Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (10): 1599-1603.doi: 10.3969/j.issn.2095-4344.3050
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Li Jun, Yu Hao, Zhang Yong, Wei Yong, Xie Jia, Jing Juehua
Received:
2020-04-11
Revised:
2020-04-17
Accepted:
2020-06-05
Online:
2021-04-08
Published:
2020-12-18
Contact:
Jing Juehua, Chief physician, Professor, Department of Orthopedics, the Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China
About author:
Li Jun, MD, Associate chief physician, Associate professor, Department of Orthopedics, the Second Hospital of Anhui Medical University, Hefei 230601, Anhui Province, China2020-04-11
Supported by:
CLC Number:
Li Jun, Yu Hao, Zhang Yong, Wei Yong, Xie Jia, Jing Juehua. Different types of hydrogel in bone defects[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(10): 1599-1603.
2.1 离子介导水凝胶 离子介导水凝胶通过与聚合物网络的二价或三价阳离子形成离子链连接而介导。聚合物中海藻酸盐的有关研究最多,由于其多糖结构(由1,4-联结的β-D-甘露糖醛酸和α-均聚物嵌段组成)具有藻酸盐链中不同位置与钙和锌阳离子交联的能力,锌阳离子对交联的选择性较低,导致藻酸锌交联的水凝胶体系更大[5]。据报道,交联的速率与所用藻酸盐浓度呈反比,而交联速率则受所存在的多价阳离子和聚古洛糖酸链段浓度的影响[6]。RUSSO等[7]设计了一种新型的以藻酸盐和胶原蛋白为核和壳的干细胞递送系统,间充质干细胞被加载到胶原溶液中,然后将其立即置于纤维结构中,同时使用新设计的核-壳喷嘴同时包裹藻酸盐。其中包封在胶原蛋白中的间充质干细胞表现出优异的生存能力,在成骨条件下被允许分化的细胞显示出良好水平的骨相关基因,包括骨钙蛋白、骨桥蛋白和骨唾液蛋白。当将核-壳纤维载体植入大鼠颅骨缺损中时骨愈合得到了显著增强,在成骨诱导间充质干细胞植入前骨愈合更为明显。根据该实验结果,新制造的核壳型胶原藻酸盐纤维载体被认为有利于组织细胞的包封并将其输送到受损组织中,包括具有缺陷可调性的骨骼,可用于骨组织工程。然后,比较了藻酸盐水凝胶构建体与支架介导的骨骼再生(不依赖于机械负荷),而藻酸盐水凝胶构建体不具有结构性支架,之前已证明它们可促进体内对骨骼形成的机械刺激。与非结构藻酸盐相比,结构支架与负载无关,减少了骨形成,特别是在支架集中区域导致功能再生受损,这归因于支架对应力的屏蔽及对细胞浸润和组织向内生长抑制的组合,这些研究质疑植入时支架与成熟组织相似的必要性,并强调发展有利于基质激活的细胞活化和最终功能再生的环境[8]。观察由天冬氨酸(RGD)-藻酸盐水凝胶与Sr原位交联并用Sr掺杂羟基磷灰石微球增强的可注射Sr杂交体系的体内反应,与类似的无Sr材料进行了比较,Micro-CT结果显示Sr杂交组形成新骨的趋势更高[9]。 近年来还有人开发了一种由3D打印聚己内酯填充水凝胶组成的混合系统用于重建长骨缺损,由于骨缺损较大,与具有类似体积和支杆厚度的3D打印网状和蜂窝状支架相比,聚己内酯的3D打印类固醇支架允许在支架中装载大量水凝胶,提供了一种由生物活性混合系统修复骨骼缺损的新方法,该系统由聚合物支架、水凝胶和人骨髓间充质干细胞组成[10]。用藻酸钙水凝胶和聚乳酸培养人牙周膜细胞与骨髓基质细胞,显示藻酸钙水凝胶具有优于聚乳酸的骨诱导骨能力[11]。将间充质基质细胞包裹在复合水凝胶中,该复合水凝胶基于两种天然来源的聚合物(藻酸盐和透明质酸盐),其中包含生物矿化的聚合物微球。水凝胶的机械性能取决于组成。与仅由天冬氨酸-海藻酸盐或天冬氨酸-海藻酸盐/透明质酸盐形成的凝胶相比,来自两种聚合物的黏性三肽精氨酸-甘氨酸-天冬氨酸在体外诱导了绵羊间充质基质细胞更大的成骨分化[12]。有研究制备了一种新的基于透明质酸/ZrO2的多孔生物陶瓷人工椎体,其携带重组人骨形态发生蛋白2/壳聚糖缓释水凝胶,以修复小猎犬的椎骨缺损,结果显示,新型的基于透明质酸/ZrO2的多孔生物陶瓷携带重组人骨形态发生蛋白2负载的壳聚糖凝胶可以促进骨缺损的修复,这可以代替临床实践中常用的骨移植物[13]。