Chinese Journal of Tissue Engineering Research ›› 2016, Vol. 20 ›› Issue (43): 6494-6500.doi: 10.3969/j.issn.2095-4344.2016.43.016
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Received:
2016-08-16
Online:
2016-10-21
Published:
2016-10-21
Contact:
Li Yan-lin, Professor, Department of Sport Medicine, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
About author:
Xiao Yu, Studying for master’s degree, Department of Sport Medicine, the First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
Supported by:
CLC Number:
Xiao Yu, Li Yan-lin, Gao Huan-yu, Wang Guo-liang, Xia Ping.
2.1 α-磷酸三钙材料特性简介 磷酸三钙的化学式为Ca3(PO4)2,钙磷比约为1.5,与正常人骨中的比例相似,化学性质和晶体结构也与人骨相似[4-6]。磷酸三钙是白色、无臭、无味晶体或无定形粉末,存在多种晶体相,除了低温β相(β-磷酸三钙)和高温α相(α-磷酸三钙)外,还有极高温α’和γ相等,熔点1 670 ℃,可溶于酸,不溶于水和乙醇。临床常用到的是α相和β相。 目前在制备α-磷酸三钙的过程中,应当注意最后一步降温的速度是整个过程中对材料纯度控制最为关键的一步,因为在高温下生成的α相需要通过淬火以“锁定”晶体结构,以减少转变为β相的量,因此整个过程应当足够迅速[6]。另外,在制作过程中还需注意氧化钙、羟基磷灰石等其他钙磷化合物对纯度的影响。现在科研中常用到的α-磷酸三钙多被制成了粉末状,能够方便塑型,以满足不同的实验需求。近年来,有报道认为α-磷酸三钙本身并不具备骨诱导能力,甚至即使只用浸泡提取液培养细胞都会造成细胞增殖能力的下降[7],但都一致承认这一材料具有良好的生物活性、生物相容性、生物降解性和骨引导能力[8-9]。Lee等[10]发现用α-磷酸三钙制得的骨水泥,在生理溶液下呈现微碱性(pH=8.2),这有助于细胞的生长、分化,并且通过细胞形态学和生存能力证实了α-磷酸三钙具有良好的生物相容性,而且α-磷酸三钙骨水泥的成型时间和最终凝固时间都明显短于一般骨移植替代材料。α-磷酸三钙有着比β-磷酸三钙更好的溶解性,以α-磷酸三钙/β-磷酸三钙为主的复合骨水泥降解的主要成分就是α-磷酸三钙。通过骨-材料接合界面发生的水固化反应[11],经溶解-转化-沉淀的过程形成稳定的、具有微孔结构的磷酸钙化合物,具有良好的骨传导性和成骨作用,在体内能够被缓慢降解吸收并转化为新生骨。 α-磷酸三钙的降解产物主要是低钙羟基磷灰石,其结构和化学性质与生物体内的磷灰石相近,具有良好的生物相容性、生物活性及可塑性[12]。因此α-磷酸三钙能够实现材料的降解并逐渐被新生骨所替代,最终实现骨的愈合。α-磷酸三钙材料因为原料和制作方法多样,所获得的材料密度、孔率、颗粒大小都会有所差异。