CN1646070A - 组织修复基质 - Google Patents

组织修复基质 Download PDF

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CN1646070A
CN1646070A CNA038089807A CN03808980A CN1646070A CN 1646070 A CN1646070 A CN 1646070A CN A038089807 A CNA038089807 A CN A038089807A CN 03808980 A CN03808980 A CN 03808980A CN 1646070 A CN1646070 A CN 1646070A
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substrate
collagen
porous
bone
insoluble
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CN1646070B (zh
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R·K·亚马莫托
M·K·关
S·D·佩斯蒂
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DePuy Spine LLC
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Abstract

本发明提供了一种可生物降解的多孔三维组织修复基质。该基质优选由矿化胶原蛋白形成,所述矿质包括固定在基质中的磷酸钙微粒。

Description

组织修复基质
发明背景
本发明涉及用于骨组织修复的材料。
迄今已研制出多种引发骨修复和/或储存或替代缺损骨的材料,以解决在特定部位刺激骨形成的问题。
在用于解决此问题的方法中,有一种是借由植入材料的构造方法,这些植入材料通常由金属陶瓷或其它无机材料制成,模仿缺损骨的形状,植入在需要替换的骨的位置。此方法存在一种风险,即接受者会排斥这种材料,或者植入物质与正常骨组织整合失败。有些陶瓷材料,如磷酸三钙陶瓷,虽然对于受者和骨组织是生物相容的,但用作植入材料时,似乎缺少足够的骨骼作为一般用途的机械性能,而且骨骼不能始终如一地长入而与植入物合成一体。
另一种办法包括用一种基质替换缺损骨组织,该基质起到支撑作用,使新骨在其中生长。原理是此基质吸引成骨路径的细胞,通过被称为骨骼传导的步骤,新骨在基质中生长或穿过基质生长。此方法使用异源的骨(非宿主自身的骨)移植物,然而这存在相当高的失败率。即使宿主接受了此移植的异源骨,与同源骨(宿主自身的骨)移植相比,与骨的结合和恢复机械应力的愈合时间长。使用异源骨还存在传入病毒的问题。
第三种方法包括已知的骨诱导方法,此方法的进行是在一种材料的诱导下,在宿主未分化细胞或组织中生长新骨,这些骨通常围绕着临时性的基质生长。许多化合物被认为具有此种能力。参见以下美国专利:4,440,750,专利权人:Glowacki;4,294,753和4,455,256,专利权人:Urist;4,434,094和4,627,982,专利权人:Seyedin等。这些化合物中最有效的似乎是促进成骨作用的蛋白质。然而,如果用自然资源进行合成,由于其含量极低,需要大量的原料才能获得极少量的用于实验的材料。通过重组方法制备这样的蛋白质可使这些蛋白质本身具有更高的实际价值。然而,这样的蛋白质可能仍需要置于适当的基质中,以运送到所要求的位点。
