Platelet-rich plasma: its application in the repair of tendon and ligament injuries

doi:10.3969/j.issn.2095-4344.1416

Abstract

Abstract:

BACKGROUND: Platelet-rich plasma contains high levels of platelets and a variety of growth factors and cytokines, which help promote ligament and tendon regeneration and the recovery of multiple musculoskeletal disorders.

OBJECTIVE: To analyze the latest publications regarding application of platelet-rich plasma in the repair of tendon and ligament injuries.

METHODS: A computer-based online search of PubMed database was performed for related literatures published during 1990-2018 with the search terms “platelet-rich plasma, ligament injury, repair of ligament, tendon injury, repair of tendon, growth factors”. A total of 64 literatures were retrieved. CNKI was searched with “platelet-rich plasma” as the search term. One related literature was retrieved. These retrieved literatures were summarized from the perspectives of preparation and classification of platelet-rich plasma, release of platelet-derived growth factor, and promotion of ligament and tendon repair by platelet-rich plasma.

RESULTS AND CONCLUSION: Although platelet-rich plasma has limited and inconclusive therapeutic effects on rotator cuff and iliac tendon lesions, ulnar collaterals and anterior cruciate ligament injury, many basic science and live animal experiments support the application of platelet-rich plasma in tendon and ligament diseases. At present, platelet-rich plasma is a feasible conservative treatment with a lower risk of complications or adverse reactions. The cause of disease may have certain effects on the injection methods of platelet-rich plasma. For example, leukocyte-poor platelet-rich plasma exhibits better therapeutic effects on the external humeral epicondylitis than leukocyte-rich platelet-rich plasma because it likely helps induce an inflammatory response to promote recovery. Platelet-rich plasma has not become one of the standard treatment methods of tendon and ligament injuries. With in-depth research on the optimal candidate, platelet-rich plasma may develop into a more common therapy in the future.

Key words: platelet-rich plasma, tendon injury, ligament injury, biological product, growth factor, cytokine, leukocyte-rich platelet-rich plasma, leukocyte-poor platelet-rich plasma

CLC Number:

Wang Haonan, Wang Jihong, Wen Shuzheng. Platelet-rich plasma: its application in the repair of tendon and ligament injuries[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(30): 4875-4881.

