Chinese Journal of Tissue Engineering Research ›› 2022, Vol. 26 ›› Issue (21): 3415-3420.doi: 10.12307/2022.653
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Tian Yuhang, Liu Yadong, Cui Yutao, Liu He, Li Shaorong, Wang Gan, Fan Yi, Peng Chuangang, Wu Dankai
Received:
2021-03-22
Accepted:
2021-05-08
Online:
2022-07-28
Published:
2022-01-28
Contact:
Wu Dankai, Chief physician, Professor, Doctoral supervisor, Department of Orthopedics, Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
Peng Chuangang, Associate chief physician, Associate professor, Master’s supervisor, Department of Orthopedics, Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
About author:
Tian Yuhang, Master candidate, Department of Orthopedics, Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
Supported by:
CLC Number:
Tian Yuhang, Liu Yadong, Cui Yutao, Liu He, Li Shaorong, Wang Gan, Fan Yi, Peng Chuangang, Wu Dankai. Application of chitosan biomaterial scaffold in the treatment of infectious bone defects[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(21): 3415-3420.
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2.1 壳聚糖生物材料的功能性 近年来,由于自体骨移植的供应不足,骨移植替代物由于其具有无限可用性、无疾病传播风险和并发症少见的优点成为治疗感染性骨缺损的热门[23]。壳聚糖生物材料由于骨传导性、抗菌性作为骨修复替代物被越来越多的人认可。 2.1.1 骨传导性 骨缺损的修复取决于多种因素,例如:骨祖细胞的增殖、骨生长因子(骨形态发生蛋白和血管内皮生长因子)和骨形成标记物(骨钙蛋白、骨连接蛋白、骨桥蛋白、碱性磷酸酶和蛋白聚糖)[24-25]。在骨组织工程中,骨替代品在损伤部位为细胞的黏附、生长和增殖提供的支持尤为重要。如前所述,由于壳聚糖具有类似天然细胞外基质的成分糖胺聚糖,创造了细胞生长的局部微环境,对成骨细胞的增殖、分化和矿化具有支持作用。因此在骨组织工程中,通常将壳聚糖作为骨传导材料和其他生物材料(如金属离子、纳米羟基磷灰石、氧化石墨烯和生物活性物质等)结合进一步促进骨再生[26]。