天然高聚物基手术缝合线的研究现状

2023-07-04 04:50杨鑫张昕潘志娟
丝绸 2023年3期
关键词:甲壳素蚕丝胶原蛋白

杨鑫 张昕 潘志娟

摘要: 医用手术缝合线种类丰富,其制备原料可分为天然材料、合成材料及金属材料等,其中天然高聚物基手术缝合线以其优异的生物相容性、低免疫原性等特性在市场上占据主体地位,但仍存在机械性能较差、降解速率难以调控等问题。为了改善天然高聚物基缝合线的性能,促进新型缝合线的研究发展,并使其进一步满足医用领域的应用需求,本文综述了蚕丝基、胶原基、甲壳素基三类天然高聚物基缝合线的研究现状,比较了三者在实际应用中的优缺点,并分析了三者存在的性能缺陷及改进方向,以期为天然高聚物基手术缝合线的研究发展提供参考。

关键词: 天然高聚物;手术缝合线;蚕丝;胶原蛋白;甲壳素;壳聚糖

中图分类号: TS101.4

文献标志码: A

文章编号: 1001-7003(2023)03-0001-07

引用页码:

031101

DOI: 10.3969/j.issn.1001-7003.2023.03.001(篇序)

手术缝合线是外科手术中一种用以缝合伤口、结缔组织的医用材料,也是最为普遍的可植入人体的材料。其种类繁多,按照生物降解性分为可吸收缝合线与不可吸收缝合线;按照原料分类分为天然高聚物基缝合线、合成材料缝合线及金属缝合线等。

20世纪50年代开始,合成材料类手术缝合线才开始进入研发阶段,其应用历史短暂[1],且生物相容性差、易引起炎症反应,使得病人在术后恢复缓慢,痛感加剧。金属缝合线的原料主要是银与合金,具有强度高、可消毒抗菌等特点,但柔韧性较差,打结处易引起组织的刺激与疼痛,目前已不常使用。相比而言,天然高聚物基缝合线应用历史悠久,5 000多年前古埃及人就开始利用棉纤维、动物鬃毛等材料缝合伤口[2];中国最早在汉代就已经有了清理创口的记载,在唐代时开始使用桑皮线进行伤口缝合。该类缝合线具有良好的生物相容性、低免疫原性等优点,因此沿用至今,且成为外科手术中最常用的手术缝合线。现如今,在科技快速发展的时代背景下,新型天然材料被不断开发利用,天然高聚物基手术缝合线的种类也逐渐丰富。基于此,本文综述了蚕丝基、胶原基和甲壳素基三类应用较为广泛的天然高聚物基缝合线的研究及应用现状,对缝合线的物理机械性能和抗菌释药功能进行比较和分析,以期为开发新型功能性天然高聚物基手术缝合线、满足不同外科手术缝合的需要提供参考。

1 蚕丝基缝合线

蚕丝是一种天然蛋白质纤维,也是人类最早利用及最早商业化使用的纺织纤维之一,在缝合线领域应用历史悠久。医用蚕丝缝合线具有优异的吸湿性、可操作性[3]和打结稳定性[4],常被用在眼科、神经外科及心血管外科手术中,是目前国内最主要的缝合材料之一。

单丝型蚕丝缝合线力学强度低,无法满足伤口缝合对缝合线的力学强度要求[5],一般需要通过加捻、编织等工艺加工成复丝缝合线后应用,但加捻缝合线在使用过程中易出现扭结,因此外科手术中大多采用结构更稳定的编织型缝合线。蚕丝作为蛋白质纤维,为微生物的生长和繁殖提供了养分[6],且编织处理后的缝合线表面存在缝隙,更容易引起伤口的细菌感染。因此,在外科手术中应用编织型蚕丝缝合线时,需要对其进行一定的抗菌处理,主要包括涂层、共混、嫁接等[7]方法,目前较为常见的是在缝合线表面负载抗菌涂层[8]。

