CN106456533B - 用于生物医学应用的包含环糊精掺入的胶原基质的组合物 - Google Patents
用于生物医学应用的包含环糊精掺入的胶原基质的组合物 Download PDFInfo
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- CN106456533B CN106456533B CN201580026744.3A CN201580026744A CN106456533B CN 106456533 B CN106456533 B CN 106456533B CN 201580026744 A CN201580026744 A CN 201580026744A CN 106456533 B CN106456533 B CN 106456533B
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Abstract
本发明的发明人使用环糊精用于作为蛋白聚糖替代物来工程化仿生的基于胶原的基质组合物。所产生的环糊精在本发明的胶原组合物中的掺入增强了胶原热稳定性并降低了胶原纤维发生。结果,形成了厚的、透明的且机械强度高的基于胶原的组合物。该环糊精‑胶原组合物具有被用作用于角膜修复的治疗性眼贴(eye patch)的极大潜力。还提供了用于制造本发明的这些组合物的方法及本发明的这些组合物的用途。
Description
相关申请的引用
本申请要求于2014年4月25日提交的美国临时专利申请第61/984,328号的权益,其为了所有目的通过引用在此被并入,如同在本文充分陈述一样。
政府利益的声明
本发明根据美国陆军授予的合同号W81XWH-09-2-0173在政府支持下进行。政府在本发明中具有一定权利。
发明背景
细胞外基质(ECM)是由蛋白、蛋白聚糖和其他可溶性分子组成的复杂的大分子混合物。胶原(动物中最丰富的蛋白)在多种生物应用中被广泛应用。然而,由于获得大量纯化的蛋白聚糖的困难,对工程化包含胶原和蛋白聚糖二者的ECM支架做出了很少的努力。在天然角膜中,蛋白聚糖通过调节胶原原纤维(fibril)直径和间距在角膜透明度中起至关重要的作用。因此,寻找蛋白聚糖替代物来开发仿生的基于胶原的ECM是有前景的研究领域,其将提供解决与临床应用诸如角膜再生相关的富有挑战的问题的新模板。
环糊精(CD)是包含6至8个葡萄糖分子的环的环状寡聚物的家族。这些环状分子的特征是内部疏水核和外部亲水环,所述环状分子可以与小分子或大的化合物的部分形成复合物。天然环糊精的溶解性非常差,并且起初这阻止环糊精成为有效的络合剂(complexingagent)。在20世纪60年代末,发现在2-、3-和6-羟基位点的化学取代将极大增强溶解性。化学取代的程度和用于取代的基团的性质决定了环糊精在水性介质中的最终的最大浓度。大多数化学改性的环糊精在水中能够达到50%(w/v)浓度。
发明概述
根据一个或更多个实施方案,本发明的发明人假设,与天然组织中的蛋白聚糖类似,环糊精在胶原基质中的掺入将调节胶原纤维发生,同时保持胶原三螺旋形成。具有原纤维结构的传统工程化的I型胶原基质是不透明的,而包含无定形胶原网络的透明凝胶则表现出不良的机械性能。预期环糊精可以作为蛋白聚糖替代物被添加至胶原基质,并且将协助优化用于角膜再生的光学和机械性能。
根据一个实施方案,本发明提供了一种组合物,所述组合物包含具有第一组分和第二组分的玻璃化基质凝胶,其中所述第一组分包含胶原,并且其中所述第二组分包含环糊精。
