Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (4): 626-631.doi: 10.3969/j.issn.2095-4344.2378
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Li Xiaozhuang, Duan Hao, Wang Weizhou, Tang Zhihong, Wang Yanghao, He Fei
Received:
2020-02-28
Revised:
2020-03-06
Accepted:
2020-04-11
Online:
2021-02-08
Published:
2020-11-25
Contact:
He Fei, Chief physician, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
About author:
Li Xiaozhuang, Master candidate, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
Supported by:
CLC Number:
Li Xiaozhuang, Duan Hao, Wang Weizhou, Tang Zhihong, Wang Yanghao, He Fei. Application of bone tissue engineering materials in the treatment of bone defect diseases in vivo[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(4): 626-631.
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2.1 天然高分子材料 2.1.1 胶原蛋白 在骨组织中最常见且含量最高的胶原蛋白为Ⅰ型胶原蛋白,由多种类型的糖蛋白构成,是一种可生物降解材料,具有出色的保水能力、低抗原性、细胞相容性和骨诱导能力[3]。Ⅰ型胶原蛋白在自然界广泛存在,易于取得,目前已被大量用于细胞培养、生长和分化,并且在骨组织工程技术中是制造复合型工程材料的理想基础材料[4]。 WANG等[5]将Ⅰ型胶原纤维膜置于仿生矿化溶液中,经处理后得到不同矿化程度的矿化胶原纤维膜,将其植入SD大鼠颅骨5 mm临界骨缺损模型中,术后12周时发现骨缺损处出现大量新生骨组织,表明经过矿化的Ⅰ型胶原纤维膜具有优秀的骨诱导能力和骨传导性。但胶原蛋白作为常用骨组织工程材料的机械强度差,难以单独作为骨修复材料,限制了其在临床上的使用,需要与其他材料复合进行物理改性[6]。LIU等[3]针对复杂骨缺损,将Ⅰ型胶原与氧化石墨烯复合制备不同石墨烯配比的4组复合物(0,0.05%,0.1%,0.2%),得到不同气凝胶的孔隙率,发现0.1%组气凝胶的Ca/P比(1.67±0.11)最接近天然骨组织(1.67),表明0.1%组气凝胶具有比其他气凝胶更好的磷灰石形成生物活性,并且MTT实验显示其有更好的细胞相容性,骨缺损修复Micro-CT检测也显示0.1%组气凝胶较其他组别具有更好的骨修复效果。就目前而言,胶原蛋白依靠其易于获取、良好的生物相容性和骨诱导能力是骨缺损修复材料中重要的组成部分。 