Figures/Tables 1

2.1 富血小板血浆治疗肌腱/韧带损伤的基础研究富血小板血浆在临床上的应用是基于先前的体外研究，探索其对肌腱和韧带愈合的影响。在肌腱中富血小板血浆已被证明能促进肌腱干细胞增殖并诱导血管生成因子[13-14]。对培养的人肌腱细干胞进行富血小板血浆检测，发现富血小板血浆能显著提高肌腱干细胞血管内皮生长因子和干细胞生长因子的含量[14]。肌腱也含有腱干/祖细胞，约占腱细胞总数的5%。多种体外研究表明，富血小板凝块释放物可诱导兔肌腱干细胞分化为活性腱细胞[15-16]。自体富血小板凝块释放物也可抑制小鼠肌腱干细胞向非腱细胞系的分化[17]。富血小板血浆还通过增加腱细胞中总胶原的合成而对肌腱干细胞具有合成代谢作用[16，18]。一项体外研究表明当血小板增加Ⅰ型胶原表达时，白细胞的加入诱导了Ⅲ型胶原的高表达，同时降低了Ⅰ型胶原蛋白表达[18]。这是很重要的，因为高Ⅲ/Ⅰ型胶原比值可能提示纤维化并降低愈合肌腱的强度[15]。尽管存在这种潜在的缺点，但白细胞的存在已显示出对感染有保护作用。与全血相比，两种富血小板血浆制剂(富白细胞富血小板血浆与贫白细胞富血小板血浆)制剂均显著降低细菌生长[19]。研究表明在急性损伤的早期阶段，富血小板血浆能加快动物内侧副韧带愈合和增强韧带强度[22-23]。Fleming等[24]证明在使用胶原-血小板的情况下，富血小板血浆对关节内韧带如前交叉韧带也是有用的。这些基础科学研究有助于支持富血小板血浆在活体环境下用于肌腱和韧带损伤的治疗。 2.2 富血小板血浆治疗肩袖肌腱病的临床研究文献报道富血小板血浆在肌腱疾病中的应用结果不同。富血小板血浆增强肌腱修复的早期研究与临床结果不一致[25-26]。一项Meta分析比较有无应用富血小板血浆注射治疗肩袖手术的效果，发现两组在再撕裂率上无显著差异[26]。然而这种Meta分析在研究数量和患者数量上是有限的。最近的一项Meta分析审查了超过18项随机对照研究 (>1 147例患者)，将富血小板血浆或富血小板纤维蛋白与单纯的关节镜修复进行比较，发现富血小板血浆显著降低了中、小型完全撕裂肌腱的不完全愈合率，还发现目测类比评分在30 d时显著下降[27]。 Verhaegen等[28]研究了富血小板血浆在关节镜下对肩袖钙化沉积的补充作用，以随机对照方式比较了使用富血小板血浆是否会影响肩袖在使用针刺技术造成缺损后的愈合过程，发现无论是否使用富血小板血浆，所有患者术后均有明显改善，超声观察两组3，6个月的肩袖缺损评估无差异。Carr等[29]在关节镜下应用富血小板血浆行肩峰成形术治疗慢性肩袖肌腱病时有类似的结果。然而在随机对照试验中与类固醇相比，富血小板血浆在6个月后并没有显示出明显的不同[30-31]。 2.3 富血小板血浆治疗髌腱病变的临床研究髌腱病的特征是由于过度使用导致的慢性髌腱疼痛。富血小板血浆近年来已成为髌腱病常见的非手术干预方法。Liddle 等[32-35]通过系统文献综述评估了富血小板血浆注射患者的临床结果，发现应用富血小板血浆在减轻疼痛和改善功能方面有显著效果，多达81%的患者能够恢复到症状前活动水平。然而研究结果并不一致，Gosens等[33]发现其研究的人群中只有22%能够恢复到症状前活动。一项将富血小板血浆与物理治疗结合和单纯物理治疗相比较的小规模研究显示，6个月时队列组之间并不存在显著差异[36]；然而与体外冲击波疗法相比，富血小板血浆在减轻疼痛和改善功能方面有显著作用[37]。富血小板血浆注射次数对治疗结果也有影响，2次注射对疗效的改善更明显。Zayni等[38]研究发现接受2次富血小板血浆注射患者的疼痛和功能改善明显大于1次注射，这一结果在2018年由Andrioloet 等进行的一次Meta分析中得到了证实。除慢性髌腱病外，富血小板血浆似乎对前交叉韧带重建后的髌骨愈合有帮助。Cervellin等[39]的一项随机对照试验发现前交叉韧带重建后应用富血小板血浆治疗患者的膝关节疼痛明显减轻，功能得到改善。然而这一发现在文献中并不一致，Walters等[40]设计的一项随机对照试验研究了富血小板血浆对前交叉韧带重建部位跪痛的作用，发现接受富血小板血浆注射患者与安慰剂治疗患者在间隔随访时的跪痛没有明显差别。 2.4 富血小板血浆治疗跟腱附着点病变的临床研究跟腱是由浅后室肌腱区组成的连体结构[41]。在运动过程中，肌腱可以对抗大于体质量约12倍的力量，是身体中最强的部位之一[42]。尽管跟腱结构坚固，但也是下肢肌腱断裂最常见的部位之一，占主要肌腱损伤的20%，这种肌腱的愈合潜力是可变的，原因不明[43]。20世纪50年代进行的解剖研究发现，肌腱的中间物质内有一个水滴区域，被认为是一个相对缺血区，易受损伤，但是最近的研究挑战了这一观点[41]。由于其相对无创性和低风险性，行富血小板血浆注射治疗以期改善跟腱损伤的愈后。 Di Vos等[44]最近进行的一项系统审查试图评估现有的文献，以期更好地阐明富血小板血浆在治疗跟腱损伤中的临床潜力，虽然12项被审查的研究中大部分是IV级证据，但一项随机双盲前瞻性试验被审查了。Devos等比较将盐水注射与富血小板血浆注射治疗跟腱损伤成年患者的效果，发现两组平均运动评定量表评分均有不同程度的提高，富血小板血浆和生理盐水在改善疼痛和功能上没有显著差异。最近的一项随机双盲前瞻性试验证实并扩展了这些结果。