Chinese Journal of Tissue Engineering Research ›› 2018, Vol. 22 ›› Issue (34): 5534-5539.doi: 10.3969/j.issn.2095-4344.0974
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Zhao Shengli1, Shi Ben-chao1, Yin Jie2, Gao Junhuai1, Yu Qinghe1, Min Shaoxiong1
Received:
2018-05-06
Online:
2018-12-08
Published:
2018-12-08
Contact:
Min Shaoxiong, MD, Doctoral supervisor, Department of Spine Surgery, Zhujiang Hospital of Southern Medical University, Guangzhou 510220, Guangdong Province, China
About author:
Zhang Shengli, Master candidate, Department of Spine Surgery, Zhujiang Hospital of Southern Medical University, Guangzhou 510220, Guangdong Province, China
Supported by:
the Natural Science Foundation of Guangdong Province, No. 2017A030313564, 2014A030313348; the Science and Technology Foundation of Guangzhou City, No. 201607010266
CLC Number:
Zhao Shengli, Shi Ben-chao, Yin Jie, Gao Junhuai, Yu Qinghe, Min Shaoxiong. Early vascularization of scaffold materials in the repair of large bone defects[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(34): 5534-5539.
2.1 促进组织工程骨血管化的支架材料的基本要求 作为促进组织工程骨血管化的理想支架材料应具备良好的生物相容性、合理内部空间结构、优良的机械性能、恒定的降解速率及有效的生物诱导作用。据文献报道,天然松质骨的孔隙率为75%-90%,孔径为50-300 μm,抗压强度为11-24 MPa[4]。在实际材料学的发展过程中,构建兼顾上述特点的支架材料存在一定困难,追求孔隙率的最大化将导致材料抗压强度的下降[4-6]。磷酸三钙是骨科常用的骨填充材料,其化学组成类似天然骨组织,具有良好的生物相容性和降解速率,但其机械强度较差,无法满足机体特殊承重部位的骨缺损修复[6],且其孔隙率、孔径、内部连通率不易控制。随着对高分子材料学的深入研究,基于聚乳酸(PLA)、聚羟基乙酸(PGA)及聚甲基丙烯酸(PMAA)等构建的支架材料以其可控的孔隙率、孔径和内部连通率迅速成为骨科材料学研究的热门,但其也存在不足之处。例如聚乳酸-聚羟基乙酸共聚物(poly(lactic-co-glycolic acid),PLGA)降解后生成二氧化碳和水,使周围形成弱酸性环境,不利于细胞黏附和生长。而且,材料表现出与机体正常组织替代不匹配的降解速度,也限制了其大规模应用[7]。为克服PLGA降解过程中对微环境pH值的影响,有研究将磷酸三钙与其制成复合材料[8],在共同降解过程中达到微环境pH的动态平衡。