CN1575188A - 生物活性物质,制备生物活性物质的方法及其使用方法 - Google Patents
生物活性物质,制备生物活性物质的方法及其使用方法 Download PDFInfo
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- CN1575188A CN1575188A CNA028212819A CN02821281A CN1575188A CN 1575188 A CN1575188 A CN 1575188A CN A028212819 A CNA028212819 A CN A028212819A CN 02821281 A CN02821281 A CN 02821281A CN 1575188 A CN1575188 A CN 1575188A
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Abstract
利用可单独使用或作为与颗粒如核/壳颗粒的组合物的丝心蛋白溶液和混悬液制备生物活性物质。将物质设计成支持机体的骨和其它组织的构建,修复,再生或增加。该溶液和混悬液可被装有核/壳型颗粒,所述核/壳颗粒包含被具有磷酸钙前体的外涂层的可生物降解聚合物包被的无机核颗粒。丝心蛋白溶液,混悬液,和组合物可被注射以填充空腔或代替缺少的组织。注射后,该物质可产生能促进组织再生、同时降解的支架。当存在时,颗粒的降解可在支架内产生额外的孔,并以可控制的方式释放其它化合物以增强组织修复所需的生长和细胞活化。注射丝心蛋白溶液,混悬液和组合物的能力可降低用于替换或修复骨和其它组织的很多类型外科外科手术程序的需要。
Description
背景
本发明涉及骨骼和组织修复领域,特别涉及用于骨骼和组织修复的物质,制备该物质的方法及使用该物质的方法。
损伤后的骨骼和其他组织的置换和修复通常需要进行外科手术程序。在美国和欧洲每年有多于300,000例髋关节假体被移植。另外,10%的人遭受牙周疾病,30%的人在他/她一生中需要牙移植。其他外科手术程序包括软骨修复和软组织整形手术。因此非常需要制造一种用于组织修复或重建的支架物质,特别是可省略许多导入过程的需要的可注射物质。这种物质应该是生物兼容的,即,没有细胞毒性或在机体内引起不利反应,优选地是具有生物活性的,即,提供动员组织构建所需的细胞活性必需的发育信号。另外优选地它们是可再吸收的,和能够经受住修复过程中由日常活动所施加的压力。
对于用于组织修复的支架已建议有几种不同的方法。目前可用于硬组织修复的物质,例如脱矿质骨,羟基磷灰石,磷酸三钙和其他无机物质与生物衍生的具有生物活性的支架不是一样有效。如在美国专利号5,939,323中公开的已将透明质酸用作支架物质。另一种方法是如在美国专利号4,490,984和美国专利号5,480,644中公开的已使用基于胶原的物质。但是,由于其较差的机械性能,难以预测的降解速率,和对胶原来说,其免疫原性反应的危险及潜在污染的危险使得这些物质潜在的用途和应用范围中受到限制。
膜,薄膜和含有丝心蛋白(蚕丝的一种蛋白成分)的织物,已被建议作为动物组织和器官生长的基质物质。特别地,PCT申请号WO 01/25403描述了从水溶液中形成丝心蛋白膜模型(cast)。这些膜在加入生长培养基和各种细胞类型的容器中进行模塑,丝心蛋白膜可支持细胞,例如成骨细胞,上皮细胞和肝细胞的生长。丝心蛋白膜和薄膜也由Tsukada等在Journal of Polymer Science:Part B:Polymer Physics 32:961-968,1994;及由Motta等“Third International Symposium on Frontiers inBiomedical Polymers Including Polymer Therapeutics From Laboratoryto Clinical Practice”,摘要,Shigha,日本,1999年5月公开。PCT申请WO 02/29141描述了通过用甲酸处理丝心蛋白茧而制备丝心蛋白非机织织物。该丝心蛋白非机织织物可用于培养细胞,如角质细胞和成纤维细胞。在体内使用这种丝心蛋白膜,薄膜或非机织织物作为用于组织修复的支架的一个缺陷是:为了将这些物质放在待重建部位需要导入性外科手术程序。
因此,迫切需要一种用于体外和体内的生物活性支架物质,特别是生物兼容的,具有生物活性的,可再吸收的物质。进一步需要一种易于应用到待重建部位的具有生物活性的支架物质,优选地不需要导入性外科手术程序。
发明概述
以上所讨论的和现有技术的其他缺陷和不足通过含有丝心蛋白溶液或混悬液的组合物来克服或减低。丝心蛋白溶液和混悬液是生物兼容的,具有生物活性,而且是可再吸收的。其中一个特别有利的特征是丝心蛋白溶液或混悬液可通过注射施用于所需部位,这将利用导入性外科手术程序的降到最小。