2.1.2 丝素蛋白 丝素蛋白是一种来自于家蚕产生的天然高分子材料,富含亲水性氨基酸侧链,可改善其亲水性和生物相容性,其降解产物也可被人体充分吸收,并且由于其良好的生物相容性和可生物降解性,优异的氧气和水蒸气渗透性足以支持细胞生长,已经作为一种生物材料得到了广泛而深入的研 究[7-8]。但是,丝素蛋白也有诸如在水中有相对较高的溶解度等缺陷,这导致了其在体内和体外应用时的不稳定性[9],因此以丝素蛋白作为支架,在其表面喷涂其他材料或与其他多种材料复合来提高材料性能是当前骨组织工程的热点。WU等[10]以静电纺丝技术制作以丝素蛋白支架为基础,在其纤维上固定由骨形态发生蛋白2肽官能化的氧化石墨烯,较单纯的丝素蛋白支架而言改善了支架的亲水性,提升了细胞黏附和增殖,并在大鼠颅骨缺损实验中验证了其具有优秀的成骨分化能力,能促进骨的再生。实验表明,与其他材料复合后的丝素蛋白支架在骨组织工程应用方面具有更大的现实意义[11]。 2.1.3 壳聚糖 壳聚糖是一种具有优异生物相容性的天然碱性多糖,是脱乙酰壳多糖的产物,主要由葡萄糖胺组成,葡萄糖胺也是细胞外基质糖胺聚糖的重要组成部分。因此壳聚糖具有出色的生物相容性、可降解性和无毒性,其中最重要的是它可以与大量水溶性阴离子聚合物(如糖蛋白、海藻酸钠等负性生物活性物质)相互作用形成聚电解质,具有特殊的正电荷,是具有广阔应用前景的天然高分子聚合物[12-15]。 国内研究人员通过冷冻干燥技术制备了壳聚糖-同种异体骨粉复合多孔支架和单纯壳聚糖支架,复合多孔支架孔隙孔径大小控制在100-450 μm,大部分孔隙孔径为200-300 μm,单纯壳聚糖支架孔隙孔径较复合多孔支架大,复合多孔支架及单纯壳聚糖支架孔隙率分别为(76.8±1.1)%及(78.4±1.4)%,分别植入双侧股骨内上髁直径为3.5 mm骨缺损模型中,术后12周时两组钻孔较前显著变小,均发现新生骨填充缺损区,且复合支架明显多于单纯壳聚糖支架[16]。这与KANG等[17]实验结果相近,表明壳聚糖具有优秀的骨诱导能力和骨传导性。BI等[18]应用冷冻加热工艺设计了壳聚糖-聚乙烯醇物理双网络水凝胶,将纳米级羟基磷灰石晶体堆叠在其表面,体外实验表明壳聚糖兼具高强度、高孔隙率、生物降解性和骨诱导能力,同时体内兔股骨外侧骨缺损修复实验也表明壳聚糖能促进骨整合和新骨生长,具有用于骨组织修复的潜力。 总而言之,天然高分子材料基本都有获取途径便利、生物相容性好、在体内降解无毒害等优点,在细胞培养方面也表现出适宜细胞增殖,但是较差的机械性能使得其应用范围受限,体内实验建立动物模型时也多考虑非应力集中区域,一定程度上对研究植入物的成骨效果造成影响。 2.2 人工合成有机高分子材料 2.2.1 聚乳酸 聚乳酸也称为聚丙交酯,属于聚酯家族,是以乳酸为主要原料聚合得到的聚合物。目前常用的聚乳酸类高分子聚合物种类较多,其中以聚乳酸、左旋聚乳酸、聚羟基乙酸及聚乳酸和聚羟基乙酸共聚体为主,具有优秀的生物相容性、生物可降解性和机械性能[19-21]。但在应用过程中也发现不少缺点:聚乳酸本身具有疏水性,影响了细胞在其上的吸附和生长;降解产物为乳酸并再往下逐级降解,形成了局部酸性环境,较低的pH值可能会导致局部无菌性炎症的发生[22-24]。因此,对聚乳酸类材料进行改性处理是增强其实际应用价值的最佳方法。张明等[25]对左旋聚乳酸进行处理后得到明胶/羟基磷灰石涂层左旋聚乳酸复合材料,在体外及体内实验中发现相较于纯左旋聚乳酸材料,复合材料的骨缺损修复能力更强。