摘要
近年来,原位凝胶作为一种局部药物递送系统,因其良好的病灶可注入性、局部药物储库功能、药物缓释作用等特点,在牙周炎治疗中受到广泛关注,将不同类型的药物(如抗菌药物、生物活性因子等)载入原位凝胶可实现不同的治疗目的。本文总结了温度敏感型、离子敏感型、pH敏感型、溶剂交换型等各类型原位凝胶在牙周给药中的应用及局限,并对原位凝胶在消除牙周炎症、修复牙周组织以及装载微球后的长效治疗作用进行了综述。
牙周炎是一种慢性牙周炎症,其主要症状为牙龈炎症、牙周袋形成、牙槽骨吸收及牙齿松动移
原位凝胶室温下通常以液态形式存在,在用药部位下受机体生理环境或其他刺激响应,发生相转变,由液态转变为半固体凝胶
当温度低于临界溶液温度时,温敏聚合物和水之间的氢键作用,阻止了聚合物链间的聚集,凝胶体系保持溶液状态。当温度高于临界溶液温度时,聚合物链之间的疏水作用增强,聚集发生胶凝化。
壳聚糖(chitosan,CS)是壳多糖(chitin)的去乙酰化衍生物,具有良好的生物相容性、生物降解性与抗菌功效,是常见的温敏凝胶材料。壳聚糖良好的黏附性可支持成骨细胞附着、增殖与分化,促进牙周组织再
泊洛沙姆(poloxamer)是由聚(环氧乙烷)[poly(ethylene oxide),PEO]结构单元A和聚(环氧丙烷)[poly(propylene oxide),PPO]结构单元B两个亲水端组成的ABA型三嵌段共聚
聚乙二醇(polyethylene glycol,PEG)是一种具有良好的生物相容性的高分子材料,是常用的温敏凝胶材料。Liu

图1 牙周用多功能水凝胶的制备及其应用示意
由于牙龈沟液(gingival crevicular fluid,GCF)存在二价钙离子,离子敏感的高分子材料可与钙离子络合,发生溶胶-凝胶相转变,形成凝
海藻酸钠(sodium alginate,SA)是一种天然多糖,属于阴离子型聚合物,生物相容性良好。SA以溶液形式注射入牙周袋内,与GCF中的钙离子交联形成凝胶网络,可实现缓释作
结冷胶(gellan gum,GG)由双螺旋段组成的微生物多糖。在一价或二价金属阳离子存在下可形成原位凝胶。Swain
含有酸性(羧基或磺酸基)或碱性基团(铵基)的聚电解质响应于周围环境中pH的改变,接受或释放质子发生胶
卡波普(Carbopol)属于一种高相对分子质量的聚丙烯酸聚合物,具有良好的生物黏附性,可作为凝胶增稠剂。常用型号Carbopol 934P,是一种pH敏感型阴离子型聚合物,在酸性条件下以溶液形式存在,在碱性条件下形成低黏度凝
二烯类化合物和亲二烯试剂,即使在没有外部偶合剂、催化剂或光引发剂的情况下,也能在水系环境下快速进行Dies-Alder点击反应。透明质酸(hyaluronic acid,HA),一种天然高分子材料,经点击化学分子修饰后,可在原位点击交联形成凝胶。HA形成凝胶后可作为牙周组织支架使各类营养物质更好地扩散,为促进人牙周膜干细胞(human periodontal ligament stem cells,hPDLSCs)的快速生长提供一个合适的三维多孔网状环
Park

图2 双管注射HA-Tet-CM和HA-TCO-CM在体内形成的Cx-HA-CM水凝胶用于人牙周膜干细胞软骨分化示意
溶剂交换型原位凝胶(solvent exchange-induced in situ forming gel,ISG)注入体液环境时,凝胶内的有机溶剂向外扩散至体液环境中,而体液中水分向内扩散到凝胶系统中,导致水不溶性聚合物基质相分离,形成固体凝胶植入
月桂酸具有良好的疏水性、生物安全性,且能抑制口腔微生物,如聚核梭杆菌(Fusobacterium nucleatum,F.nucleatum)和P.gingivalis。Chantadee
β-环糊精(beta-cyclodextrin,β-CD)具有疏水性,适宜作为ISG的基质。Rein

图3 空白和负载美洛昔康的ISG(A)以及空白和负载美洛昔康的ISM(B)暴露于PBS(pH 6.8)后转化示意
溶致液晶(lyotropic liquid crystals,LLC)即在水或其他极性溶剂中两亲性分子浓度处于一定范围内时出现的液晶相。当两亲性分子暴露于GCF中的水相时,分子的极性"头"与疏水"尾"会与水分子相互作用,自动组装形成层状相、立方相与六方相液晶。当体系中两亲性分子含量很高时,呈现反立方相、反六方相液晶,这种相态是由疏水基在外,而亲水基在内的胶团构成。液晶的形成大大增加了体系的黏度,相当于触发了溶胶-凝胶相转变。
Mei
光交联过程实质上是一种自由基反应。具有光敏基团的单体或聚合物溶液,在光引发剂存在下被紫外或可见光照射产生自由基,聚合形成水凝
Liu
龈下刮治与根面平整术(subgingival curettage and root planing,SRP)是牙周炎手术治疗的首选方案,可去除龈下牙结石上附着的直肠弯曲杆菌(Campylobacter rectum,C.rectum)等病原体,却难以去除牙周袋底部和牙根分叉处的P.gingivalis、中间普雷沃菌(Prevotella intermedia,P.intermedia)、S.aureus和E.col
Xu
牙周炎是在牙龈炎症进一步向深层牙周组织扩展而形成的,其病理变化仍以炎症为
引导组织再生术(guided tissue regeneration,GTR)通过在牙周病变周围植入具有生物相容性的物理屏障膜来选择性地分隔不同的牙周组

图4 正常牙周组织(A),患牙周炎(B)后的牙周组织,GTR手术后的牙周组织(C)示意
在图B中,可以观察到PDL纤维附着断开、牙槽骨流失和牙龈上皮组织脱落。在图C中,显示了GTR手术后的牙周再生过程。GTR膜阻止牙龈上皮组织和牙龈结缔组织在愈合过程中接触牙根表面,并允许PDL细胞重新填充牙周炎引起的牙根受损表面,促进牙槽骨的再生Ⅰ:牙龈上皮组织;Ⅱ:牙石和菌斑;Ⅲ:GTR膜;Ⅳ:牙槽骨;PDL:牙周膜
为解决上述缺陷,需要寻找其他生物可降解性材料促进PDL细胞的增殖。CS对人牙周膜细胞(human periodontal ligament cells,hPDLCs)具有良好的亲和力,有助于牙周组织的愈合和再
普通水凝胶的细胞取向和黏附性较差,并且缺乏成骨细胞发挥作用的蛋白质,不能直接与宿主骨结
为提高牙周再生潜力,还可以在凝胶骨架基础上添加生物活性因
原位凝胶虽然具有一定的局部药物储留能力,但对于亲水凝胶骨架负载的游离药物,特别是小分子亲水性药物,难以实现局部持续递送的作
有研究将游离药物与载药微球共载入壳聚糖温敏自愈性水凝胶体系,该系统是一种具有速释相与缓释相的双相释药系统,速释相快速达到抑菌浓度,短时间内发挥作用;缓释相则维持在抑菌浓度,持续发挥药
目前上市的原位凝胶产品集中于长效注射剂和局部给药制剂领域,以基于Atrige
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