涂层溶液中负载的抗菌剂及药物可以覆盖缝合线的纤维间隙和编织点,并渗透到缝合线内部,起到有效抗菌和持续释药的功能。Pethile等[9]以聚己内酯(PCL)为药物载体,联合抗菌剂磺胺甲恶唑(SMZ)制备抗菌溶液,采用浸涂法将其涂在蚕丝缝合线上,涂层溶液黏度较大,可促使抗菌性药物嵌入编织缝合线的表面,抗菌效果可维持至术后4 d左右。Wu等[10]将蚕丝(SF)编织成芯壳结构,并在缝合线表面涂覆了新型天然抗菌剂小檗碱(BB)。BB与SF间的相互作用使缝合线具有高达20.1%±1.1%的载药率,可以在人体内保持4 d以上的有效抗菌活性。相对而言,无机抗菌剂的抗菌效果更为显著,Shubha等[11]在脱胶后的蚕丝纤维表面涂覆纳米氧化锌颗粒(ZnO NPs),ZnO NPs的交联作用增强了纤维的抗拉强度,并赋予纤维良好的抗菌功能,可有效抑制微生物生长长达6 d。Cao等[12]选用多孔氧化锌(PZ)对蚕丝纤维进行改性处理,纤维对金黄色葡萄球菌和大肠杆菌的抑菌率均达到了80%左右。Syukri等[13]和Baygar等[14]将纳米银颗粒(Ag NPs)通过原位沉积法涂覆在蚕丝缝合线上,实验结果证明缝合线对金黄色葡萄球菌的抑菌率达到了99%,能稳定抗菌12周以上,且残留的微量金属离子未对人体造成伤害。表1比较了不同涂层处理后蚕丝基缝合线的性能。从表1可以看出,通过不同涂覆方法负载了不同抗菌剂的缝合线均具有较好的抗菌效果,其中无机抗菌剂持续效果最久。但在现有研究中,从纤维本身出发,制备再生蚕丝蛋白纤维并赋予其抗菌功能的研究较少,今后的研究中可以在这一方面发掘一些新的方法。此外,蚕丝缝合线能否在缝合的基础功能上进一步提升自身性能、实现功能化应用也引起了众多研究人员的关注。Liu等[15]受到天然蜘蛛丝纤维的“核—壳”多层结构的启发,以再生丝素为原料,制备了一种集仿生、抗菌、传感于一体的具有分层结构的功能性缝合线,在减少伤口部位炎症和细菌感染的基础上,附加了实时监测缝合处组织张力变化情况、控制药物和生长因子释放速率的功能,使缝合线变成一种更具生物活性和电子功能的生物组件。朱瑜等[16]开发了一种微线径、高强度的琥珀蚕丝,该蚕丝产自特殊的琥珀蚕,生物相容性和细胞毒性与桑蚕丝类似,但强度远优于桑蚕丝纤维,断裂强度高达8.92 cN/dtex,无需经过编织或加捻等工艺,直接在表面包覆涂层即可制备满足11-0#规格缝合线标准的单丝型缝合线,可应用于整容手术中细小伤口的精细缝合。通过以上分析可以发现,蚕丝缝合线在外科手术中应用较为广泛,但单丝强力低、生物降解性差、易引起感染等缺点在一定程度上限制了蚕丝缝合线的应用。这也为未来的研发人员提供了一些参考思路,可以探索能够实现广谱杀菌、缓释药物的新型涂层,也可以从蚕丝纤维本身出发,改善纤维性能并赋予其抗菌等特殊功能,均可有效提升蠶丝缝合线的性能,拓展其应用范围。

2 胶原基缝合线

胶原蛋白是由三条肽链组成的螺旋形纤维状蛋白质[18],是哺乳动物皮肤、软骨及韧带等组织中的主要成分,占总蛋白质的25%~30%。动物细胞外基质中存在多达20种不同类型的胶原,其中Ⅰ型胶原蛋白含量最为丰富,相关研究也较多,但胶原蛋白特有的三股螺旋结构无法通过人工模拟获得,因此实际应用中的胶原仍然以天然提取为主,如鱼皮胶原、水母胶原、牛筋腱胶原等,具有低免疫原性[19]、强亲水性、生物可降解性等优良的生物学特性,是一种理想的生物医用材料[20]。

