不同肩袖补片特点：应用强度、降解速率及酸性降解物的调控

doi:10.3969/j.issn.2095-4344.2015.30.023

摘要/Abstract

摘要：

背景：采用何种材料作为肩袖补片是最安全的或最有效的仍没有共识或明确的指南。
目的：综述肩袖补片材料的基础研究、临床应用现状及前景。
方法：利用计算机检索EMbase、Medline、PubMed、OVID、Cochrane Library、Springerlink、万方数据库、中国知识资源总库及维普数据库，查阅国内外肩袖补片的基础研究与治疗肩袖撕裂的相关文献，并进行总结归纳。
结果与结论：肩袖补片类型可分成肌腱补片、不可降解肩袖补片、细胞外基质肩袖补片及人工合成可降解型肩袖补片4类。肌腱补片、不可降解补片可提供相对更好的机械强度，但肌腱补片面临术后免疫排斥反应、感染风险增加、不能恢复腱骨结合点的正常结构等问题，而不可降解补片的长期安全性尚不确定；细胞外基质肩袖补片强度相对较低，肩袖修复失败概率高；人工合成可降解型肩袖补片具有相对较强的机械强度，体内长期存留的安全性较高，但生物活性细胞的迁移、补片降解速率的调控及酸性降解物的抑制是目前需要研究的难题。

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

关键词: 生物材料, 材料相容性, 肩袖补片, 肌腱补片, 不可降解补片, 细胞外基质补片, 可降解补片, 肩袖损伤

Abstract:

BACKGROUND: It is unclear what kind of material for rotator cuff repair augmentation is the safest or most effective.
OBJECTIVE: To review the basic research, clinical application and prospects of materials for rotator cuff repair augmentation.
METHODS: Eligible studies were identified from electronic databases including EMbase, Medline, PubMed, OVID, Cochrane Library, Springerlink, CNKI, WanFang, and VIP.
RESULTS AND CONCLUSION: There are four kinds of patches used for rotator cuff augmentation: tendon patches, non-degradable patches, extracellular matrix-based patches and degradable synthetic patches。 Tendon patches have good mechanical strength, but postoperative foreign body reactions and increasing risk of infection and unable to recover the normal structure are problems to be solved. Non-degradable patches also have good mechanical strength, but the long-term safety is unclear. Extracellular matrix-based patches remain a lower mechanical strength and have a higher failure rate. Degradable synthetic patches are proposed to overcome these previous issues by combining well-adjusted mechanical properties with biological additives and minimize risk of infection by completely absorbing in a time-dependent manner. However, migration of bioactive cells, regulation of degradation rate and suppression of acidic degradation products is are existing problems to be solved.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

Key words: Biocompatible Materials, Extracellular Matrix

中图分类号:

R318

任士友，江长青，张文涛. 不同肩袖补片特点：应用强度、降解速率及酸性降解物的调控[J]. 中国组织工程研究, 2015, 19(30): 4876-4881.

Ren Shi-you, Jiang Chang-qing, Zhang Wen-tao. Different materials for rotator cuff repair augmentation: intensity, degradation rate and acidity degradation products[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(30): 4876-4881.

图/表（结果） 1

2.1 肌腱补片 2.1.1 修复理念肌腱补片可以用来降低肌腱和骨之间的张力，可为生长因子和细胞生长提供支撑的附着点，有助于损伤修复。使用肌腱补片修复鼠急性肩袖撕裂，发现鼠自体细胞开始增殖并移入肌腱补片中^[6]，缺点该研究未提及自体细胞是否能在退行性病变和无血管的病变肩袖撕裂中保持活性。

2.1.2 肌腱补片分类及临床研究进展肌腱补片分为同种异体肌腱补片和自体肌腱补片。同种异体肌腱补片有引起免疫排斥反应、加大术后感染风险的可能。有研究使用同种异体跟腱补片、髌腱补片或股四头肌腱补片修复28例巨大肩袖撕裂，尽管术后患者功能有改善，但相对于病情相似且仅行肩峰成形和关节清理的患者并无明显差异^[7]。此外，在使用同种异体肌腱补片患者中，有1例出现感染，1例术后出现严重的免疫排斥反应。最新的研究报道，相对于直接清创缝合及使用人真皮补片修复，使用同种异体带骨肌腱修复犬巨大肩袖撕裂术后有更好的完整性，同种异体骨的与宿主骨完整结合^[11]。

