CN101024729A - 响应周围环境变化发生体积膨胀的水凝胶及其生产方法和应用 - Google Patents
响应周围环境变化发生体积膨胀的水凝胶及其生产方法和应用 Download PDFInfo
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Abstract
响应周围环境变化(如pH或者温度的变化)发生体积膨胀的水凝胶及其生产方法和应用。通常,通过形成液体反应混合物制备水凝胶,所述液体反应混合物含有a)单体和/或聚合物,至少部分单体和/或聚合物对环境变化(如pH或者温度的变化)敏感,b)交联剂和c)聚合引发剂。如果需要,可以将成孔剂(porosigen)引入到液体反应混合物中以生成孔。水凝胶形成之后,将成孔剂除去以在水凝胶内形成孔。还可以对水凝胶进行处理以使其呈现非膨胀体积,其中水凝胶保持非膨胀体积直到其周围环境变化使其膨胀。这些水凝胶可以被制备成多种形状如小球、细丝和颗粒状。这些水凝胶的生物医学应用包括将水凝胶植入到患者体内并且植入部位的环境条件引起水凝胶在原位膨胀的应用。
Description
本申请是申请日2002年2月28日、申请号02806384.8的专利申请的分案申请。
发明领域
本发明总的来说涉及特定的水凝胶组合物、生产这样的水凝胶组合物的方法和应用这样的水凝胶组合物的方法。更具体地说,本发明涉及响应周围环境变化表现出受控的膨胀速率的水凝胶、制备这样的水凝胶的方法和这样的水凝胶在生物医学应用(如治疗动脉瘤、瘘、动静脉畸形,和用于血管或其它管腔解剖结构的栓塞或闭塞)中的应用方法。
发明背景
通常,术语“水凝胶”一般是指可在水中溶胀的聚合物材料。水凝胶在水中的溶胀的原因是水扩散通过玻璃状聚合物引起聚合物链解开及随后的聚合物网络的溶胀。通常,通过由辐射、热、还原氧化或者亲核进攻使单体和/或聚合物交联制备现有技术中的水凝胶。烯键式不饱和单体的交联实例包括从甲基丙烯酸-2-羟基乙酯制备隐形眼镜和从丙烯酸制备吸收制品。聚合物的交联实例包括通过使用电离辐射将亲水聚合物水溶液交联得到伤口敷料和通过交联用烯键式不饱和部分改性的亲水聚合物的水溶液获得外科密封剂。
在或大约在1968年,Krauch和Sanner描述了在结晶母体周围聚合单体并随后除去结晶母体以生成互联多孔聚合物网络的方法。从那时起,已经使用盐、蔗糖和冰晶作为成孔剂(porosigen)制备多孔水凝胶。现有技术中的这些多孔水凝胶已经被用作为亲合色谱法中的膜和组织工程基质,在该基质中组织将向内生长进入多孔水凝胶网络。这些多孔水凝胶的实例参见题为用于关节软骨改造的方法和装置(MethodAnd Device For Reconstruction of Articular Cartilage)的美国专利US6,005,161(Brekke等人)、题为治疗用可植入聚合物水凝胶(ImplantablePolymer Hydrogel For Therapeutic Uses)的美国专利US5,863,551(Woerly)及题为超吸收水凝胶泡沫体(Super AbsorbentHydrogel Foams)的美国专利US5,750,585(Park等人)。
现有技术中已经包括了某些响应外界刺激如溶剂组成、pH、电场、离子强度和温度的变化而发生体积变化的水凝胶。水凝胶响应各种刺激归因于单体单元的审慎选择。例如,如果需要温度敏感性,通常使用N-异丙基丙烯酰胺;如果需要pH敏感性,通常使用带有胺基或者羧酸的单体。刺激响应性水凝胶主要被用作受控药物输送装置。