CN1378445A - 药物释放生物可降解纤维植入物 - Google Patents
药物释放生物可降解纤维植入物 Download PDFInfo
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Abstract
本发明提供了组织工程组合物和方法,其中为体外和体内使用制备了生长细胞的三维基质。此基质包含可以控制运送治疗剂的生物可降解聚合物纤维。所释放的治疗剂的空间和时间分布由在基质中使用规定非均质模式的治疗剂而控制。
Description
发明背景
本发明要求1999年8月6日提交的临时申请60/147,827的优先权。
1.发明背景
本发明涉及医学和组织工程领域,特别是涉及药物释放生物可降解植入物。
2.相关领域描述
组织工程是用活细胞替代动物或人体内由损伤、疾病或先天性缺陷造成的功能缺失的学科。这些替代细胞可以是自体的、同种异体的,或在有限的情况中为异种的。组织工程领域是医学的一项新领域和最佳程序,但仍需进一步阐明。
目前,研究者将一些初级手段用于组织工程。一种是从健康供体获得细胞,优选从同一个体,或至少从同种的适当供体获得细胞,并在体外使这些细胞生长在支架上。该支架一般为三维聚合物网,通常由生物可降解纤维组成。粘附在聚合物网上的细胞一般可以被诱导繁殖。可以将这些由细胞填充的支架植入受损宿主,其目的是这些细胞执行其生理功能并避免受宿主免疫系统破坏。到目前为止,使用纯化细胞系是非常重要的,因为非自体免疫细胞的诱导可以上调强烈的宿主免疫攻击。此方法的难点是支架必需很小,因为没有细胞可以在离氧气和营养物质几毫米远的地方存活。所以,不能用大支架,因为这种支架不能及时充分形成血管以保留内部区域的细胞。
在另一种方法中,直接将空的三维生物可降解聚合物支架植入病人,其目的是诱导宿主中适当类型的细胞迁移到聚合物支架中。优点是血管生成可以与细胞迁移到基质中同时发生。主要问题是目前没有方法可以保证适当的细胞类型迁移到支架,以及维持机械和生物特征以提供病人的生理需要。
在前面的两种方法中,支架是生物可降解的,表示它将随时间进展而被化学和机械破坏。当发生这种破坏时,细胞分泌它们自己的细胞外基质,这在细胞存活和功能中起关键作用。在正常组织中,在组织的构成细胞和细胞外周基质间存在活性和动态互利的交换。细胞外基质提供调节细胞形态学特征和表型性状的化学信号,并可以诱导细胞分裂、分化甚至细胞死亡。另外,细胞也不断重排细胞外基质。细胞降解并重建细胞外基质并分泌化学物质到基质,供它们自己或其它迁移到此区域的细胞使用。也发现细胞外基质是胚胎发育最重要的成分之一。先趋细胞分泌帮助后继细胞分化为适当终表型的化学信号。例如,这种化学信号使神经脊细胞分化为轴突、平滑肌细胞或神经元。
细胞外基质和组织细胞间的综合关系将细胞外基质确立为组织工程的一个重要参数。如果需要细胞表现特定行为,那么细胞外基质必需提供适当的环境和适当的化学/生物信号以诱导该细胞类型的这种行为。目前还不可能如实复制有生物活性的细胞外基质。所以,一些研究者使用生物可降解基质,使细胞可以在外源基质降解时建立自己的细胞外基质。
在前面所描述的组织工程方法中,聚合物支架不仅提供机械支持,而且也提供了新组织或器官需要的三维外形。由于细胞必需接近氧气和营养成分来源以便存活和行使功能,目前主要的限制是供血的限制。目前大多数方法没有提供积极帮助引入血管并使其贯串聚合物基质的特定方法。这就给聚合物基质的物理大小和外形设置了限制。目前广泛应用于临床的唯一组织工程设备为人工皮肤,根据定义有限定的厚度。本发明提供促进适当细胞类型定向迁移到制造的细胞外基质的组合物和方法。通过定向的特异性三维细胞迁移和功能模式,可以诱导定向的血管生成,这克服了目前聚合物植入物外形和大小的限制。它也保证了适当细胞类型将物理位于基质中的特定位置。提供了将表型表达调节为时间和空间的函数的组合物和方法。
发明概述
本发明提供了组织工程组合物和方法,其中为体外和体内使用制备了生长细胞的三维基质。基质包括可以控制运送治疗剂的生物可降解聚合物纤维。所释放治疗剂的空间和时间分布通过使用预定非均质模式的聚合物纤维而控制,可以作为时间的函数释放一种或更多治疗剂。名词“支架”、“支架基质”和“纤维支架”在这里也用于描述本发明的三维基质。在本发明内容中的“规定的非均质模式”表示将特定纤维引入支架基质从而达到所需要的支架基质中一种或更多治疗剂的三维分布。治疗剂在基质纤维中的分布控制试剂从聚合物纤维释放后在基质的胞间基质中的空间分布。以这种方式,可以在三维基质结构和基质紧邻环境中建立所需浓度梯度的空间轮廓。时间分布通过纤维的聚合物组合物以及通过纤维内同轴层的使用而控制。
本发明的一方面是包含生物可降解聚合物纤维支架的生物适合的植入物组合物。在本发明的各种实施方案中,纤维间的距离可以是约50微米,约70微米,约90微米,约100微米,约120微米,约140微米,约160微米,约180微米,约200微米,约220微米,约240微米,约260微米,约280微米,约300微米,约320微米,约340微米,约360微米,约380微米,约400微米,约450微米或约500微米。在各种实施方案中,纤维间的距离可以小于50微米或大于500微米。
此外,在本发明的各种实施方案中,纤维直径将为约20微米,约40微米,约60微米,约80微米,约100微米,约120微米,约140微米,约160微米,约180微米,约200微米,约220微米,约240微米,约260微米,约280微米,约300微米,约320微米,约340微米,约360微米,约380微米,约400微米,约450微米或约500微米(包括中间长度)。在各种实施方案中,纤维直径可以小于20微米或大于500微米。优选地,纤维直径将从约60微米到约80微米。
