Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (22): 3558-3564.doi: 10.3969/j.issn.2095-4344.3183
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Huo Hua1, Cheng Yuting1, Zhou Qian1, Qi Yuhan1, Wu Chao1, Shi Qianhui1, Yang Tongjing1, Liao Jian1, Hong Wei2
Received:
2020-07-07
Revised:
2020-07-11
Accepted:
2020-08-07
Online:
2021-08-08
Published:
2021-01-20
Contact:
Liao Jian, MD, Associate professor, Associate chief physician, Master’s supervisor, School of Stomatology/Stomatological Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
About author:
Huo Hua, Master candidate, School of Stomatology/Stomatological Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Supported by:
CLC Number:
Huo Hua, Cheng Yuting, Zhou Qian, Qi Yuhan, Wu Chao, Shi Qianhui, Yang Tongjing, Liao Jian, Hong Wei. Effects of drug coating on implant surface on the osseointegration[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(22): 3558-3564.
2.1 局部药物载体 种植牙药物载体是将载体与人工牙结合改变药物的给药方式,不仅能使药物在靶部位局部均匀地释放,还能够达到控制药物缓释速率的目的,从而降低药物的不良反应,提高药物生物利用度。药物的缓释速率与载体表面形貌、尺寸大小及药物分子质量的大小有关。目前常用的口腔植入载体有钙磷涂层、二氧化钛纳米管及壳聚糖等。 2.1.1 钙磷涂层 作为载体主要有羟基磷灰石、磷酸三钙,各自具有独特的物理、化学特性,应用于骨再生领域[7],制备精确的涂层结构可以采用水热法、乳化法、溶胶-凝胶法、共沉淀法等[8]。 羟基磷灰石组成为Ca10(PO4)6(OH)2,六方相结构在生理环境中非常稳定,由于其生物活性、降解性、骨传导性、骨诱导性及与宿主骨组织能形成强的黏附能力,成为最经典的牙种植载体,被广泛应用于骨组织工程[9]。简单的羟基磷灰石涂层材料缺乏与骨组织直接作用的能力,难以负载药物,纳米颗粒具有表面积大、高负载量和细胞内转运能力,通过制备纳米级的中空结构羟基磷灰石有利于药物的载药和缓释,且羟基磷灰石常与其他合适的生物相容性聚合物结合,如壳聚糖、明胶、胶原、海藻酸钠、琼脂混合而成复合材料备受关注[10]。 磷酸三钙是一种钙磷比为1.5的磷酸钙,分为α相和β相,β-磷酸三钙为六方晶结构,比α-磷酸三钙具有更稳定的结构和更高的生物降解率,发生降解后析出钙磷离子,因此β-磷酸三钙通常作为理想的骨组织材料用于骨再生。但β-磷酸三钙的稳定性不如羟基磷灰石,降解速度高于新骨形成速度,限制了其广泛应用[11]。