Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (27): 4411-4416.doi: 10.12307/2022.876
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Xu Ran1, Chen Xingyu1, Li Zhiqiang2
Received:
2021-02-04
Accepted:
2021-03-31
Online:
2022-09-28
Published:
2022-03-12
Contact:
Chen Xingyu, PhD, Associate researcher, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
Li Zhiqiang, PhD, Associate chief physician, Department of Orthopedics, Affiliated Hospital of Southwest Jiaotong University-General Hospital of Western Theater Command, Chengdu 610031, Sichuan Province, China
About author:
Xu Ran, Master candidate, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
Supported by:
CLC Number:
Xu Ran, Chen Xingyu, Li Zhiqiang. Antibacterial agents loaded on hydroxyapatite scaffolds: action mechanism between the drug and the scaffold[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(27): 4411-4416.
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常见的抗菌手段可以分为三大类:①一是对支架材料表面形貌处理来防止细菌黏附[13]。已有文献证明激光处理的超疏水表面具有抗菌性,然而材料表面的润湿性和形态在减少细菌黏附方面的相对重要性一直没有得到区分。因此,需要清楚地确定材料的亲疏水性和表面拓扑结构对细菌滞留的影响,为制造抗菌表面提供更加精确的指导。②二是通过在支架材料表面涂覆抑菌或杀菌的抗菌材料涂层[10]。例如,通过表面离子涂层来实现羟基磷灰石支架的抗菌活性,这一技术的主要问题是如何获得稳定的涂层,以确保离子的长期释放达到较为理想的抗菌效果[14]。③三是支架负载抗菌性药物,利用支架与药物之间的相互作用来控制药物释放达到抗菌的目的。第三种是目前比较常用的方法,这里重点介绍。 按照药物的受保护程度可将其负载方式分为三大类:药物直接吸附在支架的表面,且不受保护,通过扩散来释药;将药物与可降解的支架材料结合,通过支架的降解来释放药物;用微球或基质包覆药物,然后再负载于支架上,借助中间载体的降解来释药。 2.1.1 药物与支架结合 羟基磷灰石具有表面活性位点,能够吸附药物制剂[15],某些抗菌药物可以直接负载到羟基磷灰石支架上,例如万古霉素。作为糖肽家族的广谱抗生素,万古霉素杀灭金黄色葡萄球菌的效率高,而且耐药性较低,它可以通过浸渍的方式负载到羟基磷灰石支架上[16]。当万古霉素以0.3 g/L的质量浓度浸渍到Ca-Mg硅酸盐支架上时表现出单阶段释放,在其表面涂覆不同厚度的聚乳酸羟基乙酸涂层时,万古霉素的释放速率减缓[17],体现出羟基磷灰石支架载药体系受表面涂层调节的多功能性。同样地,在使用溶胶-凝胶技术合成介孔羟基磷灰石纳米粒子药物载体时,通过不断搅拌方式达到万古霉素吸附平衡的状态(极性基团之间相互作用产生氢键),而且硬脂酸的存在使羟基磷灰石粒子分散更加均匀,有利于药物的结合[18]。