“约”在本文中意指1-10微米的范围,包括此范围中的中间长度。很容易理解,在本文中的“中间长度”表示在提出范围之间的长度,如21,22,23,24,25,26,27,28,29等;30,31,32等;50,51,52,53等;100,101,102,103等;150,151,152,153等;包括所有200-500之间的所有整数。
发明者也考虑了基质可以是编织的、非编织的、编结的、接合的或者是两种或更多这些制剂的组合。例如,潜在应用如人工动脉可以很好地使用编织的、非编织的和接合的制剂或所有四种制剂的组合。在本发明的某些实施方案中,编结的组合物可以在用于肌腱和韧带时发现特殊应用。这种编结可以提供例如高强度。
在本发明的某些实施方案中,纤维包含一种或更多以规定非均质模式在支架基质中分布的治疗剂。在一种实施方案中,纤维可以包含两种或更多生物可降解聚合物含量不同的纤维亚型。纤维或纤维亚型可以包含多种同轴生物可降解聚合物层。
在本发明的另一种实施方案中,纤维或纤维亚型包含一种或更多治疗剂,使得治疗剂浓度或治疗剂沿纤维或纤维亚型纵轴而改变。活性试剂的浓度可以作为沿纤维纵轴距离的函数,以线性、对数或以任何需要的方式改变。此改变可以是单方向的,即一种或更多治疗剂的含量从纤维或纤维亚型的第一末端到纤维或纤维亚型的第二末端逐渐减小。此含量也可以以双向方式改变,即治疗剂的含量从纤维或纤维亚型的第一末端增加到最大,然后向纤维或纤维亚型的第二末端逐渐减小。
在本发明的某些实施方案中,包含支架的纤维亚型可能不含有治疗剂。对于含有一种或更多治疗剂的纤维,试剂可以包括生长因子、免疫调节剂、促进血管生成的化合物、抑制血管生成的化合物、抗炎化合物、抗生素、细胞因子、抗凝剂、促凝剂、趋化剂、促进凋亡的试剂、抑制凋亡的试剂、促有丝分裂剂、放射性试剂或成像研究的造影剂、病毒载体、多核苷酸、治疗基因、DNA、RNA、多肽、粘多糖、糖、糖蛋白。治疗剂也可包括长期维持给予病人的药物如心血管药物、包括血压、起搏、抗心律失常、β阻滞药物和基于钙离子通道的药物。本发明的治疗剂也可包括抗震颤和其它抗癫痫或其它运动疾病的药物。这些试剂也可以包括长期药疗如避孕药和生育药物。它们可以包括神经药物如多巴胺和相关药物以及生理或其它行为药物。治疗剂也可以包括化学清除剂如螯合剂和抗氧化剂。其中治疗剂促进血管生成,此试剂可以是血管内皮生长因子。治疗剂可以是合成或天然药物、蛋白质、DNA、RNA或细胞(有或无遗传改变)。根据长期执行行的专利法,在说明书和权利要求中与“包含”或“包括”结合使用的“一种”表示一种或更多。
总的说来,本发明考虑了使用药物引入到本发明的生物可降解聚合物纤维。这里用到的名词“药物”是定义为可以给予生物体,调节或改变生物体生理的化学物质。这里用到的名词“药物”更优选定义为任何用于治疗或预防疾病的物质。药物包括合成和天然存在的毒素和生物影响物质以及公认的药物,如“The Physicians DeskReference,”471st edition,pages 101-321;“Goodman andGilman’s The Pharmacological Basis of Therapeutics”8thEdition(1990),pages 84-1614 and 1655-1715;“The UnitedStates Pharmacopeia,The National Formulary”,USP X X II NFX V II(1990)所列出的,在此引入这些参考文献的化合物作为参考。名词“药物”也包括有提示特征而在美国没有发现或无法得到的化合物。名词“药物”包括药物的激活前、激活的和代谢物形式。
生物可降解聚合物可以是单聚合物或共聚合物或聚合物的混合并可以包含聚(L-乳酸)、聚(DL-乳酸)、聚己酸内酯、聚(乙醇酸)、聚酐、脱乙酰壳多糖、或磺化脱乙酰壳多糖、或天然聚合物或多肽,如重构胶原或蜘蛛丝。
本发明的一方面是包含含有一种或更多治疗剂的生物可降解聚合物纤维的药物运送纤维组合物。在一种实施方案中,纤维中的一种或更多治疗组合物的含量沿纤维纵轴改变,从而使治疗剂的含量从纤维的第一末端到第二末端逐渐减少。在另一种实施方案中,纤维包含多种同轴生物可降解聚合物层。药物运送纤维组合物可以植入身体的许多位点,包括真皮组织、心脏组织、软组织、神经、骨和眼。眼内植入特别用于治疗白内障、糖尿病诱导的增殖性视网膜病变和非增殖性视网膜病变、青光眼、黄斑变性、XXXX色素变性。
本发明的另一方面是控制纤维支架植入物内的一种或更多治疗剂的空间和时间浓度,包含将纤维支架植入宿主的方法。空间浓度可以跨多纤维或通过沿纤维长度加以浓度梯度而提供。纤维支架一般包含含有一种或多种治疗剂的生物可降解聚合物纤维,其中治疗剂以规定的非均质模式分布在纤维支架中。宿主一般是动物,优选为哺乳动物,更优选为人。
而本发明的另一方面是生产制备可以控制一种或更多治疗剂的空间和时间浓度的植入物的纤维支架的方法。这种方法一般包含在三维纤维支架中形成生物可降解聚合物纤维。这种生物可降解聚合物纤维包含一种或更多治疗剂。治疗剂以规定的非均质模式分布在纤维支架中。
进一步预见到本发明的支架可以用于定向和/或组织组织结构,细胞迁移和基质沉积并参与或促进普通伤口愈合。
