CN102753203A - 止血海绵 - Google Patents
止血海绵 Download PDFInfo
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- CN102753203A CN102753203A CN201080061630XA CN201080061630A CN102753203A CN 102753203 A CN102753203 A CN 102753203A CN 201080061630X A CN201080061630X A CN 201080061630XA CN 201080061630 A CN201080061630 A CN 201080061630A CN 102753203 A CN102753203 A CN 102753203A
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- sponge
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Abstract
本发明提供了一种止血复合海绵,其包含生物材料多孔基质和用于增强所述海绵对于被施用组织的粘附性的材料,施用时所述海绵的至少一个表面牢固地与所述被施用组织相连接;还提供了一种生产这些海绵的方法、以及它们在止血中的用途。
Description
技术领域
本发明涉及止血海绵领域,涉及所述海绵的生产方法和它们在止血中的应用。
背景技术
人们很早就知道基于人或者动物来源的凝血因子的生物胶。美国专利4,362,567、美国专利4,298,598和美国专利4,377,572已经描述了用于基于纤维蛋白原和凝血因子XIII的生产组织粘结剂的方法。这种组织粘结剂通常和含凝血酶的单独成分一起应用,凝血酶对纤维蛋白原有酶促作用以便形成纤维蛋白,对凝血因子XIII有酶促作用以便形成活性因子XIIIa,该活性因子XIIIa可与纤维蛋白交联以便得到稳定的纤维蛋白凝块。
胶原垫已经使用了很多年,以便改进伤口愈合或者终止流血。它们在止血中的作用机制是基于血小板凝集和活化,在活化的血小板表面上形成凝血酶,并且通过凝血酶在纤维蛋白原上的催化作用而形成止血纤维蛋白凝块。为了改进胶原垫或者胶原片的止血作用,建议在这种胶原垫内部包含止血因子。
在美国专利4,600,574中,描述了一种基于与纤维蛋白原和凝血因子XIII结合的胶原的组织粘结剂。此物质是以冻干的形式备用。通过用含纤维蛋白原和凝血因子XIII的溶液浸透胶原扁平材料,并且冻干所述材料,使纤维蛋白原和凝血因子XIII与胶原相结合。
WO97/37694公开一种基于胶原和均匀分布其中的凝血活化剂或者活化剂前体的止血海绵。该海绵以干燥形式提供,可以是空气干燥的或者冻干的。但是,它的含水率至少是2%。
美国专利5,614,587论述了含交联胶原(其通过使用多官能地活化的合成亲水聚合物进行交联)的生物粘结剂组合物,以及使用这种组合物以使第一表面和第二表面之间发生粘结的方法,其中第一和第二表面中的至少一个可以是天然组织表面。
美国专利5,428,024、美国专利5,352,715和美国专利5,204,382描述了含胶原的组合物被机械破坏,以便改变它们的物理性能。这些专利通常涉及纤维状的和不溶性的胶原。美国专利4,803,075描述了可注射的胶原组合物。美国专利5,516,532描述了可注射的骨/软骨组合物。WO96/39159描述了一种基于胶原的传递基质,该传递基质包含的干燥颗粒的尺寸的范围是5μm至850μm,该颗粒可以悬浮在水中并且具有特定的表面电荷密度。美国专利5,196,185描述了一种粒径是1μm至50μm的胶原制品,用作气溶胶喷雾剂以便形成伤口敷料。描述胶原组合物的其它专利包括美国专利5,672,336和美国专利5,356,614。
发明内容
本发明的主题涉及一种止血多孔复合海绵,其包含生物材料基质和用于增强所述海绵对于被施用组织的粘附性的材料,施用时所述海绵的至少一个表面牢固地与所述被施用组织相连接,其中所述材料基本上不含水凝胶形成成分。