已公开包含胶原蛋白和多种形式的磷酸钙的组合物,其有助于愈合和骨生长。
Bauer等人的专利5,338,772公开了一种复合材料,包含磷酸钙陶瓷微粒和一种生物可吸收聚合体,其中磷酸钙陶瓷按重量计算,含量至少为50%,这些微粒通过聚合体交联键相连。所公开的磷酸钙陶瓷微粒的大小约20微米到约5mm。
Piez等人的专利4,795,467公开了一种组合物,其包括混合有atelopeptide重建的纤丝状胶原蛋白的磷酸钙矿质微粒。所公开的磷酸钙矿质微粒大小在100-2,000微米范围内。
Sauk等人的专利4,780,450公开了一种用于骨修复的组合物,其包括有微粒多晶体的磷酸钙陶瓷、一种phosphophorin钙盐和一种I型胶原蛋白,重量比为775-15∶3-0.1∶1。公开的陶瓷微粒是致密的羟基磷灰石,直径大约1到10微米,或直径大于100微米的更大的致密羟基磷灰石陶瓷微粒。
Ammann等人的PCT申请WO94/15653公开了配方,其包括磷酸三钙(TCP)、TGF-β和任选的胶原蛋白。公开的TCP作为TGF-β的运送载体,TCP的粒径大于5微米,优选大于大约75微米。所公开的最优选的TCP颗粒大小范围是125-250微米。
PCT申请WO95/08304公开了羟基磷灰石与不溶性的胶原蛋白混合的多矿质的微粒前体。该多矿质微粒前体的粒径范围是0.5微米到5微米。通过水解,该前体矿质转变为羟基磷灰石。此过程被认为将矿质熔化形成整体的羟基磷灰石。
FMC公司的英国专利说明书1,271,763公开了磷酸钙和胶原蛋白的复合物。
发明概要
提供了一种组织修复基质,该基质多孔、可生物降解、三维固定并具有形状记忆功能,植入后可在一定时间内保持结构完整性和多孔性,足以加强组织的替换过程。该基质包括矿化纤丝状不溶性胶原蛋白、胶原蛋白衍生物或改良的明胶,用一种粘合剂粘结。在一个实施方式中,该矿质包括在基质内部固定的磷酸钙。得到的产物经冻干、交联、干燥和灭菌,形成一种多孔基质。此基质可用作组织修复材料和/或生物活性因子的运送载体。此基质可移植,用于骨再生,并在植入后保持多孔性和物理性状完整的时间超过14天。
具体实施方式的描述
该基质用一种不溶于水的可生物降解的生物聚合体,如胶原蛋白、胶原蛋白衍生物或改良的明胶生产。如果用明胶,应将其改造为在水环境中不溶性的。所述胶原蛋白可以来自矿化或未矿化胶原蛋白来源,通常使用未矿化胶原蛋白来源。因此,胶原蛋白可以来自骨、腱、皮等,优选I型胶原蛋白,其包括两股α2和一股α1的胶原蛋白链的结合。该胶原蛋白可来源于幼年或成年的动物,如小牛或2岁及大于2岁的母牛。胶原蛋白的来源可以是任何易得的动物来源,哺乳动物或鸟类,并且可以包括牛,猪,马,小鸡,火鸡或其它驯养动物的胶原蛋白。所用不溶性胶原蛋白组织通常被分散在一种被提高了pH值的介质中,pH至少约为8,更常用的大约为pH11-12。虽然可以使用其它氢氧化物,如其它碱金属氢氧化物或氢氧化铵,但常用氢氧化钠。
按本发明的方法,可用天然胶原蛋白。天然胶原蛋白的每一端含有无三联体甘氨酸序列的区域。这些区域(端肽)被认为是形成与大多数胶原蛋白制剂相关联的免疫原性的原因。通过用蛋白水解酶消化,如用胰蛋白酶和胃蛋白酶,除去这些区域可以减轻上述免疫原性,而生产出缺失肽-胶原蛋白。
用于矿化胶原蛋白浓度通常在大约0.1-10%(重量百分数)范围之内,更常用的大约在1-5%(重量百分数)。胶原蛋白介质的碱浓度范围通常约为0.0001-0.1N。在反应过程中pH通常保持在约10-13,优选约12。
