整性的唯一方法。在选择移植物时，需要考虑的因素较多，包括潜在并发症、力学性能以及愈合效果等。人工韧带已被广泛应用于临床ACLR，在大多数病例中表现出良好的生物相容性和短期随访结果。然而，与自体和同种异体移植物相比，市面上现有人工韧带的主要缺点是缺乏生物活性。此外，有长期随访结果揭示了人工韧带有时会出现移植物失效和相关的并发症。本文总结了旨在增强人工韧带生物活性的研究，对人工韧带赋予生物活性可能具有良好的临床转化前景，有望规避现有产品的缺陷。

Abstract

Anterior cruciate ligament (ACL) injuries are frequently caused by sports injuries and trauma. In cases involving complete tears, ACL reconstruction (ACLR) surgery is the only way to restore the ligament’s integrity. When selecting a graft, both the potential complications and the mechanical properties and healing efficacies should be considered. Artificial ligaments have been widely applied in clinical ACLR, and most have exhibited satisfactory biocompatibility and short-term follow-up results. Compared with autografts and allografts, however, the lack of bioactivity of currently available artificial ligaments is a major disadvantage. In addition, some long-term follow-up results have revealed other drawbacks of artificial ligaments, such as graft failure and other complications. Here, we summarize attempts to enhance the bioactive performance of artificial ligaments, as such modifications may have good potential for clinical translation and could improve the long-term outcomes of existing products.

关键词

前交叉韧带重建 / 人工韧带 / 生物材料 / 移植物-骨整合 / 关节内组织重塑

Key words

Anterior cruciate ligament reconstruction / Artificial ligament / Biomaterials / Graft–bone integration / Intra-articular tissue remodeling

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张昊智,陈鑫,王添欣,雷蕾,郑力真,代冰洋,童文学,傅世铨,许建坤,容树恒,秦岭. 人工韧带在前交叉韧带重建中的应用研究进展——从生物相容性到生物活性[J]. 工程（英文）, 2025, 46(3): 50-64 DOI:10.1016/j.eng.2024.10.018

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1 引言

前交叉韧带（ACL）连接股骨和胫骨，是稳定膝关节的主要结构[1]。ACL损伤会导致胫骨过度前移、膝关节不稳定，并加速软骨和骨的退变[2‒4]。全球每年开展超过40万例前交叉韧带重建（ACLR）手术[5]。在这些病例中，54%~74%的受伤者能够成功重返运动[6‒7]。ACLR术后恢复受多种因素影响，如韧带与骨隧道内骨组织的整合状态以及关节内韧带化过程决定了术后康复进程、功能恢复和重建韧带的生物力学强度[8‒9]。尽管既往研究报道ACLR的成功率超过90% [10]，且63%的受试者反馈了良好至优秀的术后结果[11]，但最近研究报道ACLR术后翻修率为10%~15% [12]。一项针对接受保守治疗的ACL损伤运动员的20年影像学随访研究也报道了出现骨关节炎症状有相近的发生率[13]。这些研究结果凸显了ACLR中对生物活性的需求。

目前人工韧带的研发与应用已取得较大的进展，一些综述型文献总结了已上市人工韧带临床应用的效果[14‒16]和改性人工韧带的临床前研究[9]，并探讨了生物活性涂层和表面改性方法在人工韧带中的可能应用[16]。然而，尚未有文献全面阐述人工韧带从基础研究到临床应用的研发过程，以及制备人工韧带的潜在新型材料和新兴技术。首先，理想的ACL替代物应具有与天然韧带组织相当的机械强度[14]。其次，由于重建的ACL愈合可大致分为骨隧道内的移植物-骨整合和关节内的韧带化两部分，因此所选择的ACL替代物应在组织再生和重塑后，在生物学和组织学特征上近似于天然韧带组织。换言之，任何能促进上述愈合过程的生物材料理论上都能加速ACL重建术后的愈合。此外，生物相容性，即材料的惰性或炎症反应性，以往被认为是选择移植物材料的基本要求[17]；然而近年来，材料的生物活性则日益被认为是促进组织愈合的重要特性[18]。因此，本文旨在介绍ACLR的移植物材料和相关愈合过程（第2、3节），评估当前在ACLR中应用人工韧带面临的挑战（第4节），并且重点阐述生物活性人工韧带的研究热潮（第5节）。