作为一种常见的医用缝合材料,胶原蛋白缝合线在基础研究和临床应用方面都取得了较大成绩。付汉斌等[21]对比了规格为2-0#的胶原缝合线与4-0#编织蚕丝缝合线在口腔种植修复手术中的临床效果,胶原缝合线比编织丝缝合线能够更有效地促进伤口愈合,提高伤口愈合等级,且伤口恢复后光滑平整,切口平整率达到了85.11%。胶原缝合线被吸收后,细菌无处附着,伤口感染风险降低,组织炎症减少。杨浮琼[22]与王秉霞等[23]探究发现,胶原缝合线直径小,疼痛反应轻,在妇产科手术中可以明显降低手术感染率和脂肪液化率,缝合处不易形成硬结与瘢痕。陈胜武[24]探究发现,在骨科手术中,胶原缝合线的单股非编织结构不易感染细菌,避免了普通蚕丝缝合线带来的傷口易感染、易化脓、易产生瘢痕的问题。由此可见,胶原缝合线因其良好的生物相容性、可降解性、不易感染等特性,在五官科、妇科、骨科等手术中广泛应用。

但与其他缝合线相比,胶原缝合线的拉伸强度及打结强度不高,研究中多采用乙二醇[25]、京尼平[26]、乙二醛[27]、碳二亚胺[28]等对其进行化学交联。Dasgupta等[27]通过微流控挤压湿法纺丝法制备了胶原蛋白微纤维,并与乙二醛进行交联,交联后的纤维细胞相容性好,炎症反应低,力学性能优异,极限拉伸强度可达到300 MPa,杨氏模量超过3 GPa,可作为缝合线在外科手术中使用。Rethinam等[25]从含铬皮革废料中

分离出胶原蛋白,并与乙二醇交联制备了一种可吸收胶原缝合线(AS),这种缝合线抗拉强度为(43.16±1.03) MPa,断裂伸长率为40.17%±0.88%,质地柔软,打结稳定,无细胞毒性。经交联处理后的胶原缝合线机械性能有所提升,基本满足手术缝合的要求,但与蚕丝缝合线等相比仍较差,在未来研究中可以继续探索合适的交联剂,进一步改善其机械性能。

另一方面,胶原缝合线在人体内受到体液浸泡和酶的作用后会逐渐水解为人体所必需的氨基酸而被吸收[29],但降解速率较快,难以与伤口愈合的速率同步,存在伤口尚未愈合而缝合线已被降解吸收的问题[30]。因此,在胶原缝合线的应用开发中,缝合线的降解速率如何能做到有效、及时地调控也是值得深入探究的关键科学问题。目前,研究人员大多通过将胶原与其他材料共混、接枝交联生物活性材料及负载涂层等方法进一步改善上述缺陷。王佃亮等[30]将胶原蛋白与壳聚糖相结合,制备了具有三层结构的新型缝合线,由内向外分别是壳聚糖纤维芯、胶原层及羧甲基壳聚糖层,壳聚糖芯层与胶原层之间通过质量分数为0.25%的戊二醛进行交联。该缝合线植入人体后,由于其三种成分的空间分布差异,导致其降解的先后顺序不同,因此可通过调整三者的比例从而调控缝合线整体降解速率,使其与伤口愈合速率同步。Younesi等[31]通过电化学沉积工艺制备了一种新型胶原缝合线。这种缝合线与肝素分子交联后与生长因子间的作用增强,可延长生长

因子的缓释时间至15 d以上,缝合线的物理机械性能也有所改善,极限抗拉强度显著增加。由上述分析可知,作为一种可吸收医用缝合材料,胶原蛋白缝合线可以起到有效缝合伤口并促进愈合、减少疤痕的作用,但其抗拉强度较差、打结强度低,且降解吸收速率难以控制。近年来,胶原缝合线的市场竞争力逐渐减弱,相关的改性研究较少,发展受到一定的限制。如果能在今后的研究中发掘新型绿色交联剂改善其机械性能,或进行化学修饰实现降解可控,胶原缝合线在临床中的应用将会得到进一步的推广。