根据另一个实施方案,本发明提供了一种组合物,所述组合物包含具有第一组分和第二组分的玻璃化基质凝胶,其中所述第一组分包含胶原,并且其中所述第二组分包含环糊精,并且所述组合物还包含至少一种生物活性剂。
根据又一个实施方案,本发明提供了一种用于制造玻璃化基质凝胶的方法,所述玻璃化基质凝胶具有第一组分和第二组分,其中所述第一组分包含胶原,并且其中所述第二组分包含环糊精,所述方法包括:a)获得胶原的水性溶液;b)获得环糊精的水性溶液;c)将a)和b)的溶液组合;和d)使c)的组合的溶液脱水持续足以允许所述溶液玻璃化的一段时间。
根据又另一个实施方案,本发明提供了以上描述的组合物作为用于修复哺乳动物的组织的基质的用途。
根据另一个实施方案,本发明提供了以上描述的组合物作为用于修复哺乳动物的眼角膜的基质的用途。
附图简述
图1描绘了包括以下的三种基于胶原的膜的差示扫描量热法(DSC)第一加热曲线:常规胶原玻璃质凝胶(vitrigel)(CV)、本发明的α-CD-col组合物和交联的CV。
图2是示出了本发明的α-CD-col组合物表现出优异的透明度的图,具有在550nm的高达96%的透光率。图中的插图示出了置于印刷的单词“eye”上的湿膜的照片。
图3是描绘了厚度分别为520μm和170μm的本发明的两种α-CD-col组合物的缝合性(suturablity)测试的荷载相对变形(displacement)的图。图中的插图示出了较厚的膜在拉伸超过5.6mm后的照片。
图4是在本发明的组合物的荷载测试中使用的装置的照片。
图5示出了细胞突起分析的示意图和不同玻璃质凝胶组合物胶原密度对牛角膜细胞的原代培养物的作用。
图6描绘了牛角膜细胞的原代培养物中的三个不同的基因标志物的基因表达如何被本发明的玻璃质凝胶组合物的原纤维纳米结构所影响。
图7是示出了不同环糊精的结构和它们在溶液中如何与胶原原纤维相互作用的示意图。环糊精分子中的空间可以被用作水不溶性药物和生物活性剂的药物贮库(drugreservoir)。
发明详述
根据一个或更多个实施方案,本发明的发明人使用环糊精用于作为蛋白聚糖替代物来工程化仿生的基于胶原的基质组合物。所产生的环糊精在本发明的胶原组合物中的掺入增强了胶原热稳定性并降低了胶原纤维发生。结果,形成了厚的、透明的且机械强度高的基于胶原的组合物。该环糊精-胶原组合物具有被用作用于角膜修复的治疗性眼贴(eyepatch)的极大潜力。
根据一个实施方案,本发明提供了一种组合物,所述组合物包含具有第一组分和第二组分的玻璃化基质凝胶,其中所述第一组分包含胶原,并且其中所述第二组分包含环糊精。
如本文使用的,术语“玻璃化”或“玻璃质凝胶(vitrigel)”意指组合物包含一种或更多种胶原和一种或更多种环糊精的混合物的水性溶液并且允许在被脱水之前形成水凝胶。在一些实施方案中,组合物的凝胶化在37℃的温度进行。在形成水凝胶之后,通过脱水,诸如例如在特定温度和湿度加热水凝胶持续允许玻璃化发生的特定时间长度来使水凝胶玻璃化。在一些实施方案中,玻璃化在35℃至45℃的温度和在约30%和50%相对湿度之间的湿度进行。在一个实施方案中,玻璃化在40℃的温度和40%的相对湿度进行。组合物的玻璃化所需的时间可以从数天到数周变化。在一个实施方案中,用于组合物的玻璃化的时间为约1周至2周。
“凝胶”指介于液体和固体之间的物质状态,并且通常被定义为在液体介质中膨胀的交联聚合物网络。通常,凝胶是包含固体和液体二者的两相胶体分散体,其中固体的量大于被称为“溶胶(sol)”的两相胶体分散体中的固体的量。如此,“凝胶”具有液体的一些特性(即,形状是有弹性的且可变形的)和固体的一些特性(即,形状足够离散以在二维表面上维持三维)。