在本发明的另一种实施方案中,提供了从脱乙酰壳多糖建立药物释放纤维的方法,包含将盐酸作为溶剂和Tris碱作为凝固浴。例如,盐酸浓度可以从约0.25%到约5%,或从约1%到约2%,包括在此范围内的所有浓度。在此方法中,tris碱浓度可以是,例如从约2%到约25%,从约4%到约17%,或从约5%到约15%,包括在此范围内的所有浓度。在本发明的一种实施方案中,此方法可以包含含有不同脱乙酰程度的脱乙酰壳多糖的非均质性混合物。此方法也可以包含建立含有不同脱乙酰程度的脱乙酰壳多糖片段的药物释放纤维。
本发明的药物释放纤维可以从例如脱乙酰壳多糖和细胞外基质建立。在依据本发明建立药物释放纤维的过程中,脱乙酰壳多糖浓度可以是,例如,从约0.5wt.%到约10wt.%,从约1wt.%到约7wt.%,从约2wt.%到约5wt.%,从约3wt.%到约4wt.%,或约3.5wt.%。在本发明的一种实施方案中,细胞外基质浓度可以从约1vol.%到约20vol.%,从约2vol.%到约15vol.%,从约3vol.%到约10vol.%,从约4vol.%到约6vol.%,包括约5vol.%。在此方法中,纤维可以包被于细胞外基质。
本发明使用的脱乙酰壳多糖可以是磺化的或非磺化的。在本发明的一种实施方案中,当使用磺化脱乙酰壳多糖时浓度可以从约0.025wt.%到约2wt.%,从约0.05wt.%到约1wt.%,从约0.1wt.%到约0.5wt.%,从约0.15wt.%到约0.3wt.%,包括约0.2wt.%。在此方法中,脱乙酰壳多糖和磺化脱乙酰壳多糖可以被挤出到纤维。
在本发明的另一种实施方案中,提供了建立药物释放纤维的方法,这种方法包括在酸和凝固浴中添加聚(L-乳酸)微球体到脱乙酰壳多糖。在此方法中,酸可以是例如乙酸或盐酸。当酸为盐酸时,浓度可以是例如从约0.25%到约5%,或从约1%到约2%,包括1.2vol.%以及在此范围内的所有其它浓度。脱乙酰壳多糖浓度可以是例如,从约0.5wt.%到约10wt.%,从约1wt.%到约7wt.%,从约2wt.%到约5wt.%,从约3wt.%到约4wt.%,或约3.5wt.%。凝固浴可以包括氢氧化钠,例如,浓度为从约1vol.%到约20vol.%,从约2vol.%到约15vol.%,从约3vol.%到约10vol.%,从约4vol.%到约6vol.%,包括约5vol.%。在本发明的一种实施方案中,这种方法包括在从约1vol.%盐酸到约2vol.%盐酸中将聚(L-乳酸)微球体添加到约3.5wt.%脱乙酰壳多糖的溶液中,并使用包含从约5vol.%tris碱到约15vol.%tris碱的凝固浴。此方法可以进一步包括将表面活性剂加入溶液,包括白蛋白,例如从约1wt.%到约5wt.%的该白蛋白,包括约3wt.%。而在本发明的另一种实施方案中,脱乙酰壳多糖纤维的组合物包含第二种聚合物的微球体,该微球体包含一种或更多生物分子。此组合物可以包含一种为生物分子的表面活性剂。
而在本发明的另一种实施方案中,组合物包含一种含有脱乙酰壳多糖和细胞外基质的纤维。脱乙酰壳多糖可以是磺化的或非磺化的。
而在本发明的另一种实施方案中,组合物包含三维支架,该支架包含编织的、非编织的或接合的纤维,其中该纤维包含前面所描述的任何组合物。在一种实施方案中,本发明的组合物可以包含含有脱乙酰壳多糖、细胞外基质和生物分子的纤维。脱乙酰壳多糖可以是磺化或非磺化的。
而在本发明的另一种实施方案中,组合物包含非均质性纤维支架和前面所描述的生物分子,其中支架的所有纤维中的生物分子并不相同。在组合物中,脱乙酰基的程度可以作为沿纤维距离的函数而不同。组合物可以是细胞外基质。在本发明的某些实施方案中,组合物也可以包括磺化或非磺化脱乙酰壳多糖。
附图简述
下列附图形成本发明说明书的一部分,包含它们是用于证明本发明的某些方面。通过参考一幅或更多附图并结合这里列出的特定实施方案的详述,可以更好地理解本发明。
图1:表示纤维构型为形成图形的复杂三维编织支架。每条纤维可以加载一种或更多治疗剂。
图2:表示纤维构型为不形成图形的三维非编织支架。每条纤维可以加载一种或更多治疗剂。所有纤维可以含相同治疗剂或同一支架中的其它纤维可以使用许多不同的试剂。
图3A和图3B:纤维可以在如支架的应用中提供给机体短期机械支持。图3A说明了单个聚合物纤维可以维持管状体如动脉、静脉或导管的腔。图3B说明多个聚合物纤维可以维持管状体的腔。
图4:纤维可以被包被而形成同轴纤维。图4表示纤维可以有多种成分的包膜,每种成分加载不同治疗剂。
图5:表示图4所示有包膜纤维的释放动力学,此纤维有两种成分的包膜,每种加载不同的治疗剂。
图6A和图6B:纤维可以沿其长度包含线性梯度。图6A说明了沿长度包含治疗剂线性梯度的纤维。图6B图示了线性梯度。
图7:表示具有沿其长度改变的一种或更多治疗剂浓度的有条带的纤维。条带的分布和频率可以根据需要改变。
图8:描绘了构造含治疗剂的聚合物纤维的设备。
图9A和图9B:通过改变聚合物乳状液注入到凝固浴的速度与车床缠绕速度之比,观察到非常惊人的机械特征改变。图9A图示了缠绕速度与注入速度之比改变时的最终强度[Mpa]。表示了10-wt%,8-wt%和7.5-wt%的聚合物的结果。图9B图示了缠绕速度(Vw)与注入速度(Vi)之比改变时的延伸百分比。
图10A和图10B:纤维的机械特征可以作为聚合物溶剂、凝固浴溶剂、溶剂系统的相互作用、缠绕速度与注入速度之比、凝固浴中的总时间、乳状液中水相与聚合物溶液相之比、以及表面活性剂质量的函数而改变。图10A图示了当缠绕速度与注入速度之比(Vw/Vi)为26.82和23.49时最终强度随聚合物浓度(wt%)的改变。图10B说明了相同比例下弹性随聚合物重量百分比的改变。