当通过电化学沉积方法制备负载万古霉素的羟基磷灰石-胶原涂层载体时,万古霉素在电解质中带净正电荷,因此在电场作用下万古霉素被吸附到涂层表面,但是在最初5 h内就释放了62%的万古霉素[19]。这种以物理吸附作用为主的载药方式通常会导致药物在初始阶段的快速释放。庆大霉素和万古霉素同为氨基糖苷类抗生素,具有广谱抗菌性,常用于骨髓炎的治疗,但口服后生物利用度低、细胞穿透性差[20],内化的庆大霉素分子在溶酶体中积累,导致其活性降低。而且,庆大霉素的高肾毒性限制了它的全身使用。早在1979年,有学者将庆大霉素封装入聚甲基丙烯酸甲酯串珠内,将其应用于清创后留下的骨开放区域,在对128例严重慢性骨髓炎患者中显示了良好的抗感染效果。DE TRIZIO等[21]进行了一些研究,将庆大霉素与可生物降解支架结合实现了庆大霉素的局部给药,延长了药物在感染组织的释放时间。此外,载有庆大霉素的可生物降解聚合物膜已被开发用于骨折固定装置的涂层和预防植入物相关感染[22]。将庆大霉素包封在硫酸钙内可以更好地治疗骨髓炎[23],例如,使用羟基磷灰石/硫酸钙生物复合材料负载庆大霉素治疗糖尿病跟骨骨髓炎[24],增加了骨保存和局部给药,减少了大截肢的需要。而且,基于羟基磷灰石的筒仓技术是一种有效的局部给药方法,可有效应用于跟骨骨髓炎的单阶段治疗。 除了简单的吸附作用,药物与载体材料的结合还可利用羟基磷灰石的纳米特性来实现。纳米羟基磷灰石具有较高的比表面积和体积比,表面活性高,能够有效地结合药物分子[25]。羟基磷灰石纳米粒子通常具有较长的生物降解时间,这对扩散控制的药物释放动力学较为重要[26]。羟基磷灰石纳米粒子可通过简单的物理吸附与带正电荷或负电荷的功能化分子结合[27]。药物的亲疏水性和亲和性也会介导其与纳米羟基磷灰石表面的偶联[28]:亲-疏水作用,例如,采用多轴静电纺丝技术将聚甲基丙烯酸甲酯与尼龙同轴纺丝,在疏水性溶剂中释放亲水性药物-氨苄青霉素,利用疏水性聚合物来控制亲水性药物的释放[29];亲和作用,如链霉亲和素和生物素的生物素化作用,IGWE等[30]生物素化人重组骨形态发生蛋白2,而且使用生物素-链霉亲和素复合物将生物素化的人重组骨形态发生蛋白2栓系在纳米羟基磷灰石/聚乳酸羟基乙酸复合支架上,表现出良好的骨诱导性。同样的,生物素-亲和素作用也可用于治疗药物与羟基磷灰石纳米颗粒的生物偶联。MA等[31]开发了一种多功能的杂化结构,首先将阿霉素与聚(L-天冬氨酸)和聚2-(2-氨基乙基)甲基丙烯酸乙酯)结合形成共聚物,然后加入质粒DNA(pDNA)以生成表面带正电荷的纳米粒子载体(D-PIC-pDNA NPs),将带有负电荷的大分子亲和素-生物素-聚乙二醇-L-谷氨酸酸共聚物包被在D-PIC-pDNANPs上,转铁蛋白在复合物表面上被功能化为靶向剂,进行药物和基因的共同递送。这种亲和力相互作用能够提供稳定的非共价键,不受环境条件(例如介质的pH值和离子强度变化)的影响。利用静电纺丝技术制备的复合纳米纤维也表现出良好的药物递送效果。将抗菌药物阿莫西林与纳米羟基磷灰石结合,然后分散于聚乳酸羟基乙酸溶液中形成阿莫西林/纳米羟基磷灰石/聚乳酸羟基乙酸复合纳米纤维,结果表明该纳米纤维具有更好的药物释放特性,且不减弱阿莫西林药物的抗菌活性[32]。LIU等[33]通过电纺丝和电化学沉积成功构建了具有长期抗菌、生物活性和成骨诱导能力的多功能左旋聚乳酸/羟基磷灰石/聚多巴胺/银纳米粒子复合纤维,但是由于药物与纳米羟基磷灰石之间较弱的相互作用,会导致其在初始阶段从纳米复合纤维中爆发性释放。抗生素如环丙沙星和米诺环素与羟基磷灰石的结合不会抑制其杀菌活性[34-35]。此外,许多抗生素可通过化学键合的方式与羟基磷灰石结合,例如阿莫西林、头孢曼多、羧苄青霉素和头孢菌素等均含有可与羟基磷灰石中钙离子和磷酸根结合的羧基。