2 前交叉韧带重建的移植物选择

2.1 自体移植物

自体移植物主要包括骨-髌腱-骨（BPTB）移植物、腘绳肌腱（HT）移植物和股四头肌腱（QT）移植物[19‒20]。以往，由于BPTB移植物具有中间为韧带、两端为骨组织的天然结构特征，外科医生视其为ACLR移植物选择的金标准[21]。然而，BPTB移植常引发术后并发症，包括前膝痛、跪地困难、髌骨骨折和髌腱断裂[22]。研究报道HT移植物比BPTB移植物引起的前膝痛更少，长期骨关节炎发生率更低[23‒24]。但HT移植物相关的并发症及其他问题仍然存在，如伸髋和屈膝无力、移植物松弛、感染率增加、女性患者客观松弛度随时间增加、取腱过程中肌腱截断以及移植物大小和长度不可控等问题[25‒26]。QT移植物是ACLR近年来新兴的替代选择，与BPTB和HT移植物相比，QT更厚且具有更优越的拉伸性能[27]。然而，QT移植物亦存在术后并发症（如供区疼痛），且移植物失败率高于BPTB或HT移植物[28‒29]。

2.2 异体移植物

ACLR临床应用的异体移植物包括BPTB、HT、QT和胫前肌腱[30‒31]。异体移植物的拉伸负荷和刚度与自体移植物相似[32]。然而，研究发现辐照灭菌会对异体移植物的生物力学性能产生不利影响，造成延迟愈合以及增加移植物失效的风险[33‒36]。异体移植物的优势包括无供区并发症、术后活动限制更少和膝关节疼痛少于自体移植物[37‒38]。此外，异体移植物在长度和直径方面较自体移植物更易控制，这些因素对愈合也很重要[39‒40]。值得注意的是，使用异体移植物的风险有免疫排斥反应和病毒传播等。有报道称新鲜冷冻异体移植物使用与术后炎症性滑膜炎相关；而细菌传播方面，如葡萄球菌和消化链球菌感染的发生率大概是0.15% [41]。此外，年轻患者（< 30岁）的异体移植物失败率是中老年患者的2.3倍[33]。

2.3 人工移植物

自20世纪50年代以来，人工韧带因其可以避免自体和异体移植物的缺点而一直是替代自体和异体移植物的热门方案[1]。多种材料已被用于制备人工韧带，包括但不限于20世纪70年代的聚丙烯（PP）、80年代的聚四氟乙烯（PTFE）和碳纤维，以及90年代的聚对苯二甲酸乙二醇酯（PET）[42]。人工韧带不存在供区并发症和疾病传播的风险。然而，慢性积液、滑膜炎和移植物失效等并发症并非罕见。迄今为止，已上市的人工韧带仍有可优化的空间[14‒15,43]（图1）。

3 重建ACL的愈合过程

重建ACL的愈合包括两部分：①骨隧道内移植物-骨整合；②关节内韧带化。骨科医生必须充分理解这两个阶段，以选择合适的移植物并能够在ACLR后启动最佳康复方案。学界普遍认为移植物愈合主要包括三个阶段：伴随组织坏死的早期阶段；涉及细胞增殖和组织重塑的中期阶段；涉及组织成熟的晚期阶段。这三个阶段在关节内和骨隧道内都会发生[44‒45]。尽管如此，这两个愈合部位在不同阶段经历了不同的愈合过程，这些过程通常持续数周到数个月（图2）。

由于现有人工韧带材料缺乏生物活性，上述愈合过程仅在使用自体和（或）异体移植物进行ACLR时发生。因此，如何在确保可靠力学性能和生物相容性的同时，通过组织工程技术提高人工韧带的生物活性是值得探索的研究课题。这种探索旨在开发更接近自体和异体移植物术后愈合过程的人工韧带。