“水凝胶”意指可以吸收水以形成弹性凝胶的遇水膨胀的(water-swellable)聚合物基质,其中“基质”是通过共价交联或非共价交联保持在一起的三维大分子网络。当放置在水性环境中时,干燥的水凝胶通过向其中获取液体而膨胀至交联度所允许的程度。如本文使用的,“玻璃化的基质凝胶”意指通过共价交联或非共价交联保持在一起的已被玻璃化的三维大分子网络的水可膨胀聚合物基质。
本发明的组合物包含胶原。第一组分的胶原选自由I型、II型、III型和IV型胶原组成的组。在一个实施方案中,用作组合物的第一组分的胶原是I型胶原。本领域普通技术人员将理解,在组合物和方法中使用的胶原可以包括多于一种类型的胶原。
本发明的组合物还包含环糊精。第二组分的环糊精选自由α-环糊精、β-环糊精和γ-环糊精组成的组。在一个实施方案中,用作组合物的第二组分的环糊精是α-环糊精。本领域普通技术人员将理解,在组合物和方法中使用的环糊精可以包括多于一种类型的环糊精。
如本文使用的,本发明的玻璃化组合物在使用前被水合。
本发明的玻璃质凝胶组合物是光学上透明的并且适合于多种用途。在一个实施方案中,玻璃质凝胶组合物具有在550nm的约96%的光学透明度。
将理解,本发明的玻璃质凝胶组合物可以被模制或形成适合于用作替代组织或组织填充物的任何特定形状。本发明提供了形成支架等的离体聚合技术,所述支架等可以被模制以采取组织缺损所需要的形状、通过刺激天然细胞修复促进组织形成并且可以通过微创注射(minimally invasive injection)被潜在地植入。
在一个实施方案中,本发明的玻璃质凝胶组合物可以被塑形,用于用作受试者的人工角膜。
根据另一个实施方案,本发明提供了一种组合物,所述组合物包含具有第一组分和第二组分的玻璃化基质凝胶,其中所述第一组分包含胶原并且其中所述第二组分包含环糊精,并且所述组合物还包含至少一种生物活性剂。
本文中“活性剂”和“生物活性剂”可互换使用以指引起期望的药理作用和/或生理作用的化学品或生物化合物,其中所述作用可以是预防性的或治疗性的。该术语还包括本文具体提及的那些活性剂的药学上可接受的、药理上有活性的衍生物,包括但不限于盐、酯、酰胺、前药、活性代谢物、类似物等。当术语“活性剂”、“药理活性剂”和“药物”被使用时,那么,应理解本发明包括该活性剂本身以及药学上可接受的、药理学上有活性的盐、酯、酰胺、前药、代谢物、类似物等。
当提及治疗剂、染料或其他物质和聚合的组合物诸如本发明的组合物使用时,“掺入的(incorporated)”、“包封的(encapsulated)”和“包埋的(entrapped)”是本领域公知的。在某些实施方案中,这些术语包括将此类剂掺入、配制或以其他方式包括在组合物中,所述组合物允许此类剂在期望的应用中缓释。术语可构思治疗剂或其他物质藉以被掺入基质中的任何方式,包括例如分布在整个基质中、附加到基质表面(通过嵌入或其他结合相互作用)、包封在基质中等。术语“共掺入”或“共包封”指治疗剂或其他物质和至少一种其他治疗剂或其他物质被掺入主题组合物中。
在本发明的一个方面中,可以制备包含玻璃质凝胶组合物和一种或更多种生物活性剂的组合物。生物活性剂可以随着组合物的预期目的而广泛变化。术语“活性”是本领域公知的并且指的是为在受试者中局部或全身起作用的生物、生理、或药理活性物质的任何部分。生物活性剂(可以被称为“药物”)的实例在公知的参考文献诸如Merck Index、Physicians’Desk Reference和The Pharmacological Basis of Therapeutics中描述,并且它们包括但不限于药物;维生素;矿物质补充剂;用于治疗、预防、诊断、治愈或减轻疾病或疾患(illness)的物质;影响身体结构或功能的物质;或前药,所述前药在将它们置于生理环境中后变为生物活性的或更有活性的。可以使用多种形式的生物活性剂,所述多种形式的生物活性剂在施用至受试者之后能够由玻璃质凝胶组合物释放到例如邻近组织或体液中。在一些实施方案中,生物活性剂可以被用于例如治疗、改善、抑制或预防与例如眼睛有关的疾病或症状。
