CN101721233A - 止血植入体 - Google Patents

止血植入体 Download PDF

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CN101721233A
CN101721233A CN200910179890A CN200910179890A CN101721233A CN 101721233 A CN101721233 A CN 101721233A CN 200910179890 A CN200910179890 A CN 200910179890A CN 200910179890 A CN200910179890 A CN 200910179890A CN 101721233 A CN101721233 A CN 101721233A
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史蒂文·贝内特
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Abstract

本公开涉及一种止血植入体，其包含多孔基质，该多孔基质具有以下述方式对其施加的第一水凝胶前体和第二水凝胶前体，即，直到植入体被置于植入部位并暴露于患者的生理液体前，第一水凝胶前体和第二水凝胶前体不相互反应。

Description

止血植入体
相关申请
本申请要求于2008年10月17日提交的美国临时申请No.61/196,543的优先权。
技术领域
此公开涉及植入体，更具体而言涉及止血植入体，该植入体包含多孔基质，该多孔基质具有对其施加的第一水凝胶前体和第二水凝胶前体。
背景技术
原位止血治疗主要集中于将患者体内的前体溶液转换成固体。用多种手段实现该转换，包括沉淀、聚合、交联和去溶剂。但是，用溶液原位止血治疗时存在明显的局限性。低粘度的溶液可能流走，并在转换和凝固发生前从施用部位被清除。此外，溶液的配方可能很复杂，如前体溶液的制备通常需要前体的重组，或者，当溶液被冷冻贮存时需解冻。
因此，最好能提供原位止血治疗，其包括与那些在水溶性生理液体存在被激活的干燥材料结合的可植入装置。可植入装置与干燥材料的结合能确保原位止血治疗在植入部位起效。
发明内容
本植入体包括多孔基质，其具有对该多孔基质第一部分施加的第一水凝胶前体和对该多孔基质第二部分施加的第二水凝胶前体。在实施方式中，对多孔基质施加作为膜的第一或第二水凝胶前体中的至少一种。在实施方式中，直到植入体被置于植入部位并暴露于患者的生理液体之前，具有对其施加了第一水凝胶前体的基质的第一部分与多孔基质的第二部分在空间上分离，以防止第一和第二水凝胶前体相互反应。将植入体暴露于生理液体引起第一水凝胶前体从多孔基质的第一部分移行到多孔基质的第二部分并与第二水凝胶前体反应。在实施方式中，本植入体在带涂层的多孔基质部分不仅显示出止血性能而且显示出抗粘连性能。
对在出血部位原位形成止血剂的方法也有所说明。按照此方法，放置具有多孔基质的植入体使其与患者的生理液体接触，该多孔基质具有施加到其第一部分的第一水凝胶前体和施加到其第二部分的第二水凝胶前体。确定植入体的方向为，第一部分比第二部分更接近患者的组织。这样定向的植入体随后与患者的组织接触，使生理液体通过多孔基质被吸入，接着溶解第一水凝胶前体，然后溶解第二水凝胶前体涂层。一经溶解，第一和第二水凝胶前体相互反应形成一种生物相容性交联材料。在实施方式中，将第一水凝胶前体作为膜施加于基质的第一部分。经与生理液体接触，该膜溶解，且第一前体被吸入到多孔基质与第二水凝胶前体接触，以形成生物相容性交联材料。
附图说明
附图已被纳入并构成本说明书的一部分，公开的示例性实施方式，连同上述公开的概括说明，以及下面给出的对实施方式的详细说明，用于解释公开的本质。
图1A-D示意性显示了：如本公开中至少一个实施方式所述，对多孔基质施加第一和第二水凝胶前体；
图2示意性显示了图1A-1C所示的实施方式的变化；
图3示意性显示了图1A-1C所示的实施方式的另一变化；
图4A-C示意性显示了：如本公开中至少一个实施方式所述，对多孔基质施加第一水凝胶前体；
图5A-C示意性显示了：如本公开中至少一个实施方式所述，对已施加了第一水凝胶前体的多孔基质施加含有第二水凝胶前体的颗粒；
图6A-C示意性显示了：如本公开中至少一个实施方式所述，对已施加了第一水凝胶前体的多孔基质施加含有第二水凝胶前体的膜；
图7A-B示意性显示了同时形成包含第一水凝胶前体的泡沫和泡沫多孔基质；以及
图8A-C示意性显示了：如本公开中至少一个实施方式所述，对已施加了第一水凝胶前体的多孔基质施加包含第二水凝胶前体的颗粒；
图9A-C示意性显示了：如本公开中至少一个实施方式所述，对已施加了第一水凝胶前体的多孔基质施加含有第二水凝胶前体的膜；