自体肌腱补片能够降低术后免疫排斥反应。有文献报道使用切除的自体肱二头肌长头腱修复肩袖撕裂，降低了肌腱和骨之间的张力，避免了在机体其他部位手术取肌腱^[8-9]。Mori等^[10]研究取自体股骨转子阔筋膜作补片修补24例肩袖巨大撕裂并冈下肌轻度脂肪退变患者的疗效(研究组)，并与不使用补片修复24例肩袖巨大撕裂并冈下肌轻度脂肪退变患者(对照组)的疗效进行对比，发现两者术后功能较术前均有很大改善，研究组Contant 评分和ASES评分均高于对照组，术后肩袖再次撕裂概率明显低于对照组。未能恢复腱骨结合点的正常结构是使用肌腱补片修复的重要问题，但现有技术对于肌腱与腱骨附着点愈合暂无好的解决方式。

总之，同种异体肌腱补片有引起免疫排斥反应、增加术后感染风险的可能，而同种异体带骨肌腱修复巨大肩袖撕裂仍需进一步试验；自体肌腱补片虽能克服免疫排斥反应，但其仍不能恢复腱骨结合点的正常结构。

2.2 不可降解型肩袖补片

2.2.1 修复理念使用不可降解型肩袖补片增加肱骨与冈上肌肌腱连接，它包含一个简单的手术：通过不可吸收锚钉、补片将肌腱固定于骨实质上的过程。这种方法类似于疝修补，是种机械修复和永久修复，修复后肩袖能自我愈合。基于这种理念开发及设计的各种非降解肩袖补片，以强大的抗拉强度、良好的组织相容性和出色的处理性能为主要特点。

2.2.2 不可降解肩袖补片材料发展第一个非对照研究中报道使用聚酯类如聚四氟乙烯(聚四氟乙烯)补片修复肩袖撕裂，25例修复中23例显示良好的疗效^[12]。通过组织学研究发现，聚四氯乙烯补片与骨、补片与肩袖之间紧密的长成一体，而且周围未发现炎症反应证据^[13]。

最新聚酯类补片植入修复肩袖撕裂的研究表明，在86个月的随访中，41例患者显示出良好的耐受性、功能明显改善和疼痛明显缓解，3例补片和肌腱之间出现再次撕裂^[14]。作者注意到新一代聚酯补片术后短期内在抗拉强度高、低摩擦和优秀的组织相容性方面有明显提高。类似的结果也出现在其他研究及聚酯类补片植入的病例报告中^[15-16]。有研究对比使用直接缝合、胶原补片、聚丙烯补片修复肩袖撕裂的疗效，3年随访发现聚丙烯补片修复较其他两修复方式在功能、力量、复发率方面占有明显优势^[17]。

其他非降解补片材料正在开发和测试，从材料方面看如聚碳酸酯聚氨酯和聚四氟乙烯很有前景^[18-20]。有研究使用聚碳酸酯聚氨酯补片修复10例肩袖巨大撕裂，术后患者的ASES评分、UCLA评分、CADL评分都有明显提高，且补片的耐用性良好^[21]。有报道通过对37例肩袖不可修复撕裂患者6个月的随访研究发现，使用膨体聚四氟乙烯补片修复肩袖巨大撕裂的临床疗效明显高于直接缝合修复^[22]。

非降解植入补片材料的主要问题是长期完整性的缺失。碳纤维补片被誉为理想的肌腱和韧带修复材料，有良好的机械强度^[23-24]，但这些材料长期体内存留后的结构完整性遭到破坏，可迁移到其他组织，引起慢性炎症和异物反应，需要进行翻修手术^[25-26]。总之，非降解材料修复肩袖撕裂可能携带一个不必要的长期风险^[27]，目前仍需要更好的临床证据来了解非降解植入材料的长期安全性。