图11A,图11B和图11C:产生不同表面质地的纤维。图11A表示有光滑表面质地的纤维。图11B表示有绒面质地的纤维。图11C表示有纵沟表面质地的纤维。
图12:说明纤维直径作为缠绕速度与注入速度之比(Vw/Vi)和重量百分比的改变。
图13:说明在“Y”连接处使用蝶形阀逐渐改变两种溶液之比,从而获得沿纤维长度的浓度梯度。
图14:说明使用独立泵和混合室而建立每厘米长度有已知浓度改变的控制良好的梯度。
图15:说明包装在硅胶或其它适当物质管中并加载了促进轴突生长的神经营养蛋白的平行列纤维。
发明详述
本发明为给组织工程应用中的生长细胞建立非均质的、编织的、接合的、或非编织的或编结的三维基质提供了组合物和方法。这些支架可以体外和体内应用,而且由于它们的非均质性而可以建立治疗剂的空间和时间分布。在本发明中,治疗剂可以包括药物、蛋白质、肽、单和双糖、多糖、糖蛋白、DNA、RNA、病毒或其它感兴趣的分子。本发明的治疗剂也包括用于帮助破坏有害组织如局部区域的肿瘤,或例如在目前支架应用中用于抑制健康组织的生长;或用于成像研究的标记物的放射性物质。A.三维纤维基质
为建立本发明的非均质性支架,可以这里描述的方法将治疗剂包被于个体纤维中。治疗剂以控制的方式从每个个体纤维缓慢释放。纤维形式作为药物运送平台与其它本领域中公知的缓释试剂如微球体、多孔栓或贴剂相比有许多优点。纤维的主要优点是它们可以在有或没有形成图形的情况下提供复杂的三维编织(图1),或非编织(图2)支架,从而允许细胞附着、扩散、分化和成熟为适当功能的细胞。因为它们可以形成图形,可以编织成“智能织物”而根据释放的特定趋化因子诱导特定类型的细胞迁移到支架的特定区域。支架在胚胎发育和胚后组织中模拟细胞外基质物质的功能。另外,在一种唯一的支架中可以形成微丝,为不是天然记忆的组织修复或重构提供生长底物。
由于编织模式诱导适当细胞类型进入特定区域的能力,可以引入诱导织物中血管形成的链。这可以通过提供释放生长因子如血管内皮生长因子(VEGF)的纤维而实现。通过适当将含VEGF的纤维定位于编织模式中,可以制造大的组织,并且可以给这些组织中的细胞提供充足供血,使它们得到氧气和营养成分并可以清除废物。
纤维也具有在如支架(图3A和3B)的应用中提供给机体短期机械支持的优点,其中聚合物纤维可以保持管状体的腔,如动脉、静脉、导管(如胆管、输尿管、尿道、气管等)、消化道器官如食道、小肠、结肠和结缔组织如肌腱、韧带、肌肉和骨骼。纤维为康复过程中支持机械强度或张力提供了有用的结构。纤维对促进神经再生或神经或脊髓重构也是有用的。
另外,纤维可以被包被,形成图4所示的同轴纤维。每个包膜可以是不同聚合物物质或聚合物的组合,每层可以释放不同治疗剂或治疗剂的组合。包膜也可以被物理分割为多个部分,表示如果需要,可以以各种方向释放不同治疗剂。例如,如图4所描绘,纤维可以有两个成分包膜,每个成分加载不同治疗剂。所以,不仅上述各种治疗剂的空间分布是可能的,而且这些试剂可以有不同的释放动力学,从而产生治疗剂的时间分布。这种包膜纤维的释放动力学如图5所示。例如,如果纤维在核心聚合物外有两层包膜,那么可以释放三种不同的治疗剂或治疗剂的组合。外层包膜将释放它的治疗剂,然后是内层包膜,最后是核心纤维。所以,每种聚合物系统有自己的释放动力学分布图,可以由聚合物类型和该特定包膜层的处理条件而调整。每层包膜由不同聚合物组成并装载不同分子。这提供了每层控释动力学的能力。在不同时间释放不同试剂的能力在组织工程中特别重要,因为迅速分裂的细胞通常不显示同类型非分裂细胞的特定功能。对于本发明,通过释放适当的治疗剂,可以诱导细胞首先迁移到特定位置,然后进入迅速分裂相而填充组织空隙,然后分化为功能形式。
另外,已知细胞遵循浓度梯度。特定因子浓度的改变对细胞迁移的定向是重要的。所以,本发明提供了沿纤维长度获得治疗剂梯度的方法。图6A和6B描绘了线性梯度。通过本发明公开的方法,这种梯度可以是沿纤维长度距离的线性、指数、或其它任何形状的函数。它也可以是双向的,表示例如它可以两端低并在中间达到最高。这诱导细胞迁移并沿纤维的特定方向生长。经过扩展,通过本发明公开的方法,也可以产生有条带的纤维。这些带的分布和频率可以根据需要改变。所以,本发明的治疗剂的运送方面远远超过了微球体或栓的范围,以纤维为基础的“智能支架”超过了一般以纤维为基础的基质,指挥可存活组织的发育,提供三维生物建筑和机械支持。B.生物可降解聚合物
本发明优选使用的聚合物包括单聚合物、共聚物或聚(L-乳酸)、聚(DL-乳酸)、聚己酸内酯、聚(乙二醇酸)、聚酐、脱乙酰壳多糖或磺化脱乙酰壳多糖。也可以使用天然存在的聚合物如重构胶原或天然丝。本领域的技术人员会理解这些聚合物只是本发明使用的一类生物可降解聚合物基质的例子。其它生物可降解基质包括聚酐、聚原酸酯和聚(氨基酸)(Peppas and Langer,1994)。可以利用任何这种机制构造本发明使用的有控制特性的生物可降解基质。其它产生非毒性降解产物的生物可降解聚合物见表1。
表1
公认为生物可降解的主要聚合物合成的
多肽
polydepsipeptides
尼龙-2/尼龙-6共聚多酰胺
脂肪族聚酯
聚(乙二醇酸)(PGA)和共聚物
聚(乳酸)(PLA)和共聚物
聚(亚烷基琥珀酸)
聚(羟基丁酸)(pHB)
聚(butylene diglycolate)
聚(ε-己内酯)和共聚物
聚二氢吡喃
聚磷腈
聚(原酸酯)
聚(氰基丙烯酸酯)天然的
经修饰的多糖
纤维素、淀粉、几丁质
经修饰的蛋白质
胶原、血纤维蛋白摘自Wong and Mooney,1997C.促进血管生成的试剂