随着生物医学3D打印技术的发展,基于不同原料制成的支架不但能实现对内部空间结构的精确调控,也有望使不同材料优势互补,使构建促进组织工程骨血管化的理想支架材料成为可能。 2.2 支架材料促进组织工程骨血管化的一般方法 2.2.1 支架材料内部结构的优化及修饰 优化材料孔隙率、孔径、连通率:孔隙率、孔径、连通率是评价骨修复支架材料的重要指标。高孔隙率、连通率、适宜的孔径可实现支架内部营养物质快速渗透,有利于干细胞及内皮细胞黏附及迁移。有文献报道,多孔支架相比无孔支架,引起机体更低的免疫反应,可能是因为它们允许炎细胞渗透并消化支架[9]。国外相关研究认为支架孔径> 200 μm有利于细胞迁入,孔径为300 μm时利于血管的形成[4,10]。为了优化材料孔隙率和孔径,Bhuiyan等[11]利用纳米级羟基磷灰石颗粒、PLGA及胶原制成类似于松质骨的nHAP-PLGA-COL多孔生物支架,评估其孔径为(270±60) μm,孔隙率达到(81±2)%。实验表明该复合材料在搭载人间充质干细胞修复骨缺损方面的综合性能优于单纯PLGA或nHAP-PLGA支架,分析认为这种均匀且相互连接的三维多孔结构为人间充质干细胞的增殖、黏附及成骨分化提供了良好的环境。为兼顾材料高孔隙率及力学抗压强度,Zhang等[12]改良了传统3D打印技术中喷头的设计,采用富含硅(Si)、镁(Mg)、钙(Ca)等离子的原料打印出内径为500 μm的中空管状复合生物陶瓷(Ca7MgSi4O16),该陶瓷抗压强度达到26 MPa,明显优于传统骨填充材料β-磷酸三钙。同时发现,陶瓷在降解的过程中可持续释放Si,Mg,Ca等离子,诱导内皮细胞迁移,促进血管形成;相比传统实心打印材料,该陶瓷明显提高了支架孔隙率,这为实现支架内部营养物质快速渗透、血管的长入提供了有利条件。目前,一部分多孔材料已成功投入使用,例如Zimmer-Biomet公司生产的多孔金属钛支架应用于临床已有36年的历史,该支架孔隙率为67%,平均孔径300 μm,植入动物体内2周可见材料内部血管化骨形成,对病例的长期随访也取得了较为满意的效果[13]。 改善细胞-支架界面状态:支架材料合理的三维空间结构对于营养物质的渗透和细胞迁入至关重要,但理想的支架材料内部通常需适合细胞黏附及生存。有文献报道聚多巴胺(polydopamine,PDA)具有改善细胞活 性[14],诱导细胞定向迁移及黏附的作用。 Kao等[15]利用3D打印技术制成直径为12 mm的聚乳酸多孔支架,支架表面及孔壁附以PDA涂层。发现相比未涂PDA支架,PDA涂层支架可显著提高细胞向支架内部的迁移、黏附及外基质的分泌,并能诱导人脂肪干细胞向成骨成血管方向分化。除了采用PDA涂层来改善细胞-支架界面状态,近年来,液晶态物质以其可流动性、有序性、快速分子自组/重组、光学各向异性等特点逐渐被应用于生物医学领域[16]。研究发现,构成生物体的蛋白、核酸、多糖、脂质等大多数以液晶态存在,以液晶态生物材料修饰或直接作为组织工程支架,可实现良好的血液相容性和细胞亲和性[17]。Nakayama等[18]将内皮细胞与液晶态胶原制成的纳米纤丝胶原支架共培养,发现支架上内皮细胞的数量及增殖率明显提高,利用该支架搭载内皮细胞修复大鼠下肢缺血模型,展现出了优良的血管生成能力。将液晶材料与3D打印技术结合,构建既具有复杂内部结构,又可促进干细胞及内皮细胞迁徙分化的三维支架,对于特殊部位的骨缺损修复意义重大。 2.2.2 支架材料与免疫调节 巨噬细胞在调节血管生成中的作用:在组织工程化材料应用于体内的过程中,为实现支架最大化植入率及支架中负载细胞的存活,通常需要预先应用免疫抑制剂抑制宿主免疫应答。随着对免疫系统的深入了解,人们发现免疫因子不仅积极地参与促/抗炎反应,而且能触发重建组织稳态的特异性前导途径[19-20]。免疫细胞可直接(通过细胞间接触或旁分泌)或间接(通过修饰周围环境,如消化支架)等影响并调控干细胞募集、活化、分化和生存。