2.3 细胞外基质肩袖补片

2.3.1 修复理念研究表明，肌腱修补后老化和修复失败与组织矩阵结构的变化、刺激细胞行为改变密切相关^[28]。基于这种理念，补片设计目的是为内在细胞种群提供一个临时的矩阵结构胶原附着点。体外实验表明将细胞植入到生物相容性好的补片上，生物细胞会自我完成撕裂组织的修复。

2.3.2 细胞外基质肩袖补片分类及临床进展此类补片包括猪小肠黏膜下层、猪真皮、血小板纤维基质构建的补片和皮肤的细胞外基质结构等。体外实验表明，此类补片是优秀的人类肌腱细胞附着点及培养基^[29-32]。

在犬模型中使用小肠黏膜下层材料来替代肌腱，结果显示补片内有新生的组织生长，补片重新塑形^[33]。然而在一项羊模型研究中，比较猪真皮补片和猪小肠黏膜下层补片的效果时，发现真皮补片在炎症血浆纤维蛋白原标志和和骨化程度方面显示出更为优越的性能。作者观察到的猪小肠黏膜下层补片退化速度比真皮快，9周内几乎完全吸收^[34]。有报道在非洲绿猴模型研究中，使用猪真皮补片修复冈上肌腱损伤，术后3，6个月的组织学研究发现，补片重新塑造出类似肌腱的结构，补片内纤维细胞均匀分布，胶原纤维平行分布，大量血管长入到肌腱中，6个月时血管减少到受体肌腱的正常水平^[35]。有研究使用人同种异体真皮补片修复肩袖巨大撕裂，对45例患者进行24-68个月的随访发现，患者术后UCLA、ASES、WORC评分均较术前明显提高，患者对手术的满意率高，极少患者需要二次手术^[36]。另有报道通过随机对照试验对关节镜下人真皮补片修复巨大肩袖撕裂的的安全性、有效性进行评价，试验组使用单排固定+肩袖补片修复，对照组使用单排固定修复，术后一二年随访发现，试验组和对照组ASES、UCLA、Constant评分均较术前明显提高，试验组术后ASES、Constant评分明显优于对照组；实验组完整修复率85%，对照组仅为40%^[37]。

Murray等^[38]2007年使用富含血小板血浆的支架使羊胫骨缺陷模型完整愈合，16周后，机械强度、生物相容性、骨诱导性明显优于对照组。有研究报道富含血小板血浆可以干扰人类破骨细胞前体的完整分化，随后有关富含血小板血浆对肌肉骨骼软组织损伤修复的研究逐渐展开^[39]。有报道通过队列研究对比使用与不使用血小板血浆修复肩袖撕裂的差别，并没有明确的数据表明血小板血浆能加速肩袖损伤的修复及临床症状的改善^[40]。研究发现，血小板纤维基质补片能降低肩袖再次撕裂发生的可能^[41]。研究发现，使用血小板纤维基质补片相对不使用补片治疗肩袖撕裂，在术后临床功能及组织结构完整性方面二者无明显差异^[42]。此外最新的循证医学证据，通过收集19个单中心实验研究、1 088例研究对象进行Meta分析，发现缺乏足够的证据证明血小板疗法治疗肌肉骨骼软组织损伤的有效性^[43]。

细胞外基质补片的缺点包括缝合固定性能及机械性能差^[23]，已有研究报告其弹性及韧性远低于正常肌腱^[44-45]。在某些情况下，为克服这些缺点加用可降解聚合物纤维等加强固定^[46]。另一个问题是，在某些细胞外基质补片中已确定有DNA和细胞内容物的痕迹存留^[47-48]，这可能引起不利的炎症反应和疾病的传播。此外，有报道细胞外基质补片与慢性炎症有关^[49]。

最近的一项临床试验结果显示，猪真皮细胞外基质补片及人真皮细胞外基质补片的临床效果有不少提高^[4]。Barber等^[50]通过前瞻性随机研究使用人真皮补片修复22例肩袖巨大撕裂患者，相对于20例直接清创缝合患者，有更高的ASES和Constant评分，肩袖完整修复比例更高，且未发生人真皮补片不良事件。然而，这些植入物的功效仍然被质疑。一项临床研究表明，使用猪小肠黏膜下层肩袖补片修复巨大肩袖撕裂的临床疗效十分差，结果有91%的复发率^[51]。这个结果被其他研究进一步证实，采用猪小肠黏膜下层补片加固组相对非加固组疗效同样差^[52-53]。而修复失败是归因于猪小肠黏膜下层补片的迅速吸收和修复撕裂后提供的机械支撑不足^[52]。