用聚合物纤维包被的一类治疗剂是促进血管生成的治疗剂。成功制造新组织要求建立血管网。血管生成的诱导由许多因子介导,其中的任何一种可以与本发明联合使用(Folkman and Klagsburn,1987,以及这里引用的参考文献,在此引入其全部内容作为参考)。血管生成因子的例子包括,但不限于:血管内皮生长因子(VEGF)或血管通透因子(VPF);成纤维细胞生长因子家族成员,包括酸性成纤维细胞生长因子(aFGF)和碱性成纤维细胞生长因子(bFGF);白介素-8(IL-8);表皮生长因子(EGF);血小板源上皮细胞生长因子(PD-ECGF);转化生长因子α和β(TGF-α,TGF-β);肿瘤坏死因子α(TNF-α);肝细胞生长因子(HGF);粒细胞-巨噬细胞集落刺激因子(GM-CSF);胰岛素生长因子-1(IGF-1);血管生长因子;促血管素;血纤蛋白和烟酰胺(Folkman and Klagsbrun,1987;Nagy et al.,1995)D.细胞因子
在某些实施方案中考虑了引入本发明聚合物纤维的特定细胞因子的使用。下面的表2是考虑用于本发明的一些细胞因子和相关因子的例子,但不限于这些。
表2
E.多核苷酸
Cytokine | Reference |
人IL-1 | March et al.,Nature,315:641,1985 |
鼠IL-1 | Lomedico et al.,Nature,312:458,1984 |
人IL-1 | March et al.,Nature,315:641,1985;Auron et al.,Proc.Natl.Acad.Sci.USA,81:7907,1984 |
鼠IL-1 | Gray,J.Immunol.,137:3644,1986;Telford,NAR,14:9955,1986 |
人IL-lra | Eisenberg et al.,Nature,343:341,1990 |
人IL-2 | Taniguchi et al.,Nature,302:305,1983;Maeda et al.,Biochem.Biophys.Res.Commun,115:1040,1983 |
人IL-2 | Taniguchi et al.,Nature,302:305,1983 |
人IL-3 | Yang et al.,Cell,47:3,1986 |
鼠IL-3 | Yokota et al.,Proc.Natl.Acad.Sci.USA,81:1070,1984;Fung et al.,Nature,307:233,1984;Miyatake et al.,Proc.Natl.Acad.Sci.USA,82:316,1985 |
人IL-4 | Yokota et al.,Proc.Natl.Acad.Sci.USA,83:5894,1986 |
鼠IL-4 | Norma et al.,Nature,319:640,1986;Lee et al.,Proc.Natl.Acad.Sci.USA,83:2061,1986 |
人IL-5 | Azuma et al.,Nuc.Acids Res.,14:9149,1986 |
鼠IL-5 | Kinashi et al.,Nature,324:70,1986;Mizuta et al.,Growth Factors,1:51,1988 |
人IL-6 | Hirano et al.,Nature,324:73,1986 |
鼠IL-6 | Van Snick et al.,Eur.J.Immunol.,18:193,1988 |
人IL-7 | Goodwin et al.,Proc.Natl.Acad.Sci.USA,86:302,1989 |
鼠IL-7 | Namen et al.,Nature,333:571,1988 |
人IL-8 | Schmid et al.,J.Immunol.,139:250,1987;Matsushimaet al.,J.Exp.Med.,167:1883,1988;Lindley et al.,Proc.Natl.Acad.Sci.USA,85:9199,1988 |
人IL-9 | Renauld et al.,J.Immunol.,144:4235,1990 |
鼠IL-9 | Renauld et al.,J.Immunol.,144:4235,1990 |
人血管生长因子 | Kurachi et al.,Biochemistry,24:5494,1985 |
人GRO | Richmond et al.,EMBO J.,7:2025,1988 |
鼠MIP-1 | Davatelis et al.,J.Exp.Med.,167:1939,1988 |
鼠MIP-1 | Sherry et al.,J.Exp.Med.,168:2251,1988 |
人MIF | Weiser et al.,Proc.Natl.Acad.Sci.USA,86:7522,1989 |
人G-CSF | Nagata et al.,Nature,319:415,1986;Souza et al.,Science,232:61,1986 |
人GM-CSF | Cantrell et al.,Proc.Natl.Acad.Sci.USA,82:6250,1985;Lee et al.,Proc.Natl.Acad.Sci.USA,82:4360,1985;Wong et al.,Science,228:810,1985 |