构建羟基磷灰石和β-磷酸三钙的双相复合载体可提高其生物反应性、载药能力和释药能力,主要通过仿生共沉积法使药物活性大分子与钙磷共沉积形成钙磷涂层,释放方式可通过药物自身溶解扩散或者钙磷涂层溶解释放。 2.1.2 二氧化钛纳米管 为提高药物载体与钛种植体表面的结合力学者们进行了大量研究,自报道二氧化钛纳米管可作为药物载体应用于种植领域以来,BALLO等[12]研究发现二氧化钛纳米管因良好的理化性能和生物相容性具有潜在的应用价值,它不仅可以抑制种植体表面金属离子的释放,而且对耐磨性和耐腐蚀性有一定增强作用,更为重要的是纳米级的表面和空腔可以吸纳更多的药物,有效增加了药物负载量,而其特殊的管状结构又可控制药物的缓释速率,从而延长药物释放周期,达到缓释的效果。同时研究表明,利用阳极氧化法制备的二氧化钛纳米管,通过改变反应条件(如电压参数)制备不同的表面结构、几何尺寸等可以控制加载量和释药速率。 2.1.3 壳聚糖 壳聚糖是带有大量阳离子的高分子碱性多糖,别名为脱乙酰甲壳素,作为天然高分子聚合物具有良好的生物相容性、可降解性、低免疫原性,不仅可以诱导成骨细胞分化,还可以抑制成纤维细胞的增殖、黏附[13-14],是一种在牙种植中拥有良好潜力的生物多功能材料。然而,由于缺乏直接与骨结合的生物活性,限制了壳聚糖单独应用于骨组织的作用,所以常作为各种药物的缓释载体应用于口腔颌面部、肝脏等局部药物的治疗[15]。研究表明,壳聚糖作为无毒、无刺激性的缓释载体应用其带正电荷的优势,通过物理结合与带负电的透明质酸、肝素等物质发生阴离子和阳离子的静电吸附作用,逐层交替沉积在种植体表面形成复合层,从而调控药物的释放与加载[16]。 2.1.4 聚合物载体 聚乳酸-羟基乙酸共聚物微球是研究的热点[17],它在人体内安全无毒,具有良好的生物相容性、生物可降解性,并且降解产物为乳酸和羟基乙酸,可经三羧酸循环后排出体外,很容易制备成理想大小的微球形状,所以常被用于医药的各个领域。聚乳酸-羟基乙酸共聚物微球系统的显著作用特点为可控制药物释放、延长药物作用周期,还可以负载水溶性、脂溶性及各种蛋白质类生长因子,其降解速率和药物释放行为与分子质量、组成比例、微球体积、表面形貌和微环境(酸碱性、温度)等有关,可根据机体环境和用途制备不同载药量和释药速率的聚乳酸-羟基乙酸共聚物微球[18]。譬如骨髓炎的特征为靶组织周围为酸性环境,在治疗过程中研究者将pH值敏感性的聚乳酸-羟基乙酸共聚物微球与磷酸钙复合植入体内,微球系统根据周围组织酸碱度的变化而发生结构改变,控制自身降解速率,从而调控释药速率,与单独负载药物的磷酸钙涂层相比能够更加准确地控制释药速率[19-20]。 2.1.5 生物分子载体 种植体通过生物分子涂层能形成一个与机体相适应的过度层,作为植入物周围细胞、基质及可溶性因子的载体,从而引导细胞黏附、增殖、分化,促进骨结合,与某些药物结合具有双重功能,这些生物分子包括多肽、胶原、纤维蛋白等[21]。 多肽结构相对简单稳定、无免疫原性,具有良好的生物相容性而备受青睐,其中精氨酸-甘氨酸-天门冬氨酸是细胞与骨桥蛋白、纤维连接蛋白等细胞外基质识别并结合的短肽序列,种植体植入后能显著提高种植体周围细胞黏附,加快种植体周围骨结合速度,有利于种植体获得更好的初期稳定性,精氨酸-甘氨酸-天门冬氨酸多肽可在种植体骨组织界面发挥积极作用[22]。其制备方法为化学偶联或物理吸附。 细胞外基质蛋白Ⅰ型胶原是应用于种植体表面的有机涂层材料,研究证实胶原涂层可以吸附药物来加强骨结合能力,提升种植体与骨组织接触面积[21],但是该蛋白的化学稳定性欠佳,易溶解,亦可能发生免疫反应。 纤维蛋白生物大分子材料具有低抗原性、易溶解、良好的组织生物相容性等特点,其凝胶形式的可塑性较强,可作为骨形态发生蛋白2的缓释载体。