2.4 人工合成可降解型肩袖补片

2.4.1 修复理念为了克服细胞外基质肩袖补片的成本和安全问题，开始出现人工合成、仿生和可降解肩袖补片。这种补片为自我修复提供一个非永久性附着点，补片可在适当长时间内被吸收，又拥有良好的生物相容性、机械性能及弹性。 2.4.2 分类、制造工艺及临床研究进展可降解肩袖补片常用的可降解聚酯材料，包括左旋聚乳酸共聚物、乳酸羟基乙酸共聚物、聚己内酯及聚丙二醇共聚物。此外，还有些研究建议使用简单合成的可降解材料^[54]，大多数强调制造模式化结构体的好处。

电纺技术的应用，可以创建和模仿与肌腱胶原纤维走向相同的补片，在某些情况下，纤维还可以在肌腱骨结合处从对齐过渡到随机走向^[55-57]。许多结构对齐的肩袖补片已被证明直接影响附着细胞的排列走向，以及影响矩阵结构蛋白的表达^[55]。通过电纺技术制造可降解肩袖补片的设计理念，还包括将生物有机体结合到生物合成补片中，如将干细胞植入补片中^[58]，制造时在里面添加基质蛋白胶原蛋白或生长因子到补片^[59-60]。模仿腱-骨结合部位物质含量的方法也已提出^[61]。因此，使用可降解肩袖补片生物修复肩袖撕裂是目前的一种趋势^[62-63]。体外研究证实，通过电纺技术加工的乳酸羟基乙酸共聚物补片和聚丙二醇补片都表现出良好的细胞反应和生物相容性^[64-65^，^70]。进一步的研究也证明对于相同材料，通过电纺技术加工比其他普通加工更能降低体内免疫反应^[66-67]。

合成可降解补片在动物模型的初步疗效测试中显示了良好的结果。将未使用电纺技术的纤维聚(乳酸)补片入山羊模型中，术后前3周表现出明显的力量改善，尽管这不是统计学上说的有意义^[68]。将通过电纺技术加工的聚己内酯补片植入大鼠模型8周后表现出良好的耐受性，具有良好的细胞渗透^[57]。一项随机对照实验表明相对于非加固修复，使用电纺技术加工的左旋聚乳酸补片修复可明显提高杨氏模量^[69]。

然而高浓度的乳酸和羟基乙酸被发现对肌腱细胞和成骨细胞有毒，无毒浓度时会减少肌腱细胞增殖和使成骨细胞分化^[65^，^70-71]。因此，降解速率和酸性降解产物的积累对人工合成可降解补片的安全性十分重要。研究也表明，在体外实验中不同聚合物降解物的毒性不同^[72]，但降解产物有组织依赖性是十分清楚的，目前没有具体的数据说明可降解补片在肩关节或肩峰下滑囊怎样降解。因此，未来的研究应该致力于使补片植入体内能完全降解，确保产品的整个生命周期中释放的酸性降解物在安全范围内。

电纺可降解补片的另一个问题是他们的机械性能相对较低，即使是对齐的结构也一样^[55]。即使使用多分子层方法，将机械性能结构更好的材料，如针织乳酸羟基乙酸共聚物纤维或快速原型聚己内酯结构融合在补片中以提高机械性能，仍不能未达到满意的程度^[64^，^73]。

电纺材料更深层次的问题是补片上毛孔间隙过小，阻止细胞进一步迁移到补片内，因此新生的组织结构并不与需要的完全一样。为了克服这个问题，最近已有多种方法被开发出来，其中包括使用盐或聚合物浸出和先进的收集系统^[74-75]。

关于这些补片性能的临床证据需要进一步收集。有研究使用左旋聚乳酸补片修复18例巨大肩袖撕裂，术后肩关节功能评分均较术前有明显提高，术后12个月修复成功率为83%，术后42个月修复成功率为78%^[75]。目前仍缺乏大样本临床研究或随机对照研究的支持。

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