MA等[26]和HAN等[27]分别对聚羟基乙酸共聚体和左旋聚乳酸进行材料复合,得出比对单纯的聚乳酸类材料,与其他材料复合或表面涂层处理都能有效提高材料的亲水性,利于种子细胞在材料上吸附和生长,表现出更好的骨修复能力。 2.2.2 聚已内酯 聚已内酯也是目前应用广泛的有机高分子材料之一,具有出色的生物相容性、生物降解性、机械性能和可加工性,可降解成在三羧酸循环中代谢的无害副产物,是可推向临床使用的高分子材料[28-29]。ZHANG等[30]采用溶液浇铸-粒子滤沥方法成功制备Ⅰ型胶原/聚己内酯复合支架和凹凸棒石/Ⅰ型胶原/聚己内酯复合支架,两种支架材料均为多孔结构,孔隙直径为200-500 μm,分别植入兔桡骨15 mm骨缺损模型,术后12周Micro-CT扫描结果显示凹凸棒石/Ⅰ型胶原/聚己内酯复合支架成骨显著高于其他组,苏木精-伊红染色也表示凹凸棒石/Ⅰ型胶原/聚己内酯复合支架植入区域内有大量新生骨形成。虽然聚已内酯有诸多优点,但其仍有不可忽视的缺陷,即缺乏细胞识别位点并且是疏水性材料[31]。 聚乳酸和聚已内酯已被广泛应用于生物医学领域,都具有好的生物相容性、生物可降解性和机械性能,但二者都为疏水性材料,在细胞增殖能力方面不如天然高分子材料,降解产物虽无毒性,但产生的酸性物质会降低局部区域的pH值,容易对研究骨修复带来负面影响。 2.3 人工合成无机材料 2.3.1 羟基磷灰石 羟基磷灰石是存在于天然骨组织中的无机成分,人工合成的纳米羟基磷灰石与天然骨组织中发现的纳米羟基磷灰石具有类似的化学结构和空间结构 [32-34],因此,羟基磷灰石具有高度的生物相容性和生物活性,有一定的骨诱导力,无炎症及排异反应,是骨组织修复和再生最常用的无机生物材料[35-36],也是骨组织置换和再生研究最深入的材料之一[37-38]。尽管羟基磷灰石被认为优秀的骨组织工程材料,但其骨诱导特性不足以治愈巨大的骨缺损[39],针对于这些缺点,包括骨生长因子骨形态发生蛋白2在内的几种生物活性分子已被用于骨组织工程[40]。 DENG等[41]在聚多巴胺(pDA)的辅助下制备了2种类型肽结合的磷灰石纳米复合物:聚多巴胺涂覆的磷灰石(HA-c-pDA)和聚多巴胺模板介导的磷灰石(HA-t-pDA),随后在弱碱性条件下获得肽缀合的磷灰石纳米复合材料(分别为HA-c-pep和HA-t-pep),透射电镜图像显示,HA-c-pDA呈典型的棒状形态,而HA-t-pDA为海绵状结构;在细胞培养实验中,HA-t-pep纳米复合材料表现出更高的细胞增殖、扩散和碱性磷酸酶活性及钙结节形成;在兔颅骨缺损模型中分析了2个月后的成骨情况,Micro-CT结果显示与HA-c-pep和原始羟基磷灰石样品相比,HA-t-pep组骨形成显著增强,其证明了对羟基磷灰石修饰后能提升其细胞增殖能力与成骨分化能力。KIM等[42]也通过负载骨形态发生蛋白2纳米颗粒的形式来改善羟基磷灰石的成骨能力,再次验证材料复合是提升羟基磷灰石成骨能力的有效途径。 2.3.2 磷酸三钙 磷酸三钙与羟基磷灰石类似,都可在天然骨组织中发现,在骨组织中主要以β-磷酸三钙的形式存在。β-磷酸三钙具有生物相容性高、骨传导性好和可在生物体降解及一定的机械强度等优点,是优秀的骨替代材 料[43-45],其缺陷在于缺乏骨刺激作用和体内降解速度较快,难以持续提供稳定的支撑作用[44-45]。