还公开了一种制备丝心蛋白混悬液的方法,其包含将丝心蛋白溶液从约-20℃加热到约50℃,从而得到丝心蛋白混悬液。另一种制备丝心蛋白混悬液的方法包含用有效制备丝心蛋白混悬液的试剂处理丝心蛋白溶液。有效试剂包含酸,醇,蛋白水解酶,可生物兼容的聚合物,或包含前述试剂的至少一种或多种的组合。
还公开了一种组织构建方法,其包含对待构建部位给药有效量的丝心蛋白溶液或混悬液以刺激细胞增殖,优选组织生长。优选地通过注射进行给药。本领域中熟练人员可通过以下详细描述和附图理解上述讨论的和其他特征和优点。
附图简述
目前参照示范图,其中在几个附图中的相同元素所用的标号相同:
图1是组织修复过程中多组分支架的示意图。
图2是通过向丝心蛋白—水溶液中加入柠檬酸水溶液而制备的丝心蛋白混悬液的环境扫描电镜显微照片。
图3是通过向丝心蛋白—水溶液中加入甘油而制备的丝心蛋白混悬液的环境扫描电镜显微照片。
图4是在室温下干燥组合物后,丝心蛋白组合物混悬液的光学显微照片,该丝心蛋白组合物混悬液包含植入到丝心蛋白基质中的羟基磷灰石/(聚)交酯核/壳颗粒。
图5是在室温下干燥组合物后,丝心蛋白组合物混悬液在更高放大倍数下的光学显微照片,该丝心蛋白组合物混悬液包含植入到丝心蛋白基质中的羟基磷灰石/(聚)交酯核/壳颗粒。
图6是在冷冻干燥组合物后,丝心蛋白组合物混悬液的光学显微照片,该丝心蛋白组合物混悬液包含植入到丝心蛋白基质中的羟基磷灰石/(聚)交酯核/壳颗粒。
图7是在冷冻干燥组合物后,丝心蛋白组合物混悬液在更高放大倍数下的光学显微照片,该丝心蛋白组合物混悬液包含植入到丝心蛋白基质中的羟基磷灰石/(聚)交酯核/壳颗粒。
图8是在兔腿节钻孔并用可注射的丝心蛋白混悬液填充的腔中进行移植一个月后(A)和用作对照的空腔(B)的组织学比较。
图9是在第二只兔腿节钻孔并用可注射的丝心蛋白混悬液填充的腔中移植一个月后(A)和用作对照的空腔(B)的组织学比较。
图10所示的是旧骨骼和图9中举例说明的移植物的丝心蛋白混悬液填充的腔中形成的新骨骼的分界面。
优选实施方案的详细描述
丝心蛋白是一种已知含有18种不同的氨基酸的组合的多肽,其中甘氨酸,丙氨酸,丝氨酸和酪氨酸大约占多肽链的90%。一般认为丝心蛋白由两个主链组成,所述主链由二硫键连接并具有约为350,000道尔顿(H-链)和25,000道尔顿(L-链)的分子量。丝心蛋白的已有研究表明由丝心蛋白衍生的制造的产品的结构和形态高度依赖于制备它们所使用的工艺条件。此处已经有利地发现可通过使用各种技术从丝心蛋白溶液产生新型的丝心蛋白混悬液,而且如此产生的丝心蛋白混悬液可用于组织构建,包括在机体的正常部位(例如,未损伤的部位)和由于例如损伤或衰老而需要修复和/或重建的部位形成组织。此处所用的“丝心蛋白溶液”是指实质上具有一个相的组合物,也就是说,组合物包含一种可充分溶解丝心蛋白的溶剂。当重量比大于95%,优选地大于98%,最优选地大于99%的丝心蛋白在溶液中时,则表明丝心蛋白充分溶解。另外,此处所用的“丝心蛋白混悬液”是指具有两相或多相(即,多相物质)的组合物,其中至少一个相包含一种溶剂,而且至少一个相包含丝心蛋白。没有所依据的理论,丝心蛋白混悬液可以各种形式存在,例如,胶体,乳液,微团,溶胶或凝胶的形式。
为了描述此处的丝心蛋白混悬液,参考使用了“丝心蛋白包含体(fibroin occlusions)”,“丝心蛋白凝胶”“丝心蛋白乳膏”和“丝心蛋白糊”,它们以易观察到的物理特性如表观粘度和相对粘度为特征。“丝心蛋白包含体”是指在水平表面可流动的丝心蛋白混悬液。包含体通常是混浊的,即表现出一定的不透明性。在水平表面上可以流动,表示当在水平表面沉淀时,1立方厘米的混悬液样品基本上立即变形。由于没有所依据的理论,包含体可以胶体,特别是溶胶形式存在,其在溶剂的连续相中包含尺寸为10-9-10-6米的固体颗粒分散体。
此处所用的“丝心蛋白凝胶”是指具有类似凝胶物理性质,例如可塑性,弹性或一定程度的刚性的丝心蛋白混悬液。根据制备凝胶的方法,凝胶可以是不透明或(半)透明的。与包含体形成对比,当放置在水平表面上时,凝胶不容易流动。但是,当施加热或机械压力,例如压力时,即,当凝胶是可逆时,凝胶可以流动或变形。没有所依据的理论,丝心蛋白凝胶可包含分散在溶剂中的三维网络的丝心蛋白。
此处所用的“丝心蛋白乳膏”是指比丝心蛋白包含体更粘稠的丝心蛋白混悬液。它通常是白色的,而且其在水平表面上实质上是非流动性的。在水平表面上实质性非流动,它表示在水平面沉淀1分钟内,1立方厘米的丝心蛋白乳膏样品未明显地变形。和丝心蛋白凝胶一样,当对该物质施加热或机械压力时丝心蛋白乳膏可变形。
此处所用的“丝心蛋白糊”是指粘度很高,当放在水平表面山时不流动的丝心蛋白混悬液。在水平表面上不流动,它表示在水平表面上沉淀1小时内1立方厘米的丝心蛋白糊样品将未明显变形。但在机械压力下该糊是可以变形的。
备选地,可根据通过特定尺寸的孔隙(即针头的孔隙)该混悬液的可注射能力来描述各种类型的丝心蛋白混悬液。丝心蛋白包含体或凝胶可用手通过小针孔,例如直径约为584微米的20-规格的注射针头很容易地进行注射。丝心蛋白乳膏粘度更大,因此可用手通过更大的针孔,例如直径约为838微米的18-规格的注射针头很容易地进行注射。糊不容易用手进行注射,除非用很大孔的注射针头,即直径大于约2毫米的那些。可以理解将丝心蛋白混悬液分为包含体(occlusion),凝胶,乳膏或糊只是为了方便描述使用丝心蛋白混悬液。