3.1 移植物-骨整合

在愈合的早期阶段，由于无血管化和营养氧气供应不足，移植物中段发生坏死[46‒47]。随后，中性粒细胞和巨噬细胞在术后一周内即被募集到移植物处[48]。在此阶段可观察到相对较少的细胞和血管[49‒50]。在坏死过程中会释放各种细胞因子和炎症因子，包括基质金属蛋白酶-1和13（MMP-1和MMP-13）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）等[50‒52]。此阶段约持续4周[53‒54]。

愈合的中期阶段以大量的细胞增殖为特征，这些细胞可能来源于多种组织，包括骨髓、滑膜、滑液和移植物本身[55‒58]。此外，血管从移植物外周边向中心部分生长，移植物-骨界面组织逐渐矿化，随后新生骨向移植物外层长入，使移植物与周围骨组织实现整合[59‒62]。这一阶段发生在重建后4~12周[53‒54]。愈合的晚期阶段为移植物和骨组织的持续重塑与整合。移植物和骨之间的胶原纤维逐渐重建连续性，最终使移植物-骨连接，即韧带起止位点得以重建[63‒65]。

既往的研究报道了两种类型的韧带起止点：直接型和间接型。前者包括四层连续但组织学上呈梯度的结构，即移植物（韧带）、非矿化软骨、矿化软骨和骨组织[65]。后者由斜行或垂直排列的纤维（称为Sharpey纤维）组成，这些纤维嵌插到周围骨组织中[66]。直接型和间接型韧带起止点都可视为良好愈合，而围绕在移植物-骨界面的软骨细胞最终会经历软骨内成骨的过程[55,67‒69]。

3.2 关节内组织重塑

关节内的组织重塑是指移植物作为原ACL替代物植入时发生的组织学改变[46]。与骨隧道内的早期阶段类似，关节内的移植物也会经历组织炎症和坏死。此外，伴随着关节液循环，移植物中段可能出现免疫细胞和细胞因子引起的持续炎症和坏死[70]。有趣的是，Rougraff和Shelbourne [71]认为BPTB移植物的关节内部分在ACLR术后3周（早期）就在移植物中央区域出现早期血管重建而非组织坏死。部分动物模型研究也报道了HT和趾长伸肌等软组织移植物术后早期未发生坏死[72‒73]。

在中期阶段，细胞增殖伴随着血管生成，组织重塑随着细胞代谢而进行[74]。从细胞数量、血管分布和细胞外基质（ECM）改变的角度来看，随着组织重塑的进行，细胞形态从椭圆形转变为纺锤形，并沿移植物长轴方向排列。早期阶段出现的血管过度增生在中期逐渐降至正常水平，再生的ECM（特别是III型胶原）随着原始ECM的逐渐降解而增加[75‒76]。

适宜的细胞再生和组织重塑速率是决定预后的关键因素[77]。一方面，细胞增殖和血管重建不足可能导致组织重塑不良，从而导致康复过程延缓[77]。另一方面，过度活跃的细胞和组织可能会削弱移植物的机械性能。过量的III型胶原（其机械强度劣于I型胶原）可能对移植物产生负面影响，导致移植物失效率增加。术后6~12个月，移植物内的过量细胞经历坏死并降至完整ACL的正常水平，血管在移植物中均匀分布[44,78]。然而，组织重塑的终点并不明确，某些变化在术后数年仍在持续[49,63]。

毫无疑问，细胞结构和成骨功能分别是影响关节内组织重塑和移植物-骨整合的关键因素。自体移植物之所以被认为是金标准，主要是由于其在细胞黏附、增殖和成骨方面的内在生物活性优势，即这些移植物含有促进愈合过程的细胞、ECM和细胞因子。相比之下，人工韧带由于生物活性差，往往缺乏组织重塑和移植物-骨整合能力[79‒80]。因此，如何提高人工韧带的生物活性仍是一个具有挑战性的课题。