生物活性剂的非限制性实例包括以下:肾上腺素能阻断剂、同化剂、雄激素类固醇、抗酸剂、镇喘剂、抗过敏物质、抗胆固醇生成剂(anti-cholesterolemic agent)和抗脂质剂、抗胆碱能药和拟交感神经药、抗凝剂、抗惊厥剂、止泻剂、止吐剂、抗高血压剂、抗感染剂、抗炎剂诸如类固醇、非类固醇抗炎剂、抗疟剂、抗躁狂剂、止恶心剂、抗肿瘤剂、抗肥胖剂、抗帕金森氏病剂、退热剂和止痛剂、镇痉剂、抗血栓剂、抗尿酸生成剂(anti-uricemicagent)、抗心绞痛剂、抗组胺剂、止咳剂、食欲抑制剂、苯并菲啶生物碱、生物制品(biological)、心脏活性剂、大脑扩张药物(cerebral dilator)、冠状动脉扩张药物(coronary dilator)、减充血剂、利尿剂、诊断剂、红细胞生成剂、雌激素、祛痰剂、胃肠镇静剂、高血糖剂、催眠药、降血糖剂、离子交换树脂、泻药、矿物质补充剂、抗有丝分裂剂、溶粘液剂(mucolytic agent)、生长因子、神经肌肉药物、营养物质、外周血管扩张剂、促孕剂、前列腺素、精神强奋剂(psychic energizer)、精神药物、镇静剂(sedative)、兴奋剂、甲状腺剂和抗甲状腺剂、镇定剂(tranquilizer)、子宫松弛剂、维生素、抗原物质和前药。
可以使用不同形式的生物活性剂。这些包括但不限于诸如以下的形式:不带电荷的分子、分子复合物、盐、醚、酯、酰胺、前药形式等,其当被植入、注射或以其他方式置于受试者中时被生物活化。
玻璃质凝胶组合物将以符合良好的医疗实践的方式配制、计量和施用。在本文中考虑的因素包括待被治疗的特定紊乱、待被治疗的特定哺乳动物、个体患者的临床状况、紊乱的原因、剂的递送部位、施用方法、施用的时间表和医疗从业者已知的其他因素。待被施用的生物聚合物的“治疗有效量”将根据此类考虑因素决定,并且可以是预防、改善或治疗目的紊乱必需的最小量。如本文使用的,术语“有效量”是指疗法(例如,预防剂或治疗剂)的量的等效短语,其足以降低疾病的严重度和/或持续时间、改善其一个或更多个症状、预防疾病的发展或引起疾病消退,或其足以引起疾病或其一个或更多个症状的发展、复发、发作或进展的预防、或增强或提高可用于治疗疾病的另一个疗法(例如,另一种治疗剂)的预防和/或治疗作用。
在一个实施方案中,修复受损的组织可以在任何标准外科手术程序(包括开放式手术和腹腔镜技术)的环境中进行,以允许接近并修复组织。接近受损的组织之后,使本发明的玻璃质凝胶组合物(如果需要,和任何手术上可接受的贴片或植入物一起)接触受损的组织而放置。
根据又一个实施方案,本发明提供了一种用于制造玻璃化基质凝胶的方法,所述玻璃化基质凝胶具有第一组分和第二组分,其中所述第一组分包含胶原,并且其中所述第二组分包含环糊精,所述方法包括:a)获得胶原的水性溶液;b)获得环糊精的水性溶液;c)将a)和b)的溶液组合;和d)使c)的组合的溶液脱水持续足以允许所述溶液玻璃化的一段时间。
如本文使用的,胶原的水性溶液是溶解于适合缓冲液中的任何胶原溶液。胶原的浓度是可变的,然而,具有在1mg/ml至约10mg/ml的范围内的浓度的胶原溶液可根据本发明的方法被使用。在一个实施方案中,水性溶液中的胶原浓度为约5mg/ml。