丝心蛋白混悬液可在体外或体内制备。体外制备丝心蛋白混悬液可包含用有效制备混悬液的试剂,例如热,蛋白酶,酸,醇或可生物兼容的聚合物处理丝心蛋白溶液。备选地,可向动物注射或另外给药丝心蛋白溶液而在体内制备丝心蛋白混悬液。没有所依据的理论,认为当对动物机体中的一个部位给药后,丝心蛋白溶液可以很快地消耗多余水分,从而产生混悬液,为例如凝胶形式。丝心蛋白混悬液也可以在体内改变形式。例如,丝心蛋白包含体在体内给药动物机体的一个部位后,可以转变形成丝心蛋白凝胶。
丝心蛋白的便利来源是来自于家蚕(Bombyx mori)的茧,其含有丝心蛋白和丝胶蛋白。丝是由蜘蛛和不同的昆虫,其中众所周知的是蚕(特别是家蚕)所产生的纤维状蛋白。丝纤维已用作缝合线,但已发现编织的丝缝合线经常产生非免疫性的异物反应,甚至在手术多年后引发肉芽瘤(Kurosaki等,Nippon Ika Daigaku Zasshi 66:41-44,1999)。然而,已证实观察到的非免疫性的异物反应是由天然丝中存在丝胶蛋白产生的,纯的丝心蛋白不引发免疫反应。
优选地,将丝心蛋白进行纯化以除去毒素或其他物质如可在机体中引起不利反应的丝胶蛋白。大部分的丝胶蛋白可通过例如脱胶,即在98℃,存在或不存在十二烷基磺酸钠的情况下在碳酸钠中洗涤而除去。
然后将纯化的丝心蛋白溶解于溶剂中,例如每单位体积含有约10%重量的丝心蛋白的溴化锂水溶液。丝心蛋白溶液可以任选地包含其他组分,例如缓冲剂(buffers)和其他不显著影响丝心蛋白结构和稳定性的添加剂。丝心蛋白可进一步被纯化,优选地大于约90%,更优选地大于约95%,最优选地大于约99%重量。溴化锂通过用蒸馏水透析而除去,其他杂质可通过过滤除去。纯化后,可将丝心蛋白进行冷冻干燥,得到粉末并存贮。然后通过用热,蛋白酶,酸,醇或可生物兼容的聚合物处理从纯化的丝心蛋白溶液而制备丝心蛋白混悬液。
在一个实施方案中,通过对丝心蛋白溶液进行热处理可产生丝心蛋白混悬液。例如,为了生产凝胶,将丝心蛋白溶液在约-20℃保持约2到约24小时,然后加热到约40℃到50℃。改变热处理的条件可产生上述各种性质的混悬液,这可以由本领域的普通技术人员根据特定施用进行选择。
在另一个实施方案中,通过用在特定氨基酸之间进行特异切割的蛋白酶处理丝心蛋白溶液可产生丝心蛋白混悬液。这类蛋白酶包括但不限定于来源于灰色链霉菌(Streptomyces griseus)的蛋白酶,木瓜蛋白酶,胰凝乳蛋白酶等。不受理论的束缚,假定蛋白酶处理可通过降低丝心蛋白聚合物的平均分子量而产生混悬液。可选择特定的氨基酸序列以产生具有所需分子量和氨基酸序列的片段。片段大小可被剪切,以满足特定施用的特定要求,例如生物活性及丝心蛋白物质的降解速率。特定平均分子量的选择依赖于多种因素,包括末端用途,所需粘度,其他成分的添加,分子量分配,载体类型等。蛋白酶处理后丝心蛋白的平均分子量约为200到约0.1千道尔顿(Kd),优选地约为50到约0.2Kd,更优选地约为20到约0.5Kd。
在另一个实施方案中,可通过用酸处理丝心蛋白溶液而制备丝心蛋白混悬液。不受理论的束缚,认为通过将丝心蛋白溶液的pH降到其等电点以下,则溶剂中的丝心蛋白溶混性将被降低,从而促进混悬液的形成。酸是能够将丝心蛋白的pH降到其等电点pH3.8以下(即低于或约等于pH3.7)的酸。优选的酸是柠檬酸,抗坏血酸,乳酸,前述酸的组合等。加入酸的量足以将溶液pH降到所需pH,这可被本领域中的技术人员容易地确定。
备选地,可用醇处理丝心蛋白溶液而制备丝心蛋白混悬液。不受理论的束缚,认为醇可改变丝心蛋白的构象,从而促进混悬液的形成。优选地醇可与溶剂混合,并且可以是例如甘油,乙二醇,乙醇,异丙醇及包含前述醇一种或几种的混合物。优选的醇是甘油。当加入到丝心蛋白溶液中时,加入醇的量约为总体积的约10体积%到约50体积%。
在另一个实施方案中,通过用一种或多种可生物兼容的多聚物,例如聚乙二醇,聚环氧乙烷,聚乙烯吡咯烷酮等与丝心蛋白溶液混合而制备更粘稠的丝心蛋白溶液。可生物兼容的聚合物应以约2到约20%重量的量与丝心蛋白溶液混合。
可使用各种添加剂以改善丝心蛋白溶液和混悬液的功效,例如,具有生理活性例如诊断或治疗活性的生理活性试剂。因此,活性试剂可包括用于在体内检测被释放试剂位置的可检测标记(例如放射性标记)。活性试剂也包括用于治疗疾病或健康状况的治疗试剂。生理活性试剂包括,例如抗生素或其他抑制感染的化合物;治疗骨质疏松症的治疗试剂,其他作用于骨和骨架的因子,骨形态发生蛋白(BMPs)及其它刺激组织生长,骨再生或伤口愈合的细胞因子等。生理活性试剂也可以是细胞,例如取自患者的一个部位并在丝心蛋白混悬液中培养的细胞。