图10示意性显示了：如本公开中至少一个实施方式所述，一种针织纤维性多孔基质，该多孔基质具有包含施加于其第一部分的第一水凝胶前体的颗粒和包含施加于其第二部分的第二水凝胶前体的膜；
图11示意性显示了：如本公开中至少一个实施方式所述，一种针织纤维性多孔基质，该多孔基质具有包含施加于其第一部分的第一水凝胶前体的涂层和包含施加于其第二部分的第二水凝胶前体的膜；以及
图12示意性显示了：如本公开中至少一个实施方式所述，一种无纺纤维性多孔基质，该多孔基质具有包含施加于其第一部分的第一水凝胶前体的颗粒和包含施加于其第二部分的第二水凝胶前体的膜。
具体实施方式
根据此公开的止血植入体包含多孔基质，该多孔基质具有对此多孔基质第一部分施加的第一水凝胶前体和对此多孔基质第二部分施加的第二水凝胶前体。使用时，确定植入体的方向为，施加第一水凝胶前体的部分更靠近组织，具有对其施加的第二水凝胶前体的部分远离组织。在实施方式中，第一和第二部分可以通过添加对比染料、表面纹理、颜色或其他视觉线索而相互区别。例如，一旦接触组织，如受伤的组织，植入体将吸收生理液体且第一水凝胶将被液体溶解。由于液体被吸入并迁移透过植入体，它会带着溶解的第一水凝胶前体一直通过植入体。最后，液体将移动通过植入体足以达到施加了第二水凝胶前体的第二部分，从而溶解第二水凝胶前体。然后，第一和第二水凝胶前体反应以形成生物相容性交联材料，从而协助止血。在一些实施方式中，由第一和第二水凝胶前体反应生成的生物相容性交联材料，不仅具有止血性能还具有防粘连性能。
植入体的多孔基质在其表面的至少一部分具有开口或孔隙。孔隙可以在植入前或植入后在基质中形成。如下详述，形成多孔基质的合适材料包括但不限于：纤维结构(例如，针织结构、纺织结构、无纺结构等)和/或泡沫(例如，开孔或闭孔泡沫)。在实施方式中，孔隙可能有足够的数量和大小以相互连接穿过整个多孔基质的厚度。纺织物、针织物和开孔泡沫是孔隙能够有足够的数量和大小以相互连接穿过整个多孔基质厚度的结构的例证性例子。在一些实施方式中，孔隙不相互连接穿过整个多孔基质的厚度。闭孔泡沫或带胶无纺材料(fused non-woven material)是孔隙不相互连接穿过整个多孔基质厚度的结构的例证性例子。泡沫多孔基质的孔隙可跨越整个多孔基质的厚度。还有一些实施方式，孔隙不扩展到多孔基质的整个厚度，而是处于其厚度的一部分。在实施方式中，开口或孔隙位于多孔基质表面的一部分，而多孔基质的其他部分具有非多孔质地。在其他的实施方式中，孔隙可以在原位植入后形成。可采用任何适合的方法原位进行孔隙的形成。一些非限制的例子包括接触石刷术、活性自由基光敏聚合物(LRPP)体系和盐沥滤法的使用。阅读了本公开的本领域技术人员将可以预想其他的多孔基质的孔隙分布形式和布局。
如果多孔基质为纤维性，这种纤维可以是适合针织或纺织的丝或线，或者可为切断纤维(staple fiber)，如那些经常用于制备无纺材料的纤维。该纤维可由任何生物相容性材料制成。因此，这种纤维可由天然材料或合成材料形成。形成纤维的材料可以是生物吸收性的或非生物吸收性的。显然应该了解的是，可将任何天然、合成、生物吸收性和非生物吸收性材料的组合用于形成该纤维。制造纤维的材料的一些非限制性例子包括但不限于聚(乳酸)、聚(羟基乙酸)、聚(丙交酯)、聚(乙交酯)、聚(三亚甲基碳酸酯)、聚(对二氧环己酮)(poly(dioxanone))、聚(羟基丁酸酯)、聚(膦嗪)、聚酯、聚对苯二甲酸乙二酯、超聚合物量聚乙烯、聚乙二醇、聚氧化乙烯、聚丙烯酰胺、聚甲基丙烯酸羟乙酯、聚乙烯吡咯烷酮、聚乙烯醇、聚丙烯酸、聚乙酸酯、聚己内酯、聚丙烯、脂肪族聚酯、甘油、聚(氨基酸)、(醚-酯)共聚物、聚亚烃基草酸酯、多糖、聚酰胺、聚(碳酸亚胺酯)、聚亚烃基草酸酯、聚草酸酯、聚原酸酯、聚磷腈、生物聚合物、聚合物药物和共聚物、嵌段共聚物、均聚物、共混物及其组合物。
如果多孔基质为纤维性，可使用任何适合形成纤维结构的方法形成多孔结构，其包括但不限于针织、纺织、无纺技术、湿纺法、电纺法、挤压法，共挤压法等。制备纤维结构的适合技术是在本领域技术人员的技术范围内。在实施方式中，纺织物具有三维结构，如美国专利No.7,021,086和6,443,964所述的纺织物，其公开的内容以引用的方式全文并入本文。
在实施方式中，多孔基质由氧化纤维素的纤维制成。这种材料是已知的，且包括商品名称为
Figure G2009101798906D0000061
的市售可得的氧化纤维素止血材料。制备氧化纤维素止血材料的方法对于本领域技术人员是已知的，而且已被公开，如美国专利Nos.3,364,200、4,626,253、5,484,913和6,500,777，其公开的内容以引用的方式全文并入本文。
多孔基质为泡沫材料时，该多孔基质可使用任何适合形成泡沫或海绵的方法形成，其包括但不限于对组合物的冻干或冷冻干燥。泡沫可以为交联的或不交联的，并可以包含共价键或离子键。制备泡沫的适合技术是在本领域技术人员的技术范围内。