综合来看,基于羟基磷灰石的局部药物递送仍存在一些挑战:其一,药物在载体表面的附着力不够,尽管将抗生素与仿生材料混合再涂覆到支架表面[19],可以在一定程度上缓解药物释放过快的问题,但是仍然不能达到理想的释放速率;其二,羟基磷灰石载体负载药物的量有限,因为考虑到药物对载体机械强度的影响;其三,药物掺入载体的非标准化程序如手动混合等,使得药物在载体中的分散性不均一,难以获得适宜的释放条件[2]。 2.1.2 药物通过可降解的支架释放 抗菌性药物与支架结合后的释放速率与支架材料的性能、成分组成和微观结构有关。BARROUG等[2,36]为了增强药物分子的附着力,开发了几种方法来修饰药物载体的微结构表面。研究表明,低结晶度样品的表面会导致更高的药物亲和力,因为表面缺陷会形成活性结合位点。在可降解的生物聚合物中,聚乳酸羟基乙酸是FDA批准使用的共聚物,也是药物传递系统开发设计最多的聚合物之一[37],聚乳酸羟基乙酸-脂质杂化纳米颗粒具有较高的药物负载能力,在生理条件下具有良好的稳定性[38]。在不使用交联剂的情况下,由琼脂糖、明胶和羟基磷灰石制备的可降解复合支架载阿莫西林显示出较长时间的药物释放效果,而且对革兰阳性菌显示出良好的抗菌作用[39]。一些天然药用化合物也可通过可降解聚合物载体来递送。最近的一项研究使用3D打印的磷酸钙支架加载姜黄素,并且在该体系中使用一定比例的亲疏水性聚合物,提高了姜黄素的生物利用度和成骨性能[40]。 2.1.3 药物通过可降解的基质释放 可降解的聚合物载体与羟基磷灰石结合而成的药物递送系统,能够达到更好的释药效果[41]。以羟基磷灰石微球和可生物降解的聚乳酸为载体,将庆大霉素直接封装入聚乳酸,或者封装入羟基磷灰石微球后再与聚乳酸结合,结果发现,羟基磷灰石微球与聚乳酸结合的载药体系改善了药物的稳定性和利用率,并控制了药物的释放速率[42]。值得注意的是,与直接将药物载入羟基磷灰石支架相比,借助可降解微球载入羟基磷灰石支架用于药物递送,能够更好地控制药物的释放。在以头孢他啶为模型药物的抗生素给药体系中,借助乙基纤维素微球包埋药物,然后将其载入羟基磷灰石/聚氨酯复合支架中,结果表明该药物递送体系可显著减缓初始爆发性释放,使头孢他啶在较长时间内以可控、持续的方式释放[43]。明胶微球、聚乳酸羟基乙酸微粒子、生物活性玻璃、壳聚糖/葡聚糖硫酸盐微粒子等已被用于羟基磷灰石复合支架中[44],这些微球载体的发现使得多种药物分子与羟基磷灰石复合支架的结合成为可能。 FERRAZ等[45]用海藻酸钠/纳米羟基磷灰石复合微球负载青霉素、红霉素等不同类型的抗生素,均表现出良好的缓释效果。SON等[46]将地塞米松与聚乳酸羟基乙酸微球结合,并将其固定在羟基磷灰石骨支架上,通过4周的浸泡处理观察地塞米松的释放效果,可看到药物突释之后是持续较长时间的缓释,表明药物与微球结合后能够更持久地释放;而且与单纯使用羟基磷灰石支架相比,负载地塞米松的聚乳酸羟基乙酸微球的羟基磷灰石支架可以更好地促进体内骨再生。 2.2 载抗菌性药物的种类 抗菌性药物可分为抗生素和非抗生素类抗菌药物。许多抗生素,如氨基糖苷类的庆大霉素、头孢菌素类的头孢氨苄和糖肽类的万古霉素都已经被作为与磷酸钙骨水泥结合的抗生素[46-47],它们能有效吸附在羟基磷灰石表面,与羟基磷灰石复合支架结合发挥抗感染的作用。 2.2.1 抗生素类药物 四环素类的米诺环素与纳米羟基磷灰石结合后能有效治疗牙周炎[48]。多西环素和羟基磷灰石微球组成的骨靶向给药系统显示出长达7 d的抑菌效果,1个月后有新骨形成[49]。前文中提到庆大霉素和万古霉素是治疗骨髓炎的常用药物,然而在骨再生方面,庆大霉素和万古霉素有一定的不足,庆大霉素被认为会影响细胞的活力、增殖和代谢,而万古霉素在低浓度下扩散性较差,无明显促骨效 果[50]。有研究表明,较高浓度的头孢菌素会抑制成骨作用。在由骨髓炎导致的骨缺损患者中,手术清除死骨和随后的全身抗生素治疗通常对消除金黄色葡萄球菌感染无效[51]。已有研究表明,环丙沙星与凝胶蛋白-羟基磷灰石支架结合具有细胞相容性,可以同时靶向细胞内和细胞外的金黄色葡萄球菌,具有局部给药及治疗术后感染的巨大潜力[52]。