4 人工韧带从生物相容性到生物活性的经验与启示

在过去几十年中，已有许多研究尝试通过组织工程的方法构建更为理想的人工韧带，使用的材料从合成聚合物到天然丝蛋白、种子细胞和各种生长因子等。组织工程生物材料的选择一直强调生物相容性[81]。再生医学和工程技术的进步大大拓展了生物材料的概念。例如，在人工韧带构建领域，临床实践已证明生物相容性不是生物材料的唯一要求。成血管和成骨等生物学效应在ACLR术后愈合过程中也起着关键作用[82]。本文整理了使用不同材料的人工韧带（包括韧带支架和固定装置）的研发情况。尽管某些类型的人工韧带因中长期随访结果不理想而被舍弃，但由于各类运动的普及导致运动相关损伤增加，全球对人工韧带的需求持续增长。因此，针对新型人工韧带的研发工作对满足这些需求尤为重要。

4.1 韧带支架

迄今为止，已有几种类型的材料（主要是聚合物）被用来构建韧带支架。由于人工韧带用于ACLR的完整历史超出本文的叙述范围，因此本文仅列出具有代表性的材料及产品。在Cochrane Library（1996年至2023年6月30日）、Embase（1910年至2023年6月30日）和PubMed（1979年至2023年6月30日）中使用以下关键词进行了文献检索：“anterior cruciate ligament reconstruction”“Active Biosynthetic Composite”“ABC ligament”“Goretex”“Gore-Tex”“Kennedy ligament augmentation device”“Kennedy-LAD”“ligament augmentation and reconstruction systems”“LARS”“Leeds-Keio”和“LK ligament”。纳入标准包括使用上述人工韧带进行初次ACLR手术的研究文章（包括随机对照试验、观察性研究、对比研究、队列研究和至少10个受试者的病例系列研究），且最短术后随访时间为2年。排除动物研究、尸体研究、综述类文献、评论性文献、撤回的研究、无法获得全文的研究、无术后定量评分的研究、ACL翻修手术研究和少于10个受试者的病例系列研究。对于包含相同患者队列但报道不同随访时间点的队列研究，仅纳入最新发表的文章。文献选择过程如图3所示。

25篇研究文章被纳入本文并进行定性分析；然而，由于研究的异质性和结果报道的不一致，无法对这些研究进行Meta分析。本文记录了筛选的研究中包括最终随访的受试者总数、随访时间、术后主观临床评估[Lysholm评分、Tegner评分和国际膝关节文献委员会（IKDC）评分]和并发症在内的临床结果。移植物失效被定义为重建的韧带部分或完全断裂，或纳入研究记录的“移植物失效”。如果研究中报道了不同术后主观临床评估的评分和并发症的发生情况则予以记录。否则记为“未记录”。不同人工韧带的临床结果见表1至表5 [83‒107]。

Gore-Tex韧带（W. L. Gore公司，美国）是由PTFE制备的永久性韧带，在20世纪80年代开始应用于临床ACLR [84‒86]。表1 [84‒86]显示了Gore-Tex韧带应用研究的临床结果。随访时间范围为2~15年，Lysholm评分随时间呈下降趋势；最常报道的并发症是移植物失效、积液和感染。

活性生物合成复合（ABC；Surgicraft公司，英国）韧带由碳纤维和聚酯纤维编织而成，在20世纪80年代末至90年代初被广泛应用[83,87‒89]。使用ABC韧带进行ACL重建的研究主要集中在中期（3~7年）随访结果（表2 [83,87‒89]）。Bashaireh等[83]报道与自体移植物相比，ABC韧带的IKDC评分较差。与ABC韧带相关的并发症主要包括移植物失效、关节僵硬和膝关节滑膜炎。

Kennedy韧带增强装置（Kennedy-LAD；3M公司，美国）由PP编织而成，主要用于移植物增强[90‒96]。相关研究主要比较了Kennedy-LAD与自体移植物在ACLR短期（2~4年）和长期（25~30年）随访结果方面的差异。结果显示，平均Lysholm和Tegner评分的临床结果在两种移植物类型间相似，然而Kennedy-LAD的移植物失效率较高（表3 [90‒96]）。