人们已经发现,以前的用于伤口愈合的纤维状生物材料衬垫,尤其是胶原衬垫,在止血减损(impaired hemostasis)的状况下(例如在肝素化后)不能诱导止血。本发明的海绵可改善止血性。
人们进一步发现,如果另一种材料存在于生物基质材料的表面上作为活性止血层,则该层趋向于不稳定,因为所述另一种材料倾向于与海绵相分离,特别是在将海绵施用于组织上期间、并且当被调节成所述组织的几何形状时。
人们还发现,缺少其他水凝胶形成成分比如颗粒材料、例如明胶颗粒时,会有有利的特性,特别是就海绵总体而言具有较低的膨胀性质。
本发明的海绵可以克服这些缺陷。
本发明的另一个方面涉及一种制造止血多孔海绵的方法,该方法包括:
a)提供一种具有生物材料基质的多孔海绵,
b)提供一种用于增强所述海绵对于被施用组织的粘附性的材料,该材料呈悬浮液、溶液或者粉末形式,其中所述材料基本上不含水凝胶形成成分,
c)使得步骤a)的多孔海绵与步骤b)的材料相接触,以使得b)的材料牢固地与所述海绵的至少一个面相连接,从而得到止血复合海绵,任选地
d)对步骤c)中获得的复合海绵进行干燥,任选地
e)对在步骤c)或d)中获得的所述复合海绵进行灭菌。
本发明的另一个方面涉及一种处理损伤的方法,包括将止血多孔复合海绵给药至损伤位点。
本发明还提供一种用于制备伤口敷层的试剂盒,其包含在此公开的海绵和药物活性物质。该试剂盒及其组分尤其可用于制造用于处理损伤的医用海绵。
本领域的技术人员会容易地理解,下面所公开的优选的实施方式是具体的实施方式的例子,并不是必要地限制本发明的一般构思。此外,如果不是互相排斥的情况,所有具体的实施方式可以从任何组合的所有发明方面和实施方式上理解。本领域的技术人员认为的所有等同的或者显而易见的改变或变型都包括在本发明中。
具体实施方式
本发明的目的在于提供一种止血多孔复合海绵,其包含生物材料基质和用于增强所述海绵对于被施用组织的粘附性的材料,施用时所述海绵的至少一个表面牢固地与所述被施用组织相连接,其中所述材料基本上不含水凝胶形成成分。
根据本发明的术语“牢固地相连接”是指,在所述海绵施用于组织、并且调节成所述组织的几何形状期间,即使在施用期间海绵例如被弄弯时,用于增强所述海绵对于被施用组织的粘附性的材料也可与海绵稳固地保持连接。
优选生物材料是胶原、蛋白质、生物聚合物、或者多糖。特别优选生物材料选自下组:胶原,明胶,纤维蛋白,多糖例如壳聚糖、以及它们的衍生物。更多优选胶原和壳聚糖,特别优选胶原。
海绵是生物材料的多孔网络,当被施用于损伤位点时能吸附体液。另外,该海绵通常是柔韧的,并且适合于施用在具有不同形状的不同组织和位置上。
用于本发明的胶原能够选自任何适合于形成凝胶的胶原,包括能够被加工成多孔或纤维状基质的呈液体的、糊状的、纤维状的或者粉末的胶原性材料。用于生产海绵的胶原凝胶的制备例如在EP 0891193中有描述(将其引入本发明作为参考),并且可以包括酸化直至发生凝胶形成、和随后的pH中和。为了提高形成凝胶的能力或者溶解度,可以将胶原(部分地)水解或者改性,只要当被干燥时形成稳定海绵的特性不被减弱即可。
优选根据本发明的胶原海绵的密度比胶原薄膜的密度低。优选胶原海绵的密度是约至5至约100mg/cm3,相反胶原薄膜的密度是高于大约650mg/cm3。特别优选根据本发明的胶原海绵的商品名是Matristypt。
海绵基质的胶原或明胶优选是动物来源,优选牛的或者马的来源。然而,在病人对于异体蛋白质有超敏反应的情况下,也可以使用人类胶原。海绵中的其他组分优选是人类来源,这会使得所述海绵特别合适应用于人类。
在一种优选的实施方式中,用于形成海绵多孔网络的纤维状生物相容性聚合物的基质材料占干燥后多孔海绵的1-50w/w%、1-10w/w%、优选大约3w/w%。
在一种优选的实施方式中,用于增强所述海绵对于被施用组织的粘附性的材料,在下文中称为“(该)材料”,是两种预聚合物的混合物,该混合物包含第一可交联成分和第二可交联成分,第二可交联成分在可启动反应的条件下可与第一可交联成分进行交联、或者与一种与所述海绵相关的形成的聚合物进行交联。