如本文使用的,环糊精的水性溶液是溶解于适合缓冲液中的任何环糊精溶液。环糊精的浓度是可变的,然而,具有在2.5mg/ml至约10mg/ml的范围内的浓度的环糊精溶液可根据本发明的方法被使用。
根据本发明的方法,本发明的组合物的脱水和玻璃化包括在约5℃至40℃的温度、在约30%至50%之间的相对湿度并且持续约3天至约28天的时间干燥包含胶原溶液和环糊精的溶液。在一个实施方案中,本发明的组合物的玻璃化包括在39℃的温度持续约7天加热包含胶原溶液和环糊精的溶液。在另一个实施方案中,本发明的组合物的玻璃化包括在39℃的温度持续约14天加热包含胶原溶液和环糊精的溶液。
术语“载体”指治疗剂借助其而通过本发明的玻璃质凝胶组合物提供的稀释剂、佐剂、赋形剂或媒介物。此类生理学载体可以是无菌液体,诸如水和油,包括石油、动物、植物或合成来源的那些,诸如花生油、大豆油、矿物油、芝麻油等。当药物组合物被静脉内施用时,水是适合的载体。盐水溶液和水性右旋糖和甘油溶液也可被用作液体载体,特别是用于可注射溶液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻、面粉、白垩(chalk)、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂乳粉、甘油、丙二醇、水、乙醇等。如果需要,组合物还可以包含少量润湿剂或乳化剂,或pH缓冲剂。
缓冲液、酸和碱可以被掺入组合物中以调节pH。还可以包括增加从组合物中释放的剂的扩散距离的剂。
缓冲剂辅助维持pH在接近生理条件的范围内。缓冲液优选地以从约2mM至约50mM的范围的浓度存在。用于根据本发明使用的适合缓冲剂包括有机酸和无机酸二者以及其盐,诸如柠檬酸盐缓冲液(例如,柠檬酸单钠-柠檬酸二钠混合物、柠檬酸-柠檬酸三钠混合物、柠檬酸-柠檬酸单钠混合物等)、琥珀酸盐缓冲液(例如,琥珀酸-琥珀酸单钠混合物、琥珀酸-氢氧化钠混合物、琥珀酸-琥珀酸二钠混合物等)、酒石酸盐缓冲液(例如,酒石酸-酒石酸钠混合物、酒石酸-酒石酸钾混合物、酒石酸-氢氧化钠混合物等)、富马酸盐缓冲液(例如,富马酸-富马酸单钠混合物、富马酸-富马酸二钠混合物、富马酸单钠-富马酸二钠混合物等)、葡萄糖酸盐缓冲液(例如,葡萄糖酸-葡萄糖酸钠混合物、葡萄糖酸-氢氧化钠混合物、葡萄糖酸-葡萄糖酸钾混合物等)、草酸盐缓冲液(例如,草酸-草酸钠混合物、草酸-氢氧化钠混合物、草酸-草酸钾混合物等)、乳酸盐缓冲液(例如,乳酸-乳酸钠混合物、乳酸-氢氧化钠混合物、乳酸-乳酸钾混合物等)和乙酸盐缓冲液(例如,乙酸-乙酸钠混合物、乙酸-氢氧化钠混合物等)。可以使用磷酸盐缓冲液、碳酸盐缓冲液、组氨酸缓冲液、三甲基胺盐诸如Tris、HEPES和其他此类已知的缓冲液。
防腐剂可以被添加以阻碍微生物生长,并且可以以从0.2%-1%(w/v)范围的量被添加。用于根据本发明使用的适合防腐剂包括苯酚、苯甲醇、间甲酚、十八烷基二甲基苄基氯化铵、苄烷铵卤化物(例如,氯化物、溴化物和碘化物)、六甲氯铵、对羟基苯甲酸烷基酯诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、儿茶酚、间苯二酚、环己醇和3-戊醇。
存在等渗剂(isotonicifier)以确保本发明的液体组合物的生理等渗性并且包括多元糖醇,优选地三元或更高级的糖醇,诸如甘油、赤藓醇、阿拉伯糖醇、木糖醇、山梨醇和甘露醇。考虑到其他成分的相对量,多元醇可以以按重量计约0.1%至约25%之间、优选地1%至5%之间的量存在。