抗生素的例子包括四环素,氨基糖苷类,青霉素类,头孢菌素类,磺胺类药物,氯霉素琥珀酯钠,红霉素,万古霉素,林可霉素,氯林肯霉素,制霉菌素,两性霉素B,金刚胺(amantidine),疱疹净,对-氨基水杨酸,异烟肼,利福平,放线菌素D(antinomycin D),光辉霉素,柔红霉素,氯已定(chlorexidine),阿霉素,博来霉素,长春碱,长春新碱,甲基苄肼,咪唑羧基酰胺(imidazole carboxamide)等。
示例性治疗骨质疏松症的治疗试剂及其他作用于骨和骨架的因子的包括钙,阿仑磷酸钠(alendronate),骨Gla肽,甲状旁腺素及其活性片段,组蛋白H4-相关的骨形成和增殖肽及其突变体,衍生物和类似物。
示例性细胞因子包括转化生长因子(TGFs),成纤维细胞生长因子(FGFs),血小板衍生生长因子(PDGFs),表皮生长因子(EGFs),结缔组织激活肽(CTAPs),生骨因子(osteogenic factor)及这类生长因子的生物活性类似物,片段和衍生物。特别优选的是转化生长因子(TGF)超基因家族的成员,它们是多功能调节蛋白。TGF超基因家族成员包括β转化生长因子(例如TGF-β1,TGF-β2,TGF-β3);骨形成蛋白(例如BMP-1,BMP-2,BMP-3,BMP-4,BMP-5,BMP-6,BMP-7,BMP-8,BMP-9);肝素结合生长因子(例如成纤维细胞生长因子(FGF),表皮生长因子(EGF),血小板衍生生长因子(PDGF),胰岛素样生长因子(IGF));抑制素(例如抑制素A,抑制素B);生长分化因子(例如GDF-1);和活化素(活化素A,活化素B,活化素AB)。生长因子可分离自天然或自然来源,例如分离自哺乳动物细胞,或通过合成而制备,例如用重组DNA技术或通过各种化学过程来制备。另外,可以使用这些因子的类似物,片段或衍生物,只要它们表现出天然分子的至少某些生物活性。例如,这些类似物可通过表达通过位点特异的突变或其他遗传工程技术改变的基因而进行制备。
生理活性试剂也可以是分化或未分化的细胞。例如,可递送间充质干细胞到组织中,以产生与该组织相同类型的细胞。间充质干细胞是未分化的,因此由于存在活性剂或局部组织环境的作用(化学,物理等),可分化形成各种类型的新细胞。分化的间充质干细胞的例子包括成骨细胞,软骨细胞和成纤维细胞。成骨细胞可被递送到骨缺陷部位以产生新的骨;软骨细胞可被递送到软骨缺陷部位以产生新的软骨;成纤维细胞可被递送到任何需要新的结缔组织的部位以产生胶原蛋白;等。这些细胞或基因的来源可以是同种异体的或异源的。例如,细胞可以来自于不同于已被遗传改变的宿主物种的一种物种。
生理活性试剂可简单地加入到丝心蛋白溶液和混悬液中或与另一种成分共价连接。备选地,生理活性试剂可以以可控释放的方式加入。一种可控释放的制剂包含分散或以包封在缓慢降解的,无毒非抗原性的聚合物例如共聚(乳酸/乙醇酸)中,如Kent等在美国专利号4,675,189中所述。另一种缓慢释放制剂对熟练工作人员来说是很显然的。参见,例如,Sustained and Controlled Release Drug Delivery Systems,J.R.Robinson编辑.,Marcel Dekker,Inc.,纽约,1978,和R.W.Baker,Controlled Release of Biologically Active Agents,John Wiley& Sons,纽约,1987。
在另一个实施方案中,丝心蛋白溶液和混悬液可以包含影响诸如孔隙率和生物降解因素的设计大小和化学组成的有机,无机和/或蛋白包含体。在一个优选的实施方案中,丝心蛋白溶液和/或混悬液可进一步包含颗粒,例如可在凝胶中建立额外孔隙率的核/壳颗粒,从而在注射后形成支架。
能够协助骨生长和形成的有机或无机颗粒的例子包括,例如羟基磷灰石,磷酸三钙,海洋动物衍生的颗粒,例如珊瑚和脱乙酰壳多糖等。
优选的形成孔的颗粒是核/壳颗粒,其中无机核由可生物降解的有机壳包裹。这种颗粒可同时用作临时支持结构和定形支架的内部基质。壳的可控生物降解可对丝心蛋白支架提供额外的孔隙率。核/壳颗粒将在下面进行详细描述。
优选的核是无机核。无机核的组成,大小和形状可根据不同用途的需求进行改变。例如,核可以是羟基磷灰石,磷酸三钙或海洋动物衍生的颗粒,例如珊瑚和脱乙酰壳多糖,从而协助骨生长。核的最大直径可以从约1纳米到约500微米,可以是球状,板状,纤维状等。
在核上可任选放置一层反应层,从而增强核与聚合物壳的附着作用。合适的反应层依赖于核与壳的组成,并且在本领域中是已知的。特别有用的一类化合物包括反应性的钛酸盐,锆酸盐和硅烷,例如,γ-环氧丙氧丙基三乙氧基硅。
壳可包含至少一种可生物降解的聚合物。一种或多种聚合物的组成和分子量可进行选择,从而达到以下所述的合适生物降解速率。壳的合适的可生物降解聚合物的组合物包含一个或多个聚乳酸,聚乙醇酸,聚已酸内酯,聚碳酸三甲酯,聚二丙烯酸乙二醇酯类,聚酐类,聚原酸酯类,聚膦嗪(polyphosphazines)类,聚缩醛类,聚酯类,聚脲类,聚碳酸酯类,聚氨基甲酸酯类,聚α-羟酸类,聚酰胺类,聚氨基酸类和其他具有合适的生物降解速率且是可生物兼容的可生物降解聚合物或共聚物。