目前,孔径大小、孔隙率、贯通率已可通过对制备过程中的温度、pH等因素的调节来进行调整,最终达到与骨近似的生理状态,这有助于在体内环境中周围组织的生长和血管的长入,能为细胞的附着和细胞外基质分泌提供支架作用,最终有利于新生组织的生成[6]。就炎症反应而言,虽然Lange等[13]研究认为钙磷移植物的颗粒组成、粒子大小都会不同程度的引起局部炎症,但用纯α-磷酸三钙或是α-磷酸三钙为主的复合材料置入动物模型后,即使未长期使用抗生素,Vamze等[14]也没有发现其移植部位的炎症反应。这些优点都是α-磷酸三钙作为自凝骨水泥、可降解生物陶瓷或骨修复复合材料的基础。 但是α-磷酸三钙总体质地较脆、生物力学性能不理想,再加上无诱导成骨作用,水固化反应过程中会发生体积的膨胀,引起局部强度降低。另外,磷酸钙材料都要经过较长的自凝时间才能获得最大强度,而且自凝时间不易控制,过久会导致材料的碎裂,在移植部位有渗血的情况下需要更长的自凝时间,因此并不适宜用于承重部位及血供丰富部位的骨缺损填充治疗[10,15]。 目前为了改善α-磷酸三钙的缺陷,大致使用3种方法:改变α-磷酸三钙晶体结构,从理化性质根本上解决材料缺陷[16-17];添加或混合其他化合物补充原有不足[18];附和药物增加细胞贴附,以加强成骨效果[7,19]。从所使用的原料上分大致可分为无机材料和有机材料。 2.2 改良后的α-磷酸三钙 2.2.1 α-磷酸三钙与无机盐 α-磷酸三钙在室温下保持着亚稳定状态,其稳定性高低取决于化学分子构型中的离子取代情况[16]。在分子结构中加入或者替换原有的基团和离子,可在提高α-磷酸三钙的稳定性的同时,对骨组织再生时发生的生化反应产生较大影响[7,20]。以硅为例,硅是目前使用最多的α-磷酸三钙稳定剂,能使常温下的α-磷酸三钙更稳定状态,并且能够增加α-磷酸三钙的抗压强度,改善因水解引起的α-磷酸三钙抗压强度降低[21]。对于细胞而言,有硅混合的磷酸三钙复合物与纯磷酸三钙材料相比表现出了更好的力学特性和物理稳定性,并且能够刺激间质细胞分化、促进成骨细胞活动,由此改善以α-磷酸三钙为基础的骨水泥的生物化学特性[22]。de Aza等[23]在动物模型实验中证实了在α-磷酸三钙中加入硅离子,能促进材料-骨界面的骨重建。除了硅,锶元素目前也被认为是影响骨生长发育的重要元素之一。Saidak等[24]发现了锶元素在骨质疏松中扮演了重要角色,锶在生理上与钙离子有着共同通路并且能够在骨中蓄积 。除此之外,锶还能促使破骨细胞凋亡和成骨前体细胞的增殖分化、促进胶原合成。有研究报道[25],含锶α-磷酸三钙的自凝时间能够延长并且达到手术所需的时间,这意味着使用这种骨水泥的术口能够更早关闭,避免了长时间伤口的开放。而且锶不会影响α-磷酸三钙在体内的化学反应或是降解,即使在浸泡生理盐溶液48 h之后,含锶α-磷酸三钙依然能够承受30 MPa压力强度。除了上述的几个,还有报道铜、镊等二价盐与α-磷酸三钙结合制作骨移植材料[20]。 2.2.2 α-磷酸三钙与磷酸钠钙 除了上述的加入离子或基团,化合物与α-磷酸三钙复合也是改进单一α-磷酸三钙的重要方法。Masashi等[18]通过向α-磷酸三钙中混入磷酸钠钙、柠檬酸获得一种新型复合材料,在室温下材料内的钙离子和柠檬酸可在短时间内发生螯合,最终可缩短自凝时间,而且材料强度也明显强于主要由磷酸钠钙、磷酸四钙和β-磷酸三钙组成的普通磷酸钙水泥,并且在生理盐溶液中该材料经水解可产生Na+、Ca2+和PO4-,局部高浓度的Ca2+、PO4-有助于磷灰石的形成;此外,这些离子或离子团还能够加强材料-骨界面的骨传导性,并使溶液呈现出弱碱性,利于细胞的生长、增殖,适用于较为常见的骨损伤治疗。 