在壳聚糖/明胶中加入羟基磷灰石和纳米生物活性玻璃显著改善了人骨肉瘤成骨样细胞的黏附和增殖[27]。在壳聚糖/明胶支架中加入氧化石墨烯不仅可以促进成骨细胞的分化,还能增强蛋白质吸附、生物矿化和可控降解,促进大鼠胫骨缺损愈合,在骨组织工程中有潜在的应用能力[28]。 不仅如此,还可以通过将壳聚糖和化学聚合物结合形成支架来促进骨再生。YE等[29]采用融合沉积建模技术制备了聚羟基丁酸联合羟基戊酸酯/半水硫酸钙3D打印支架并在支架表面涂覆壳聚糖溶液,在干燥中和后,壳聚糖水凝胶在支架表面形成聚羟基丁酸联合羟基戊酸酯/半水硫酸钙/壳聚糖支架;与单纯半水硫酸钙和聚羟基丁酸联合羟基戊酸酯/半水硫酸钙支架相比,聚羟基丁酸联合羟基戊酸酯/半水硫酸钙/壳聚糖支架可通过上调成骨基因表达水平,促进大鼠骨髓间充质干细胞的黏附和增殖,增强大鼠骨髓间充质干细胞分化为成骨细胞的能力;体内实验进一步证明,聚羟基丁酸联合羟基戊酸酯/半水硫酸钙/壳聚糖支架可以有效促进新骨形成。因此,证明了将3D打印聚羟基丁酸联合羟基戊酸酯/半水硫酸钙支架与壳聚糖水凝胶相结合是一种促进成骨特性的新策略,展示了修复骨缺损的足够潜力。LU等[30]将纳米铜颗粒加入到阴离子羧甲基壳聚糖和海藻酸盐的混合物中形成一种支架,羧甲基壳聚糖比单纯壳聚糖的水溶性更好,它的加入不仅提高了整个支架作为填充材料在感染性骨缺损中促进骨形成的能力,还能协同铜离子杀死细菌修复感染。ZHAO等[31]通过仿生矿化法制备羟基磷灰石包覆的静电纺羧甲基壳聚糖纳米纤维,通过体外细胞实验发现,羧甲基壳聚糖-羟基磷灰石复合纳米纤维提高了碱性磷酸酶活性,在体内临界尺寸的大鼠颅骨骨缺损模型中,进一步证实了复合纳米纤维促进新骨形成的能力。在该研究中,羧甲基壳聚糖可以螯合Ca2+,诱导羟基磷灰石沉积;此外与电纺壳聚糖相比,羧甲基壳聚糖的水溶性更强,避免了酸性盐被去除。 2.1.2 抗菌性 创伤及术后继发感染导致的感染性骨缺损,尤其合并慢性骨髓炎的治疗一直是难题,而且依赖抗生素治疗会引发耐药性,同时对抗生素抗性菌株的处理仍然是一大问题。壳聚糖是一种天然的可生物降解无毒生物聚合物,对广泛的细菌、丝状真菌和酵母的活性具有固有的抑制作用[32]。作为抗菌材料,壳聚糖对多种病原菌具有良好的敏感性,关于其抗菌机制的研究主要包括以下3个方面[33]:第一种是带正电荷的壳聚糖分子与细胞表面带负电荷的细菌分子发生反应,从而改变了细胞的渗透性并导致营养物质停止进入细胞,或营养物质从细胞泄漏而抑制了其代谢,从而导致细菌死亡[34];第二种是壳聚糖和细菌DNA的结合,使抑制细菌基因表达的蛋白质合成;第三种是金属螯合,壳聚糖抑制微生物生长所需基本元素的吸收,结合微生物所需的金属离子,从而达到抑菌的目的[35]。在目前的研究中,通过对壳聚糖进行修饰所获得的壳聚糖衍生物或者将壳聚糖与其他材料联用可发挥更优良的抗菌效果[36]。 基于以上理论,WANG等[37]研究了一种壳聚糖衍生物-季铵化壳聚糖作为强力的抗菌剂,和骨形态发生蛋白2形成可控制释放系统来修复感染性骨缺损,季铵化壳聚糖对耐甲氧西林金黄色葡萄球菌的最低杀菌浓度为40 mg/L,季铵化壳聚糖质量浓度在40 mg/L下不影响前成骨细胞的增殖,也不影响骨形态发生蛋白2诱导的碱性磷酸酶活性、骨钙素表达和基质矿化;体外释放谱显示季铵化壳聚糖呈爆发性释放,骨形态发生蛋白2呈缓慢释放,并且只在含骨形态发生蛋白2组中观察到体内骨形成,同时季铵化壳聚糖不影响仿生磷酸钙吸收和骨形态发生蛋白2诱导的骨形成,该结果表明,季铵化壳聚糖的加入使该复合物在体内外均表现出较强的抗菌作用和较强的骨诱导作用,并且作为药物载体具有较好的性能,可作为潜在的治疗感染性骨缺损的新材料。