可生物降解的聚合物可以是预聚物或在核上沉积的时间进行聚合。可生物降解的聚合物层可用本领域中已知的方法,例如通过在稀释的反应单体或聚合物的有机溶剂中制备核颗粒浆,将其限制在反应层或核本身。在一个实例方案中,壳的单体或聚合物可被化学修饰,从而包含末端基团,例如在机体内与细胞相互作用的肽,例如,在刺激组织修复或骨再生方面有活性的末端基团。例如这种末端基团可包括含有精氨酸-甘氨酸-天冬氨酸序列的肽,信号分子和许多前述的生理活性试剂,例如,骨形态发生蛋白。
选择可生物降解的壳以在支架的临时机械稳定性和发展额外的内部多孔性间提供一种平衡。核/壳组分的体积比可从约95/5到5/95进行广泛改变,优选的核/壳比例是20/80。
当聚合物在核上吸附后,可任选地加入悬浮固体的稳定剂。核/壳浆可以与包含少量,例如约0.5重量%到约3重量%的高分子量聚乙二醇或聚乙烯醇的稀释水溶液混合。
当核/壳颗粒形成为淤浆时,该淤浆可与钙源,和任选地与磷酸源(phosphate source)混合,从而在形成的颗粒的聚合物壳的外部形成包被。提供钙和任选磷酸源的前体的例子是钙盐(例如醋酸钙)的缓冲的水-醇溶液,钙盐和磷酸酯或配制的血浆流体。掺入钙离子的外包被可作为具有生物活性的丝心蛋白基质的界面。
得到的核/壳颗粒在水相中以相对稳定的混悬液存在。干燥后,例如冷冻干燥,颗粒可被轻轻研磨成核/壳粉末。一旦形成,随后可将核/壳与丝心蛋白溶液或混悬液混合。混合物的水含量可进行调整,从而维持流动性。颗粒与丝心蛋白溶液或混悬液的相对数量根据特定应用进行改变。典型地,溶液或混悬液可包含约10体积%到约50体积%(体积百分比),优选约30体积%到约50体积%的颗粒相。
一旦形成,可将丝心蛋白溶液和/或混悬液在体内用作用于组织构建的支架,或给药动物,例如哺乳动物,如兔,狗,猫,马,人等用于组织构建。此处所用的“组织构建”意图包括在未损伤部位,例如在整形手术中,形成硬组织或软组织,或在损伤部位进行修复或重建。
如果丝心蛋白混悬液是包含体或凝胶形式,则优选丝心蛋白混悬液通过注射给药至组织构建体部位。用于注射的丝心蛋白凝胶是可逆的凝胶,即,在例如使用热或机械压力下,可回复为粘度更低的状态的凝胶。机械压力可包括在注射过程中施加到凝胶上的压力。备选地,如果丝心蛋白混悬液以乳膏或糊形式存在,则丝心蛋白混悬液可通过例如外科手术放置或通过涂敷(即局部给药)放置在组织构建部位(即需要进行组织修复的部位)。没有所依据的理论,认为无论何种给药方式,一旦使用,则丝心蛋白混悬液可形成基质或支架,其可允许用于组织构建的细胞的渗透和生长。
可以以适于注射或其他给药方式的形式向从业者提供丝心蛋白溶液和混悬液。当与颗粒混合时,在用单注射器或双注射器技术注射时,可选择丝心蛋白溶液和混悬液的特征。在单注射器技术中,颗粒与丝心蛋白溶液或混悬液的相对数量根据用途由从业者提供,然后混合,并放置在具有针头的常规单注射器中并注射。备选地,颗粒与丝心蛋白溶液或混悬液可在单独药包中提供,在放入注射器前在混合室中进行混合。使用这种在放置期间允许各种混合的设备使从业者具有能够改变支架组成,从而更好地在给定部位(例如骨或软组织)匹配性质的改变。对两组分的水含量进行选择,从而使其允许进行快速混合和注射。
在应用中,丝心蛋白溶液和混悬液以各种目的对人或动物给药,例如为了填充空腔,代替丢失的组织或为了进行软组织或关节修复。丝心蛋白溶液或混悬液以例如注射或局部施用方式(即作为乳膏应用于皮肤)进行给药。没有可依据的理论,对溶液的情况,认为溶液可以快速将多余水分分散到机体中,直到在注射物质与周围体液之间建立准平衡为止,从而在体内产生可形成支架的混悬液。对包含体的情况,认为一旦放入机体中,则包含体可发生诸如溶胶—凝胶转换的变化,从而产生可以是支架形式的凝胶。在所有情况下,优选是一旦注射,物质是多孔的。
没有可依据的理论,认为当注射的丝心蛋白溶液或混悬液包含核/壳颗粒时,则多聚壳随时间的降解可在混悬液中产生额外的多孔,即,以凝胶的形式,形成增强组织修复所需细胞的渗透和生长的支架。例如,一旦注射,丝心蛋白可以含有一个包裹核/壳颗粒分散体的凝胶形式的三维网格(或蜂房)。图1所示的是组织修复过程中假设的三维网格的示意图。丝心蛋白1被细胞渗透和核/壳颗粒2发生至少部分降解。核/壳颗粒聚合物的大小和状态控制支架的额外多孔。新形成的组织3可在孔中进行组织。丝心蛋白基质的组成和形态是控制生物活性的主要因素。
多孔的丝心蛋白支架可促进细胞贴附,增殖和活化,该支架在愈合过程中缓慢降解。另外,丝心蛋白的降解可产生分子量为约20千道尔顿或更小的肽,它们可释放到周围的生物流体中,从而增强周围细胞的代谢活性。没有可依据的理论,进一步推测通过暴露最终与生长因子,药物分子和介导细胞贴附的特异肽相互作用的特异活性位点,热或蛋白酶处理可增加丝心蛋白的生物降解率。