有研究表明,负载骨形态发生蛋白2的纤维蛋白凝胶涂层显著增强了骨诱导性,当纤维蛋白降解时间与骨形态发生蛋白2诱导成骨的作用时间匹配时可使得骨形态发生蛋白2持续稳定的释放,有效增加骨结合能力[23-24]。 2.2 抑制骨吸收作用的药物 2.2.1 唑来膦酸 目前上市的3代双膦酸盐药物中唑来膦酸药效最强,是临床治疗骨代谢异常疾病的主要用药。唑来膦酸咪唑侧链上的2个氮原子能与骨骼中的羟磷灰石高度结合,从而附着在骨小梁表面,干扰破骨细胞的分化、结构及骨吸收功能[25]。 唑来膦酸是抗骨质疏松药理活性最强的药物。LIU等[26]研究发现唑来膦酸可以挽救53%的骨质吸收,实验组大鼠种植体二氧化钛介孔层涂层唑来膦酸局部缓释高达21 d,其骨质吸收情况较对照组显著减少,唑来膦酸涂层可促进种植体周围新骨形成,提高骨结合和稳定性。PYO等[27]通过不同浓度唑来膦酸涂层也得出相似结论,在骨质疏松大鼠中比较4组(0,8,80,800 mg/L唑来膦酸)种植体的骨体积,差异有显著性意义,得出唑来膦酸涂层种植体均可明显改善骨质结构、增加种植体骨结合的结论。JAKOBSEN等[28]用犬作为实验动物,通过组织形态计量学和推出实验研究也得出类似的结果,该研究将唑来膦酸在体外涂覆到含聚D,L-丙交酯种植体的羟基磷灰石涂层上,在犬体内通过种植体表面聚D,L-丙交酯载体的缓慢持续释放,唑来膦酸涂层不仅保留了板层骨,增加了更多新编织骨形成,而且种植体骨固定是对照组的3倍。而ABTAHI等[29]报道了16例经唑来膦酸涂层种植体治疗的患者,1例未涂层种植体作为对照,结果在8周内涂层与未涂层种植体早期稳定性无显著差异,但涂层种植体边缘骨丢失较少。文献报道仅呈现短期内的效果,且目前研究样本量较少,从临床角度出发,唑来膦酸局部应用有效避免了双膦酸盐相关性颌骨坏死并发症的风险[30],若要将唑来膦酸大量应用于临床还需更多临床试验验证。 2.2.2 降钙素 降钙素是已知的调节骨代谢3大重要激素之一,由甲状腺滤泡旁细胞分泌,可直接作用于破骨细胞上的降钙素受体,降低破骨细胞活性,与种植体周围骨结合后发挥抑制骨吸收的作用[31]。此外,降钙素能平衡骨骼中钙离子水平,通过破骨细胞介导的骨吸收抑制作用调节钙离子代谢的生理作用,降低血钙,优化破骨细胞骨吸收的动态平衡[32]。 HUANG等[33]实验证实了降钙素涂层的局部用药效果,将降钙素采用层层组装的方式沉积于壳聚糖/明胶多层膜上,同时沉积骨形态发生蛋白2并植入兔股骨内,壳聚糖/明胶作为载体持续调节降钙素和骨形态发生蛋白2的释放,比较种植后1,3个月种植体周围骨密度、骨小梁微结构、骨-种植体接触面、种植体的机械稳定性,结果发现降钙素和骨形态发生蛋白2协同作用组在种植体周围可显著促进新骨形成和改建,抑制骨吸收,体内推出实验进一步证实该组具有最高的界面剪切强度和更好的骨-种植体结合。同样CHEN等[34]在最新研究中也得出类似的结论,在种植体表面负载降钙素和维生素D3,载体为壳聚糖,体内外实验结果表明,释放的降钙素和维生素D3分别上调种植体周围成骨细胞钙结合蛋白和骨形态发生蛋白2的表达,促进钙沉积和分化,与其他治疗组相比共负载界面剪切强度显著提高,骨结合明显改善。目前研究中尚未发现降钙素能单独局部应用于牙种植中,大多数都与其他药物联合应用时体现最佳效果。 2.2.3 雷洛昔芬 雷洛昔芬属于选择性雌激素受体调节剂类,在骨组织中表现出雌激素样作用。选择性雌激素受体调节剂不仅可以激活成骨细胞上的雌激素受体α来改善成骨细胞的功能和分化,还可以激活破骨细胞上的雌激素受体β来诱导破骨细胞发生凋亡性改变。雷洛昔芬作为代表性药物,能抑制破骨细胞的骨吸收活性,降低骨转换率,减少骨吸收[35]。 