稀释剂的实例包括磷酸盐缓冲的盐水、用于缓冲胃中的胃酸的缓冲液,诸如包含蔗糖的柠檬酸盐缓冲液(pH 7.4)、单独的碳酸氢盐缓冲液(pH7.4)或包含抗坏血酸、乳糖或阿斯巴甜的碳酸氢盐缓冲液(pH 7.4)。载体的实例包括蛋白,例如,如在脱脂乳粉中发现的蛋白;糖,例如蔗糖;或聚乙烯吡咯烷酮。通常,这些载体以约0.1%-90%(w/v)的浓度使用,但优选以1%-10%的范围的浓度使用。
待被用于体内施用的制剂必须是无菌的。这可以通过例如通过无菌滤膜的过滤实现。例如,本发明的制剂可以通过过滤灭菌。
实施例
按照三步顺序制备掺入了不同环糊精的基于I型胶原的膜:凝胶化、玻璃化和再水合。测试并比较了3种环糊精,即α-CD、β-CD和γ-CD。
首先,将I型胶原溶液(5mg/ml)与(以2.5mg/ml至约10mg/ml的浓度范围)包含CD的2%HEPES溶液以1:1v/v的比快速并完全混合。将混合的溶液在37℃和5%CO2下凝胶化2小时。
其次,在约39℃和约40%的相对湿度的加湿器中使CD-胶原(CD-col)凝胶玻璃化1周。
第三,在使用前将这些col-CD膜在水中或缓冲溶液中再水合至少2小时。按照之前描述的方法(Biomaterials 34(2013)9365-9372)制备两种胶原膜,即胶原玻璃质凝胶和交联的玻璃质凝胶,作为对照。与常规玻璃质凝胶相比,交联的玻璃质凝胶在凝胶化过程之前通过在胶原介质混合物中添加额外的0.6%1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC)和0.6%N-羟基琥珀酰亚胺(NHS)来制造。使用差示扫描量热法(DSC,Perkin Elmer,Waltham,MA)评价胶原和CD之间的特异性相互作用。使用Synergy 2酶标仪(BioTek,Winooski,VT)测量CD-col膜的吸光度。使用Electroforce 3200测试仪器(Bose,EdenPrairie,MN)用10-0尼龙缝线测试膜缝合性。
使用依序的(sequential)胶原酶(2型,Worthington Biochemical Corp.,Lakewood,NJ)消化从全层角膜(full-thickness cornea)分离角膜细胞。收集经消化的细胞并在1400rpm离心10分钟。将细胞沉淀物重悬并在一般组织培养板(TCP)或在CV覆盖的板上在37℃和5%CO2下培养。使用无血清培养基或基于血清的培养基。无血清培养基由DMEM/F-12、1%10U/mL青霉素-链霉素和0.5%1.25mg/mL两性霉素B(Life Technologies,Carlsbad,CA)组成。基于血清的培养基包含DMEM/F-12、10%FBS、1%10U/mL青霉素-链霉素和0.5%1.25mg/mL两性霉素B。使用无血清培养基将细胞以5000细胞/cm2的浓度铺板,而使用基于血清的培养基则将细胞以1000细胞/cm2的浓度铺板。在成像和基因表达分析之前,将角膜细胞在无血清培养基中培养超过3周,或在基于血清的培养基中培养6天。通过用生存力/细胞毒性试剂盒(Life Technologies)染色来检查角膜细胞的形态。通过将玻璃化的膜浸泡在0.1%吲哚美辛滴眼液中一段时间将吲哚美辛包封于玻璃质凝胶中。使用高效液相色谱(HPLC)测量吲哚美辛从玻璃质凝胶中的洗脱。使用乙腈:水为51:49(v/v)的流动相、C18柱和设定在318nm的UV/VIS检测器测试释放溶液。
实施例1