多孔基质可为至少0.1厘米厚，在实施方式中为约0.2～约1.5厘米厚。多孔基质中孔隙大小可为约2微米～约300微米，在实施方式中为约50微米～约150微米。可以预见，可以以任何方式在基质中排列基质的孔隙。例如，可以以随机或均匀的方式分布空隙。在一些实施方式中，可通过使用藻酸铜形成空隙来产生蜂巢状的多孔基质。在另外一些实施方式中，可分布孔隙以在多孔基质中形成梯度。该梯度可进一步提高多孔基质的吸收生理液体的能力，并引导携带第一水凝胶前体的生理液体向第二水凝胶前体移动。
在实施方式中，植入体是由非变性胶原或由通过加热或任何其他方式至少已部分失去其螺旋结构的胶原制成，其主要由非水解α链组成，分子量接近100KDa。术语“非变性胶原”是指没有失去其螺旋结构的胶原。本植入体中用于植入体的胶原可为天然胶原或缺端胶原(atelocollagen)，特别是通过胃蛋白酶消化和/或在如先前定义的适度加热后获得的胶原。胶原可以通过氧化、甲基化、乙基化、琥珀酰化或其他任何已知的方法被预先化学修饰。胶原也可和任何适合的交联剂交联，如京尼平(genipin)、异氰酸酯及醛。胶原的来源和类型可如上述对非植入体的描述。
在实施方式中，植入体可以通过将浓度为2～50g/l、初始温度为4～25℃的胶原的酸性水溶液冷冻干燥获得。胶原在溶液中的浓度可为约1g/l～约30g/l，在实施方式中为约10g/l。此溶液有利地中和为pH值约6～8。
植入体也可以通过冷冻干燥由胶原或加热胶原的溶液制备的流体泡沫，并分别在不同量体积的空气(空气的体积：水的体积在约1～约10间变化)存在下乳化获得。
多孔基质具有对其施加的第一个水凝胶前体和对其施加的第二水凝胶前体。术语“第一水凝胶前体”和“第二水凝胶前体”各自指可参与反应以形成网状交联分子的聚合物、功能聚合物、大分子、小分子或交联剂，例如，水凝胶。
在实施方式中，第一或第二水凝胶前体中的至少一种是约1000Da以下的小分子，且其被称为“交联剂”。交联剂在水溶液中优选具有至少1g/100mL的溶解度。交联分子可以通过离子或共价键、物理作用力或其他吸引力交联。
在实施方式中，第一或第二水凝胶前体中的至少一种是大分子，且其被称为“功能聚合物”。当与交联剂反应结合时，大分子的分子量优选至少比小分子交联剂大5～50倍，且可以小于约60,000Da。在实施方式中，大分子的分子量比所用的交联剂大7～30倍，而且，在实施方式中所用大分子的重量有约10～20倍的不同。此外，所用的是分子量为5,000～50,000的大分子。此处所用的术语聚合物，是指由至少3个重复基团形成的分子。
第一和第二水凝胶前体都是多官能的，也就是说，它包括两个以上亲电子或亲核官能团，即，例如，第一水凝胶前体的亲核官能团可与第二水凝胶前体的亲电子官能团反应形成共价键。第一或第二水凝胶前体中的至少一中包含两种以上的官能团，这样，由于亲电子-亲核反应，前体结合形成交联聚合产物。此反应被称为“交联反应”。
在实施方式中，第一和第二水凝胶前体都只包含一类官能团，或者只有亲核官能团或者只有亲电子官能团，只要是亲核和亲电子前体都被用于交联反应中。因此，举例来说，如果第一水凝胶前体具有如胺的亲核官能团，则第二水凝胶前体可具有如N-羟基琥珀酰亚胺的亲电子官能团。另一方面，如果第一水凝胶前体具有如磺基琥珀酰亚胺的亲电子官能团，则第二水凝胶前体可具有如胺或硫醇的亲核官能团。因此，可以使用功能聚合物，如蛋白质、聚(烯丙胺)、苯乙烯磺酸或胺-封端的双或多官能聚(乙二醇)(PEG)。
第一和第二水凝胶前体可具有无生物活性和水溶性的内核。当聚合物的内核是水溶性聚合区域时，优选的可用聚合物包括：聚醚，例如，聚环氧烷如聚乙二醇(“PEG”)、聚氧化乙烯(“PEO”)，聚氧化乙烯聚氧化丙烯共聚物(“PPO”)、聚氧化乙烯嵌段共聚物或无规共聚物和聚乙烯醇(“PVA”)；聚(乙烯吡咯烷酮)(“PVP”)；聚(氨基酸)；多糖，如葡聚糖、壳聚糖、海藻酸盐、羧甲基纤维素、氧化纤维素、羟乙基纤维素、羟甲基纤维素、透明质酸；以及蛋白质，如白蛋白、胶原、酪蛋白和明胶。聚醚，更具体而言是聚(氧化烯)或聚(乙二醇)或聚乙二醇特别被使用。当内核实际上是小分子时，多种亲水性功能体的任一个都可以用来使第一和第二水凝胶前体溶于水。例如，像羟基、胺、磺酸盐和羧酸盐的水溶性官能团，可以用来使前体溶于水。此外，N-羟基琥珀酰亚胺(“NHS”)硬脂酸酯不溶于水，但通过向琥珀酰亚胺环上增加一个磺酸盐基团，可使NHS硬脂酸酯溶于水，而不影响其对胺基的活性。