由此可见藻酸盐在骨缺损中的应用潜力很大。 2.2 化学交联水凝胶 化学交联水凝胶彼此之间具有高亲和力,在可注射介质中显示出显著溶解性的聚合物可以进行修饰,以在递送点形成共价连接的网络[14]。网络的形成程度、系统的稳定性和动力学与分子的亲和力呈正比。骨样羟基磷灰石/聚氨基酸支架已显示出某些成骨性和骨传导性,其还具有可控的生物降解性和无毒性,由于其具有递送抗生素和促进骨骼再生的能力,负载万古霉素的骨样羟基磷灰石/聚氨基酸具有修复感染性骨缺损的巨大潜力[15]。聚合物也可以通过酶促反应进行交联,在过氧化氢(H2O2)和过氧化物酶的存在下酚基团进行自交联,当蛋白质与H2O2和过氧化物酶反应时酪氨酸的酚基发生氧化,形成二和酪氨酸的交联蛋白结合[16],诸如壳聚糖、葡聚糖、透明质酸和明胶之类的聚合物,可以在3,4-羟苯基丙酸或酪胺的存在下通过使其羧基或胺基反应而在其结构上引入酚基[17]。聚(赖氨酸-co-苯丙氨酸)和转谷氨酰胺酶介导的谷氨酰胺官能化的聚乙二醇,也已被报道显示出化学交联特性,代替钙铁蛋白并利用钙离子作为辅因子[18]。因此当掺入蛋白质衍生的生物活性物质形成化学交联聚合物的稳定网络时,在组织工程水凝胶系统中具有巨大潜力。 2.3 天然高分子水凝胶 透明质酸是D-葡萄糖醛酸和n-乙酰D-葡萄糖胺的高分子聚合物,几乎存在于所有组织中,以透明质酸为基础的水凝胶系统,凭借其良好的生物相容性和可降解性可作为药物和蛋白质分子的递送载体[19]。透明质酸不具有热响应性,但可与具有热响应性的聚合物结合变为具有生物相容性和热响应性的水凝胶[20]。向CaCO3水凝胶中添加不同浓度的肉桂醛,研究其对拉伸强度、老化膨胀、凝胶裂解、肉桂醛释放、抗菌作用和细胞毒性的影响,结果发现肉桂醛降低了CaCO3水凝胶的降解速率,对人牙龈成纤维细胞没有毒性作用[21]。IVIGLIA等[22]设计了一种壳聚糖-果胶水凝胶,粒径为100-300 μm,扫描电子显微镜显示该水凝胶的多糖性接近天然骨骼,可填充骨缺损,陶瓷颗粒的加入使其在不同pH值下保持相对稳定。磷酸钙陶瓷和多糖基水凝胶支架与间充质干细胞的结合也可用于大鼠骨缺损的修复,其修复机制和吸收动力学截然不同:水凝胶能够从骨缺损边缘诱导出致密的骨矿化结构,而陶瓷则能激发编织骨的生成并与陶瓷表面紧密接触,成骨性和血管生成特性与水凝胶的快速吸收性相结合,使水凝胶成为一种很有前途的陶瓷替代品[23]。儿茶酚功能化透明质酸水凝胶可促进骨组织缺损中人脂肪干细胞的血管生成和成骨作用,用儿茶酚功能化透明质酸水凝胶增强干细胞介导的血管生成和成骨作用,由于其优异的组织黏附性,儿茶酚功能化透明质酸水凝胶能够介导脂肪干细胞高效植入到骨缺损区域。同时,儿茶酚功能化透明质酸水凝胶增强了脂肪干细胞介导的治疗性血管生成和骨骼重建,这项研究证明了使用仿生儿茶酚功能化透明质酸水凝胶作为功能性生物材料来改善关键组织缺损中组织再生的可行性[24]。HSIAO等[25]构建不同组织工程结构来治疗骨缺损,结果表明水凝胶与间充质干细胞结合可获得最大程度的骨再生。GARCíA等[26]用聚乙二醇设计了整合素特异性水凝胶,在血管化和骨再生中的具有重要作用。MISHRA等[27]设计了酶促交联羧甲基壳聚糖/明胶/纳米羟基磷灰石注射用凝胶,结果表明羧甲基壳聚糖/明胶/纳米羟基磷灰石可注射凝胶用于骨细胞递送及不规则骨缺损修复的临床损伤小,疗效可靠。PUéRTOLAS等[28]研究了双相磷酸钙和双相磷酸钙-琼脂糖支架在骨骼再生中的作用,结果也颇为满意。Ⅰ型胶原蛋白以细长纤维形式存在于骨中[29],具有低抗原性和极好的生物相容性,已被用于各种骨缺损的修复。羟基磷灰石包裹的双网络(鱼胶原蛋白为原料)凝胶作为柔软和弹性的陶瓷,具有良好的生物力学性能和与骨骼的牢固结合能力[30],功能化的丝素蛋白水凝胶对骨缺损修复的作用增强了骨髓间充质干细胞的成骨作用[31]。Laponite纳米血小板是一种可以促进成骨细胞生长的生物活性黏土,再生丝素蛋白/Laponite纳米血小板水凝胶可注射,还可以促进成骨细胞的增殖和分化[32],算得上是一种理想的骨缺损修复材料。 2.4 合成高分子水凝胶 由于天然聚合物作为热敏性水凝胶载体缺乏通用性和响应性,而合成聚合物则不同,可以根据临床需求进行不同的设计,更加灵活多样。CHO等[33]通过改变水凝胶的临界温度将可生物降解的聚合物合成为聚(N-异丙基丙烯酰胺)。磷酸钙骨水泥在临床中被用于骨缺损修复,但存在一定的局限性,将磷酸钙骨水泥与逆热响应水凝胶组合效果不错,能实现可注射性[34]。几乎所有天然衍生的水凝胶都显示出良好的生物相容性,包括结合域的聚乙二醇凝胶。有研究描述了不适于酶降解的聚乙二醇凝胶引发的炎症反应,虽然不一定与毒性有关,但水凝胶的膨胀性的确是影响临床应用的一个重要因素,为保障临床应用的安全性,需要对其进行充分的论证和实验。 "
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