优选用不溶性的纤丝状胶原蛋白,可用常规方法制备。典型方法是:先与异丙醇(IPA)、乙醚、己烷、乙酸乙酯或其它适当的溶剂混合,然后分离胶原蛋白。pH通常降到大约3,然后冷却到约4℃,并且使其溶胀。得到的淤浆可以被均化,直到达到想要的粘度。
将均化的匀浆加入溶剂搅拌,并且提升pH至大约7。分出纤丝状胶原蛋白,用去离子水冲洗,并且冻干。为了生产矿化纤丝状胶原蛋白,可将精制的不溶性胶原蛋白纤维放入反应器均化,在搅拌下控制速度向反应器中加入氯化钙(典型地为0.05m)和磷酸三钠(典型地为0.03m)。在这期间,根据需要用氢氧化钠调节pH至11.0±0.5。在矿化以后,用去离子水或磷酸盐缓冲液冲洗胶原蛋白,与粘合剂结合,并调节PH为8.0±2.0。加入磷酸盐和钙离子的方法参见美国专利5,231,169的描述。
所述磷酸钙可以包含其它离子,比如碳酸盐、氯化物、氟化物、钠或铵。碳酸盐的存在导致产生一种具有碳酸磷灰石(碳酸羟基磷灰石)性质的产物,而氟化物产生氟化磷灰石性质的产物。碳酸盐的重量百分含量通常不超过10%,氟化物的重量百分含量通常不超过2%,优选在0至1之间。这些离子可以与钙和/或磷酸盐源结合而存在,只要这些离子相容,且不在试剂溶液中导致沉淀。
钙和磷酸盐离子加入的速度通常是大约1小时并且不超过72小时,以使粒径达到约5微米或更小。通常,加入时间大约在2至18小时,更常用的约4至16小时。使用适度的温度,通常不超过40℃,优选范围在大约15℃到30℃。胶原蛋白与磷酸钙矿质的重量比通常约为20∶1-1∶1,典型地约为7∶3。
其它添加剂如,非胶原蛋白样的蛋白质,因子或药物,如BMP′s、TGF-β、降钙素、抗生素均可包含在基质中,方法是在加入钙和磷酸盐之前或之后加到胶原蛋白浆中。这样的添加剂的用量通常是基于用作基质的生物聚合体(比如胶原蛋白)重量的约0.0001-2%。
矿化产物中胶原蛋白的量,以除去粘合剂的胶原蛋白纤维的重量计,通常约占95%-30%。
为形成具有形状记忆功能的多孔三维固定的组织修复基质,将矿化生物聚合体纤维与一种粘合剂混合。
优选用精制的可溶胶原蛋白作为粘合剂,通过首先将可溶胶原蛋白与一种溶剂如异丙醇(IPA)混合,然后分离出胶原蛋白。将pH降至约3.0,当胶原蛋白溶解后,升高pH至5.0,用溶剂洗两次,再用去离子水冲洗、过筛并且冻干。
其它可被应用的粘合剂包括,但是不限于明胶、聚乳酸、聚乙醇酸、乳酸和乙醇酸共聚物、聚己酸内酯、羧甲基纤维素、纤维素酯(比如甲酯和乙酯)、醋酸纤维素、葡萄糖、葡聚糖、脱乙酰壳多糖、透明质酸、ficol、硫酸软骨素、聚乙烯醇、聚丙烯酸、聚丙二醇、聚乙二醇、水溶性的甲基丙烯酸酯或丙烯酸酯的聚合体。
为制备多孔基质,将优选的可溶胶原蛋白粘合剂加至一种矿化生物聚合体匀浆并混合。优选地,不溶性胶原蛋白是生物聚合体,并使用可溶胶原蛋白对不溶性胶原蛋白为约10%(重量比)比例。根据需要,将pH调节至8.0±2.0。当达到所需要的混合水平时,将此分散体在-20℃到-80℃下冷冻。
将此冷冻的匀浆冻干。此多孔基质可以被交联,以提高物理稳定性,增加基质的再吸收时间,并使终产物易于处理。所述冻干基质交联优选在戊二醛溶液(典型的浓度为0.01%)或水蒸气中进行。如果用溶液,在除去过量试剂以后,将上述基质冷冻干燥。
多孔基质还可以通过过滤矿化胶原蛋白纤维和粘合剂的匀浆形成,形成网状物。然后将经干燥的网状物交联。