3 甲壳素基缝合线

甲壳素(甲壳质)及其衍生物壳聚糖在自然界中的分布极为广泛,是仅次于纤维素的第二大生物聚合物,主要存在于节肢动物外壳、昆虫表皮及藻类等植物的细胞膜中[32]。甲壳素化学名称为β-(1,4)-2-乙酰氨基-2-脱氧-D-葡萄糖,是由乙酰氨基葡萄糖结构单元以β-1,4糖苷键构成的直链聚多糖,甲壳素脱去乙酰基后的产物即为壳聚糖[33],甲壳素与壳聚糖的化学结构式如图1所示。壳聚糖中的—NH3+可以与细菌表面的负电荷发生电中和反应,破坏其细胞壁与细胞膜的完整性,抑制细菌的生长与繁殖,使其快速死亡,从而具备广谱、高效抗菌的功能。

甲壳素与壳聚糖都是良好的生物医用材料,可制成缝合线、水凝胶[34]、黏合剂等材料加以应用。与其他缝合线相比,由甲壳素、壳聚糖制成的甲壳素基缝合线具有众多独特的优点:1) 降解速率中等,满足伤口愈合全过程对缝合线强度的要求;2) 止血止痛,可以黏附血液中的血小板,诱导血液凝固[35];3) 消炎抗菌,降低伤口感染风险,加快伤口愈合[36]。Avila等[37]比较了壳聚糖缝合线与聚卡普隆类合成缝合线在兔腹腔镜和盲肠手术中的应用情况,并观察了25 d内伤口的恢复情况。两种手术缝合线均能够有效防止伤口外翻或内脏脱落等严重并发症,使用壳聚糖缝合线的兔子腹部伤口无明显纤维蛋白,组织纤维化程度低,发生创面肉芽增生现象的概率较低。Huaixan等[38]比较了壳聚糖缝合线与羊肠线对于绵羊子宫伤口愈合情况的影响。研究发现,羊肠线降解速率较快,容易引起较严重的组织反应,实验动物伤口黏连现象发生率高达70%。壳聚糖缝合线组的实验动物均未出现伤口黏连现象,缝合处Ⅰ型胶原蛋白含量显著增加,结缔组织形成速度加快,相比而言,壳聚糖缝合线更能够有效促进组织修复。

甲壳素的生物惰性使得缝合线植入人体后不易引起并发症或组织反应,但缝合线的机械强度较差,因此目前研究的重点在于通过共混、化学修饰或开发新的纺丝工艺来提升缝合线的性能。Zhang等[39]将甲壳素(CT)与氧化石墨烯(GO)共混,以环氧氯丙烷为交联剂,制备了一种新型GO-CT单丝型外科缝合线。GO的加入可以增强缝合线的机械性能,GO-CT缝合线的断裂强度可达到(2.01±0.33) cN/dtex,打结强度可达到(1.07±0.12) cN/dtex,均高于纯甲壳素缝合线。Shao等[40]以一种多功能酰基酯二乙酰甲壳素(DAC)为原料,制备了可吸收外科缝合线。这种缝合线满足常规缝合的强度要求,同时具有一定的柔韧性和伸长率。该缝合线打结稳定性良好,在人体内14 d后其断裂强度仍能保持在原始值的63%左右,同时具备良好稳定的物理和生化功能。Wu等[41]将甲壳素与纤维素纳米晶体(BCNCs)共混制备再生甲壳素缝合线,通过调整BCNCs的添加量可调控缝合线的降解速率。甲壳素也可与纤维素、聚乳酸、海藻酸钙等高分子材料混合,制备可植入型医疗复合材料。此外,甲壳素现有的提取工艺较为复杂,溶解条件较为苛刻,如能探索出绿色环保、简便高效的提取方法,也更有助于甲壳素基产品的研发与应用。