Leeds-Keio（LK；Neoligaments公司，英国）人工韧带由PET组成，于1982年由利兹大学的Seedhom和庆应义塾大学的Fujikawa共同设计[97‒99,108]。5年随访分析显示LK韧带与自体移植物在Lysholm和Tegner评分方面无显著差异，尽管其他研究报道LK韧带的评分较差[97]。移植物失效和运动时疼痛是LK韧带最常被报道的并发症（表4 [97‒99]）。

先进韧带增强系统（LARS；Surgical Implants and Devices公司，法国）是另一种由PET编织成的人工韧带，自21世纪初开始在临床应用[100‒107]。一系列临床研究将LARS与多种移植物（包括自体移植物、异体移植物和其他人工韧带移植物）进行了比较。术后4~16.5年的随访结果显示，根据Lysholm、Tegner和IKDC评分，LARS临床结果令人满意。然而，值得关注的主要并发症包括移植物失效、螺钉松动和膝关节滑膜炎（表5 [100‒107]）。如表1至表5所示，与ACLR中其他类型的人工韧带相比，LARS韧带在短期至长期随访结果方面，迄今为止表现出最令人满意的临床结果。

4.2 固定装置

骨隧道内最广泛使用的固定装置是钛（Ti）界面螺钉，因其良好的机械强度而受到青睐[109‒111]。除了永久性的金属界面螺钉外，研究人员还开发了一些使用聚-L-乳酸（PLLA）、聚乳酸（PLA）和聚羟基乙酸（PGA）等聚合物制成的可降解螺钉[2,112‒113]。近期的研究关注点已从提供稳定固定转向加速骨隧道内新骨形成。此外，随着手术技术的进步，使用钛袢进行皮质骨悬吊固定，以及同时使用界面螺钉和皮质骨悬吊的混合固定方法的报道也越来越多[114‒116]。在过去数年中，一些临床研究评估了可降解界面螺钉的疗效，一些研究者还研究了在ACLR中使用含有骨诱导材料[如β-磷酸三钙（β-TCP）和羟基磷灰石（HA）]的混合螺钉。随访时的Lysholm、Tegner和IKDC评分与钛螺钉相比无显著差异[117‒125]。然而，关于混合螺钉的研究报道了骨水肿、囊肿、骨隧道扩大和螺钉断裂等并发症；因此，向固定装置中添加何种骨诱导材料以及如何添加仍然是有争议的话题。

4.3 人工韧带的改性

如前文所述，一些人工韧带因移植物失效发生率高而被弃用；此外，某些韧带可能引发关节反复积液或异物反应性滑膜炎。目前，LARS韧带因其相对较低的并发症发生率而成为最常用的人工韧带（尤其是在我国）[42]。值得注意的是，LARS韧带由PET制成，与其配套的钛界面螺钉虽均是生物相容性材料，但二者均不属于生物活性材料。

表6 [43,80,82,126‒145]列出了关于PET韧带支架和固定装置各种改性方法的研究。向韧带支架中添加包括透明质酸（HA）和胶原在内的ECM成分，可增强细胞黏附和增殖，从而促进组织再生[132,134]。使用丝素蛋白（SF）等ECM类似物改性PET韧带被证实可促进体外成纤维细胞的黏附和增殖，并促进自体组织向关节内的韧带生长[51,84,138,146]。此外，Wang等[144]尝试用不同材料替代PET，他们开发了一种用于兔和山羊ACLR的分级螺旋碳纳米管韧带。与使用PET韧带的对照组相比，实验组表现出更强的骨隧道内的骨整合以及更高的拔出力。

其他关于固定装置改性的研究在动物模型中进行，主要为使用各种有前景的材料替代不可吸收的金属（主要是钛）螺钉。改性研究主要集中在改善移植物-骨整合过程中的成骨作用。一种常见方法是将骨组织成分羟基磷灰石添加到PET韧带的骨隧道内部分或界面螺钉中；体内实验结果显示，与单独使用PET韧带或PLLA螺钉相比，这种方法促进了新骨形成[80,136]。另一种方法涉及添加生物活性金属或金属化合物。研究人员在动物模型中观察到，用氢氧化钠（NaOH）和GRGDSPC肽或铜生物活性玻璃涂覆PET韧带的骨隧道内部分可改善移植物-骨界面的骨再生情况；从机制上看，这种效果可能源于S100A10、BMP2和OCN等成骨基因表达增强[82,127]。