用于增强所述海绵对于被施用组织的粘附性的材料基本上不含水凝胶形成成分,特别是不含颗粒状水凝胶形成成分例如明胶颗粒材料或者明胶颗粒,其中施用海绵时所述海绵的至少一个表面牢固地与所述被施用组织相连接。
更优选所述第一可交联成分和/或第二可交联成分包含聚乙二醇(PEG)的衍生物,例如,该衍生物能够在特定条件下进行反应。优选可交联成分中的一个可交联成分能够与组织进行共价反应。
这样的适合于用作止血剂的海绵的材料例如在WO2008/016983(将其全部内容引入本发明作为参考)中被公开,并且市售商标为CoSeal。优选的材料可独立地介导辅助性的止血,并且能够适合于渗血区域的机械密封。这些材料例如是可生物再吸收的(bioresorbable)聚合物,尤其是那些刚一暴露于体液就交联并固化的聚合物。在另一个实施方式中,该材料是可再吸收的并且/或者是生物相容的,并且能够在少于6个月、少于3个月、少于1个月或少于2星期内被个体、特别是人类个体降解。
用于增强所述海绵对于被施用组织的粘附性的特殊材料可以包含第一可交联成分和第二可交联成分,所述第二可交联成分在可启动反应的条件下可与第一可交联成分交联,其中第一可交联成分与第二可交联成分交联从而形成一层。
第一可交联成分能够包括多个亲核基团,并且第二可交联成分能够包括多个亲电基团。一旦与生物液体相接触、或者在其他启动反应的条件下,可发生交联的第一可交联成分和第二可交联成分就进行交联,从而形成具有空隙的多孔基质。
在一些方面,所述材料中的第一可交联成分包括具有m个亲核基团的多个亲核性多亚烷基的氧化物,并且第二可交联成分包括多个亲电性多亚烷基的氧化物。所述多个亲核性多亚烷基的氧化物能够包括两个以上亲核基团,例如NH2、-SH、-H,-PH2、和/或-CO-NH-NH2。在一些情况中,所述多个亲核性多亚烷基的氧化物包括两个以上伯氨基团。某些情况下,所述多个亲核性多亚烷基的氧化物包括两个以上硫醇基。所述多个亲核性多亚烷基的氧化物可能是聚乙二醇或其衍生物。某些情况下,聚乙二醇包括两个以上亲核基团,其可以包括伯氨基和/或硫醇基。所述多个亲电性多亚烷基的氧化物可以包括两个以上亲电基团,比如CO2N(COCH2)2、-CO2H、-CHO、-CHOCH2、-N=C=O、-SO2CH=CH2、N(COCH)2、和/或-S-S-(C5H4N)。所述多个亲电性多亚烷基的氧化物可以包括两个以上琥珀酰亚胺基。所述多个亲电性多亚烷基的氧化物可以包括两个以上马来酰亚胺基。某些情况下,所述多个亲电性多亚烷基的氧化物可以是聚乙二醇或其衍生物。
在具体的实施方式中,第一可交联成分和/或第二可交联成分是合成聚合物,优选包含PEG。该聚合物可以是PEG的衍生物,该衍生物包含适合于交联并且粘附至组织的活性侧基。优选粘合剂包含琥珀酰亚胺基、马来酰亚胺基和/或硫醇基。在一个两聚合物的架构(twopolymer set-up)中,第一个聚合物可以具有琥珀酰基或者马来酰亚胺基,而第二个聚合物可以具有能够附接于第一个聚合物上所述基团的硫醇基或者氨基。粘合剂上的这些基团或者额外的基团可以促进对于组织的粘附。
优选用于增强所述海绵对于被施用组织的粘附性的材料、比如在面前提及的改性PEG材料的含量范围为5至50mg/cm2生物材料例如胶原,优选10至20mg/cm2生物材料。
所述海绵总体上是可生物降解的,适合于在体内进行生物分解;或者是可生物再吸收的,即,能在体内被再吸收。完全再吸收意味着没有残留明显的胞外片段。可生物降解的材料不同于不能生物降解的材料之处在于,可生物降解的材料能够被生物学分解成可以从生物***中除去并且/或者化学地并入所述生物***的单元。在一种优选的具体材料的实施方式中,基质材料或者海绵总体上能够在少于6个月、少于3个月、少于1个月或少于2星期内被个体、特别是人类个体所降解。