通过将生物聚合体胶原蛋白纤维、粘合剂和可滤去的微粒(可溶盐,比如氯化钠)和/或高蒸气压固体混合,也可以获得多孔结构,所述固体在后来可通过升华除去。可以将匀浆干燥,然后可以除去可滤去的微粒或可升华的微粒,以形成多孔结构。所述多孔基质可以被交联。
交联基质的其它优点包括增加植入驻留时间和形状保持性(不发生植入物的破碎)。所述基质有一种形状记忆功能,意味着它可从初始的大小、形状和多孔性被压缩,也可以从压缩状态回复到它初始的大小、形状和多孔性。而且,上述过程中它的纤维或粘合剂不出现实质性的损失。在植入后,就其物理性状完整方面,所述基质还将保持其多孔性超过约14天,尤其当被用于骨生长时。
可用其它交联方法和交联剂,如甲醛、铬盐、二异氰酸盐、碳二亚胺、双官能的酰基氯、双官能的酐、双官能的琥珀酰亚胺、二溴异丙醇、环氧氯丙烷、二环氧化物;交联方法包括脱氢热交联、干燥时紫外辐射,或E-射线辐射,或在水溶液中进行γ辐射。
最终产物可使用γ辐射、E-射线辐射、干热或环氧乙烷方法灭菌。
本发明的一个优点是胶原蛋白纤维和被固定的磷酸钙矿质形成一种基质,特别适于骨的置换或增加。在骨置换情形中,当植入生理环境后,该基质的物理性状完整和它的多孔性可保持超过约14天。物理性状完整意味着基质也保持其多孔性,这对组织置换或增加的步骤是很重要的。如上所述,该基质也有形状记忆功能。这使得基质可以压缩为一种转送载体,比如插管,此转送载体可以引入到所需组织生长的位置,通过在该位点从转送载体释放基质,该基质回复到它的初始的大小,形状和多孔性,它的纤维和粘合剂没有实质性的损失。这与组合物的情形相反,所述组合物在植入组合物后立即,或不久后就崩解为无定型的、无孔的物质,并且丢失矿质。
本发明的基质将最终被生物降解或被再吸收,所以在有限的期间之后,不能保持物理性状完整和多孔性。此过程通常平均历时约2到12周,并且当然取决于所植入基质的大小。然而,只要在骨置换或增加过程之前没出现基质的全吸收或生物降解,此生物降解速度是足够的。
本发明的一个方面,磷酸钙矿质(典型为羟基磷灰石)被固定在基质上,但相反在基质中又可自由移动。已发现本发明的磷酸钙矿质固定在基质内部。由于吞噬细胞比如巨细胞和巨噬细胞在微粒物质周围更为突出,经常形成肉芽瘤,可以改变细胞反应。当微粒小到足以被吞噬,即大约3到5微米或更小时,可被吞噬细胞吞噬,这更进一步促进局部的组织反应。例如观察到,在骨医治期间发现在相邻组织的巨噬细胞中存在与人造关节有关的微粒磨损碎片,并且在一种剂量依赖方式的动物模型中与增加的骨吸收有关。(″巨噬细胞/微粒的相互使用:大小、组合物和表面区域的影响″,Shanbhag AS等,J.Biomed.Mater.Res.28(1),81-90(1994))。因此本发明的一个优点是被固定的磷酸钙矿质始终以5微米或更小的微粒被释放,这是吞噬细胞可吞噬的理想大小。本发明的另一优点是任何磷酸钙矿质微粒的释放均受到控制,这是由于矿质固定在基质内部的结果。粒径大小和固定的优点见后面的实施例III。
本基质材料可用于组织或软骨修复,或在脊柱融合术、充填骨缺损、骨折修复和移植齿根膜的缺损中作为骨传导骨移植材料。通过将此组合物与成骨性的材料结合,如自生的骨或自体抽出的骨髓,或骨传导骨生长因子BMP′s、降钙素或其它生长因子,可进一步增加骨诱导和生长。所述组合物还可以含有其它添加剂,比如药物和特别的抗生素。此基质也可以作为一种基材,粘结生长因子,以使宿主产生的或外部引入的因子集中在此基质中。所述组合物可在组织或软骨修复、骨折修复、maxifacial重建、脊柱融合术、关节再建及其他整形外科的手术上得到应用。
提供以下实施例用于说明,但并不意味着以任何方式限制本发明。
实施例I植入骨