假如有需要，从第一和第二水凝胶前体的反应产生的生物相容性交联聚合物是可生物降解的或可吸收的，一种或多种第一和第二水凝胶前体可在官能团间存在可生物降解的键。可选的，可生物降解的键也可以作为一种或多种前体的水溶性内核。替代或补充的，也可以选择第一和第二水凝胶前体的官能团，以使它们之间的反应产物产生可生物降解的键。对于每一种方法，可以选择可生物降解的键，以使得到的可生物降解的生物相容性交联聚合物会在所需时间内降解、溶解或被吸收。优选地，选择在生理条件下降解为无毒产物的可生物降解的键。
可生物降解性的键，可为螯合物、可化学或酶水解或吸收。示例性的可化学水解的可生物降解键，包括乙交酯、消旋-丙交酯、左旋-丙交酯、己内酯、二噁烷酮和碳酸亚丙酯的聚合物、共聚物和低聚物。示例性的可酶水解的可生物降解键，包括可由金属蛋白酶和胶原酶裂解的肽键。示例性的其他可生物降解键，包括多(羟基酸)、聚(原碳酸酯)、聚(酸酐)，聚(内酯)，聚(氨基酸)，聚(碳酸酯)，多糖和聚(膦酸酯)的聚合物和共聚物。
在实施方式中，可生物降解的连接可含有酯键。一些非限制的例子包括琥珀酸、戊二酸、丙酸、己二酸或氨基酸的酯，以及羧甲基醚。
在实施方式中，可将如三赖氨酸的多官能亲核聚合物用作第一水凝胶前体，而将如用多个NHS基团官能化的多臂PEG的多官能亲核聚合物用作第二水凝胶前体。例如，用多个NHS基团官能化的多臂PEG可具有四、六或八臂，且具有约5,000～约25,000的分子量。许多其他合适的第一和第二前体的例子记载于美国专利Nos.6,152,943；6,165,201；6,179,862；6,514,534；6,566,406；6,605,294；6,673,093；6,703,047；6,818,018；7,009,034和7,347,850中，其各自公开的全部内容通过引用方式并入本文。
将第一水凝胶前体施加于多孔基质的第一部分而将第二水凝胶前体施加于多孔基质的第二部分。例如，前体可以在干燥的形式下使用，例如颗粒状物质或为如膜或泡沫的固体或半固体状态。在实施方式中，第一或第二水凝胶前体中的至少一种是以膜施加于多孔基质。在实施方式中，具有对其施加了第一水凝胶前体的基质的第一部分与具有对其施加了第二水凝胶前体的基质的第二部分在空间上分离。第一和第二水凝胶前体在空间上相互分离防止了在植入体被置于植入部位并接触患者的生理液体前第一和第二水凝胶前体相互反应。
可使用任何本领域技术人员已知的合适方法对多孔基质施加第一水凝胶前体，该方法包括但不限于喷涂、刷涂、浸渍、浇注、层压等。在实施方式中，可将第一水凝胶前体在形成多孔基质前与多孔基质结合。在其他实施方式中，可将第一水凝胶前体在基质形成后置于多孔基质的孔隙内或多孔基质的表面上。在又一其他实施方式中，可在施加第一水凝胶前体前压延多孔基质，从而使第一前体穿透基质上在压延过程中形成的开口。在又一其他一些实施方式中，可在溶液中对多孔基质施加第一水凝胶前体，然后蒸发或者冻干溶剂。在实施方式中，可将第一水凝胶前体作为涂层施加于多孔基质的至少一面或者作为膜层压到基质的至少一面。
同样，可使用任何本领域技术人员已知的合适方法对多孔基质施加第二水凝胶前体，该方法包括但不限于喷涂、刷涂、浸渍、浇注、层压等。在实施方式中，第二水凝胶前体可以任何能形成止血植入体的浓度、尺寸和形状作为涂层施加于基质上。在实施方式中，第二水凝胶前体涂层可穿透多孔基质的孔隙。涂层可形成无孔层或多孔层。在实施方式中，第二水凝胶前体可作为层压在基质的至少一面上的膜被施加于多孔基质。
在实施方式中，当第一或第二水凝胶前体中的任一种形成无孔层，即膜时，膜的厚度可足以使在植入体封闭伤口前仅有部分水凝胶前体与其他水凝胶前体反应。在这些实施方式中，剩余的未反应的水凝胶膜可充当伤口与周围组织的屏障层，以防止粘连的形成。在形成水凝胶植入体中，前体也可赋予生理液体某些特性，如抗粘连性。生理液体水凝胶也可充当伤口与周围组织的屏障层，以防止粘连的形成。在实施方式中，多孔基质还可包含已知能减少或防止粘连的如透明质酸等的非活性材料。在这些实施方式中，非活性物质可防止第一和第二水凝胶前体相互作用后粘连的形成。
除了能够止血以外，植入体还可用于生物活性剂的传送。因此，在一些实施方式中，至少一个生物活性剂可与第一水凝胶前体或第二水凝胶前体中的任一种结合和/或分别施加于多孔基质。试剂可游离地与前体混合，或者可通过多种化学键的任一种与前体链接。在这些实施方式中，本植入体也可作为传递生物活性剂的载体。此处使用的术语“生物活性剂”，意为其最广泛的意义，并包括任何有临床用途的物质或物质混合物。因此，生物活性剂本身可以或不可以具有药理活性，例如，染料或香料。或者，生物活性剂可以是任何具有治疗或预防效果的试剂，影响或参与组织生长、细胞生长、细胞分化的化合物，抗粘连化合物，能引起如免疫反应的生物反应或者可以在一个或多个生物过程中具有任何其他作用的化合物。可以预见的，生物活性剂可以以任何适当的物质形式应用于本植入体，例如，膜、粉末、液体。凝胶等。