在一种优选的实施方式中,海绵具有用于增强所述海绵对于被施用组织的粘附性的材料,所述材料在所述海绵的至少一个表面上呈连续层或者不连续层的形式。
本发明的海绵优选的具有小于2.5mm的总厚度,更多优选大约1mm至约2.5mm。
本发明的海绵优选被用于最小侵袭性的外科手术中,例如用于腹腔镜手术应用。
该海绵可以被干燥,并且在干燥以后,所述海绵可以具有至少0.5w/w%(在此指重量百分率)的含水量。在特定的实施方式中,海绵能够被冻干或者空气干燥。
海绵可以进一步包含凝血的活化剂或者活化剂前体,包括纤维蛋白原、凝血酶或凝血酶前体,如同例如在US5,714,370(将其引入本发明作为参考)中公开的那些。凝血酶或者凝血酶的前体应被分别地理解具有凝血酶活性的蛋白质、和当其与血液接触时或者在施用于病人之后可诱导凝血酶活性的蛋白质。其活性被表示为凝血酶活性(NIH单位)或者拓展对应的NIH单元的凝血酶等效活性。海绵中的活性可以是100-10000,优选500-5000。在下文中,凝血酶活性应被理解为包含凝血酶的活性和任何等效活性。具有凝血酶活性的蛋白质可以选自下组:α-凝血酶,中间凝血酶(meizothrombin),凝血酶衍生物,或者重组体凝血酶。合适的前体可能选自下组:凝血酶原,任选地与磷脂一起的因子Xa,因子IXa,活化的凝血酶原复合物,FEIBA,具有内在或外在凝血性的任何活化剂或活化剂前体,或者它们的混合物。
根据本发明的止血海绵可以与其他生理学物质一起使用。例如,该海绵优选还包括药理活性的物质,其中有抗纤维蛋白溶解的物质比如纤溶酶原激活物抑制剂(plasminogenactivator inhibitor)或者血纤维蛋白溶酶抑制剂、或者溶解血纤维蛋白的物质的钝化剂。优选抗纤维蛋白溶解的物质选自下组:抑肽酶或者抑肽酶衍生物,alpha2-巨球蛋白,蛋白质C或者活化的蛋白质C的抑制剂或者钝化剂,可结合于胞浆素而与天然底物竞争性地作用的底物模拟物,以及可抑制溶解血纤维蛋白活性的抗体。
而其他药理活性的物质,抗生素比如抗细菌抗生素或者抗真菌的抗生素可以与根据本发明的海绵一起使用,优选该物质作为均匀地分布在海绵中的成分。另外,生物活性物质比如生长因子和/或止痛药也可能出现在本发明的海绵中。这样的海绵例如可以被用于伤口愈合。
其他组合物优选具有特异性的酶或者酶抑制剂,其可以调控即促进或者抑制海绵的再吸收。它们中包括胶原酶、其增强剂或者抑制剂。而且,合适的防腐剂可以与海绵一起使用,或者可以被包含在海绵中。
虽然优选的实施方式涉及含有凝血活化剂或者凝血活化剂前体作为唯一活性成分的止血海绵的用途,但是可以包含其他可影响凝血、止血速度和密封质量比如抗拉强度、内部(粘合)强度和耐久性的物质。
可以使用可增强或者改善内在或外在凝血的前凝血剂,比如凝血性因子或者凝血辅助因子、凝血因子XIII、组织因子、凝血酶原复合物、活化的凝血酶原复合物、或这些复合物的部分、凝血酶原酶复合物、磷脂和钙离子。在需要精确密封的外科手术操作的情况中,在将止血海绵施用于病人之后、以及在影响凝血之前,可以优选延长工作时间。如果根据本发明的海绵还包括适当含量的凝血抑制剂,则将会确保凝血反应的延长。优选抑制剂比如抗凝血酶III任选地与肝素、或任何其他的丝氨酸蛋白酶抑制剂一起使用。
还优选在所述材料中均匀分布有这些添加剂,特别是凝血酶或凝血酶前体,以便防止所述材料的局部不稳定或者凝固性过高。即使具有特定的含水量,凝血酶活性也惊人地稳定,这可能是由于在均匀混合物中凝血酶与胶原密切接触之故。尽管如此,根据本发明,可以使用优选选自下组的凝血酶稳定剂:多元醇,多糖,聚二醇,氨基酸或它们的混合物。山梨糖醇、甘油、聚乙二醇、聚丙二醇、单糖或二糖比如葡萄糖或蔗糖、或者任何能够稳定凝血酶活性的糖类或者磺化氨基酸的示例性应用是优选的。
在另一个实施方式中,能够吸收液体的生物相容的、可再吸收的水凝胶被包含在本发明的海绵内。