为了解决其不足之处,CALVO-GUIRADO等[46]制备了由60%羟基磷灰石和40%β-磷酸三钙混合的复合颗粒,在部分材料内加入3%的硅得到第2种材料,植入新西兰白兔颅骨双侧12 mm圆形缺损模型中,用Micro-CT检测缺损部位的新骨生成情况,结果显示两组材料均能促进新骨生成,混入硅后促成骨作用增加且降低了材料的吸收率。许多研究也将羟基磷灰石和β-磷酸三钙按比例混合制作复合双相磷灰石陶瓷,作为骨组织工程材料广泛应用于骨缺损修复实验当中[47-49]。 2.3.3 生物陶瓷 生物陶瓷是指用作特定的生物或生理功能的一类陶瓷材料,可直接用于人体,具有良好生物相容性、力学相容性和稳定的物理、化学性质[50],常见的有氧化锆生物陶瓷、氧化铝生物陶瓷、碳素材料等。氧化锆陶瓷是生物惰性陶瓷的主要成分,具有高断裂韧性、强度和低弹性模 量[51],常用作掺入材料和氧化铝作为骨替代材料如髋关节假体应用于临床[52]。而其他研究将外消旋聚乳酸与大量的石墨烯/多壁碳纳米管氧化物(质量分数50%)结合起来开发复合支架, 体外结果显示该支架无细胞毒性,并允许成骨细胞样细胞相互作用和矿化基质结节的形成,显著增强了成骨细胞碱性磷酸酶活性;体内实验则表明该支架对骨细胞活性具有更强的影响,可促进更多的新骨形成[53]。 从总的来说,无机材料都具备良好的生物相容性、骨传导性和一定的机械强度,但是普遍缺乏骨诱导能力,如果要作为骨组织工程材料则需要与其他材料进行复合或者作为喷涂材料依附于其他材料表面来达到骨修复作用。 2.4 金属材料 金属材料如钛合金、钴铬合金等具有优越的生物相容性及足够的材料强度,已被广泛应用于骨科领域,但由于金属材料在人体内降解速度极慢,多用做钢板或牙种植体,阻碍了其成为优秀的骨组织工程材料,于是与其他材料混合来改善金属材料的理化性质,是研究金属材料在骨组织工程中应用的热点问题。 钛(Ti)及钛合金作为目前应用最多的金属材料,具有较好的生物相容性、低密度、高比强度、较好的耐腐蚀性和抗疲劳性,被认为是目前最有应用潜力的生物金属材料。对钛及钛合金进行物理结构改造和化学表面改性是目前最常见的技术手段,其中多孔钛及钛合金独特的孔隙结构,有利于体液和营养物质的输送,粗糙的表面有利于干细胞的成骨分化,使新生骨组织向其内部生长,促进孔隙内成骨并与外部骨组织的有效链接[54-55]。多孔结构赋予了钛及钛合金更接近于人骨组织的弹性模量和孔隙率。有研究表明,多孔钛合金在兔桡骨缺损中具有良好的生物相容性及骨传导性,能作为骨修复材料[56]。VAN HOUDT等[57]在透明质胶中掺入脱矿质骨基质并填充在多孔钛支架内,将支架植入大鼠颅骨8 mm的圆形骨缺损模型中,8周后评估缺损部位新骨生成量发现,复合支架和单纯多孔钛都有明显新骨生成,复合支架较单纯支架生成量多。除多孔钛外,也有的研究制备了钛纤维板,在体外和体内实验都得出其具有好的细胞增殖能力,能促进骨组织在其表面生长[58]。 其他金属材料如锌(Zn)、镁(Mg)等微量元素都在人骨组织中被发现,认为它们参与了骨骼的生长,并且有着维持骨密度的作用[59-60]。已有研究表明,锌和镁与羟基磷灰石混合后作为材料涂层都有着促骨组织增殖分化的能力[61-62]。锶(Sr)也被发现具有刺激骨生成并抑制骨吸收的能力[63]。有研究发现,无表面活性剂水热合成产生的摩尔百分比3.22%Sr-羟基磷灰石多孔微球对比纯羟基磷灰石显示出人类成骨细胞样MG63细胞的最佳增殖、成骨分化和血管生成因子表达[64]。将锶掺入包括生物活性玻璃和磷酸钙在内的成骨材料中,随着锶含量的增加,磷酸钙的溶解度和生物玻璃的生物活性也会明显改变,表现出更佳的促成骨能力[65-68]。