将本发明的矿化胶原蛋白基质植入8周龄顶骨缺损大鼠模型。在第14和第28天进行组织学评定。在14天以后,观察到骨从缺损处切割边缘进入胶原蛋白基质生长。围绕着残余的基质块和疏松结缔组织区域重新形成编织骨,所述结缔组织区域中血管形成明显。至28天,出现了有意义的改变,遍及新骨呈现出骨细胞。由于骨继续生长,在第14天看到的结缔组织空腔变小。
实施例II用骨髓或自体移植物植入骨
将实施例I的磷酸钙矿化胶原蛋白基质添加骨髓后植入成年的雄性新西兰白兔(3.7到4.1公斤)。在右前臂内侧面中轴部位做一个切口,以暴露桡骨。用一种风钻除去1.5厘米桡骨,造成严重缺损。在截骨术期间进行冲洗,使过热和对骨的破坏程度减到最小。用矿化胶原蛋白基质与骨髓或自体移植物混合,将缺损处充满。所述骨髓从同一动物的胫骨中抽取。自体移植物是松质骨,从髂嵴获得,类似于通用的骨增大或移植方法。
手术后每日观察动物,并且在前八周每两周一次、以后每月一次进行射线照相检查被手术的桡骨,直到在第12周进行尸体剖检。此实验兔预定在术后存活12和24周。
在尸体剖检时,除去左右两桡骨,评价手术桡骨总的医治情况(形成愈合组织和骨折愈合)。检查包括指示愈合的骨的存在,或表明有软骨、软组织的存在,或指示一种可能不稳定愈合的缺损内部的裂缝。
然后将桡骨固定在10%中性缓冲的福尔马林中,进行组织学和形态测定的估价。
在0、2、4、6、8、12周所拍的射线照片表明,早在二周时就出现了明显的愈合作用,缺损部位继续改善,向重新组成正常的桡骨皮质发展。在磷酸钙胶原蛋白基质处理组和自体移植物对照组之间出现了一致的渐进性的愈合。从射线照相愈合来看,在上述两个交联组之间几乎无差别。
在较早的研究中,已经表明缺损留下的空洞或未经治疗的(阴性对照)含有极少新骨,或几乎没有新骨。在此研究中,自体移植物(阳性对照)形成一种稳定的骨愈合。含有骨髓的磷酸钙胶原蛋白处理的缺损也显示出稳定的与新骨的连接,其效果与自体移植物相当。
实施例III(比较实施例)
制备一批不加胶原蛋白的磷酸钙矿质。获得此矿质,冲洗,并且冻干为干燥粉末。红外光谱显示与羟基磷灰石相符。
将不溶性纤丝状胶原蛋白纤维与可溶胶原蛋白以9/1重量比混合,总固体为4%(重量),制备成混合基质。手工混合此匀浆,加入游离矿质制成25%(重量)的总固体。将此匀浆倾入2平方英寸聚四氟乙烯模子,约5mm深,在-80℃冷冻至干。用戊二醛使干燥基质交联30分钟,冲洗,然后再冻干。得到的基质约4mm厚,用此基质制成直径为8mm的冲压样品用于植入。用于对比,新近制备的一批矿化胶原蛋白(固定矿质),灰分含量为28%(重量),用于制造8mm直径的冲压植入片。
在第3、7、14天的时间点将两个同样类型材料的植入物经皮下放置在四只大鼠胸廓筋膜。在尸体剖检时,记录植入物的组织反应,并取组织进行组织学检查,在每个时间点观察各个动物H&E染色的植入物和周围组织的切片,以确定组织反应和累积效应。
尸体剖检观察结果
     混合配方组(非固定矿质)       矿化胶原蛋白组
3天  周围组织清楚                 周围组织清楚
     植入物含糊不清               植入物柔软
7天  周围组织清楚                 周围组织清楚
     植入物柔软,但感觉变厚       植入物柔软至坚实
14天 周围组织发炎                 周围组织清楚
     植入物坚实,但感觉变厚       植入物坚实