上述丝心蛋白溶液和混悬液可应用于例如各种骨和组织修复程序。示例性程序包括但不限定于矫形的,上颌面,牙齿和一般外科手术程序,例如肿瘤切除和整形手术。例如,丝心蛋白溶液和混悬液可应用于通过粘结进行骨折修复,通过重建受损骨骼而进行骨质疏松症和骨关节炎中的骨骼复原。这些物质也可用作骨粘固粉(例如对于假肢),以填充或增加组织,以改变组织大小或形状,在牙周袋,用作为牙齿和关节移植物的稳定剂,以及作为髋关节,膝关节和其他假体和骨骼间所产生裂隙的填料,从而使假体固定,并促进骨再生。例如,丝心蛋白溶液和混悬液也可用于填充牙周患者牙齿周围形成的孔洞,从而允许部分骨再生,并尽可能降低细菌感染;和填充骨骼和移植物之间,例如髋关节或膝关节移植物之间的缝隙。填充这种缝隙可潜在地导致假体稳定,并增加假体的服务时间。丝心蛋白溶液和混悬液也可用于填充组织缺陷,例如那些由骨肿瘤手术和重建手术引起的组织缺陷,并增强骨和组织修复,例如,诱导钙沉淀,或成骨细胞增殖和活性,从而形成新形成的骨组织。
含有核/壳颗粒的丝心蛋白溶液和混悬液在骨修复中是特别有用的。没有可依据的理论,认为在这种情况下,骨修复过程可能如下所述发生。第一个降解的组分可能是核/壳颗粒的搀杂钙离子的壳,从而使体液扩散到富含钙离子的水层中,其作为可生物降解的壳和包裹的丝心蛋白网格的界面区。丝心蛋白基质的多孔和通过壳降解产生的额外多孔使成骨细胞在多孔支架中渗透,其与支架的具有生物活性的网格相互作用和启动新的组织和骨生长。第二步可能是反应层的生物降解,如果存在,例如,通过将可生物降解的壳连接到矿物核的-SiO-键上的水合作用,如此将可再吸收的矿物核引入剩余水凝胶的流体中。修复过程伴随着丝心蛋白的生物降解过程,并产生新的骨。至少在骨再生的第一个阶段期间,合成的支架(composite scaffold)可维持三维的机械稳定的高表面区的网格的机械稳定性。
丝心蛋白溶液和混悬液的一个特别有利的特征是:通过修饰具有生物活性的基质和核/壳可生物降解的颗粒,可以很方便地改变物质的形态和机械性质,从而满足特定应用的需要。设想不同于丝心蛋白的具有生物活性的可生物降解的凝胶和聚合物也可与此处所述的核/壳颗粒联合使用形成支架。
丝心蛋白溶液,混悬液和组合物可诱导如成骨细胞,角质细胞,成纤维细胞,周细胞,内皮细胞等类型细胞的增殖。由于丝心蛋白溶液和混悬液可增强许多类型细胞的增殖,因此它们也用于骨组织之外的组织,例如,整形手术后的软组织的重建,人工皮肤应用,软骨修复等。
通过以下非限定实施例进一步阐述本发明。
实施例
实施例l:丝心蛋白的纯化
通过本领域中已知的技术,首先将家蚕的蚕茧进行脱胶。胶状的丝胶蛋白通过在碳酸钠(Na2CO3)水溶液中反复洗涤而去除,如下所述。蚕茧首先在1.1g/l(克/升)Na2CO3水溶液中98℃洗涤1小时,然后在含有0.4g/l Na2CO3的水溶液98℃漂洗1小时。然后将蚕茧在温度从98℃降到室温下在蒸馏水中反复洗涤,从而得到无丝胶蛋白的丝心蛋白。粗丝心蛋白在水中的量是10g/l。然后将脱胶的丝心蛋白以最初组分100g丝心蛋白/l溶液在65℃在9.3摩尔的溴化锂(LiBr)水溶液中溶解3小时。当溶解完成时,通过加入蒸馏水将水溶液稀释到5%重量/体积丝心蛋白。剩余的杂质和未溶解的纤维通过用孔径n.1的过滤器过滤除去。然后用截留分子量为3500的再生纤维素膜通过对蒸馏水进行72小时的透析而从丝心蛋白混合物中除去盐。透析的丝心蛋白最终浓度为1-2%纯丝心蛋白。
实施例2:通过对丝心蛋白水溶液进行热处理制备混悬液
将丝心蛋白水溶液(20ml(毫升))倾注到在-20℃到50℃温育2到24小时的聚苯乙烯胶囊中。将在-20℃温育的溶液加热至和维持在室温,直至发生凝胶化。其他保持在从4℃到50℃的恒定温度下的丝心蛋白溶液发生凝胶化所需的温育时间是2到24小时。由热重量分析测定的凝胶中的水含量从95到98重量%变化。混悬液的均一性依赖于它们温育的时间和温度。因此,证实丝心蛋白的流变学特性可通过热处理而进行改变。
实施例3:丝心蛋白的酶处理
用各种与特定氨基酸的肽键位点反应的蛋白酶处理水性丝心蛋白混合物。其目标是降低平均分子量,增加生物降解速率,并暴露出与介导细胞贴附因子特异的肽,生长因子和药物分子最终相互作用的特异活性位点。对以下酶进行研究:
蛋白酶(来源于灰色链霉菌):该酶在谷氨酸的羧基位点水解肽键。已表明具有谷氨酸的末端基团的丝心蛋白的肽链阻止形成有规则的丝心蛋白β结构。该酶反应在酶-底物浓度为50μl/1ml(微升/毫升)下进行,37℃反应1小时后,溶液变成白色,且更加粘稠。形成的溶胶是一种能够形成凝胶的可注射物质。加热至50℃将酶灭活。由电泳分析所测定的丝心蛋白肽链中谷氨酸含量约为1%。存在显著的具有比处理前丝心蛋白混合物中存在的低的分子量的肽。
木瓜蛋白酶:该酶与亮氨酸(丝心蛋白的0.5%)和甘氨酸(丝心蛋白的44%)的化学键特异反应。处理条件和酶-底物浓度比可进行改变,从而得到粘度水平不同的获得的丝心蛋白溶胶或溶液。在这种情况下,电泳分析测定产物包含的肽的分子量在20Kd-2Kd。
胰凝乳蛋白酶:用该酶处理导致二硫键水解,所述二硫键连接Cp(重链)部分(主要由甘氨酸-丙氨酸-丝氨酸组成)和包含纯丝心蛋白物质中存在的其他氨基酸的Cs部分(轻链;短肽链的混合物)。在40℃向丝心蛋白水溶液中加入缓冲的酶溶液。水解程度由反应时间控制。不同的处理时间能启动不同量的水解。反应完毕后,得到的水介质包含溶液形式的Cs或轻链部分和Cp或重链部分的凝胶沉淀。