本发明还提供了一种包含根据本发明的海绵的伤口敷层。海绵和所有的附加层能够以合适的尺寸被提供于即可使用的伤口敷层。所述海绵和/或所述敷层可以是衬垫或薄片,取决于适应症,优选具有至少3mm或者至少5mm和/或直至20mm的厚度。当相对厚的柔韧的海绵被施用于伤口时,重要的是在形成纤维蛋白之前,血液和纤维蛋白原能够被吸附于整个海绵,该纤维蛋白可以用作进一步的伤口分泌物吸收的屏障。
本发明的另一个方面涉及一种制造止血多孔海绵的方法,该方法包括:
a)提供一种包含生物材料基质的海绵,
b)提供一种用于增强所述海绵对于被施用组织的粘附性的材料,该材料呈悬浮液、溶液或者粉末形式,
c)使得步骤a)的海绵与步骤b)的材料相接触,以使得b)的材料存在于所述海绵的至少一个面上,以及任选地
d)对步骤c)中获得的海绵进行干燥。
干燥可以包括冷冻干燥或者空气干燥,并且包括除去液体中的挥发性组分。
在另一个方面,本发明提供了一种可通过如上所述根据本发明的方法获得的止血多孔海绵。如上所述止血海绵的所有优选实施方式还可以适用于该可获得的海绵。
本发明还提供了一种处理损伤的方法,包括施用止血多孔复合海绵,所述海绵包含生物材料基质和用于增强所述海绵对于被施用组织的粘附性的材料。损伤可以包含伤口、出血、受损组织和/或出血组织。
附图说明
图1至4显示了根据实施例1(图1)、4(图2)、5(图3)和6(图4)制备的海绵在实施例10中描述的动物模型中的止血性能。
以下通过实施例进一步例举本发明,但并不限制本发明。
使用下面的缩写:
实施例
实施例1:用两种反应性PEG的酸性溶液处理的胶原海绵
制备出PEG浓度(COH102和COH206为1∶1)为10mg/cm3、35mg/cm3、70mg/cm3和100mg/cm3的COH102和COH206的酸性水溶液(pH 3.0,HCl),并且装入9x7cm的PET托盘中。将市售的与此前填充了PEG溶液的托盘体积相同的9x7cm牛胶原海绵(Matristypt)置于溶液的顶部。在吸收PEG溶液后,胶原材料被冻干。
在冻干后,干燥后的海绵可以与干燥剂一起被包装在不渗透水蒸气的袋中,并且可以进一步进行γ-灭菌,例如用25kGray的γ射线灭菌。
实施例2:用两种反应性PEG的EtOH溶液处理的胶原海绵
将COH102和COH206溶于完全干燥的EtOH中。制备出PEG浓度(COH102和COH206为1∶1)为10mg/cm3、35mg/cm3、70mg/cm3和100mg/cm3的溶液,并且将所述溶液装入9x 7cm的PET托盘中。将市售的与此前填充了PEG溶液的托盘体积相同的9x7cm牛胶原海绵(Matristypt)置于溶液的顶部。在吸收PEG溶液后,胶原材料在真空箱中被干燥。
干燥后的海绵可以与干燥剂一起被包装在不渗透水蒸气的袋中,并且可以进行γ灭菌,例如用25kGray的γ射线灭菌。
实施例3:胶原/反应性PEG构造物的制备
制备出22ml含有不同牛真皮胶原浓度(2.15mg/cm3、4.3mg/cm3和7.2mg/cm3)和PEG(COH102和COH206为1∶1)浓度(7.2mg/cm3、14.3mg/cm3、28.6mg/cm3和57.3mg/cm3)的酸性水溶液(pH 3.0,HCl),装入9x7cm的PET托盘中,并且冻干。
干燥后的海绵可以与干燥剂一起被包装在不渗透水蒸气的袋中,并且可以进行γ灭菌,例如用25kGray的γ射线灭菌。
实施例4:双层胶原/反应性PEG构造物的制备
11ml和22ml在实施例3中描述的胶原/PEG酸性溶液(pH 3.0,HCl)被装入PET托盘中,并且立即在-20℃下冷冻。在冰相的顶部,施加11ml或者22ml的1%牛真皮胶原溶液,pH 3.0(HCl),并且获得的构造物被冻干。
干燥后的海绵可以与干燥剂一起被包装在不渗透水蒸气的袋中,并且可以进行γ灭菌,例如用25kGray的γ射线灭菌。
实施例5:用反应性PEG均匀涂覆胶原海绵
将COH102和COH206的1∶1粉末混合物均匀地分布到市售胶原海绵、或者按照实施例1、2、3和4中之一描述的方法制备的海绵的一个表面上。含量为2mg/cm3、7mg/cm3、10mg/cm3、14mg/cm3和20mg/cm3的PEG被用于涂敷。PEG粉末混合物例如通过熔化、比如通过将海绵与PEG粉末混合物一起置入60至65℃预热的烘箱中保持4分钟而被固定在海绵的表面上。