2.2.3 α-磷酸三钙与β-C2S β-C2S是硅酸盐骨水泥中重要的成分之一,在体外有良好的生物活性和生物相容性。当溶液中液体/粉末比例适当时能制成可注射水泥,该水泥经水合反应凝固变硬形成C-S-H凝胶[26]。Correa等[27]对添加了硅酸盐的钙磷材料进行理化性能检测时发现α-磷酸三钙骨水泥的抗压强度降低了,但是体外长时间浸泡在生理溶液中仍能保证其材料强度高于正常人骨小梁。Hasan等[28]进一步的研究发现,在体内C2S能够加快α-磷酸三钙的降解,早期就能在材料周围检测到生成的降解产物CDHA,为骨修复提供足够的钙离子原料[29],并且还C2S还能诱导低钙羟基磷灰石向骨组织天然的构型转化,局部适宜浓度的硅离子甚至能够加强骨形成相关基因的表达,刺激细胞增殖[30-31]。由此得知,β-C2S不但改善了α-磷酸三钙本身强度过大的缺点,在承重形变上更满足生理需要,而且能够激发细胞相关成骨基因表达,从种子细胞和支架材料两个方面补充了α-磷酸三钙支架的现有的不足,但缺陷在于硅离子浓度需要精确掌握,过高的浓度可以导致细胞的死亡[31]。 2.2.4 α-磷酸三钙与凝胶 磷酸钙材料和人体骨相比力学强度较低。为了改变这一缺陷,有人注意到了乙烯吡咯烷酮和聚丙烯酸复合以改善强度不足的可能性[19]。在生物医学工程领域,上述化合物都是制备凝胶的常用单体物质。在α-磷酸三钙中加入乙烯吡咯烷酮和聚丙烯酸,虽然会引起材料孔隙度降低,但抗拉和抗压能力都得到了不同程度的增加,并且展现出了更好的生物相容性,能在不影响材料的力学特性的前提下促进新生血管长入材料中,还具有较高的亲水性和稳定的药物释放能力,可作为移植材料修补损伤的同时,携带药物或细胞因子加强局部的修复作用[19]。 2.2.5 α-磷酸三钙与聚L乳酸纤维 经纤维强化的骨水泥能够改善磷酸钙骨水泥本身较低的力学强度以及受压后容易碎裂的脆性[32];也能明显缩短水泥自凝时间;还可通过诱导机体内纤维空隙中的液体吸收,引起α-磷酸三钙发生降解所需的液体微环境的减少,导致转变时间相对延长,最终导致α-磷酸三钙降解减缓,抑制α-磷酸三钙转变为低钙羟基磷灰石,最终因为有更小的晶体结构、更低的磷灰石相结晶度而使得材料整体结构更为紧密。并且因为纤维自身的可吸收特性,在被吸收之后可遗留下孔隙结构,利于新生组织的长入[33]。虽然短时间内由于α-磷酸三钙晶体数量相对较多,会引起复合材料诱导骨生成能力降低,并减弱了一定的力学强度;但从长远来看,转变时间的延长使得材料能够长时间维持一定的形变能力和抗压能力。这都充分说明了纤维强化骨水泥作为骨替代材料可用于恢复时间较长的损伤当中的潜力。 2.2.6 α-磷酸三钙与儿茶素 儿茶素是绿茶中的一种儿茶酚,也是公认的茶多酚中含量最多、最有效的活性成分。现普遍认为儿茶素能够抗炎抗肿瘤,也能降低血脂,控制血压,调节免疫,增加骨密度,减少骨质疏松的发生,还能诱导多核细胞(如破骨细胞)的凋亡[34]。儿茶素改善骨的健康状况主要通过4个机制:减少氧化应激反应[35];增加抗氧化酶活性[36];减少炎症因子的释放;促进成骨细胞标记基因表达[37]。从许多报道中都可以看出,通过将儿茶素与α-磷酸三钙材料复合,可诱导大量骨形成蛋白2生成,进而促进了骨的生成[38-39],并且儿茶素对成骨细胞的增殖分化不会造成影响[40-42]。说明了以α-磷酸三钙材料本身加上儿茶素对骨的多机制作,可在不影响α-磷酸三钙特性和修复细胞活性的前提下提高骨的修复作用,是最大限度不改变α-磷酸三钙以保持原有优点和缺陷上对其不足之处的补充。"
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