近年来，镁（Mg）已引起医学研究者的广泛关注，特别是在骨科创伤和运动医学领域[147]。镁已被证实可通过增加脊髓背根神经节细胞释放降钙素基因相关肽（CGRP）来有效促进成骨作用[59,148]。骨膜来源干细胞（PDSCs）中的下游细胞和信号分子，如cAMP响应元件结合蛋白1（CREB1）和骨特异性转录因子（SP7），被上调从而增强了镁的成骨效应[148]。此外，研究发现血管内皮生长因子（VEGF）升高在骨干骺端、骨膜和骨内膜中促进了H型（CD31hiEndomucinhi）血管的新生[149‒150]，进而促进骨再生[146]。近来使用镁改性界面螺钉的研究取得了显著进展。在ACLR动物实验中，使用镁界面螺钉加速移植物-骨界面处纤维组织矿化，并形成明显的纤维软骨过渡区，而使用钛螺钉时未见这些效应[137‒139,144]。从机制上看，镁促进了骨髓间充质干细胞（BMSCs）向植入物周围骨组织的募集，并使局部骨形态发生蛋白2（BMP-2）、VEGF、TGF-β1和血小板衍生生长因子（PDGF）-BB的表达上调，同时下调MMP-13的表达[137‒140,144]。人们还研究了镁基合金螺钉的使用，以平衡固定装置的机械性能、降解速度和生物活性。在动物实验中，镁基合金螺钉被证实可增加骨隧道周围骨量，从而在移植物和骨之间建立充分连接（图4）[140‒141]。

使用韧带支架加固定装置是ACLR的常见搭配。然而，材料和技术的进步导致搭配模式和手术技术越来越多样化。Li等[132]开发了一种由丝素支架和TCP/PEEK锚固件组成的一体化人工韧带，并在猪ACLR模型中证实了其使用效果。研究结果显示，TCP显著促进了移植物-骨连接，且从丝素移植物到骨的过渡区（表现为再生纤维软骨）类似于原生附着点。我们团队开发了一种可缝合到韧带移植物骨隧道内部分的镁基合金（MgZnGd）丝，用于促进早期愈合阶段的骨形成，并增强晚期愈合阶段的纤维软骨样组织形成[145]。丝素的成纤维效应和镁的成骨效应等生物活性，以及新兴的ACLR全内重建技术，将继续启迪生物活性人工韧带的研发进程。

然而，这些研发首先应当平衡可行性、安全性和愈合效果，同时弥合动物研究和临床需求之间的差距[151‒152]。可行性可通过更先进的技术和更好的材料来提高，而愈合效果可通过确保安全性来改善。换言之，通过借鉴以往动物实验和临床试验的结果，并通过对体外和体内实验进行细致验证，我们旨在解决既往研究的局限性，在可行性、安全性和愈合效果方面达到新的、更好的平衡。

5 总结与展望

迄今为止，人工韧带及固定装置的设计理念反映了前交叉韧带损伤的普遍性，以及研究者对于持续改善手术效果的努力。早期ACL相关植入物的设计主要基于材料力学性能考虑生物相容性，强调植入材料的生物安全性或惰性。近来的研究则倾向于通过赋予材料生物活性来加速术后愈合过程，旨在通过增强新生组织以达到最终替代ACL的目的。本文涉及的研究表明，除生物相容性外，考虑术后再生过程中血管生成、骨形成和纤维合成的需求具有重要的意义。