根据本公开可利用的生物活性剂的种类的例子包括抗粘连剂、抗微生物药、镇痛剂、退热剂、麻醉剂、抗癫痫剂、抗组胺剂、消炎剂、心血管药物、诊断试剂、拟交感神经药、拟胆碱能剂、抗毒蕈碱药、镇痉剂、激素、生长因子、肌肉松弛剂、肾上腺素能神经元阻滞剂、抗肿瘤药、免疫原性剂、免疫抑制剂、胃肠药物、利尿剂、类固醇、脂类、脂多糖类、多糖、血小板活化药物、凝血因子和酶。同样意指的是，可组合使用生物活性试剂。
可将抗粘连剂用于防止植入式医疗装置与靶组织对面的周围组织之间形成粘连。此外，可将抗粘结剂用于防止植入式医疗装置涂层与包装材料之间形成粘连。这些试剂的一些例子包括但不仅限于亲水性聚合物，如聚(乙烯基吡咯烷酮)、羧甲基纤维素、透明质酸、聚氧化乙烯、聚乙烯醇及其组合物。
可包含于本公开的生物活性涂层中作为生物活性剂的适合抗微生物剂包括：三氯生、也被称为2，4，4′-三氯-2′-羟基二苯醚；双氯苯双胍己烷及其盐，包括醋酸双氯苯双胍己烷、葡萄糖酸双氯苯双胍己烷、盐酸双氯苯双胍己烷和硫酸洗必泰；银及其盐，包括醋酸银、苯甲酸银、碳酸银、柠檬酸银、碘酸银、碘化银、乳酸银、月桂酸银、硝酸银、氧化银、棕榈酸银、蛋白银和磺胺嘧啶银；多粘菌素；四环素；氨基糖甙类，如妥布霉素和庆大霉素；甲哌利福霉素(利福平)；杆菌肽；新霉素；氯霉素；咪康唑；喹诺酮类，如噁喹酸、诺氟沙星、萘啶酸、培氟沙星、依诺沙星、环丙沙星；青霉素类如苯唑西林和哌拉西林；壬苯醇醚9；夫西地酸；头孢菌素；及其组合。此外，本公开的生物活性涂层中可包含作为生物活性剂的抗微生物蛋白和肽，如牛乳铁蛋白和乳铁蛋白B。
按照本公开施加的可作为涂层组合物中包含的生物活性剂的其他生物活性剂包括：局部麻醉剂；非甾体类抗生育剂；拟副交感神经剂；精神治疗剂；镇静剂；减充血剂；镇静催眠剂；类固醇；磺胺药剂；拟交感神经剂；疫苗；维生素；抗疟疾剂；抗偏头痛剂；抗帕金森剂如左旋多巴；抗痉挛剂；抗胆碱能剂(如奥昔布宁)；镇咳剂；支气管扩张剂；心血管药物如冠状血管扩张药物和硝酸甘油；生物碱；镇痛剂；麻醉剂如可待因、二氢可待因酮、度冷丁、吗啡等；非麻醉剂如水杨酸盐、阿司匹林、对乙酰氨基酚、d-丙氧酚等；阿片受体拮抗剂，如纳曲酮和纳洛酮；抗癌药物；抗惊厥药；止吐药；抗组胺剂，抗炎剂如激素制剂、氢化可的松、泼尼松龙、泼尼松、非激素制剂、别嘌呤醇、吲哚美辛、苯丁唑酮等；前列腺素及胞毒药物；化学治疗剂，雌激素；抗菌剂；抗生素；抗真菌剂；抗病毒剂；抗凝血剂；抗抽搐药；抗抑郁剂；抗组胺剂和免疫制剂。
其他可包含在涂层组合物中的适合的生物活性剂的例子包括：病毒和细胞，肽，多肽和蛋白质，同工体(analog)，突变蛋白及其活性片段，如免疫球蛋白，抗体，细胞活素(如淋巴因子、单核因子、化学增活素)，凝血因子，造血因子，白介素(IL-2、IL-3、IL-4、IL-6)，干扰素(β-IFN、(α-IFN和γ-IFN))，促红细胞生成素，核酸酶，肿瘤坏死因子，集落刺激因子(如，GCSF、GM-CSF、MCSF)，胰岛素，抗肿瘤剂和肿瘤抑制剂，血蛋白(bloodprotein)，纤维蛋白，凝血酶，纤维蛋白原，合成凝血酶，合成纤维蛋白，合成纤维蛋白原，促性腺激素(例如，FSH、LH、CG等)，激素及激素类似物(如生长激素)，疫苗(如肿瘤、细菌和病毒抗原)；生长抑素；抗原；凝血因子；生长因子(如神经生长因子、胰岛素样生长因子)，成骨蛋白，TGF-B，蛋白抑制剂，蛋白拮抗剂以及蛋白激动剂；核酸，如反义分子、DNA、RNA、RNAi；寡核苷酸；多核苷酸以及核酶。
现在转到图1A-D，其显示了一个顺序，其中，将第一水凝胶前体施加于多孔基质的孔隙中并将第二水凝胶前体施加于多孔基质的第二部分。在图1A中，多孔基质20是具有多个局限于基质内的孔隙25的泡沫。将包含溶于溶剂的第一水凝胶前体的溶液35贮存在容器19中。将多孔基质20浸入并完全淹没在溶液35中。如图1B所示，取出后，干燥植入体，从溶液35中去除溶剂并在基质20的孔隙25中沉积了包含第一水凝胶前体30的颗粒。
在图1C中，将包含第一水凝胶前体的多孔基质20与第二水凝胶前体的熔体45接触。冷却后，第二水凝胶前体的熔体45会固化形成覆盖在基质20的至少一部分的膜40。施加第二前体的膜40后，可将植入体修整成任何所需的尺寸和形状。图1D显示了具有第一水凝胶前体和第二水凝胶前体的植入体10，将颗粒30形式的第一水凝胶前体施加于多孔基质20的第一部分22，而将膜40形式的第二水凝胶前体施加于多孔基质20的第二部分24。
除了多孔基质120为具有对其施加的颗粒130形式的第一水凝胶前体和以对其施加的膜140形式第二水凝胶前体的网状材料外，以与图1A-D顺序所示类似的方式制备图2的植入体110。预判可使用无纺布材料(未显示)代替图1A-D所示的泡沫或图2所示的网状物作为多孔基质。