四环素类抗生素如盐酸多西环素(强力霉素)已用于治疗多种感染,包括牙周炎[53]、骨髓炎等,对耐甲氧西林金黄色葡萄球菌的杀灭效果也很好[47],相比庆大霉素和万古霉素,强力霉素即使在低浓度下也能促进骨再生。青霉素类的阿莫西林也可与纳米羟基磷灰石和聚乳酸羟基乙酸结合形成复合纳米纤维,对金黄色葡萄球菌具有良好的抑菌效果[32]。喹诺酮类的左氧氟沙星与介孔二氧化硅微球/纳米羟基磷灰石/聚氨酯复合支架结合,表现出对慢性骨髓炎骨缺损良好的治疗效果[54]。 2.2.2 非抗生素类药物 除抗生素外,一些非传统的抗生素类药物也具有良好的抗感染功效。洗必泰(CHX)是广泛应用于口腔微生物的阳离子抗菌剂[55],研究表明羟基磷灰石表面纳米结构有利于洗必泰吸附,而且抗菌活性位点没有被洗必泰/羟基磷灰石相互作用所阻断[56]。实验表明,将洗必泰以一定的浓度吸附在羟基磷灰石微球上的抗菌活性超过5 d,羟基磷灰石微球的表面结构为药物持续释放提供了充分条件,且有利于口腔的植入。广谱杀菌剂洗必泰也能通过结合羟基磷灰石支架起到良好的杀菌效果,但是它的生物相容性与浓度相关,而且浓度过高会破坏成骨作用[57]。抗菌肽是由一系列氨基酸组成的不同长度的寡肽,抗菌肽中的氨基酸使它们具有两亲性,而且抗菌肽结构和功能非常多样化,具有不同于传统抗生素的独特作用机制,应用范围广泛[58-59]。抗菌肽的诱导抗性水平较低[59]。近年来,使用抗菌肽治疗骨科感染已成为替代抗生素治疗的一个有吸引力的选择,利用功能化肽载体将抗菌肽作为生物分子治疗剂结合到磷酸钙(Ca-P)沉积的钛纳米管表面,提高了植入物的骨整合能力,而且在植入物表面提供了抗菌保护[60]。抗菌肽的缺点包括制造和筛选成本高、对蛋白水解敏感及对哺乳动物细胞的毒性倾向[59,61]。除了抗菌肽,羟基磷灰石复合支架载溶葡萄球菌酶也能达到很好的杀菌效果[62]。 2.3 药物对支架的影响 将活性药物掺入支架的方法有多种,但是制备出具有药物传递功能的支架的方法较少,一些方法或者工艺制备出的载体材料不适合大规模生产或临床应用[63]。抗生素的掺入会对支架材料的理化性质产生一定影响,例如,抗生素的加入会改变磷酸钙骨水泥的固化时间[64];将磷酸钙骨水泥与抗生素(头孢氨苄、诺氟沙星)混合后的体外观察药物释放行为实验显示,这两种药物与磷酸钙骨水泥的混合不影响其固化过程[65],具体的作用机制还有待进一步的探究。 2.3.1 支架孔隙对负载药物的影响 羟基磷灰石支架负载药物的方式、支架孔径大小、孔隙率及孔道的连通程度都会影响药物的装载与释放。载体材料的孔径大小(微孔孔隙< 2 nm,介孔孔径2-50 nm,大孔孔径>50 nm)是生物医学应用中的一个重要特性,其中适当的介孔孔径具有较高的孔容积与载药效率。将介孔二氧化硅与磷酸钙结合制备双相药物载体[66],延长了盐酸多西环素的释放。另外,药物通过物理吸附作用与支架结合时,药物的吸附量与载体总孔隙率相关。研究表明,当β-磷酸三钙的孔隙率从20%增至40%时,万古霉素的吸附量增加了2倍;当羟基磷灰石支架的总孔隙率从2%增加到10%时,头孢曲松的载药量从38%增加到71%[2]。除此之外,孔径大小和互通程度都会影响药物的吸附动力学,浸渍的载药方式正是利用了材料孔隙对药物溶液的毛细作用实现的。因此当载体孔径较大时,药物溶液对载体的浸渍也更快。介孔羟基磷灰石因为具有适当的孔径大小和孔隙率更有利于药物的吸附、储存和释放。 2.3.2 小结 已有研究表明,与羟基磷灰石结合不会抑制环丙沙星、米诺环素等抗生素的杀菌活性,但药物的掺入会潜在地影响磷酸类支架材料的力学性能[64]。目前制备抗菌性药物递送体系的挑战在于:在不影响载体机械性能的同时负载足够量的药物分子,同时也要考虑该浓度对细胞和组织的毒性大小。在保证药物活性不被破坏的前提下促使药物分子与载体有效结合,不同药物分子与载体结合的方式值得继续探究。"
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