在优化人工韧带设计方面，以下几个方面尤为重要：首先，静电纺丝和三维打印等新兴制造工艺可能有助于改善人工韧带的物理和生物学性能，从而提升术后效果。Legnani和Ventura [16]综述了涂层和表面改性方法（特别是表面浸泡）在人工韧带制造中的应用研究。这些研究报道了成血管和成骨效应的增强，但也存在生物活性成分分布不均匀和细胞亲和性低等问题。目前，表面浸泡并非改善PET等聚合物纤维的理想方法，因为表面的活性成分可能发生局部聚集，由此限制了其发挥生物学功能的范围。此外，表面浸泡的方法难以控制涂层材料的形态、厚度和降解速度[153]。以静电纺丝为代表的组织工程技术在制备具有均匀分布涂层组分的多孔支架方面显示出良好的应用前景。Shalumon等[154]采用共轭电纺方法制备了表面涂层材料分布均匀的PCL纱束电纺纤维，研究证实该材料能够促进趾伸肌腱缺损模型中的组织再生。Lui等[155]则开发了一种采用三维打印技术制备的多孔多相骨-韧带-骨支架，该支架在体外模型中展现出良好的细胞亲和性以及均匀的细胞分布特性。

其次，材料的直接改性也是优化人工韧带的关键因素。具有可靠力学性能和细胞亲和性的天然丝材料越来越受到关注，蚕丝便是其中之一。Li等[132]研发了一种基于蚕丝的人工韧带，并且在猪ACLR模型中观察到移植物-骨界面出现了稳固的移行区域。但天然蚕丝表面的丝胶蛋白若去除不彻底，则可能引起宿主免疫反应[132]。蜘蛛丝作为另一种天然丝材料，具有比蚕丝更好的力学性能和更低的免疫原性[156]。Kornfeld等[157]将天然蛛丝作为人工神经支架植入到神经缺损模型中，其结果显示蛛丝纤维具有与自体神经移植物相当的支持轴突再生的能力。但是，蜘蛛同类相食的习性和蜘蛛的饲养难以实现规模化，使得天然蛛丝的产量有限[158]。因此，研究者使用转基因技术以期实现重组蛛丝蛋白（spidroin）的规模化生产。Kaplan等[159‒161]研发了一系列基于蛛丝蛋白的材料，如重组嵌合蛛丝蛋白薄膜，其被证实能促进人间充质干细胞的生长、增殖及成骨向分化。这些重组蛛丝蛋白有望在骨科及运动医学领域（包括人工韧带的制造等方面）发挥重要作用。

最后，材料组分的生物学特性也具有重要价值。多种生物活性材料已被用于人工韧带的改性实验，包括但不限于蛋白质、细胞和金属元素等[127,129,140]。然而，添加更多的生物活性材料并不一定意味着更好的临床效果。我们需要更多的研究来探索关键的上游生物学效应，以及如何使用尽可能少的材料类型来激发这些效应。以ACLR的再生过程为例，充分理解移植物-骨整合以及关节内组织重塑这两个过程具有重要意义，因为移植物的这两个不同区域需要采用不同的再生和整合策略。虽然前交叉韧带康复过程受多种因素影响，但其中的关键因素目前仍未完全明了。未来需进一步研究以阐明愈合过程中的信号通路机制（如CGRP的下游分子），并深入探讨连接神经感知、成骨作用和血管生成的细胞因子调控网络。

尽管目前在临床中对于生物材料的应用非常有限，但这些创新研究可以推动人工韧带的不断优化。然而，如何平衡和优化人工韧带的力学和生物学性能仍然是一个具有挑战性的问题。目前，确保力学强度往往需要在一定程度上牺牲生物学性能；反之亦然。未来的研究应聚焦于生物材料创新、新型结构设计（如一体化装置以提高整体力学强度）以及手术技术改进三方面。这些尝试可能会为未来使用人工韧带的ACLR手术带来更好的临床结果。

总之，ACLR术后植入物的愈合状态是决定临床效果的重要因素，也是评估手术预后的关键标准。传统生物相容性材料正逐渐向促进组织再生和整合的生物活性材料转变，但当前产品的效果仍无法与天然韧带相比。本文通过综述人工韧带领域的研究进展，为当前ACLR相关认知提供参考。一方面，材料改性和技术创新极大促进了组织再生和生物工程的研究，推动了从材料的生物相容性向生物活性的转变。另一方面，从实验室研究到临床应用的转化过程仍需克服诸多障碍。

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