这些刺激响应性水凝胶的实例参见题为含有磺酰胺的pH敏感性聚合物及其合成方法(pH-Sensitive Polymer Containing Sulfoamide And ItsSynthesis Methos)的美国专利US6,103,865(Bae等人)、题为使用刺激敏感性水凝胶的脉动药物运输装置(Pulsatile Drug Delivery DeviceUsing Stimuli Sensitive Hydrogel)的美国专利US5,226,902(Bae等人)及题为以含有偶氮键并表现pH依赖性溶胀的交联水凝胶为基础的结肠靶向口服药物剂型(Colonic-Targeted Oral Drug-Dosage Forms BasedOn Crosslinked Hydrogels Containing Azobonds And ExhibitingpH-Dependent Swelling)的美国专利US5,415,864(Kopeck等人)。
尽管水凝胶材料的性能取得了这些进展,但尚未开发出可允许细胞生长、并且无需非水溶剂或涂层就具有最适宜通过微导管或导管输送的受控膨胀速率的的水凝胶材料。因此,在现有技术中仍需要开发这样一种水凝胶,其可用于多种用途,包括但不限于医学植入应用,其中水凝胶与动脉瘤、瘘、动静脉畸形和血管闭塞会合结合使用。
发明概述
本发明提供了可响应环境变化如pH或者温度变化而发生受控体积膨胀的水凝胶(即,它们是“刺激-可膨胀的”)。在实施方案中,水凝胶具有足够的多孔性以允许细胞向内生长。通过形成液体反应混合物来制备本发明的水凝胶,所述液体反应混合物包含a)单体和/或聚合物并且至少部分的单体和/或聚合物对环境变化(如pH或者温度的变化)敏感,b)交联剂和c)聚合引发剂。如果需要,可将成孔剂(如氯化钠、冰晶和蔗糖)加入到液体反应混合物中。随后从获得的固体水凝胶中除去成孔剂(如通过反复洗涤)产生多孔性。通常,还将使用溶剂以溶解固体单体和/或聚合物。然而,在仅仅使用液体单体的情况下,可不必引入溶剂。通常,通过引入带有可离子化官能团(如胺、羧酸)的烯键式不饱和单体而赋予本发明的可控膨胀速率。例如,如果将丙烯酸引入交联网络中,在低pH溶液中培养水凝胶以使羧酸质子化。在已漂洗除去过量的低pH溶液并且干燥水凝胶之后,可将水凝胶通过充满生理pH盐水或者血液的微导管导入。直到羧酸基团去质子化水凝胶才可发生膨胀。相反地,如果将含胺的单体引入交联网络中,在高pH溶液中培养水凝胶以使胺去质子化。在已漂洗除去过量的高pH溶液并干燥水凝胶之后,可将水凝胶通过充满生理pH盐水或者血液的微导管导入。直到胺基质子化水凝胶才可以发生膨胀。
可选择地,本发明的刺激-可膨胀的水凝胶材料可为辐射透不过的,以利射线照相成像时显像。在液体反应混合物中引入辐射透不过的颗粒(如钽、金、铂等)可使整个水凝胶具有辐射不透性。另外可在液体反应混合物中引入辐射透不过的单体以使整个水凝胶具有辐射不透性。
根据本发明,提供了通过植入(如通过套管、导管、微导管、针或者其它导入装置注射、滴注、手术植入或者其它植入或者放置)本发明的刺激-可膨胀的水凝胶材料用于治疗人或者动物患者的各种疾病、疾病状况、畸形或者障碍的方法,该刺激-可膨胀的水凝胶材料在体内植入部位内占据第一体积,通过植入部位条件(如pH,温度)引起水凝胶膨胀到比第一体积大的第二体积。特别地,可将本发明的水凝胶皮下植入到伤口内、肿瘤内或向肿瘤供应血液的血管内、器官内、畸变血管或者血管结构内、组织或者解剖结构之间的腔内、或者外科手段产生的囊或者腔内。具有本发明的受控膨胀速率的水凝胶以这种方式可用于治疗动脉瘤、瘘、动静脉畸形、血管闭塞和其它医学应用中。
对于本领域的那些技术人员来说,通过阅读下面的示例实施方案的详细说明,本发明另外的方面将是显而易见的。
附图说明
图1是表示一般方法的流程图,通过该方制备本发明的环境响应的可膨胀水凝胶。
图2是表示具体方法的流程图,通过该方法可以制备本发明的pH响应性的可膨胀水凝胶小球。
发明详述
提供下面的详细说明和实施例仅是为了对本发明的示例实施方案进行有限的说明,而不是为了彻底描述本发明的所有可能的实施方案。
A.从单体溶液制备pH响应的可膨胀水凝胶的优选方法