所有3种环糊精,特别是α-CD,表现出与I型胶原三螺旋的强相互作用,导致形成透明的且机械强度高的CD-col膜。如在图1中示出的,常规玻璃质凝胶在热流中在55℃表现出大且宽的吸热峰,这表明胶原膜以40.8J/g的焓经历热变性。相比之下,在交联的玻璃质凝胶的对照样品中没发现可辨别的峰,表明由于交联反应胶原膜的变性特征。与常规玻璃质凝胶相比,在胶原膜中添加α-CD产生升高的变性温度,表明增强的热稳定性。在α-CD-col中仅观察到单个较窄的峰,这意味着基质具有均匀结构。如果我们假设,所有焓来自胶原三螺旋的热转化,α-CD-col的变性焓为来自常规玻璃质凝胶的变性焓的70.1%,表明降低的胶原纤维发生。在β-CD-col和γ-CD-col中也观察到相似的结果。
实施例2
与传统胶原膜相比,CD-col膜示出了极大提高的透明度(图2),其可以用降低的胶原纤维发生来解释。
实施例3
本发明的组合物证明了优越的机械性能。当它们的厚度与人角膜的厚度相当时(即~500μm),它们变得足够强韧以用于缝合。如在图3中示出的,将尼龙缝线拉动穿过具有520μm的厚度的α-CD-col膜中的孔。在缝线的压力下,厚膜中的孔仅拉伸,而不是如在具有170μm的厚度的薄膜中观察到的撕裂膜(图4)。
实施例4
胶原纳米结构限定了细胞应答。在具有低和高的胶原密度的玻璃质凝胶组合物上培养牛角膜细胞的原代培养物。如在图5中示出的,当与常规玻璃质凝胶对照相比时,本发明的组合物的胶原密度允许角膜细胞在培养物中具有更大的突起面积。此外,角膜细胞的细胞突起的总数目随着本发明的玻璃质凝胶组合物的胶原密度的增加而显著增加(图5)。
实施例5
角膜细胞基因表达取决于原纤维结构。在对照玻璃质凝胶上或用本发明的玻璃质凝胶组合物培养角膜细胞,其中玻璃质凝胶在5℃或39℃的温度脱水。在基于血清的培养基中生长6天后,收获细胞并分析角膜蛋白、醛脱氢酶(ALDH)和双糖链蛋白聚糖(biglycan)的基因表达。通过以下分析这些基因的表达:使用TRIzol试剂(Life Technologies)从培养的角膜细胞分离总RNA,使用SuperScript II第一链合成试剂盒(Life Technologies)逆转录成cDNA,并随后在StepOnePlus Real-Time PCR System(Applied LifeTechnologies)上使用实时PCR反应测试cDNA。如在图6中示出的,当与对照相比时,当细胞在于高温脱水的玻璃质凝胶组合物上生长时,角膜蛋白和ALDH的基因表达极大提高。当与对照相比时,双糖链蛋白聚糖的表达于在低温和高温的玻璃质凝胶组合物中降低。
实施例6
本发明的玻璃质凝胶组合物可以被用于递送生物活性剂。如上所述制备玻璃质凝胶组合物,并在使玻璃质凝胶水合后,使用2滴持续10分钟或在1mL滴眼液中浸泡过夜将乙醇中的商购可得的0.1%吲哚美辛的滴眼液制剂的溶液添加至组合物,并使用HPLC测试释放动力学。发现玻璃质凝胶组合物经过5小时的时期从玻璃质凝胶组合物释放吲哚美辛。
开发了本发明的I型胶原-CD组合物,所述I型胶原-CD组合物具有用于角膜再生的优化的光学和机械性能。不限于任何特定理论,这些性能可能由于环糊精掺入的胶原组合物中经调节的胶原原纤维发生(图7)。本发明的这些组合物具有被用作用于角膜修复和治疗的治疗性眼贴的极大潜力。本文公开的组合物和方法也可以用于来源于形成原纤维的胶原的其它结缔组织诸如软骨、皮肤以及血管的再生。
本文引用的所有参考文献,包括出版物、专利申请、以及专利通过引用在此并入,其程度如同每个参考文献单独地且具体地被指示通过引用被并入并且以其整体在本文被陈述。