除了多孔基质220为具有对其施加的涂层230形式的第一水凝胶前体和对其施加的膜240形式的第二水凝胶前体的网状材料外，以与图1A-D顺序所示类似的方式制备图3的植入体210。第一水凝胶前体的涂层230可通过将多孔基质220浸入到第一水凝胶前体的溶液或第一水凝胶前体的熔融物中形成。或者，第一水凝胶前体可在施加于基质前与成膜聚合物结合而得到涂层230。阅读了本公开的本领域技术人员将可以预想到将包含第一水凝胶前体的涂层施加于基质的其他方法和材料。
现在转到图4A-C，其显示了一个顺序，其中，将第一水凝胶前体施加于多孔基质的第一部分。在图4A中，多孔基质320是具有多个局限于其内的孔隙325的泡沫材料，其至少具有第一部分322和第二部分324。将包含溶于溶剂的第一水凝胶前体的溶液335贮存在容器319中。将多孔基质320置于溶液335中，其第一部分322朝向溶液335而第二部分324背离溶液335。
在图4B中，如图4A的箭头表示，通过将多孔基质320向溶液335的方向移动，将多孔基质320的第一部分322部分浸入溶液335中。只有多孔基质320的第一部分322与溶液335接触，因此可将足够量的溶液335施加并填充多孔基质320的第一部分322的孔隙325。如图4C所示，取出后，干燥植入体，去除溶液335中的溶剂，并将包含第一水凝胶前体330的颗粒沉积在第一部分322内。颗粒330包含干燥形式的第一水凝胶前体且在空间上局限在第一部分322中。
在图5A-5C中，显示了一个顺序，其中，将包含溶于溶剂的第二水凝胶前体的溶液345施加于多孔基质320的第二部分324，其中包含第一水凝胶前体的颗粒330之前已进入多孔基质320的第一部分322(见图4A-4C)。将多孔基质320置于溶液345中，其第二部分324朝向溶液345而第一部分322背离溶液345。
如图5B所示，如图5A的箭头所示，通过将多孔基质320向溶液345的方向移动，将多孔基质320的第二部分324部分浸入溶液345中。只有多孔基质320的第二部分324与溶液345接触，因此可将足够量的溶液345施加于第二部分324。取出后，干燥植入体以使包含第二水凝胶前体的颗粒340沉积于第二部分324内。颗粒340包含干燥形式的第二水凝胶前体且空间上局限在第二部分324中。图5C所示的多孔基质320，其具有施加于基质第一部分的第一水凝胶前体和施加于多孔基质第二部分的第二水凝胶前体，且基质的第一部分与多孔基质的第二部分在空间上分离。
另外的实施方式中，可以不同的形式对植入体施加第一和第二水凝胶前体。例如，在图6A-6C中，显示的多孔基质含有包含施加于第一部分422的第一水凝胶前体的颗粒430，并且第二部分424朝向包含已施加于支撑体429的第二水凝胶前体的成膜溶液445A。
在图6B中，通过将多孔基质420按图6A中箭头所示的方向移动，使多孔基质420的第二部分424与成膜溶液445接触并且/或者部分浸入成膜溶液445中。只有多孔基质420的第二部分424与成膜溶液445接触，因此可将足量的445材料施加于第二部分424。将成膜溶液445固化(加热或不加热)形成膜覆盖第二部分424的至少一部分。图6C所示的多孔基质420，其具有施加于基质第一部分的颗粒形式的第一水凝胶前体和施加于多孔基质第二部分的膜形式的第二水凝胶前体，且基质的第一部分与多孔基质的第二部分在空间上分离。
现在转到图7A-7B，显示的是一起形成多孔基质和包含第一水凝胶前体的多孔层。在图7A中，容器519包含预定形成多孔基质的溶液525和含有第一水凝胶前体的第二溶液535，其中，两种溶液实际上保持在分离的层中。采用本领域技术人员已知的任何方法将两种溶液冻干以形成如图7B所示的多孔基质，该多孔基质包括与由第二溶液535冻干制得的第二多孔层530的由第一溶液525冻干制得的第一多孔基质520。第二多孔层530包含了第一水凝胶前体，并通过第一部分522连接到第一多孔基质520上以形成具有两层多孔材料的植入体。
在图8A-8C中，显示了一个顺序，其中，将包含第二水凝胶前体的溶液545施加于多孔基质520的第二部分524，其中多孔基质520已具有包含与第一部分522的孔隙结合的第一水凝胶前体。将多孔基质520置于溶液545中，其第二部分524朝向溶液545而第一部分522和第二多孔层530背离溶液545。
如图8B所示，如图8A的箭头表示，通过将多孔基质520向溶液545的方向移动，将多孔基质520的第二部分524部分浸入具有溶于溶剂的第一水凝胶前体的溶液545中。只有多孔基质520的第二部分524与溶液545接触，因此可将足量的溶液545施加于第二部分524。取出后，干燥植入体或使其干燥以去除溶剂并使颗粒540沉积于第二部分524。第二颗粒540包含干燥形式的第二水凝胶前体且空间上局限在第二部分524中。图8C所示的多孔基质520，其具有施加于基质第一部分的泡沫形式的第一水凝胶前体和施加于多孔基质第二部分的颗粒形式的第二水凝胶前体，且基质的第一部分与多孔基质的第二部分在空间上分离。