下面是用于制备本发明的pH响应的可膨胀水凝胶的方法说明。
单体的选择和加入
在本实施方案中,单体溶液由烯键式不饱和单体、烯键式不饱和交联剂、成孔剂和溶剂组成。选择的单体中至少部分单体,优选10-50%的单体,更优选10-30%的单体必须是pH敏感的。优选的pH敏感的单体为丙烯酸。甲基丙烯酸和这两种酸的衍生物也将赋予pH敏感性。因为仅仅用这些酸制成的水凝胶的机械性能差,应当选择单体以提供附加机械性能。用于赋予机械性能的优选单体为丙烯酰胺,其可与一种或者更多种上述pH敏感的单体结合使用以赋予附加压缩强度或者其它机械性能。单体在溶液中的优选浓度范围为20-30%w/w。
交联剂的选择和加入
交联剂可以是任何多官能烯键式不饱和化合物。N,N’-亚甲基双丙烯酰胺为优选交联剂。如果需要水凝胶材料为生物降解的,应当选择可生物降解的交联剂。交联剂在溶液中的优选浓度为小于1%w/w,更优选小于0.1%w/w。
成孔剂的选择和加入
成孔剂在单体溶液中的过饱和悬浮赋予了水凝胶材料的多孔性。也可以使用不溶于单体溶液但溶于洗涤液的成孔剂。氯化钠是优选的成孔剂,但也可以使用氯化钾、冰、蔗糖和碳酸氢钠。优选控制成孔剂的颗粒大小为小于25微米,更优选小于10微米。小的颗粒大小有助于成孔剂在溶剂中的悬浮。优选成孔剂在单体溶液中的浓度范围为5-50%w/w,更优选10-20%w/w。另外可以不使用成孔剂而制造非多孔水凝胶。
溶剂的选择和加入(如果需要)
如果必要,以单体、交联剂和成孔剂的溶解性为基础选择溶剂。如果使用液体单体(如甲基丙烯酸-2-羟基乙酯),不必使用溶剂。优选溶剂为水,然而也可以使用乙醇。溶剂的优选浓度范围为20-80%w/w,更优选为50-80%w/w。
交联密度充分地影响这些水凝胶材料的机械性能。通过改变单体浓度、交联剂浓度和溶剂浓度可最好地控制交联密度(及因此控制机械性能)。
引起单体溶液交联的引发剂的选择和加入
可通过还原氧化、辐射和热完成单体的交联。使用紫外线和可见光与合适的引发剂一起、或者通过电离辐射(如电子束或者γ射线)不用引发剂,可完成单体溶液的辐射交联。优选类型的交联引发剂为通过还原氧化起作用的引发剂。可用于本发明实施方案的这样的还原/氧化引发剂的具体实例是过硫酸铵和N,N,N’,N’-四甲基乙二胺。
洗涤除去成孔剂和任何过量单体
在聚合完成之后,用水、乙醇或者其它合适洗涤液洗涤水凝胶以除去成孔剂、任何未反应的残余单体和任何未包含在内的低聚物。优选首先在蒸馏水中洗涤水凝胶而完成洗涤。
处理水凝胶以控制水凝胶的膨胀速率
如上讨论,通过存在于水凝胶网络上的可离子化官能团的质子化/去质子化完成水凝胶膨胀速率的控制。一旦水凝胶制备好并且过量单体和成孔剂已经被洗涤除去,就可以进行膨胀速率的控制步骤。
在带有羧酸基团的pH敏感单体被引入水凝胶网络的实施方案中,在低pH溶液中培养水凝胶。溶液中的自由质子将水凝胶网络上的羧酸基团质子化。培养时间和温度及溶液的pH影响膨胀速率的控制量。通常,培养时间和温度与膨胀控制量成正比,而溶液pH与膨胀控制量成反比。本发明者已经确定处理溶液中水含量也影响膨胀控制。在这方面,水凝胶在处理溶液中能够膨胀更多并且认为有更多数量的羧酸基团可发生质子化。需要水含量和pH的最佳化以对膨胀速率实现最大控制。培养结束后,洗涤除去过量的处理溶液并干燥水凝胶材料。我们已经发现用低pH溶液处理的水凝胶干燥后比未处理水凝胶干燥后的尺寸小。这是理想的效果因为需要通过微导管运输这些水凝胶材料。
如果带有胺基的pH敏感单体被引入到水凝胶网络中,在高pH溶液中培养水凝胶。在高pH下去质子化发生在水凝胶网络的胺基上。培养时间和温度及溶液的pH影响膨胀速率的控制量。通常,培养的时间、温度和溶液pH与膨胀控制量成正比。在培养结束之后,洗涤除去过量的处理溶液并干燥水凝胶。
实施例1
(制备pH响应的可膨胀水凝胶小球的方法)