当免疫系统被激活时,作为抗原提呈细胞,巨噬细胞通过其可塑性协调局部宿主免疫反应[21]。巨噬细胞按类型分为M1,M2和M3型,其中M2型又分为M2a,M2b,M2c三种亚型[20]。在促进炎症部位血管生成的过程中,不同类型巨噬细胞作用各异。研究表明,M1型巨噬细胞在局部可分泌高水平血管内皮细胞生长因子[22],M2a型巨噬细胞可分泌稳定管周细胞的血小板源性衍生因子BB,M2c型巨噬细胞可分泌参与血管重塑的基质金属蛋白酶9[23]。同时,研究发现巨噬细胞在消化支架的过程中与其内搭载的间充质干细胞实现双向互动[20,24]: ①M1型巨噬细胞可释放白细胞介素1β,白细胞介素6,肿瘤坏死因子α和干扰素γ等相关细胞因子抑制间充质干细胞生长,而M2型巨噬细胞及其相关细胞因子(白细胞介素10,转化生长因子β1,转化生长因子β3和血管内皮细胞生长因子)可促进间充质干细胞生长;②间充质干细胞释放的免疫调节因子如TGS-6,前列腺素E2,白细胞介素6和CXCL1等减弱多形核白细胞和巨噬细胞在急性损伤模型中促炎细胞因子的产生和释放,抑制T细胞活化和分化并降低T细胞增殖和干扰素γ释放;③巨噬细胞刺激间充质干细胞产生M2型诱导性细胞因子(白细胞介素4,13),促进自身M1型向M2型的转化。 组成支架材料的不同元素对血管生成的影响:支架在降解过程中释放的离子同样可激活免疫反应。Mg是构成人体的常量元素,对维持机体正常生理状态十分重要。文献报道M2型巨噬细胞有利于组织工程骨血管 化[23],Chen等[25]通过用β-磷酸三钙包被Mg支架成功将Raw264.7巨噬细胞(一种鼠类白血病单核-巨噬细胞系)诱导分化为M2抗炎表型。此外,通过检测发现,该支架中的Raw264.7巨噬细胞血管内皮细胞生长因子和骨形态发生蛋白2的表达显著上调,表明经过Mg诱导的M2型巨噬细胞具有辅助血管生成及骨生成的特性。 Si是人体另一重要元素,广泛参与人体骨形成及维持正常心血管功能。Sun等[26]利用硅酸胶原支架修复大鼠颅骨3 mm骨缺损,micro-CT评价术后12周缺损部位血管生成情况发现,硅酸胶原支架组在血管体积、连通率、管壁厚度等方面优于异体松质骨组,两组血管各向异性程度没有统计学差异,但均低于空白对照组。体内实验证实其可诱发机体免疫反应,通过巨噬细胞中介,刺激单核细胞分化以及释放多种细胞因子,招募外周血中存在的间充质干细胞和内皮祖细胞向炎症部位迁徙,促进缺损部位骨化及血管化。Zhang等[12]将Si,Mg,Ca等离子混合制成多孔支架,也得到了相似的促血管生成效果。 锶(Sr)是维持正常人体生理活动的一种微量元素,具有促进骨形成和抑制骨吸收的双重作用[27]。人体中99%的锶存在于骨骼中。锶的化合物雷尼酸锶作为首个上市(2004年获欧盟批准)的药物广泛应用于骨质疏松的治疗。近年来,锶在促血管生成方面的作用逐渐被人们所探知。其中,将锶与聚磷酸钙结合制成掺锶聚磷酸钙支架修复骨缺损的研究较多。研究证实,掺锶聚磷酸钙体外可上调成骨细胞血管内皮细胞生长因子和碱性成纤维细胞因子等促血管生成因子的表达[28]。Fu等[29]将掺锶聚磷酸钙多孔支架与外周血来源的内皮祖细胞和间充质干细胞共培养,实现了良好的组织工程支架预血管化。由此可见,锶作为具有成骨成血管效应的元素具有广阔的研究价值,但目前对锶元素如何影响机体免疫系统,调节成骨细胞及内皮细胞的分子学机制尚不清楚,这一点有望成为今后研究的方向。 2.2.3 构建搭载活性成分的控释系统 基于材料体内自然降解缓释模式:生理状态下,组织器官在损伤修复再生期间,生物活性分子的表达在空间和时间上都受到严格的调节。在局部缺血组织再血管化过程中,血管内皮细胞生长因子的表达需持续至少4周才能使新形成的血管成熟稳定[30]。这要求支架材料不仅具有一定的承载率,而且能够达到对因子持续稳定的释放。