Boesen等[45]对60例成年男性跟腱损伤患者分别注射高剂量甲基强的松龙注射液、富血小板血浆至少3个月，除注射外每个参与者都通过集中康复程序进行标准化的康复运动，结果显示出富血小板血浆在恢复功能和减轻疼痛方面有更明显效果。 2.5 富血小板血浆治疗外上髁炎的临床研究肱骨外上髁炎是肱骨外侧上髁处关节伸肌附着点常见的退行性肌腱损伤，治疗方式包括休息、行为改变、理疗、支撑、抗炎药物和顽固性病例的手术治疗[46-47]。虽然这些疗法对急、慢性患者有所帮助，但固有肌腱的生物愈合潜力很差，增加了人们对富血小板血浆生物增强术的兴趣[48]。最近发表的几项研究将富血小板血浆与其他治疗方法进行了比较，包括手术和非手术干预[49-52]。在一项关于富血小板血浆在韧带和肌腱损伤中使用的一级随机对照试验Meta分析中，发现富血小板血浆在短期(<6.5个月)和长期(>1年)随访期减轻疼痛方面较各种对照组更为有效[48]。对患者和临床医生来说，在考虑不同干预措施时疗效的开始和持续是一个重要的考虑因素。最近的2份报道进行了富血小板血浆与皮质类固醇注射在肱骨外上髁炎患者治疗中的对比[49-50]。Ben-Nafa等[50]的系统综述表明，富血小板血浆的治疗起效较慢，但与皮质类固醇相比富血小板血浆具有更长的临床疗效，腹腔注射富血小板血浆未发生明显的不良反应，并且富血小板血浆受体的临床改善持续时间长达2年[50]。也没有证据表明富血小板血浆可导致皮下组织萎缩或色素沉着等这些已知的皮质类固醇并发症[53]。这些结果与Mi等[49]的Meta分析结果一致，该分析描述富血小板血浆注射治疗的功能障碍评分与皮质类固醇注射相比逐渐改善，直至1年随访，而6个月后注射富血小板血浆患者的临床结果更好。如前所述，富血小板血浆注射类型也很重要，因为外侧上髁炎由于血管不佳和不能诱导炎症反应而经常无法愈合。Mishra等[51]研究发现注射富含白细胞的富血小板血浆治疗外侧上髁炎的长期疗效优于主动局部麻醉注射组。外科手术也适用于患侧肘肌腱病的患者，尤其是难治性病例。2017年的一项研究报道了接受富血小板血浆注射或关节镜下外侧肘关节清创术患者术后的疼痛和功能结果，发现虽然这两种手术都是安全的并为患者所接受，但关节镜在长期疼痛和功能预后方面优于富血小板血浆。 2.6 富血小板血浆治疗尺内侧副韧带的临床研究尺内侧副韧带损伤是由于外力外翻造成的，在高空投掷运动员中很常见[54]。对于完全撕裂的韧带或进行保守治疗没有明显效果的韧带损伤可行手术治疗，但手术成功率从83%到90%不等，一般术后9-12个月能够恢复正常[54]。Hoffman等[56]的一个案例研究详细描述了1例25岁职业投手的尺内侧副韧带重建结果，在富血小板血浆和间充质干细胞中通过真皮同种异体移植重建，发现患者在术后4个月恢复投球。事实上，部分尺内侧副韧带撕裂通常不用手术治疗，保守治疗通常包括休息、支持疗法和口服药物。最近，人们对富血小板血浆注射的潜在作用也产生了极大的兴趣。Podesta等[55]跟踪了34名投掷运动员通过单次富血小板血浆注射治疗尺内侧副韧带部分厚度撕裂的进展，发现34名运动员中有30名能够在平均12周的时间内恢复到同等水平或更高水平。Dines等[57]进行的类似研究回顾了44名接受富血小板血浆注射治疗部分尺内侧副韧带撕裂的专业投球运动员的治疗进展，发现44名中有32名取得了好到优秀的结果，在12周后恢复了比赛。在一个更大的案例系列中，Deal等[58]进行了用2次注射富含白细胞的富血小板血浆治疗25名2级尺内侧副韧带撕裂运动员的病例系列研究发现，25名运动员中有22名能够恢复比赛，其中20名在MRI上显示出完全重组的尺内侧副韧带。尽管有这些不同的病例报道，但目前还没有随机对照试验来检查富血小板血浆对尺内侧副韧带的有效性。目前尚不清楚富血小板血浆是否在尺内侧副韧带损伤时加速了其恢复速度。 2.7 富血小板血浆治疗前交叉韧带的临床研究膝关节前交叉韧带对膝关节的稳定性至关重要，其断裂需要外科手术来恢复功能。Figueroa等[59]对富血小板血浆辅助前交叉韧带修复的系统综述显示，在临床结果、骨隧道愈合/拓宽、移植物成熟等方面均有不同的结果。如前所述，研究表明富血小板血浆对术后疼痛和手术部位的愈合有帮助[38]，但是在隧道愈合和扩大方面，富血小板血浆几乎没有显示出任何效果[60-61]，只有一项研究得出富血小板血浆在2.5个月时使隧道皮质骨数量显著增加(36.2%，22.5%)的结论，然而这种差异在6个月时保持不变(67.1%，53.5%)[62]。 Vogrin等[63]进行了一项随机对照试验，用增强富血小板血浆重建前交叉韧带，发现富血小板血浆试验组前后膝关节稳定性有统计学意义上的改善，然而在12个月后MRI检查时，富血小板血浆治疗组与手术组关节内部分的愈合没有差别。Magnussen等[64]比较了富血小板血浆在同种异体前交叉韧带重建基础上的应用情况，发现不论是否使用富血小板血浆，2年随访时患者预后无差异，但使用富血小板血浆可能在部分撕裂中表现出更好的作用。Di Mateo等[65]对富血小板血浆用于部分前交叉韧带撕裂的两项研究进行的系统评价表明：70%-84%的患者在未经手术情况下恢复到以前的活动水平。对于应用富血小板血浆治疗前交叉韧带损伤的初步研究显示，富血小板血浆在诱导各种移植细胞生长方面具有良好的应用前景。然而，目前还没有足够的研究来得出最佳的富血小板血浆注射组合来诱导最好的愈合。"

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