干燥后的海绵可以与干燥剂一起被包装在不渗透水蒸气的袋中,并且可以进行γ灭菌,例如用25kGray的γ射线灭菌。
实施例6:用反应性PEG不连续地涂覆胶原海绵
按照在实施例5中描述的方法制备衬垫,不同之处在于,在涂敷之前将网格放置到胶原海绵的表面上,以使得衬垫的表面被部分地遮蔽、并且部分地不被PEG粉体覆盖。筛孔尺寸为5mm和10mm的网格模具被使用,并且在粉末分布之后被除去。按照在实施例5中描述的方法进行粉体的固定、包装和灭菌。
这些模型允许血液更好地渗透入胶原衬垫,其中由于胶原的促凝血活性而发生凝血。反应性PEG保障了衬垫对于伤口表面的粘附性。
实施例7:具有交联PEG的胶原构造物的制备
a)用市售的喷雾施加器在牛胶原海绵上面喷雾反应性PEG(COH102和COH206为1∶1),所述喷雾施加器由两重注射器和气驱喷头(Duplospray,百特)组成。一个注射器含有pH 3.0的COH102和COH206,第二个注射器含有pH 9.4的缓冲液。两种PEG成分的聚合作用在沉积后即刻发生在胶原的表面上。海绵可以在真空箱中干燥。
b)按照在实施例1中描述的方法用酸性PEG溶液处理胶原海绵。为了启动在两个PEG成分和胶原基质之间的交联反应,湿海锦用碱性缓冲体系处理,然后可以被冻干。
实施例8:用反应性PEG连续涂敷壳聚糖/明胶海绵
将1∶1的COH102和COH206粉末混合物均匀地分布到市售壳聚糖/明胶(Chitoskin,Beese Medical)海绵的一个表面上。含量为14mg/cm3的PEG被用于涂敷。PEG粉末混合物例如通过熔化、比如通过将海绵与PEG粉末混合物一起置入60至65℃预热的烘箱中保持4分钟而被固定在海绵的表面上。
干燥后的海绵可以与干燥剂一起被包装在不渗透水蒸气的袋中,并且可以进行γ灭菌,例如用25kGray的γ射线灭菌。
实施例9:用反应性PEG涂敷氧化纤维素织物
将1∶1的COH102和COH206粉末混合物均匀地分布到市售氧化纤维素织物(Traumstem,Bioster)的一个表面上。含量为14mg/cm3的PEG被用于涂敷。PEG粉末混合物例如通过熔化、比如通过将海绵与PEG粉末混合物一起置于60至65℃预热的烘箱中保持4分钟而被固定在海绵的表面上。
干燥后的海绵可以与干燥剂一起被包装在不渗透水蒸气的袋中,并且可以进行γ灭菌,例如用25kGray的γ射线灭菌。
实施例10:临床前的应用
在肝脏磨损模型的肝素化猪(1.5倍ACT)中,对根据上述实施例制备的海绵进行测试。使用旋转研磨机,在肝叶的表面上产生直径1.8cm的圆形流血伤口。施用3x 3cm的海绵,并且用一片浸了盐水缓冲液的纱布适度地压在伤口上保持2分钟。在除去纱布后,取得了较好的止血性能,如图1至4所示。
Claims (10)
1.一种止血复合海绵,其包含生物材料基质的多孔海绵和用于增强所述海绵对于被施用组织的粘附性的材料,施用时所述海绵的至少一个表面牢固地与所述被施用组织相连接,其中所述材料基本上不含水凝胶形成成分。
2.如权利要求1所述的海绵,其特征在于,所述生物材料选自下组:胶原,明胶,纤维蛋白,多糖例如壳聚糖,以及它们的衍生物。
3.如权利要求1或2所述的海绵,其特征在于,用于增强所述海绵对于被施用组织的粘附性的所述材料是两种预聚合物的混合物,该混合物包含第一可交联成分和第二可交联成分,其中第二可交联成分在可启动反应的条件下可与第一可交联成分进行交联、或者与一种预形成的聚合物进行交联。
4.如权利要求1至3中任一项所述的所述海绵,其特征在于,所述第一可交联成分和/或第二可交联成分包含聚乙二醇的衍生物。
5.如权利要求1至4中任一项所述的海绵,其特征在于,用于增强所述海绵对于被施用组织的粘附性的所述材料在所述海绵的至少一个表面上形成连续层或者不连续层。
6.如权利要求1至5中任一项所述的海绵,其特征在于,总厚度为约1mm至约2.5mm。