在另一实施方式中，如图7B所示的多孔基质可与包含第二水凝胶前体的成膜材料结合。如图9A-9C所示，多孔基质620包括第一部分622和第二部分624，其中包含第一水凝胶前体的第二多孔层630在第一部分622与多孔基质620连接。所示第二部分624朝向施加于支撑体629的成膜溶液645。成膜材料645包含第二水凝胶前体和溶剂。
在图9B中，通过将多孔基质620按图9A中箭头所示的方向移动，将多孔基质620的第二部分624与成膜溶液645接触并且/或者部分浸入成膜溶液645中。只有多孔基质620的第二部分624与成膜溶液645接触，因此可将足量的645材料施加于第二部分624。成膜溶液645可以在第二部分624的至少一部分形成膜。图9C所示的多孔基质620，其具有施加于基质第一部分的泡沫形式的第一水凝胶前体和施加于多孔基质第二部分的膜形式的第二水凝胶前体，且基质的第一部分与多孔基质的第二部分在空间上分离。
应当理解的是，除了如图4-9所示的泡沫，多孔基质还可以是纤维结构。因此，在实施方式中，如图10-12的示意性显示，多孔基质可以是纤维结构，即，纺织或无纺结构。采用上述与对泡沫多孔基质20实质上相同的技术，将第一和第二水凝胶前体施加于纤维多孔基质。因此，如同上述泡沫多孔基质，当多孔基质是纤维性时，可施加第一和/或第二水凝胶前体，例如，从溶液中沉积颗粒、干燥成膜溶液形成的无孔膜，或者作为泡沫施加于纤维多孔基质的至少一部分。如图10所示，例如，植入体710包括针织多孔基质720，其包含多个局限于其中的孔隙725，且具有第一部分722和第二部分724。例如，以与上述对泡沫多孔基质20实质上相同的方式，如图4A-C所示，将包含干燥形式的第一水凝胶前体的颗粒730施加于第一部分722。例如，以与上述对泡沫多孔基质720实质上相同的方式，如图5A-C所示，将包含第二水凝胶前体的膜750施加于第二部分724。植入后，将第二部分750施加于需要止血的组织。一旦与组织接触，生理液体会渗透植入体710并以箭头A表示的方向移动，从而在到达颗粒730前与膜750相互作用并使其液化。可以预见，随着液体向基质720的第一部分722被吸入，膜750的溶液将与也将被生理液体溶解并混合的颗粒730接触。此混合将活化第一和第二前体，并使他们相互作用并交联以形成协助植入体止血功能的密封。在实施方式中，此新形成的水凝胶/生理液体植入体也起到粘连屏障的作用。
进一步的考虑，可从包含第一和/或第二水凝胶前体的熔体，而不是从溶液施加第一和/或第二水凝胶前体。例如，在图11中，植入体810包括具有第一部分822和第二部分824的针织多孔基质，其中第二部分824又包括了含有第二水凝胶前体的膜850。在此实施方式中，将第一水凝胶前体830从熔体作为涂层，而不是从溶液作为颗粒施加于第一部分822。如其所示，熔体830基本上涂覆了基质820的第一部分822的至少一部分纤维，同时使孔隙825保持足够的开口以允许流体通过多孔基质820移动。应当理解的是，涂层830可能是不连续的，使基质820的832部分可不被涂覆。
如上所述，多孔基质可以是无纺纤维多孔基质。例如，在图12中，植入体910以具有第一部分922和第二部分924的无纺多孔基质920显示，其中，将包含第一水凝胶前体的颗粒930施加于第一部分922而将包含第二水凝胶前体的膜940施加于第二部分924。
实施例
制备三赖氨酸的饱和硼酸盐缓冲溶液。该溶液每毫升溶液包含20.6毫克三赖氨酸。该溶液的pH值约为9.2。将一片氧化纤维素浸入溶液中，然后固定在架上干燥。将该架置于真空烘箱中。烘箱被泵抽吸到约50mTorr并在约25℃的温度保持约3天，以减少水汽水平至小于2wt％。将具有约15000分子量的八臂N-羟基琥珀酰亚胺基官能化聚乙二醇在约50℃的热板上熔化。放置含三赖氨酸的干燥的氧化纤维素片并使其与熔化的PEG组分接触。冷却后，PEG组分在植入体一面形成了膜。
将得到的产品修整成2英寸×2英寸的正方形，干燥并用箔容器包装。
在使用时，打开箔包装，将植入施加于流血的伤口，PEG膜的一面对着伤口。几秒钟之内，即产生止血作用。
可以理解的是，可以对本公开的实施方式做各种修改。例如，可将两种以上的前体施加于多孔基质以形成止血植入体。又例如，可各自以膜对多孔基质施加第一和第二前体。因此，本领域技术人员将可以设想在权利要求的实质和范围内的其他修改。

Claims (33)

1.一种植入体，该植入体包含多孔基质，所述多孔基质具有对该多孔基质施加的第一水凝胶前体和对该多孔基质施加的含有第二水凝胶前体的膜。
2.权利要求1所述的植入体，其中，所述多孔基质为泡沫。
3.权利要求1所述的植入体，其中，所述多孔基质为针织物。
4.权利要求1所述的植入体，其中，所述多孔基质为无纺布。
5.权利要求1所述的植入体，其中，所述多孔基质由生物吸收性材料制成。
6.权利要求1所述的植入体，其中，所述多孔基质由非生物吸收性材料制成。