尸体剖检的临床观察表明,与在大鼠皮下植入固定矿化胶原蛋白的模型相比较,混合配方组发生了严重许多的炎症反应和降解效应。观测结果描述了在第3天植入物含糊不清的情况。在第7和14天,组织学观察到植入物变厚,可能是由于混合配方引起了严重的纤维囊反应。在所有三个时间点,相对比的带有固定矿质的配方表现出清楚的周围组织的和正常的植入物外观。
组织学检查显示,从晚期(14天)的PMN活性和早期(3天)的巨细胞活性看,混合配方组导致了严重的急性和慢性炎症。上述巨细胞表明吞噬细胞的活性正被组织起来,这可能是为了应对大量松散联合的矿质微粒。还观察到成纤维细胞侵入,并且组织坏死不明显。
相反,矿质微粒固定在胶原蛋白纤维上的配方显示出更有代表性的植入物组织反应。在3天时,观察到急性炎症,其迅速地平息,在7天时成为更长期性的植入物反应,仅在成纤维细胞的侵入和在植入物周围有新血管形成期间发生中度炎症。在第14日,可见到炎症增加的迹象,也许这表示因为胶原蛋白降解,胶原蛋白纤维释放出额外的矿质。
胶原蛋白和羟基磷灰石矿质成分的混合配方表明,其在大鼠皮下植入时发生显著的急性炎症性反应。在矿化胶原蛋白组合物中固定矿质成分似乎可减少矿质的生物利用度,减少炎症的发生,而在愈伤期间继续支撑组织整合。
实施例IV在软组织部位植入
将本发明的矿化胶原蛋白基质植入5-6周龄的Sprague Dawley大鼠皮下组织,并在4周和8周时用组织学方法进行评价。在4周以后,观察到向内生长的纤维组织进入嗜曙红细胞插入物的卵形块。同时也观察到中度到明显的慢性炎症性反应,并伴有淋巴细胞的浸润。外周存在致密纤维组织和多核巨细胞。在此时间点,仍有适量的矿化胶原蛋白植入物存留。在8周时,矿化胶原蛋白的植入物显示出精细而致密的纤维组织和小的空隙空间。也观察到中度的炎症,主要是在外周,伴随着慢性炎性细胞和分散的巨多核细胞的浸润。6个样本中有3个显示少量残留植入物材料,而其余3个植入物部位仅含痕量的植入物。
实施例V植入的矿化胶原蛋白基质的存留时间
将本发明的矿化胶原蛋白基质与自体骨髓结合,并植入新西兰白兔的桡骨1.5cm部分的缺损处。在12周以后,对植入部位进行组织学评价,显示存留残余矿化胶原蛋白基质并紧密附着在骨基质上。
实施例VI MP52的释放
将本发明的矿化胶原蛋白基质与形态发生蛋白-52(MP52)水合,制成浓度为0.1mg MP52/cc基质。将此含水基质冻干。冻干基质在37℃置于PBS,检测基质释放的MP52。在下列时间点:15分钟、30分钟、1小时和18小时,累积释放分别为5%,、7%、9%和10%。18小时以后,从该基质中回收到90%加入的MP52。
实施例VII抗生素的释放
将本发明的矿化胶原蛋白基质与万古霉素水合,浓度是10mg万古霉素/cc基质。将此含水基质冻干。冻干基质在37℃置于PBS,检测基质释放万古霉素。在下列时间点:6小时、24小时、51小时、73小时和97小时,累积释放分别为40%、63%、72%、80%和83%。
实施例VIII形状记忆
将本发明的矿化胶原蛋白基质放在液体中,基质可以容易地水合。在水合以后基质保持其完整性和形状。含水基质可以被压缩并人工穿过一条窄通路,但是当再水合时又回复到它的原始大小和形状。在操作和压缩期间基质保持其完整性,纤维没有任何实质性的损失。

Claims (26)

1.一种可移植的、多孔、可生物降解、三维固定的具有形状记忆功能的基质,其包括不溶于水的矿化生物聚合体纤维构成的网状结构、药物和通过交联可变为不溶性的水溶性粘合剂。
2.一种可移植的、多孔、可生物降解、三维固定、用于骨生长、具有形状记忆功能、并在植入骨生长所需的生理环境后其多孔性保持超过约14天的基质,其包括不溶性的矿化生物聚合体纤维、药物和通过交联可变为不溶性的水溶性粘合剂。