壳聚糖作为甲壳素的脱乙酰化产物,具有优秀的抗菌性,无需添加其他抗菌剂即可赋予缝合线良好的抗菌功能。壳聚糖缝合线的机械性能略优于甲壳素缝合线,但仍低于临床常用的蚕丝缝合线等。因此,目前壳聚糖缝合线的研究方向以充分发挥抗菌功能、提升机械性能为主。Zhu等[42]将五倍子单宁(GTs)与壳聚糖共混,通过湿法纺丝制备了CS/GTs复合纤维,断裂强度为(0.75±0.55) cN/dtex,比纯CS纤维提高了43.4%。此外,GTs的加入使得复合纤维对金黄色葡萄球菌的抵抗率提高至99.7%,抗菌性能显著提升。Deng等[43]制备了一种壳聚糖/角蛋白/PEG/PCL复合可吸收缝合线,并用双氯芬酸钾(DP)对其进行药物洗脱处理,这种缝合线热稳定性好,力学性能优良,且无细胞毒性,是缝合肌肉、肌腱等软组织的理想缝合线。Da Sliva M C等[44]通过湿法纺丝制备了负载了n-乙酰-d-氨基葡萄糖(GlcNAc)的壳聚糖纤维,CS/GlcNAc纤维的断裂强度为(2.00±0.79) cN/dtex,打结断裂强度为(1.05±0.27) cN/dtex,符合6-0#规格缝合线标准。Vega-cazarez等[45]将聚乙烯醇(PVA)与壳聚糖混合制备复合纤维,当PVA添加量为45%时,复合纤维断裂强度高达(3.67±0.78) cN/dtex。在当前研究中,壳聚糖作为涂层材料涂覆于其他缝合线表面以发挥其抗菌功能的情况较多,壳聚糖缝合线应用相对较少。因此,如何提升壳聚糖缝合线机械性能,拓展其应用的方法仍需进一步探索。

与其他缝合线相比,甲壳素基缝合线具有独特的止血止痛、抗菌消炎等生理功能,不需进行额外的涂层、接枝处理。表2对甲壳素基缝合线的性能进行了比较,表明目前可实际应用的甲壳素基缝合线基本都具有抗菌功能,但机械性能与蚕丝缝合线等相比略差,且脱去乙酰基后的壳聚糖缝合线拉伸断裂强度普遍优于甲壳素缝合线。由此可见,改善物理机械性能、扩大应用范围将是甲壳素及壳聚糖缝合线今后研究发展的主要方向。

4 结 语

随着外科手术覆盖范围的增大、难度的提高,对缝合材料的性能要求更为严格,这在一定程度上促进了缝合线的快速研究与应用发展。蚕丝基、胶原基及甲壳素基等天然高聚物基缝合线具有良好的生物相容性、低免疫原性、可生物降解性等优点,在外科缝合线市场上占据主要地位。通过综述分析三类手术缝合线的研究结果发现:1) 蚕丝基缝合线机械性能较好,适用范围广泛,但存在单丝强力低、生物降解性差、易引起感染等缺点,国内外研究大多侧重于涂层改性方法的完善,有关改善纤维本身性能的研究较少,仍需进一步深入探究。2) 胶原基缝合线可在人体内降解吸收,并具有一定的促愈功能,适用于精细部位的缝合,但受限于机械性能较差、降解速率难以控制等缺陷,相关研究较少,发展受到一定的限制。3) 甲壳素基缝合线具有独特的止血止痛、抗菌消炎的功能,但机械性能差、提取及溶解工序较为繁琐,成为今后研究的重点方向。针对天然聚合物基缝合线的上述问题,今后可基于发展先进制造技术、开发新型缝合材料、实现缝合线的多功能化等方面开展深入系统的研究。

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Research status of natural polymer-based surgical sutures

YANG Xin1, ZHANG Xin1, PAN Zhijuan1,2

(1.College of Textile and Clothing Engineering, Soochow University, Suzhou 215021, China;2.National Engineering Laboratory for Modern Silk, Suzhou 215123, China)