实施例4:通过向丝心蛋白溶液中加入酸或醇形成混悬液。
通过向丝心蛋白溶液中加入柠檬酸或甘油诱导凝胶化。
将柠檬酸逐滴加到10ml丝心蛋白溶液中,直到pH达到3.7(等电点为3.8)。约6小时后发生凝胶化,产生白色不透明的多孔凝胶,其含有约95重量%水分。图2所示的是所形成物质的环境扫描电镜显微照片。
当将3ml甘油加到7ml丝心蛋白溶液中,在约20小时发生凝胶化,产生白色(半)透明凝胶,其含有约90重量%水分。图3所示的是所形成物质的环境扫描电镜显微照片。
实施例5:体外制备可注射的丝心蛋白凝胶/羟基磷灰石/聚交酯组合物支架
制备聚合物包被的羟基磷灰石颗粒的核/壳颗粒粉末。用分子量约为6,000的聚交酯(PLA)作为可生物降解聚合物的壳。将2克硅烷处理的羟基磷灰石加到含有6克聚交酯的50ml丁醇中。将溶液加加热到70℃2小时,冷却到室温,并与50ml 2%重量/体积的聚乙二醇水溶液混合。为了维持包被过程的相对均一性,包被颗粒的装配速率需要足够慢。搅拌核/壳混合物,倾倒入Petrie玻璃皿中,在50℃干燥,并轻轻研磨成粉末。得到的物质是一种相当广泛大小分布的聚合物包被的球形聚合体。
将2克核/壳粉末与10ml丝心蛋白凝胶混合。粉末很容易地分散在凝胶中形成糊。包含核/壳颗粒的糊在2天内干燥,即冷冻干燥和同样在室温下缓慢干燥。图4-7是得到的支架的光学显微照片。在室温下缓慢干燥,形成具有明显结构完整性的充满颗粒的丝心蛋白物质。该冷冻干燥的样品表现出期望的形态结构,即丝心蛋白包被的广泛分布。
实施例6:丝心蛋白混悬液的体外实验
人成骨细胞样细胞(MG63)在丝心蛋白凝胶中培养72小时,该凝胶是通过向丝心蛋白水溶液中加入甘油和通过在4℃处理丝心蛋白水溶液而制备的。为了测定细胞增殖和活性,对在待测物质上生长的MG63和在空聚苯乙烯孔中生长作为对照的MG63的生化和免疫酶学参数。
当与对照比较时,通过热处理制备的纯丝心蛋白凝胶上的细胞增殖显著降低,但同时,凝胶有利于成骨细胞活性和分化,如分别通过增强的ALP(碱性磷酸酶)活性(16.71+/-1.80相对于对照10.10+/-1.61)和TGFβ-1(转化生长因子β1)水平(487+/-29相对于对照432+/-42)来证明。当与对照比较时,在通过加入甘油制备的凝胶中的细胞增殖显示很少的差异。
没有凝胶诱导细胞毒性,如通过LDH(乳酸脱氢酶)水平(纯丝心蛋白凝胶:14.67+/-2.04;具有甘油的凝胶:18.03+/-0.23;对照:14.63+/-2.19)。
实施例7:丝心蛋白混悬液的体内实验
将柠檬酸衍生的丝心蛋白凝胶移植到兔股髁钻孔得到的空腔(直径6mm,深度10mm)中。无移植物的空腔作为对照。在移植1月后将兔杀死,并将移植部位的组织学结果与那些无移植物的部位进行比较。
移植1月后,在一个由丝心蛋白凝胶填充的腔中的洞中完全被新形成的骨填充(图8A)。观察到带有一些残余丝心蛋白4的几乎完全的骨骼愈合。没有加入丝心蛋白的空腔则未表现出骨骼的再生(见图8B)。观察到原来的骨骼5和空的缺陷6。在4个填充了丝心蛋白凝胶的空腔中,空腔几乎被新形成的骨7填满,仍存在一小部分残余的空腔8(图9A)。在图9A,空腔宽度为1.08毫米,长度为1.7毫米。图10所示的是原来骨骼5与新生骨骼7之间的界面。新生骨骼形成良好组织的径列条,其从原来骨径列条处增殖,而不在新生骨骼和原来骨骼之间产生任何缝隙。观察到作为经历矿化作用9的结缔组织而产生的残余空腔8。观察到轻微的炎症,没有产生任何肉芽肿和明显的不利免疫反应。仅有最初的丝心蛋白凝胶的片段仍然是可见的,证实凝胶以与增殖再生一致的速率进行降解,因此提供证据丝心蛋白混悬液可以用于所建议的应用。
已经公开了新的丝心蛋白混悬液和组合物。这种丝心蛋白混悬液可用纯化的丝心蛋白溶液利用加热,蛋白酶,酸,醇或可生物兼容的聚合物制备。丝心蛋白混悬液可以是包含体,凝胶,乳膏或糊形式。丝心蛋白混悬液,组合物及溶液具有专门用于骨骼和组织构建,修复和再生的应用。由于丝心蛋白溶液,混悬液和组合物可被注射,因此可降低对许多导入性外科手术,特别是整形外科的需求,从而减小感染的潜在危险,缩短所需的恢复时间,降低医疗过程的全部花费。
尽管参考优选的实施方案已经描述了本发明,本领域中的熟练工作人员应理解,在未脱离本发明的精神的条件下,可进行各种改变,和对于其元素可可替代等价物。另外,在脱离其基本范围的条件下,可进行许多修改以使特定情形或物质适合本发明的教导。因此,本发明并不限定于作为实施本发明的最佳方式所公开的特定实施方案,但本发明将包括所有落在后附的权利要求范围内的实施方案。
Claims (19)
1.一种包含丝心蛋白混悬液和任选形成多孔的颗粒物质的组合物。
2.权利要求1的组合物,其中所述丝心蛋白混悬液为包含体,凝胶,乳膏或糊的形式。
3.权利要求1的组合物,其中所述丝心蛋白包含家蚕丝心蛋白。