7.权利要求1所述的植入体，其中，所述多孔基质由氧化纤维素制成。
8.权利要求1所述的植入体，其中，所述第一水凝胶前体包含颗粒。
9.权利要求1所述的植入体，其中，所述第一水凝胶前体为泡沫。
10.权利要求1所述的植入体，其中，所述第一水凝胶前体为膜。
11.权利要求1所述的植入体，其还包含生物活性剂。
12.一种植入体，该植入体包含多孔基质，所述多孔基质具有对该多孔基质的第一部分施加的第一水凝胶前体和对该多孔基质的第二部分施加的第二水凝胶前体，所述基质的第一部分与所述多孔基质的第二部分在空间上分离。
13.权利要求12所述的植入体，其中，所述多孔基质为泡沫。
14.权利要求12所述的植入体，其中，所述多孔基质为针织物。
15.权利要求12所述的植入体，其中，所述多孔基质为无纺布。
16.权利要求12所述的植入体，其中，所述多孔基质由生物吸收性材料制成。
17.权利要求12所述的植入体，其中，所述多孔基质由非生物吸收性材料制成。
18.权利要求12所述的植入体，其中，所述多孔基质由氧化纤维素制成。
19.权利要求12所述的植入体，其中，所述第一水凝胶前体包含颗粒。
20.权利要求12所述的植入体，其中，所述第一水凝胶前体为泡沫。
21.权利要求12所述的植入体，其中，所述第一水凝胶前体为膜。
22.权利要求12所述的植入体，其中，所述第二水凝胶前体包含颗粒。
23.权利要求12所述的植入体，其中，所述第二水凝胶前体为泡沫。
24.权利要求12所述的植入体，其中，所述第二水凝胶前体为膜。
25.权利要求12所述的植入体，其还包含生物活性剂。
26.一种方法，其包括
对多孔基质施加第一水凝胶前体；以及
对多孔基质施加含有第二水凝胶前体的膜。
27.权利要求26所述的方法，其中，对所述多孔基质施加第一水凝胶前体包括
至少将所述多孔基质的至少第一部分局部浸没于含所述第一水凝胶前体和溶剂的溶液中；以及
蒸发溶剂以使所述第一水凝胶前体沉积在所述多孔基质的孔隙中。
28.权利要求26所述的方法，其中，对所述多孔基质施加第一水凝胶前体包括
使所述多孔基质与含有所述第一水凝胶前体和溶剂的成膜组合物接触；以及
蒸发溶剂以使含有所述第一水凝胶前体的膜沉积在所述多孔基质的至少一部分上。
29.权利要求26所述的方法，其中，对所述多孔基质施加所述第一水凝胶前体包括
同时冷冻干燥第一和第二组合物，该第一组合物形成多孔基质，而含有所述第一水凝胶前体和溶剂的该第二组合物形成含有所述第一凝胶前体的泡沫。
30.一种方法，其包括
对多孔基质的第一部分施加第一水凝胶前体；
对所述多孔基质的第二部分施加第二水凝胶前体，
所述基质的第一部分与所述多孔基质的第二部分在空间上分离。
31.一种方法，其包括：
对具有施加到多孔基质第一部分的第一水凝胶前体和施加到多孔基质第二部分的第二水凝胶前体的多孔基质确定方向，使所述第一部分比第二部分更接近患者的组织；以及
使定向的植入体与患者的组织接触，藉此，生理液体通过所述多孔基质被吸入，接着溶解所述第一水凝胶前体，然后溶解所述第二水凝胶前体涂层。
32.权利要求20所述的方法，其中，对所述多孔基质施加作为膜的所述第一水凝胶前体。
33.权利要求20所述的方法，其中，所述基质的第一部分与所述多孔基质的第二部分在空间上分离。
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EP2179753A2 (en) 2010-04-28
ES2727816T3 (es) 2019-10-18
EP2179753A3 (en) 2011-01-12
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EP2815774A1 (en) 2014-12-24
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EP2815774B1 (en) 2016-12-14
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CA2682464A1 (en) 2010-04-17
CN101721233B (zh) 2014-07-09
ES2527302T3 (es) 2015-01-22
JP5793279B2 (ja) 2015-10-14
EP2177239A3 (en) 2011-01-12
US20100100123A1 (en) 2010-04-22
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EP2179753B1 (en) 2014-12-03

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