可以各种形状和构造如板、填块、球、小球、细丝等形状制备并使用本发明的水凝胶材料。图2表示本发明优选方法的具体例,该方法可被用于生产本发明的固体小球形状的pH响应的可膨胀水凝胶。在这一方法中,含有烯键式不饱和单体、烯键式不饱和交联剂、成孔剂和任何溶剂的初始反应混合物在合适的容器中混合。然后在混合物中加入引发剂,此时仍为液体形式的反应混合物被进一步混合,并被吸入注射器或者其它合适的注射装置中。将管(如内径为0.038-0.254厘米(0.01 5-0.100英寸)并优选0.064厘米(0.025英寸)的的聚乙烯管,用于形成适用于脑或者其它血管应用的小球)与注射器或者注射装置连接并将反应混合物注射到管内,在管内混合物聚合。水凝胶在管内充分聚合之后,然后将其中包含水凝胶的管切割成所需长度(如5.08厘米(2英寸)片段)的单个段。然后将这些水凝胶段从每个管片段的腔中取出并放置于一系列漂洗浴中以洗涤除去成孔剂和任何残留单体。这些漂洗浴如下所示:
漂洗浴1...蒸馏水55℃10-12小时漂洗浴2...蒸馏水55℃至少2小时漂洗浴3...蒸馏水55℃至少2小时 |
在暴露于这些漂洗浴中水的过程中,水凝胶片段可能溶胀。为抑制这些水凝胶小球的溶胀,将其放置在可从水凝胶中置换至少一些水的溶胀抑制液中。这种溶胀抑制液可以是醇、含有足够醇以控制溶胀的醇/水溶液、丙酮或者其它合适的非水脱水剂。在图2所表示的具体例中,将前述漂洗的水凝胶片段放置于溶胀抑制浴中,如下所示:
溶胀抑制浴...70%水和30%乙醇55℃至少2小时 |
水凝胶片段从溶胀抑制液中被取出之后,可将水凝胶的圆柱片段切割成更小段(如0.254厘米(0.100英寸)长的段)。然后可将这些单个段沿着圆柱水凝胶部分的长轴串在铂线圈和/或铂丝上。串完之后,将这些段在55℃真空干燥至少2小时。然后将水凝胶部分进行酸化处理,优选将其浸渍到37℃的酸化溶液如50%盐酸:50%水中约70小时。然后洗涤除去过量酸化溶液。这可通过将水凝胶部分放置于一系列浴中完成,如下所示:
酸化处理浴1...70%异丙醇和30%水约5分钟酸化处理浴2...纯异丙醇约15分钟酸化处理浴3...纯异丙醇约15分钟酸化处理浴4...纯异丙醇约15分钟 |
完成酸化处理之后(如从酸化处理浴4中被取出之后)将水凝胶片段(即“小球”)在真空烘箱中在约60℃干燥约1-2小时。这样完成了小球的制备。当这些小球与生理pH(即,pH约为7.4)的液体(如血液)接触时将充分膨胀。
正如下文所述,下面的实施例2-4是用于说明具有受控膨胀速率的多孔水凝胶的许多生物医学应用中的一些应用。尽管这些实施例局限于水凝胶被植入人体或者动物患者体内的一些生物医学应用,可以理解本发明的水凝胶材料可用于除了下文所述的具体实施例以外的许多其它医学和非医学应用中。
实施例2
(动脉瘤栓塞)
对于动脉瘤栓塞,将1.52g(0.021moles)丙烯酰胺,0.87g(0.009moles)丙烯酸钠,0.005g(0.00003moles)N,N’-亚甲基双丙烯酰胺,7.95g水和4.5g氯化钠(<10微米的粒径)加入到琥珀色广口瓶中。加入53微升N,N,N’,N’-四甲基乙二胺和65微升的20%w/w过硫酸铵水溶液作为引发剂,并将溶液吸入到3cc注射器中。然后将溶液注射到0.025”ID管中并使其聚合2小时。将管切割成5.08厘米(2英寸)的段并在真空烘箱中干燥。使用心轴将干燥水凝胶从管中取出。聚合的水凝胶在蒸馏水中洗涤3次,时间分别为10-12小时、至少2小时和至少2小时,以除去成孔剂、任何未反应单体和任何未引入的单体。将水凝胶切割成约0.254厘米(0.100英寸)长度的段(“小球”)并用铂线圈/丝装置串起来。然后这些小球在乙醇中脱水并在约55℃干燥真空约2小时。