4.权利要求1的组合物,其中所述丝心蛋白包含蛋白酶降解的丝心蛋白。
5.权利要求1的组合物,其中所述形成孔的颗粒物质包括羟基磷灰石,磷酸三钙,陶瓷,珊瑚,脱乙酰壳多糖,或包含一种或多种上述物质的组和。
6.权利要求1的组合物,其中所述形成孔的颗粒物质包含一种核/壳颗粒,所述核/壳颗粒包含任选的钙化合物,任选磷酸源,和任选的反应层。
7.权利要求1的组合物,其中所述壳包含可生物降解的聚合物。
8.权利要求6的组合物,其中所述核包含羟基磷灰石,基于磷酸钙的矿物质,可再吸收的玻璃填料,或包含一种或多种前述物质的组合,其中所述壳包含聚乳酸,聚乙醇酸,聚己酸内酯,聚碳酸三甲酯,聚二丙烯酸乙二醇酯类,聚酐类,聚原酸酯类,聚膦嗪类,聚缩醛类,聚酯类,聚脲类,聚碳酸酯类,聚氨基甲酸乙酯类,聚α-羟酸类,聚酰胺类,聚氨基酸类或包含一种或多种前述可生物降解聚合物的组合。
9.权利要求1的组合物,其中所述丝心蛋白混悬液还包含生理活性剂。
10.权利要求9的组合物,其中所述生理活性剂包含抗生素,骨形态发生蛋白,刺激组织生长的化合物,刺激骨再生的化合物,刺激伤口修复的化合物,细胞或,包含一种或多种前述试剂的组合。
11.一种形成丝心蛋白混悬液的方法,其包含用一种试剂处理丝心蛋白溶液以形成丝心蛋白混悬液,所述试剂包含热,酸,醇,蛋白酶,可生物兼容的聚合物,或包含一种或多种前述试剂的组合。
12.权利要求11的方法,其中所述丝心蛋白混悬液是包含体,凝胶,乳膏或糊的形式。
13.权利要求11的方法,其中用热处理包含加热到约-20℃到约50℃的温度。
14.权利要求11的方法,其中所述醇包含甘油,其中所述酸包含柠檬酸,抗坏血酸,乳酸或包含一种或多种前述酸的组合,其中所述可生物兼容的聚合物包含聚乙二醇,聚环氧乙烷,聚乙烯吡咯烷酮,或包含一种或多种前述可生物兼容聚合物的组合,其中所述蛋白酶包含来源于灰色链霉菌的蛋白酶,木瓜蛋白酶,胰凝乳蛋白酶,或包含一种或多种前述蛋白酶的组合。
15.权利要求11的方法,还包含向所述丝心蛋白混悬液中加入形成孔的颗粒物质,生理活性剂,或包含一种或多种前述试剂和物质的组合。
16.一种用丝心蛋白溶液和混悬液处理哺乳动物的方法,其包含对组织构建部位给药有效量的丝心蛋白溶液或混悬液以刺激组织形成,其中所述丝心蛋白溶液或混悬液对所述丝心蛋白物质任选包含形成孔的颗粒物质,生理活性剂,或包含一种或多种前述试剂和物质的组合。
17.权利要求16的方法,其中所述丝心蛋白混悬液是包含体,凝胶,乳膏或糊的形式。
18.一种用丝心蛋白溶液或混悬液处理细胞的方法,其包含用有效量的丝心蛋白溶液或混悬液接触细胞以诱导细胞增殖。
19.权利要求18的方法,其中所述丝心蛋白混悬液是包含体,凝胶,乳膏或糊的形式。
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- 2002-10-25 US US10/281,096 patent/US7727542B2/en not_active Expired - Fee Related
- 2002-10-25 ES ES02784287T patent/ES2321915T3/es not_active Expired - Lifetime
- 2002-10-25 AU AU2002348072A patent/AU2002348072A1/en not_active Abandoned
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JP2005510268A (ja) | 2005-04-21 |
US7727542B2 (en) | 2010-06-01 |
ATE420671T1 (de) | 2009-01-15 |
AU2002348072A1 (en) | 2003-05-06 |
US20120040907A1 (en) | 2012-02-16 |
WO2003035124A2 (en) | 2003-05-01 |
CN1277584C (zh) | 2006-10-04 |
JP4669662B2 (ja) | 2011-04-13 |
EP1446169A2 (en) | 2004-08-18 |
CA2466001C (en) | 2012-01-03 |
DE60230907D1 (de) | 2009-03-05 |
US20030099630A1 (en) | 2003-05-29 |
WO2003035124A3 (en) | 2003-09-12 |
US20070190099A1 (en) | 2007-08-16 |
CA2466001A1 (en) | 2003-05-01 |
EP1446169B1 (en) | 2009-01-14 |
US8071118B2 (en) | 2011-12-06 |
ES2321915T3 (es) | 2009-06-15 |
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