DAVID 等[38]利用壳聚糖、明胶和掺锶羟基磷灰石以生物锚定的方法制备了钛合金支架来治疗骨髓炎,对耐甲氧西林金黄色葡萄球菌和甲氧西林敏感的金黄色葡萄球菌的抗菌性显著提高,能在足够长的时间内控制药物的释放以缓解感染,并且在壳聚糖加入后提高了该材料整体的生物相容性和生物整合性,有利于成骨。该种金属支架满足了理想的感染性缺损治疗标准,提供了一个有前景的治疗方向。 2.2 壳聚糖复合支架在感染性骨缺损中的应用 虽然壳聚糖具有生物相容性、生物可降解性、抗菌性等一系列优点,但是由于单纯壳聚糖的机械力学性能较弱、水溶性较差、生物降解率较低,通常将壳聚糖进行改性来增加其性能。该文将从涂层壳聚糖、化学修饰壳聚糖、可注射水凝胶3个方面介绍壳聚糖复合支架的应用。"
2.2.1 涂层壳聚糖 在骨组织工程中,可植入生物材料的发展带动了局部可控药物释放系统的进步,极大提高了对感染性骨缺损的治疗效果。生物陶瓷、聚合物、金属离子已经被研究用于作为释放药物的载体来输送抗生素、生长因子和抗炎药物到感染部位,然而这些载体常因为药物爆发性释放或载体自身快速降解及缺乏生物相容性等缺点而限制了其应用范围。由于壳聚糖的阳离子性质,能够吸附带负电荷的细胞因子和生长因子,可保护和集中其在局部的分泌,加快愈合[39]。因此,壳聚糖和壳聚糖涂层材料特别有利于靶向肺、角膜、肠道和胃黏膜组织,壳聚糖的阳离子性质也有助于与带负电荷的核酸如DNA、RNA和siRNA及细胞膜结合。同时,壳聚糖具有良好的骨传导性和可控的生物降解性,可以通过物理吸附、化学反应、电沉积等方法实现壳聚糖在植入合金表面的涂层,以控制药物释放[40]。常见的有电沉积壳聚糖涂层结合生物玻璃可持续性地给药氨苄西林,通过壳聚糖的自身抗菌性和药物释放控制感染,并促进细胞的黏附和成骨分化。 不仅可以利用壳聚糖作为涂层,还可以利用其他材料制备双涂层来治疗感染性骨缺损。NANCY等[41]利用工业纯钛通过电泳进行双层涂层改性,其中第1层是二氧化钛和锶羟基磷灰石,第2层是吸收了万古霉素的壳聚糖/明胶涂层,通过对金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌和甲氧西林敏感金黄色葡萄球菌抗菌实验及体外细胞培养研究表明,第2层即吸收万古霉素的壳聚糖/明胶涂层表面具有双重作用。该壳聚糖涂层既可以抑制细菌黏附又增强细胞在涂层上的相互作用,壳聚糖的加入不仅提高了细胞活性,还实现了对药物释放的可控性,证实了壳聚糖涂层作为治疗骨髓炎的材料很有前景。 2.2.2 化学修饰壳聚糖 由于生物分子与生物材料之间的相互作用弱,传统的表面改性技术(如物理吸附)往往无法实现生长因子的长期保留,在固定生物活性分子方面有很大的局限性[42]。另一方面,新颖的固定化策略,如涂层和等离子体处理、电沉积、分层和静电纺丝等,由于它们的多步骤过程耗时,可能导致不一致的结果与不理想的控制输送性能。因此,通过对壳聚糖生物材料进行化学改性,可使其理化性质和生理功能得到改善,常见的改性材料有季铵化壳聚糖、羧甲基壳聚糖、硫酸壳聚糖、甲基丙烯酸酯壳聚糖等。和壳聚糖相比,季铵化壳聚糖不仅可溶于水还增加了电荷密度,使其黏附性和渗透性增强,非常适合用来药物输送。羧甲基纤维壳聚糖和纳米羟基磷灰石结合后作为搭载甲状腺素来促进血管生成,并且具有良好的可折叠性和拉伸性[43]。如前所述,将壳聚糖的负电荷基团由硫酸盐基团取代后可以展现抗凝血、抗病毒和抗硬化活性,这是因为其结构和天然抗凝血肝素形似。