然后将干燥的小球放置于50%盐酸/50%水中并在37℃培养约70小时。经培养之后,连续漂洗除去小球上的过量盐酸溶液,连续漂洗为a)70%异丙醇:30%水约5分钟,b)100%异丙醇约15分钟,c)100%异丙醇约15分钟和d)100%异丙醇约15分钟。水凝胶小球在55℃真空干燥至少2小时。
使用这种方法制备的经处理的干燥水凝胶小球具有的直径适合通过充满盐水或者血液的0.036厘米(0.014英寸)或者0.046厘米(0.018英寸)(ID)的微导管传输。材料可以流动方式(如,将水凝胶小球或者颗粒与液体载体混合并通过套管或者导管将液体载体/水凝胶混合物注射或者灌注到植入部位)注射通过带有或者连接有可分离传输系统的微导管(水凝胶附着在线或者系绳上,这样的线或者系绳可向前穿过导管腔进入希望的植入部位,在植入部位水凝胶将通常与线或者系绳保持附着直到操作者使其分离或者直到植入部位的某些环境条件引起线/系绳和水凝胶之间的连接退化、断裂或者切断)。如果使用可分离传输系统,只要在水凝胶发生充分溶胀之前线或者绳保持连接至少15分钟,水凝胶小球通常可从微导管中推出或者拉回到微导管中(如果必要可反复进行)。在生理pH(约7.4)下约1小时之后水凝胶小球充分溶胀(直径达约0.089厘米(0.035英寸))。
实施例3
(动静脉畸形栓塞)
为制备适用于动静脉畸形栓塞的材料,将1.52g(0.021moles)丙烯酰胺,0.87g(0.009moles)丙烯酸钠,0.005g(0.00003moles)N,N’-亚甲基双丙烯酰胺,7.95g水和4.5g氯化钠(<10微米的粒径)加入到琥珀色广口瓶中。加入53微升N,N,N’,N’-四甲基乙二胺和65微升的20%w/w过硫酸铵水溶液作为引发剂,并将溶液吸入到3cc注射器中。使溶液在注射器内聚合2小时。使用剃刀片除去注射器,将水凝胶在真空烘箱中干燥。
干燥的水凝胶在蒸馏水中洗涤干燥3次,分别为10-12小时、2小时和2小时,以除去成孔剂和任何未反应单体和任何未包含在内的低聚物。然后将水凝胶在乙醇中脱水在约55℃真空干燥约2小时。将干燥的水凝胶切割成所需大小的颗粒,通常直径为100-900微米。然后在约37℃将干燥的水凝胶在50%盐酸:50%水的酸化溶液中培养约22小时,培养之后,连续漂洗除去小球上的过量盐酸溶液,连续漂洗为a)70%异丙醇:30%水约5分钟,b)100%异丙醇约15分钟,c)100%异丙醇约15分钟和d)100%异丙醇约15分钟。处理过的水凝胶颗粒在约55℃真空干燥约2小时。使用这种方法制备的经处理的干燥水凝胶颗粒具有的直径适用于动静脉畸形栓塞,并且可以以流动方式注射通过标准微导管。这些水凝胶颗粒在生理pH约7.4下约15分钟后充分溶胀。
实施例4
(血管或者其它腔解剖结构闭塞)
为制造血管闭塞插栓,将1.52g(0.021mole)丙烯酰胺,0.87g(0.009moles)丙烯酸钠,0.005g(0.00003moles)N,N-亚甲基双丙烯酰胺,7.95g水和4.5g氯化钠(<10微米的粒径)加入到琥珀色广口瓶中。加入53微升N,N,N’,N’-四甲基乙二胺和65微升的20%w/w过硫酸铵水溶液作为引发剂,并将溶液吸入到3cc注射器中。然后将溶液注射到不同大小的管中并使其聚合2小时。需要各种大小的管以制造不同大小的血管闭塞插栓。如在0.025”ID管中聚合可得到直径为约0.035”的血管插栓。在0.019”ID管中聚合可得到直径为约0.026”的血管插栓。将管切割成5.08厘米(2英寸)长的段并在真空烘箱中干燥。用心轴将干燥水凝胶从管中取出。聚合的水凝胶在蒸馏水中洗涤3次,分别为约10-12小时、约2小时和约2小时,以除去成孔剂、任何未反应的单体和任何未包合在内的低聚物。然后将水凝胶切割成长度约1.27厘米(0.500英寸)的段或者小球并用铂线圈/丝装置串起。然后将这些被串着的水凝胶小球在乙醇中脱水并在约55℃真空干燥约2小时。然后将串着的、干燥的小球放置在50%盐酸:50%水的酸化溶液中约22小时并在约37℃培养。培养之后,连续漂洗除去小球上的过量盐酸溶液,连续漂洗为a)70%异丙醇:30%水约5分钟,b)100%异丙醇约15分钟,c)100%异丙醇约15分钟和d)100%异丙醇约15分钟。完成乙醇漂洗之后,将这些经处理的水凝胶小球在约55℃真空干燥约2小时。