HARMANKAYA等[36]的研究证实,雷洛昔芬涂层可增加骨质疏松大鼠种植体周围骨固定,且比阿仑膦酸钠涂层修复的种植体具有更强的骨重塑活性。但亦有学者持有不同观点。MU等[37]认为雷洛昔芬同阿仑膦酸钠协同应用于二氧化钛涂层种植体可显著促进种植体周围新骨形成,并且可以增强骨质疏松兔的骨结合,两者相加作用可能对骨质量较差时种植义齿修复有一定的加强效应。另有学者研究表明,以聚乳酸-羟基乙酸共聚物为载体负载雷洛昔芬,所制备的植入物成功地在大鼠胫骨中形成了均匀的骨结构,同时药物在体外实验中局部释放长达2个月,实验结果也支持雷洛昔芬的有效性[38]。 2.3 促进骨形成作用的药物 2.3.1 磷酸钙 磷酸钙为钙与磷酸根离子形成的化合物与骨组织可发生化学性结合,促进成骨细胞的早期黏附、增殖,具有骨引导作用[39]。 磷酸钙不仅越来越多的作为药物的缓释载体,而且因其较好的生物活性和与骨矿物质相近的组成成分等特性而被广泛应用于骨再生领域[40]。BOSE等[41]评价磷酸钙加入对种植体骨结合的影响,具体步骤是通过3D打印技术制备孔隙率为25%的二氧化钛纳米管,采用仿生法对多孔钛种植体表面进行磷酸钙涂层,体内推出试验与组织学分析显示,磷酸钙涂层增加了种植体表面新骨形成,缩短了骨愈合时间并促进早期骨结合。由于钙、磷元素本身可诱导骨再生,少数研究认为种植体表面特殊处理并没有起到协同作用,譬如PRADO等[42]将有无磷酸钙涂层、单独或联合砷化镓铝低强度激光处理的粗螺纹种植体植入体内后发现,短期内单纯磷酸钙组、砷化镓铝低强度激光治疗组及两者联合治疗组均明显高于对照组,且单纯磷酸钙组与联合处理组在种植体植入6周时拆卸扭矩值均较高,结果说明磷酸钙涂层单独应用或者联合砷化镓铝低强度激光应用均可短期内促进成骨细胞生成,提高骨-种植体接触面积,增强种植体固定率。因此,磷酸钙涂层种植体表面的特殊处理并不干涉种植体骨结合,在该研究中采用砷化镓铝低强度激光处理的种植体与对照组无统计学差异,可能与种植体的微观粗糙度、涂层厚度、钙磷溶解度和纳米结构等因素相关。 2.3.2 甲状旁腺激素 甲状旁腺激素是甲状旁腺主细胞分泌的单链多肽类激素,具有促进成骨分化、血管生成的作用,同时可逆转成骨与破骨之间的失衡,使骨吸收转变为骨再生,是被认可的应用于口腔领域的药物[43]。另外,甲状旁腺激素是一类具有双向作用的药物,小剂量的甲状旁腺激素对骨有同化作用,可刺激成骨细胞生成;大剂量时则发挥骨吸收作用。 TANG等[44]将甲状旁腺激素通过逐层电组装技术沉积到透明质酸/ε聚赖氨酸多层膜上,体外实验观察到甲状旁腺激素涂层种植体较未涂层组有较多成骨细胞生成,而植入体内2周后观察到含有甲状旁腺激素涂层的种植体可明显促进骨质疏松大鼠的新骨形成和改建,载体不仅可以控制甲状旁腺激素的局部缓释,还可以提高种植体的长期稳定性。YU等[45]研究将含不同剂量的甲状旁腺激素/磷酸钙涂层钛种植体植入小鼠胫骨内,4周后观察到含甲状旁腺激素的种植体骨结合呈剂量依赖性,种植体周围甲状旁腺激素浓度越高骨形成越多,而甲状旁腺激素的浓度可能存在临界值,只有达到该值时才能表现出促进骨形成的作用,含甲状旁腺激素组比仅有磷酸钙涂层更加显著改善了种植体骨结合。除此之外, ARDURA等[46]发现甲状旁腺激素在糖尿病和年龄相关性骨量减少的情况下促进骨再生,表现为骨体积、骨小梁、皮质层厚度的增加及骨小梁间距的减少,对于老年患者及糖尿病患者是一种有效的策略。 2.3.3 维生素D和生长因子 维生素D又叫骨化三醇,其活性形式1,25二羟维生素D[1,25-(OH)2D3]可直接作用于成骨细胞表面的维生素D受体,促进骨形成和矿物质的沉积,抑制骨吸收,与骨形态发生蛋白2联合应用具有协同作用[47-48]。