将壳聚糖与骨形态发生蛋白2结合可以促进颅骨缺损的愈合[44]。也可通过增加季铵化壳聚糖的取代度来提高壳聚糖的细胞相容性和抗菌活性,然后利用3D打印技术将季铵化壳聚糖接枝到聚丙交酯乙交酯共聚物和羟基磷灰石形成一种具有抗感染和骨修复双重功能的复合支架,再采用甲氧西林敏感金黄色葡萄球菌分别建立了感染性股骨干缺损和股骨髁缺损模型[45],8周后季铵化壳聚糖-聚丙交酯乙交酯共聚物/羟基磷灰石组的细菌数都显著低于聚丙交酯乙交酯共聚物组、聚丙交酯乙交酯共聚物/羟基磷灰石组,细菌负荷也较该两组低,可见在加入季铵化壳聚糖后可以显著提高复合支架的抗菌性;对股骨干缺损模型周围形态学观察可以发现,在4周左右季铵化壳聚糖-聚丙交酯乙交酯共聚物/羟基磷灰石组开始有新生骨组织形成, 8周时骨缺损部位主要位于股骨干的边缘,并且骨连接不断增加;对股骨髁缺损周围形态学观察可以发现,季铵化壳聚糖-聚丙交酯乙交酯共聚物/羟基磷灰石组仅在植入后8周就出现骨长入,骨缺损较其他组愈合明显。该研究证实了此种支架具有抗菌和成骨的双重功能,季铵化壳聚糖- 聚丙交酯乙交酯共聚物/羟基磷灰石组复合支架在两种感染骨缺损模型中均表现出增强的抗感染和骨修复能力,在修复受感染的皮质和松质骨缺损方面具有潜在的应用前景。 2.2.3 可注射水凝胶 可注射水凝胶因其具有无创或微创植入的能力而广受欢迎。此外,可注射的生物材料具有填充所需形状的能力,并且易于与各种治疗药物结合,这为任何形状的骨缺损修复提供了巨大的潜力。同时,水凝胶具有高含水量和多孔结构的特点,能够很好地模拟人体组织的细胞外基质,促进营养物质和代谢废物的交换。壳聚糖在化学上类似于葡糖胺聚糖,具有良好的生物相容性和最小的组织毒性,微分子和大分子与壳聚糖游离氨基的结合促进了其在可注射水凝胶中的应用[46]。利用壳聚糖可制备不同性质的水凝胶,温敏性水凝胶、pH敏感性水凝胶,并且可提高水凝胶的机械性能、生物相容性、骨诱导性能[47]。可以利用壳聚糖/纳米羟基磷灰石/胶原形成可注射性水凝胶,搭载骨髓间充质干细胞来促进体内异位骨形成[48],也可以利用骨保护素-壳聚糖凝胶来修复兔临界性颅骨缺损[49]。 ZHANG等[50]通过将纳米羟基磷灰石和壳聚糖结合作为可注射性复合材料来治疗兔股骨髁骨缺损,分别使用纯壳聚糖和空白修复作为对照组,术后8,12周通过X射线平片和计算机定量断层扫描检测缺陷桥接,收集组织样本进行大体观察和组织学检查,以确定新骨形成的程度;植入复合材料8周后,纳米羟基磷灰石/壳聚糖复合材料组不规则骨组织形成较纯壳聚糖组多,术后12周纳米羟基磷灰石/壳聚糖组骨缺损完全愈合,壳聚糖组骨缺损仍可见,但缺损深度有所减少,表明了该复合材料作为骨替代物的可行性。WANG 等[51]将聚甲基丙烯酸甲酯骨水泥与季铵化壳聚糖水凝胶结合搭载纳米羟基磷灰石,并在其中加入甘油磷酸盐制备了多孔聚甲基丙烯酸甲酯/季铵化壳聚糖-甘油磷酸盐/纳米羟基磷灰石温敏性水凝胶,一系列测试结果表明,季铵化壳聚糖-甘油磷酸盐温敏水凝胶产生相互连通的孔隙,并使骨水泥具有良好的抗菌活性;壳聚糖的加入使该水凝胶的抗菌性能显著增加,并且增加了材料的力学性能;同时纳米羟基磷灰石颗粒提高了骨水泥的生物矿化能力,但不影响其力学性能。 这些结果表明,由聚甲基丙烯酸甲酯/季铵化壳聚糖-甘油磷酸盐/纳米羟基磷灰石组合而成的多孔可注射多功能水凝胶,在骨骼重建方面具有良好的应用前景。"
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