使用这种方法制备的经处理的干燥水凝胶小球具有的直径适用于传输通过充满盐水或者血液的0.036厘米(0.014英寸)或者0.046厘米(0.018英寸)(ID)微导管。这种材料可以流动方式注射通过微导管或者通过连接有可分离运输系统的微导管传输。如果使用可分离系统,水凝胶材料在发生充分溶胀之前的约5分钟可以在微导管内外回到原位。在约15分钟之内材料充分溶胀。
可以理解在本发明的任一实施方案中,水凝胶可以进一步包含或者合并药剂(如药物、生物制剂、基因药物、基因治疗制剂、诊断剂、成像对比材料、生长因子、其它生物因子、肽或者其它生物活性的治疗或者诊断物质),以在植入部位或者附近产生希望的医药效果(治疗、诊断、药理或者其它生理效果)。可被引入到本发明水凝胶中的某些类型医药的实例描述参见美国专利US5,891,192(Murayama等人)、US5,958,428(Bhatnagar等人)和US6,187,024(Block等人)及PCT国际公报WO O1/03607(Slaikeu等人),这些文献特意通过参考引入本发明。
本文仅参考某些实施例和实施方案说明本发明。没有试图彻底描述本发明的所有可能的实施例和实施方案。实际上,本领域的那些技术人员将理解在不脱离如下面的权利要求书所述的本发明的精神和范围的情况下可对上述的实施例和实施方案作各种增加、删除、修改和其它改变。所有这些增加、删除、修改和其它改变都被包括在下面的权利要求书的范围内。
Claims (12)
1.一种制备环境敏感的水凝胶聚合物的方法,所述的方法包括步骤:
(A)形成水凝胶,该水凝胶含有一种或多种烯键式不饱和单体或预聚物,所述烯键式不饱和单体或预聚物的至少一些具有可离子化官能团;和
(B)在预定温度下使水凝胶与具有预定pH的处理溶液接触预定长的时间,使水凝胶的质子化状态以预定方式发生改变,从而当处于特定pH时,该质子化状态将再次发生变化并且水凝胶将以预定速率膨胀。
2.根据权利要求1的方法,其进一步包含步骤:
(C)将水凝胶干燥。
3.根据权利要求1的方法,其中步骤B包括将水凝胶与处理溶液接触,使水凝胶的官能团质子化。
4.根据权利要求3的方法,其中水凝胶用于随后植入到患者体内已知pH的植入部位,且其中步骤B包括将水凝胶与处理溶液接触使水凝胶的官能团质子化,从而所述质子化的官能团随后在暴露于植入部位的已知pH时将会去质子化。
5.根据权利要求1的方法,其中步骤B包括将水凝胶与处理溶液接触,使水凝胶的官能团去质子化。
6.根据权利要求5的方法,其中水凝胶用于随后植入到患者体内已知pH的植入部位,且其中步骤B包括将水凝胶与处理溶液接触使水凝胶的官能团去质子化,从而所述去质子化的官能团随后在暴露于植入部位的已知pH时将会质子化。
7.根据权利要求1的方法,其中步骤A包括将一种或多种单体或预聚物与交联剂和聚合引发剂相结合。
8.根据权利要求4或6的方法,其中在将水凝胶在植入部位植入时,水凝胶膨胀的预定速率使得其在首次被输送到植入部位之后至少约5分钟仍保持足够小从而能被收回到导管中。
9.根据权利要求1的方法,其进一步包括通过添加成孔剂对水凝胶赋予多孔性的步骤。
10.根据权利要求9的方法,其中赋予多孔性的步骤以使得制造出充分多孔的水凝胶从而允许细胞向内生长至水凝胶中的方式进行。
11.根据权利要求1的方法,其进一步包括向水凝胶中添加辐射不透性材料的步骤。
12.根据权利要求4、6或8的方法,其中植入部位的已知pH为大约7.4。
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