鼠GM-CSF | Gough et al.,EMBO J.,4:645,1985 |
人M-CSF | Wong,Science,235:1504,1987;Kawasaki,Science,230;291,1985;Ladner,EMBO J.,6:2693,1987 |
人EGF | Smith et al.,Nuc.Acids Res.,10:4467,1982;Bell et al.,NAR,14:8427,1986 |
人TGF- | Derynck et al.,Cell,38:287,1984 |
酸性人FGF | Jaye et al.,Science,233:541,1986;Gimenez-Gallego etal.,Biochem.Biophys.Res.Commun.,138:611,1986;Harper et al.,Biochem.,25:4097,1986 |
人-ECGF | Jaye et al.,Science,233:541,1986 |
碱性人FGF | Abraham et al.,EMBO J.,5:2523,1986;Sommer et al.,Biochem.Biophys.Res.Comm.,144:543,1987 |
鼠IFN- | Higashi et al.,J.Biol.Chem.,258:9522,1983;Kuga,NAR,17:3291,1989 |
人IFN- | Gray et al.,Nature,295:503,1982;Devos et al.,NAR,10:2487,1982;Rinderknecht,J.Biol.Chem.,259:6790,1984 |
人IGF-I | Jansen et al.,Nature,306:509,1983;Rotwein et al.,J.Biol.Chem.,261:4828,1986 |
人IGF-II | Bell et al.,Nature,310:775,1984 |
人-NGF链 | Ullrich et al.,Nature,303:821,1983 |
人NT-3 | Huang EJ.Et al.,Development.126(10):2191-203,1999May. |
人PDGF A链 | Betsholtz et al.,Nature,320:695,1986 |
人PDGF B链 | Johnsson et al.,EMBO J.,3:921,1984;Collins et al., |
Nature,316:748,1985 | |
人TGF-1 | Derynck et al.,Nature,316:701,1985 |
人TNF- | Pennica et al.,Nature,312:724,1984;Fransen et al.,Nuc.Acids Res.,13:4417,1985 |
人TNF- | Gray et al.,Nature,312:721,1984 |
鼠TNF- | Gray et al.,Nucl.Acids Res.,15:3937,1987 |
人E-选择蛋白 | Bevilacqua et al.,Science,243:1160,1989;Hensley etal.,J.Biol.Chem.,269:23949,1994 |
人ICAM-1 | Simmons et al.,Nature,331:624,1988 |
人PECAM | Simmons et al.,J.Exp.Med.,171:2147,1990 |
人VCAM-1 | Hession et al.,J.Biol.Chem.,266:6682;Osborn et al.,Cell,59:1203,1989 |
人L-选择蛋白(膜结合) | Ord et al.,J.Biol.Chem.,265:7760,1990;Tedder et al.,J.Exp.Med.,170:123,1989 |
人L-选择蛋白(可溶形式) | Ord et al.,J.Biol.Chem.,265:7760,1990;Tedder et al.,J.Exp.Med.,170:123,1989 |
人降钙素 | Le Moullec et al.,FEBSLett.,167:93,1984 |
人蛭素(大肠杆菌优化) | Dodt et al.,FEBS Lett.,165:180,1984 |
引入本发明的聚合物纤维中的多核苷酸包括全部范围的分子。此核苷酸因此包括基因组DNA,cDNA,单链DNA,双链DNA,三链DNA,寡核苷酸,Z-DNA,mRNA,tRNA和其它RNA。一般优选DNA分子,甚至用DNA表达治疗RNA,如核酶或反义RNA。
编码所选蛋白或RNA的“基因”或DNA节段一般是指含有编码所选蛋白或RNA序列的DNA节段,但是从获得DNA的种属的总基因组DNA中分离出或纯化。DNA节段和这些节段的更小的片段以及重组载体包括,例如,质粒、粘粒、噬菌体、逆转录病毒、腺病毒等都包括在名词“基因”和“DNA节段”的范围内。
为了简便,名词“基因”用于指功能蛋白或肽编码单位。本领域的技术人员将理解,此功能性名词包括基因组序列和cDNA序列。“基本从其它编码序列中分离出”表示感兴趣的基因形成DNA节段编码区的重要部分,且该DNA节段不包括天然存在编码DNA大的部分,如大的染色体片段或其它功能基因或cDNA编码区。当然,这是指原始分离出的DNA节段,且不排除由人工加入到节段中的基因或编码区,如编码前导肽或引导肽的序列。