Abstract:

The surgical suture, a kind of medical material used to suture wound and connective tissue in surgery, is also the most common implantable material. Medical-surgical sutures are abundant in raw materials, including natural materials, synthetic materials and metal materials. Among them, natural polymer-based surgical sutures occupy a dominant position in the market due to their excellent biocompatibility, low immunogenicity and other characteristics. However, there are still some problems, such as poor mechanical properties and difficulty in regulating the degradation rate. In order to improve the property of natural polymer-based sutures and promote the development and application of new sutures, we summarize the research status of silk-based sutures, collagen-based sutures and chitin-based sutures. We compare their merit and demerit in practical application and analyze their existing performance defects and improvement direction, so as to provide a reference for the development of natural polymer-based surgical sutures.

Silk-based sutures have a long history of application in the field of sutures because of their excellent hygroscopic properties, operability and knotting stability. However, the disadvantages of monofilament sutures such as poor biodegradability and susceptibility to infection limit the application of silk sutures. Therefore, medical silk sutures generally require antibacterial treatment. The common method is to load antibacterial coatings on the surface of the sutures and new coatings capable of broad-spectrum bactericidal and drug slow-release functions are still being explored. Most of the studies domestically and overseas focus on the improvement of coating modification methods, while there are few studies on the improvement of fiber properties. Based on silk fibers, researchers can improve the performance of the fiber and endow it with special functions such as antibacterial function in future studies, which can effectively improve the performance of silk sutures and expand their application ranges.

As an absorbable medical suture material, the collagen-based suture can effectively suture wounds, promote healing and reduce scars. However, compared with other sutures, collagen-based sutures exhibit lower tensile strength and knot strength. In addition, the degradation rate of collagen-based sutures is fast, which makes it difficult to keep pace with the rate of wound healing, resulting in the problem that the sutures have been degraded and absorbed before the wound is healed. In recent years, there are few studies on the modification of collagen-based sutures, which gradually weakens their market competitiveness and restricts their development. If new green crosslinking agents can be developed to improve the mechanical properties of collagen-based sutures, or the sutures can be chemically modified to achieve controllable degradation, the clinical application of collagen-based sutures will be further promoted.

Chitin-based sutures, including chitin sutures and chitosan sutures, have unique physiological functions such as hemostasis, pain relief, and antibacterial and anti-inflammatory functions, without additional coating or grafting treatment. Due to the biological inertness of chitin, sutures are less likely to cause complications or tissue reactions after implantation, but the mechanical strength of sutures is poor. Therefore, current research focuses on improving the performance of sutures by blending, chemical modification or developing new spinning processes. The mechanical properties of chitosan sutures are slightly better than those of chitin sutures, but are still lower than those of common silk sutures. Therefore, the current research direction of chitosan sutures is mainly to make the most of antibacterial function and improve mechanical properties. The existing extraction process of chitin is relatively complex, and the dissolution conditions are relatively harsh. If a green, simple and efficient extraction method can be explored, it will be more conducive to the research and application of chitin-based products. Improving the physical and mechanical properties and expanding the application range will be the main direction of the research and development of chitin-based sutures in the future.

Nowadays, in the era of rapid development of science and technology, new natural materials are constantly developed and used, and the types of natural polymer-based sutures are gradually expanded. With the increasing coverage and difficulty of surgical procedures, the performance of suture materials is becoming increasingly strict in surgery, which promotes the rapid research and application of sutures to a certain extent. In view of the above-mentioned characteristics and problems of natural polymer-based sutures, researchers can develop advanced manufacturing technology, develop new suture materials and realize multi-functional sutures to carry out in-depth and systematic research in future study.

Key words:

natural high polymer; surgical sutures; silk; collagen; chitin; chitosan

收稿日期:

2022-04-22;

修回日期:

2023-01-17

基金項目:

作者简介:

杨鑫(1998),女,硕士研究生,研究方向为新型纺织材料。通信作者:潘志娟,教授,zhjpan@suda.edu.cn。

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