维生素D缺乏对种植体骨结合会产生负面影响,且随着缺乏程度的增加,早期种植失败率呈增加的趋势[49-50]。FRETWURST等[51]报道的2例病例报告表明,维生素D缺乏出现早期种植失败,而补足维生素D后重新种植治疗则获得良好的骨结合。 骨诱导生长因子目前在临床上应用广泛,其单独应用或与其他植牙修复材料联合应用于牙槽骨组织再生的生物活性屏障,增强骨结合能力[52-53]。胰岛素样生长因子[54]、血管内皮生长因子[55]、重组人转化生长因子[56]、骨形态发生蛋白2涂层钛种植体是增强种植体骨结合的新策略[57],促进种植体周围骨形成的作用已得到证实。TENG等[58]在比格犬下颌骨内分别植入3组种植体,即对照组、骨形态发生蛋白2组、骨形态发生蛋白2/仿生帽组,3个月后发现,骨形态发生蛋白2组在增加周围骨形成中相比对照组有更理想的效果,而骨形态发生蛋白2/仿生帽组又较骨形态发生蛋白2组效果更佳。生长因子近年来发展迅速,被临床医生重点关注,因其具有多方面的作用,不仅在骨诱导、骨传导、骨形成方面有优势,还可用于软组织损伤的修复,打破了以往单一的组织损伤修复方式,在牙种植中具有良好的应用前景。 2.4 促进骨形成/抑制骨吸收作用的药物 2.4.1 辛伐他汀 辛伐他汀目前在临床上用于抑制胆固醇生物合成的辅酶,但有关辛伐他汀对骨作用机制的报道很多,可通过刺激骨形态发生蛋白2、血管内皮生长因子等一系列分子的表达促进成骨细胞活化,亦有抑制破骨细胞活性的作用[59-60]。 LIU等[61]研究通过采用四环素接枝辛伐他汀聚合物将其负载到二氧化钛涂层种植体中,结果显示在体外可促进大鼠成骨细胞的分泌、黏附,同时增强骨形态发生蛋白2的表达,说明辛伐他汀可作用于骨形态发生蛋白2并刺激其表达,在体内表现出良好的生物学效应,改善了局部骨再生和骨结合。同时,为了证实辛伐他汀浓度的增加是否影响种植体骨结合,FANG等[62]在骨质疏松大鼠胫骨内进行实验,通过电化学方法在种植体表面负载辛伐他汀/羟基磷灰石涂层并植入胫骨内,结果表明随着辛伐他汀浓度的增加,使种植体周围骨改建明显加强,但其量效关系还有待进一步研究。然而,最新的少数研究认为辛伐他汀的局部应用并不能影响种植体骨结合。DUNDAR等[63]在去卵巢大鼠体内进行4周的实验发现,辛伐他汀涂层组和对照组骨-种植体接触率、骨充填率比值均无统计学差异,此结论仅体现在该研究中。 2.4.2 雷尼酸锶 雷尼酸锶是应用于临床抗骨质疏松的新药,可使成骨与破骨达到一种动态平衡,同时促进成骨细胞功能和抑制破骨细胞功能,通过双重效应影响骨代谢[64]。 大量研究表明锌、镁和锶对骨生长均有促进作用,对骨再生有积极作用,而锶应用时与其他药物相比效果更佳,尤其对于骨质疏松患者。TAO等[65]采用电化学方法在种植体表面沉积锌、镁、锶来取代羟基磷灰石涂层,均可提高钛种植体表面的新骨形成能力和推出力,在骨质疏松动物模型中能明显改善种植体骨结合,但含10%雷尼酸锶涂层的种植体效果更好。同时,LIN等[66]将采用水热法沉积的雷尼酸锶涂层种植体植入骨质疏松兔体内,也体现了相类似的结论,在骨质疏松和正常情况下均能促进种植体早期骨结合。然而ZHAO等[67]通过体内实验发现,采用微弧氧化法制备的雷尼酸锶/辛伐他汀/羟基磷灰石涂层种植体骨结合得到了显著改善,两者协同作用使种植体周围骨矿化沉积速率加快,骨形成方式良好(大量接触成骨,少量距离成骨),骨与种植体的接触强度和拔出强度增加,可起到多重效应的效果。药物的联合应用对种植体骨结合有积极影响,通过长期的基础研究并联系临床实践,单一的药理作用可能很难满足复杂的口腔微环境及骨质较差患者,所以药物协同作用具有潜在的应用价值。 "
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