只要使用的编码节段编码选择的蛋白或RNA并且不包括对靶细胞有严重不良作用的编码和调节序列,则本发明不要求使用高度纯化的DNA或载体。所以,也需要理解有用的核酸序列可以包括附加残基,如附加的编码区5′或3′部分的侧翼非编码序列,或可以包括各种内部序列,即已知在基因内出现的内含子。
可以从现有的,包括商业来源获得许多合适的DNA节段。也可以用一种或更多本领域技术人员公知的分子生物技术获得编码感兴趣蛋白的新DNA节段。例如,可以用具有设计序列的引物或探针筛选cDNA或基因组文库。多聚酶链式反应(PCR)也可以用于产生编码感兴趣蛋白的DNA片段。
在识别适当选择的基因或DNA分子后,可以将其插入本领域中公知的一种或多种载体,使得它可以在掺入靶细胞时指导选择的蛋白的表达和产生。在重组表达载体中,DNA节段的编码部分在启动子/增强子元素的控制下定位。启动子可以以与选定基因天然相关的启动子的形式存在,可以通过使用例如重组克隆和/或PCR技术分离位于编码节段或外显子上游的5′非编码序列而获得。
在另一种实施方案中,考虑了通过在重组或异源启动子的控制下定位编码DNA节段将获得某些优点。这里用到的重组或异源启动子意指正常情况下与其它选定基因在其天然环境中不相关的启动子。这些启动子可以包括正常情况下与其它选定基因和/或从细菌、病毒、真核动物或哺乳动物细胞分离的启动子相关的启动子。在天然情况下,使用有效指导DNA节段在所选靶细胞中表达的启动子是很重要的。
使用重组启动子来获得蛋白表达是分子生物学领域中的技术人员所公知的,例如,见Sanbrool et al.(1989;在此引入作为参考)。使用的启动子可以是构成的或可诱导的,并可以在适当的条件下使用从而指导引入DNA节段的高水平或调节的表达。在构成启动子控制下的基因表达不要求特异性底物的存在而诱导基因表达,并且将在细胞生长的所有条件下出现。相对地,由可诱导启动子控制的基因表达对诱导剂的存在与否是有反应的。
在这里可以使用从在哺乳细胞中生长的病毒基因组中分离的启动子,如RSV,痘苗病毒7.5K,SV40,HSV,腺病毒MLP,MMTV LTR和CMV启动子,以及由重组DNA或合成技术产生的启动子。目前的优选启动子如CMV,RSV LTR,单独的SV40启动子,和与SV40增强子组合的SV40启动子。
显示组织特异性的组织特异性启动子/增强子元素和转录控制区的例子包括,但不限于:在胰腺腺泡细胞中有活性的弹性蛋白酶I基因控制区;在胰腺细胞中有活性的胰岛素基因控制区;在淋巴细胞中有活性的免疫球蛋白基因控制区;在肝中有活性的白蛋白、1-抗胰蛋白酶和胎蛋白基因控制区;在骨髓细胞中有活性的珠蛋白基因控制区;在脑寡突细胞中有活性的髓鞘质碱性蛋白基因控制区;在骨骼肌中有活性的肌凝蛋白轻链-2基因控制区;以及在下丘脑中有活性的促性腺素释放激素基因控制区。为引入对前面所描述元素的进一步描述的参考,在此引入1996年4月12日提出的美国申请No.08/631,334,1997年4月11日提出的PCT申请No.PCT/US97/07301作为参考。
对插入蛋白编码序列足够的翻译也需要特异的起始信号。这些信号包括ATG起始密码子和邻近序列。当整个编码序列,包括起始密码子和邻近序列插入适当表达载体时,不再需要附加的翻译控制信号。然而,当只插入编码序列的一部分时,应该提供外源性翻译控制信号,包括ATG起始密码子。起始密码子必需与蛋白编码序列的读框相协调,以保证整个插入序列的翻译。这些外源性翻译控制信号和起始密码子可以是多种来源的,可以是天然的和合成的。可以通过包含转录衰减序列、增强子元素等增强表达的效率和控制。
可以使用许多载体,包括但不限于,由重组细菌噬菌体DNA、质粒DNA或粘粒DNA衍生的载体。例如,可以使用质粒载体如pBR322,pUC19/18,pUC118,119和M13mp载体系列。噬菌体载体可以包括gt10,gt11,gt18-23,ZAP/R和EMBR噬菌体载体系列。可以使用的粘粒载体包括,但不限于pJB8,pCV103,pCV107,pCV108,pTM,pMCS,pNNL,pHSG274,COS202,COS203,pWE15,pWE16和卡隆粒载体系列。允许RNA体外转录的载体,如SP6载体也可以用于产生大量可以掺入基质中的RNA。
选定的基因和DNA节段也可以以DNA插入片段的形式存在于重组病毒,如重组疱疹病毒、逆转录病毒、痘苗病毒、腺病毒、腺病毒相关病毒或牛乳头瘤病毒的基因组中。尽管可以使用整合载体时,通常优选在许多世代中不将基因产物转移到子代细胞的非整合系统。以这种方式,基因产物在确定的生物过程如伤口愈合中表达,当基因癌传代中稀释时,基因产物的表达量减少。
在这些实施方案中,为使基因与靶细胞接触,应该准备重组病毒颗粒,其基因组包括基因插入片段的,并通过从本发明的聚合物纤维释放而接触靶细胞或组织,病毒感染细胞并转移遗传物质。在此引入下面的美国专利作为对病毒基因治疗进一步举例说明的参考:关于腺病毒、逆转录病毒、腺病毒相关病毒、疱疹病毒和巨细胞病毒基因治疗的美国专利5,747,469,关于腺病毒基因治疗的美国专利5,631,236;以及关于疱疹病毒基因治疗的美国专利5,672,344。
本发明也考虑了使用具有不同于文献中描述的序列的基因,只要改变或修饰基因仍然编码以需要(直接或间接)的方式行使功能而影响靶细胞的蛋白。这些序列包括那些由点突变、遗传密码简并或天然存在等位基因变异以及由基因工程即人工引入的进一步修饰导致的序列。