7.如权利要求1至6中任一项所述的海绵,其特征在于,用于最小侵袭性的外科手术,例如用于腹腔镜手术应用。
8.如权利要求1至7中任一项所述的海绵,其特征在于,用于增强所述海绵对于被施用组织的粘附性的材料以5至500mg/cm2生物材料、优选以5至100mg/cm2生物材料之间的浓度存在。
9.一种制造止血复合海绵的方法,包括下述步骤:
a)提供一种生物材料基质的多孔海绵,
b)提供一种用于增强所述海绵对于被施用组织的粘附性的材料,该材料呈悬浮液、溶液或者粉末形式,其中所述材料基本上不含水凝胶形成成分,
c)使得步骤a)的多孔海绵与步骤b)的材料相接触,以使得b)的材料牢固地与所述海绵的至少一个面相连接,从而得到止血复合海绵,任选地
d)对在步骤c)中获得的复合海绵进行干燥,任选地
e)对在步骤c)或d)中获得的所述复合海绵进行灭菌。
10.处理伤口、出血、受损组织和/或出血组织的方法,包括施用如权利要求1至7中任一项所述的止血复合海绵。
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- 2010-12-16 JP JP2012543413A patent/JP2013514093A/ja active Pending
- 2010-12-16 WO PCT/AT2010/000486 patent/WO2011079336A1/en active Application Filing
- 2010-12-16 EP EP10798713A patent/EP2512535A1/en not_active Withdrawn
- 2010-12-16 MX MX2012007056A patent/MX2012007056A/es active IP Right Grant
- 2010-12-16 AU AU2010339045A patent/AU2010339045B2/en not_active Ceased
- 2010-12-16 CN CN201080061630XA patent/CN102753203A/zh active Pending
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US20140378928A1 (en) | 2014-12-25 |
CO6541650A2 (es) | 2012-10-16 |
AU2010339045B2 (en) | 2014-06-05 |
MX2012007056A (es) | 2012-09-28 |
JP2013514093A (ja) | 2013-04-25 |
EP2512535A1 (en) | 2012-10-24 |
US11071804B2 (en) | 2021-07-27 |
KR101811070B1 (ko) | 2017-12-20 |
BR112012014773A2 (pt) | 2015-11-03 |
CA2784432C (en) | 2019-01-15 |
US8771258B2 (en) | 2014-07-08 |
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US20170080119A1 (en) | 2017-03-23 |
US9872934B2 (en) | 2018-01-23 |
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AU2010339045A1 (en) | 2012-07-12 |
WO2011079336A1 (en) | 2011-07-07 |
US9517287B2 (en) | 2016-12-13 |
CA2784432A1 (en) | 2011-07-07 |
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