3.如权利要求1或2所述的基质,其中所述基质可从其初始大小、形状和多孔性状态下被压缩,并可从压缩状态回复,而所述纤维或粘合剂无实质性损失。
4.如权利要求1或2所述的基质,其中所述药物包括抗生素。
5.如权利要求1或2所述的基质,其还含有生长因子。
6.如权利要求1或2所述的基质,其还含有骨髓。
7.如权利要求1或2所述的基质,其中所述粘合剂选自可溶胶原蛋白、明胶、聚乳酸、聚乙醇酸、乳酸和乙醇酸共聚物、聚己酸内酯、羧甲基纤维素、纤维素酯、葡萄糖、葡聚糖、脱乙酰壳多糖、透明质酸、ficol、硫酸软骨素、聚乙烯醇、聚丙烯酸、聚丙二醇、聚乙二醇、水溶性的聚丙烯酸酯和水溶性的聚甲基丙烯酸酯。
8.如权利要求1或2所述的基质,其中所述生物聚合体包括纤丝状胶原蛋白。
9.如权利要求1或2所述的基质,其中所述矿质包括羟基磷灰石。
10.如权利要求2所述的基质,其中所述矿质在骨置换期间,随时间释放进入所述生理环境,并在所述时间内保持所述多孔性。
11.如权利要求1或2所述的基质,其中所述矿化生物聚合体纤维以含约30-95%重量胶原蛋白的矿化胶原蛋白的形式存在。
12.权利要求1或2所述的基质,其还包括自体骨。
13.一种修复纤维组织或软骨的方法,其包括以下步骤:在修复的目标部位引入一种组合物,所述组合物包括有效量的多孔、可生物降解、三维固定的具有形状记忆功能的基质,该基质包括不溶性的矿化生物聚合体纤维和通过交联可变为不溶性的水溶性粘合剂,所述组合物足以促使新的纤维组织或软骨形成。
14.一种修复纤维组织、软骨或骨骼的方法,其包括以下步骤:
(a)在修复的目标部位引入运送载体,所述载体含多孔、可生物降解、三维固定的具有形状记忆功能的基质,该基质包括不溶性的矿化生物聚合体纤维和通过交联可变为不溶性的水溶性粘合剂,以一种与所述基质初始大小、形状和多孔性相关的压缩状态存在;
(b)从所述运送载体中释放所述基质,由此所述基质回复到所述初始大小、形状和多孔性。
15.如权利要求13或14所述的方法,其中所述基质回复为所述的初始大小、形状和多孔性,而所述纤维和粘合剂的量不发生实质性的损失。
16.如权利要求13或14所述的方法,其中所述基质还包括添加剂。
17.如权利要求16所述的方法,其中所述添加剂包括药物。
18.如权利要求17所述的方法,其中所述药物包括抗生素。
19.如权利要求16所述的方法,其中所述添加剂包括生长因子。
20.如权利要求13或14所述的方法,其中所述基质还包括骨髓。
21.如权利要求13或14所述的方法,其中所述粘合剂选自可溶胶原蛋白、明胶、聚乳酸、聚乙醇酸、乳酸和乙醇酸共聚物、聚己酸内酯、羧甲基纤维素、纤维素酯、葡萄糖、葡聚糖、脱乙酰壳多糖、透明质酸、ficol、硫酸软骨素、聚乙烯醇、聚丙烯酸、聚丙二醇、聚乙二醇、水溶性的聚丙烯酸酯和水溶性的聚甲基丙烯酸酯。
22.如权利要求13或14所述的方法,其中所述生物聚合体包括纤丝状胶原蛋白。
23.如权利要求13或14所述的方法,其中所述矿化生物聚合体纤维的矿质包括羟基磷灰石。
24.如权利要求13或14所述的方法,其中所述基质包括胶原蛋白和固定化的磷酸钙,以含约30-95%重量胶原蛋白的矿化胶原蛋白的形式存在。
25.如权利要求13或14所述的方法,其中所述基质还包括自体骨。
26.如权利要求21所述的方法,其中所述粘合剂包括可溶胶原蛋白。
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