除非本文另外指示或与上下文明显矛盾,否则在描述本发明的上下文中(尤其是在以下权利要求书的上下文中)使用的术语“一(a)”和“一(an)”以及“该(the)”和相似的指示物,被解释为覆盖单数和复数两者。除非另外注明,否则术语“包括(comprising)”、“具有(having)”、“包括(including)”以及“包含(containing)”被解释为是开放式的术语(即,意指“包括但不限于”)。除非本文另外指示,否则本文列出的值的范围仅仅预期用作单独指示落在该范围内的各个单独的值的简写方法,并且各个单独的值被并入本说明书,如同其在本文单独列出。除非本文另外指示或另外与上下文明显矛盾,否则本文描述的所有方法可以以任何合适的顺序进行。除非另外声明,否则本文所提供的任何以及所有实施例或示例性语言(例如,“诸如”)的使用仅仅预期更好地说明本发明且对本发明的范围不施加限制。本说明书中的语言不应解释为指示任何未要求保护的要素作为对本发明的实践必不可少。
本文描述了本发明的优选的实施方案,包括本发明人已知用于进行本发明的最佳方式。在阅读前述描述之后,那些优选的实施方案的变化形式对于本领域常规技术人员可以变得明显。本发明人预期技术人员视需要采用此类变化形式,并且本发明人预期本发明以不同于如本文具体描述的方式被实施。因此,本发明包括如被适用的法律允许的在此所附的权利要求书中列出的主题的所有修改形式和等同物。此外,除非本文另外指示或另外与上下文明显矛盾,否则呈其所有可能的变化形式的上文描述的要素的任何组合被本发明包含。
Claims (14)
1.一种组合物,所述组合物包含具有第一组分和第二组分的玻璃化基质凝胶,其中所述第一组分包含胶原,且其中所述第二组分包含环糊精,其中所述第一组分的胶原为I型胶原。
2.如权利要求1所述的组合物,其中所述第二组分的环糊精选自由α-环糊精、β-环糊精和γ-环糊精组成的组。
3.如权利要求2所述的组合物,其中所述组合物还包含至少一种生物活性剂。
4.如权利要求3所述的组合物,其中所述组合物在使用前被水合。
5.如权利要求2所述的组合物,其中所述组合物形成适用于用作人工角膜的形状。
6.如权利要求2所述的组合物,其中所述组合物具有在550nm的高于90%的光学透明度。
7.如权利要求1至6中任一项所述的组合物在制备用于修复哺乳动物的组织的基质中的用途。
8.如权利要求1至6中任一项所述的组合物在制备药物中的用途,其中当被使用时,所述组合物被水合,并且然后经手术植入眼中。
9.一种用于制造玻璃化基质凝胶的方法,所述玻璃化基质凝胶具有第一组分和第二组分,其中所述第一组分包含胶原,且其中所述第二组分包含环糊精,所述方法包括:
a)获得胶原的水性溶液;
b)获得环糊精的水性溶液;
c)将a)和b)的溶液组合以产生组合的溶液;和
d)使c)的组合的溶液脱水持续足以允许所述溶液玻璃化的一段时间;
其中所述胶原是I型胶原。
10.如权利要求9所述的方法,其中胶原和环糊精的溶液具有在1mg/ml至10mg/ml的范围内的胶原相对于水的浓度以及在2.5mg/ml至10mg/ml的范围内的环糊精相对于水的浓度。
11.如权利要求9所述的方法,其中所述环糊精选自由α-环糊精、β-环糊精和γ-环糊精组成的组。
12.如权利要求11所述的方法,其中所述环糊精是一种或更多种不同环糊精的混合物。
13.如权利要求9所述的方法,其中所述脱水包括使c)的组合的溶液在5℃至40℃的温度、在20%至80%之间的相对湿度并且持续在3天至28天之间的时间干燥。
14.如权利要求9至13中任一项所述的方法,所述方法还包括步骤e)使所述玻璃化基质凝胶再水合。
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