总之,大量金属材料都具备骨修复或骨替代材料的潜质,有待于更多的研究与发现。 2.5 复合材料 骨组织主要由Ⅰ型胶原和羟基磷灰石构成,还囊括了诸多其他类型的成分,可以看作是一种具有分层结构的矿化胶原蛋白复合物。而单一材料有着明显缺陷(表1),如高分子材料虽然具有较好的生物相容性、适合细胞增殖发育、能在体内降解,但普遍缺乏足够的机械强度,难以在高应力区域修复骨缺损。类似于羟基磷灰石等材料虽有一定的机械强度,但没有好的骨传导性,而绝大部分的金属材料难以在体内降解,植入物需二次手术取出,带来了其他风险。所以进行材料复合来弥补单一骨修复材料的局限性,是研究骨组织工程在骨损伤修复中的重要部分。 有研究采用浸泡和真空冷冻干燥技术制备了聚赖氨酸-珊瑚羟基磷灰石(PLL-CHA)复合支架,并对其表面形貌,理化性质和细胞相容性进行了表征[69]。然后,诱导兔脂肪来源间充质干细胞分化为成骨细胞和血管内皮细胞,构建了兔间充质干细胞复合体。在体外用兔间充质干细胞复合物和聚赖氨酸-珊瑚羟基磷灰石支架构建血管化的骨组织工程材料(DCS-PLL-CHA),MTT结果显示DCS-PLL-CHA组的细胞数最高,经修饰后支架的细胞黏附和增殖都明显高于修饰前,碱性磷酸酶活性测定也是DCS-PLL-CHA组更高。之后建立了兔桡骨15 mm的缺损模型,扫描电镜发现在第12周时DCS-PLL-CHA组的支架孔基本上充满了组织,愈伤组织表面不平坦,并且胶原样组织丰富,苏木精-伊红染色表明兔间充质干细胞复合物-珊瑚羟基磷灰石组和对照组的骨基质都随着时间推移而显著成熟,而兔间充质干细胞复合物-珊瑚羟基磷灰石组比珊瑚羟基磷灰石对照组具有更成熟的骨基质。这些结果都表明了在经修饰后,DCS-PLL-CHA复合材料相较于珊瑚羟基磷灰石可以有效促进细胞的黏附、增殖和分化,并且拥有更好的骨再生能力。 ZHANG等[70]针对聚已内酯疏水性的缺点,应用胶原蛋白表面包被的方法,将掺有辛伐他汀聚乙酸-乙醇酸共聚物微球的胶原蛋白涂在聚已内酯框架上,得到复合材料聚己内酯/Ⅰ型胶原/辛伐他汀-聚乙酸-乙醇酸共聚物[71-73]。体外细胞实验中聚已内酯的细胞播种效率为(54±2.2)%,聚己内酯/Ⅰ型胶原/辛伐他汀-聚乙酸-乙醇酸共聚物为(89±1.6)%。与单独的聚己内酯相比,聚己内酯/Ⅰ型胶原/辛伐他汀-聚乙酸-乙醇酸共聚物表现出明显更高的效率,并且表现出更高的碱性磷酸酶活性和更多的矿化结节。RT-qPCR检测也显示,聚己内酯/Ⅰ型胶原/辛伐他汀-聚乙酸-乙醇酸共聚物组在第7天和第14天表现出明显更高的所有成骨基因表达水平。体内实验构建了SD大鼠股骨干5 mm的节段性缺损,植入材料12周后Micro-CT结果表明,与聚已内酯组相比,聚己内酯/Ⅰ型胶原/辛伐他汀-聚乙酸-乙醇酸共聚物获得了更好的结果,根据3D重建图像计算出的新骨骼体积表明,聚己内酯/Ⅰ型胶原/辛伐他汀-聚乙酸-乙醇酸共聚物组表现出更好的骨骼再生能力。这些实验表明复合材料中添加某些细胞因子对促进血管化和骨再生有着重要意义[74]。 回顾文章涉及到的所有实验,有46篇文献中的实验结果表示相较于单一材料,复合材料具有更高效的骨修复能力,同时,在复合材料的基础上负载种子细胞(如骨髓间充质干细胞)或促细胞成骨相关因子(如骨形态发生蛋白等)更能提高骨修复效率,这也是现阶段应用骨组织工程技术治疗骨缺损疾病的实验依据。"
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