当前研究的功能化的生物材料在因子递送的时间和剂量上具有一定的可控性,但有文献报道,采用纤维蛋白支架搭载碱性成纤维细胞因子构建缓释系统的过程中,由于支架对该因子具有较高的亲和力,在局部降解释放过程中一部分活性物质与支架紧密结合而无法进入周围组织[31],导致支架局部碱性成纤维细胞因子的异常高浓集而周边组织的相对低浓度,进而诱发异常的血管生长[32]。为寻找一种与承载物低亲和力、高释放率的材料,Gaudiello等[33]对比胶原海绵支架与普通蛋白支架负载经基因编辑的脂肪干细胞对血管内皮细胞生长因子释放量的影响,通过酶联免疫吸附分别测定共培养后支架和培养基中血管内皮细胞生长因子含量,发现胶原海绵支架中几乎不含该因子,接近100%的生长因子被释放入培养基中,而普通蛋白支架发现尚有25%的生长因子与支架结合而无法释放入上清液,实验将此种脂肪干细胞接种入普通蛋白支架中培养14 d,发现了异常的病理血管结构。相比普通蛋白支架,胶原海绵支架与血管内皮细胞生长因子具有更低的结合率,这有效防止了因局部活性成分浓集而造成的异常血管生成。 据报道,体积大于1 cm3的工程化组织中心通常处于处于缺氧环境[1],尽管材料中搭载生长因子,但是诱导血管长入的过程仍较慢,这通常造成坏死中心的形成和仅在组织周边的细胞存活[34]。寻找一种合适的释氧材料,维持材料内部血管长入前细胞生存必需的氧浓度成为当前研究的重要方向之一。有学者将过氧化氢,过碳酸钠,过氧化钙和吡啶类过氧化物等作为产氧物质,但其本身及释氧过程中的副产物存在细胞毒性,且释氧的过程及量不受控制[35]。为制造一种释氧稳定且无细胞毒性的产氧材料,Seifu等[36]将氟化沸石氧载体颗粒均匀嵌入聚氨酯支架中,该释氧材料的嵌入不影响支架孔隙率及孔径,实验观察到材料中培养的冠状动脉平滑肌细胞增殖明显,细胞浸润深度是单纯聚氨酯支架的2倍,说明该释氧体在材料深部达到了输送维持细胞正常生存氧浓度的作用。Lee等[37]采用复乳溶剂挥发法制成直径为100-500 μm,内填充全氟辛烷乳剂的聚己酸内酯微粒,该材料平均载氧量达到23.62 mg/L,体外培养MC3T3-E1(鼠源成骨细胞)发现细胞增殖数量第6天达峰,随后出现下降,约10 d恢复初始细胞数量,而对照组(内填PBS组)细胞数量呈持续下降态势;体内实验发现移植10 d后实验组细胞均匀分布于材料内部,并在内部形成丰富的血管网络。 基于材料体外干预控释模式:除了利用材料自身降解过程释放活性成分,可选择特定技术实现对材料状态的体外精确控制。1956年,随着瑞典L Leksell教授将工业超声引入医学领域,超声波依靠其非侵入性、亚毫米级精确度、穿透力强及方向性好的优势迅速应用于疾病诊断。将超声应用于生物医学工程领域,利用超声,使包被活性成分的声敏材料暴露于特定声频下,造成材料结构的改变,从而将活性成分释放到周围环境,可达到材料内部活性成分的体外控释[38-39]。通过对超声体外控释的研究,人们不断优化声源及声控材料相关参数,以期达到更加精确的时间和剂量控制。与未聚焦、低频(即20 kHz-1 MHz)超声相比,使用聚焦高频(即> 1 MHz)超声可提高深部组织的空间分辨率,更加高效精准地提高支架材料有效载荷的释放[40]。Moncion等[41]利用混入全氟化碳乳剂的蛋白水凝胶制成声学响应支架,通过超声照射(声频:2.5 MHz,峰值舒张声压:8 MPa,空间峰值时间平均声强:86.4 mW/cm2)实现了体外对支架良好的时间控释调制,并且该实验在未添加任何生长因子的情况下观察到实验组血管生成量明显多于对照组,提示全氟化碳乳剂蛋白水凝胶支架在诱导血管生成方面存在的潜力。虽然采用超声控释活性物质相比传统缓释材料具有明显优势,但有文献报道,超声可影响生长因子的活性,经持续超声照射后蛋白质出现了结构性改变,这种情况下活性成分能否发挥正常生物学效能,其远期作用尚需深入研究[42]。 "
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