设计在核苷酸序列中引入改变而改变被编码蛋白或多肽的功能特征的技术在本领域中是公知的,如美国专利4,518,584,在此引入作为参考,其技术在这里也有进一步详述。这种修饰包括碱基去除、插入或替换以及由此引起的氨基酸序列改变。也可进行改变而增加蛋白质活性,增加其生物稳定性或半衰期,改变其糖基化模式,赋予温度敏感性或改变蛋白质的表达模式等。所有这些核苷酸序列的修饰都包含在本发明的范围内。
本发明的优点是在基因转移方法和组合物中可以使用一种或一种以上选定的基因。这样核酸运送方法可以要求给予一种、两种、三种或更多选定的基因。可以应用的最大基因数仅仅由实际考虑而限制,如同时制备大量基因构建体需要的努力或甚至引发不良毒性反应的可能性。可以选择基因的特定组合来改变相同的或不同的生化途径。例如,生长因子基因可以与激素基因组合;或第一激素和/或生长因子基因可以与编码能够与第一基因的多肽产物相互作用的细胞表面受体的基因组合。
在使用多种基因的情况下,它们可以在一种或更多启动子的控制下在单基因构建体上结合,或者它们可以作为相同或不同类型的分离构建体而制备。这样,可以使用几乎无限的不同基因和基因构建体的组合。某些基因组合可以设计为,或它们的使用会导致,获得对细胞刺激和组织生长的协同作用,这些组合的任何一种或全部都包含在本发明的范围中。实际上,在科学文献中描述了许多协同作用,所以本领域的常规技术可以很容易识别协同基因组合或甚至基因-蛋白质组合。
也应该理解,如果需要,核酸节段或基因可以与其它试剂如蛋白质或多肽或各种药物活性试剂结合给予。只要遗传物质形成组合物的一部分,假设附加试剂与靶细胞或组织接触时不会导致严重不良反应,则对其它可以包含的成分基本没有限制。这样核酸可以与各种其它试剂一起运送,例如,在某些实施方案中,可以希望给予血管生成因子,如美国专利5,270,300所公开的,在此引入作为参考。
由于基因的化学性质,即作为一串核苷酸是基本不变的,并且因为基因转移和表达的过程是基本相同的,可以理解由本发明的纤维基质转移的基因类型基本是无限的。这一概念从用于DNA接种而转移表达抗原性或免疫原性片段的遗传物质的混合物扩展到细胞功能的刺激,如在创伤修复中;到细胞杀伤方面,如将肿瘤抑制基因、反义癌基因或凋亡诱导基因转移到癌细胞。
仅仅通过实施例,本发明提供的基因包括,但不限于那些编码和表达:激素、生长因子、生长因子受体、干扰素、化学因子、细胞因子、集落刺激因子和趋化因子、转录和延伸因子、细胞循环控制蛋白,包括激酶和磷酸酶、DNA修复蛋白、凋亡诱导基因、凋亡抑制基因、癌基因、反义癌基因、肿瘤抑制基因;血管生成和抗血管生成蛋白;免疫应答刺激和调节蛋白;细胞表面受体、辅助信号分子和运输蛋白;酶和抗细菌和抗病毒蛋白的基因。F.试剂盒
本发明的各方面需要的基本物质和试剂可以集中在试剂盒中。本发明的试剂盒通常也包括将含有需要成分的小管包含在封闭限制结构中进行商业销售的方法,如保存所需小管的注射或吹气式塑料容器。不考虑容器的数量或类型,本发明的试剂盒一般按使用试剂盒成分的说明书包装。
G.实施例
引入下面的实施例来证明本发明的优选实施方案。本领域的技术人员应该赞同,实施例中公开的按照本发明者发现的代表技术的技术在本发明的执行中有良好作用,这样可以认为是为其实行建立了优选模式。然而,本领域的技术人员按照本公开内容,应该赞同在不离开本发明的精神和范围的前提下,可以在公开的特定实施方案中进行许多改变,仍然获得同样或相似的结果。
实施例1
构造含有治疗剂的聚合物纤维
在本发明的一种实施方案中,用下列程序建立药物释放纤维。此装置如图8所描绘。首先将生物可降解聚合物如聚(L-乳酸)(PLLA)、聚(DL-乳酸)、聚已酸内酯、聚(乙醇酸)、聚酐、或这些或其它生物可降解聚合物的共聚物或混合物溶解于根据聚合物类型,浓度从5到30wt%的适当溶剂(A)中,PLLA优选10wt%。在这种实施方案中,溶剂(A)与水有低可混性,与凝固浴溶剂(B高度可混。优选溶解(A)包括氯仿和二氯甲烷。当聚合物溶解后,将含有感兴趣的生物分子和表面活性剂的水溶液加入聚合物溶液。水乳状液的浓度一般为聚合物溶液的1到50%v/v,对于单微丝PLLA纤维,最典型为4-10%。表面活性剂可以是一种或几种本领域技术人员熟悉的物质的结合,如牛血清白蛋白(BSA)、聚(乙烯醇)、环氧乙烷与环氧丙烷的嵌段共聚物、或生物表面活性剂如磷脂族。通过扩展也包括其它在这里没有特别提及,但本领域技术人员已知的表面活性剂。在一种典型的使用中,将BSA以比感兴趣的生物分子高10倍到100倍的浓度用作表面活性剂,一般浓度为水相的10wt%到50wt%。
通过使用一些形式的机械能如超声波、涡流或迫使液体通过小口产生的剪切力,在水和有机相间形成油包水类型的乳状液。乳状液必需在比挤出要求的时间长得多的时间段中保持稳定。分散水相液滴的大小主要取决于表面活性剂的质量和给予系统形成乳状液的机械能的量。水相的大小是纤维释放动力学和机械特征的重要变量。
然后将乳状液挤入含溶剂(B)的凝固浴。然后将聚合物乳状液通过规格从16号到30号的分散头挤出到凝固浴。溶剂(B)必需与溶剂(A)高度可混,必需对于聚合物是非溶剂;异丙醇是最典型的选择,但任何对于聚合物是非溶剂并与溶剂(A)高度可混的溶剂都可以。例如,己烷与二氯甲烷高度可混并且是聚合物的非溶剂,所以,二氯甲烷和己烷产生很好的溶剂和凝固浴组合。因为溶剂(A)与凝固浴溶剂(B)高度可混合,它通过聚合物溶液流自由扩散到凝固浴中。然而,聚合物在溶剂(B)中不可溶,所以开始沉淀,形成纤维外鞘并将乳状液的几乎全部分散水相包入形成的纤维。以这种方式,使纤维加载了感兴趣的药物或蛋白。形成的纤维可以在凝固浴中通过一系列滚柱从而提供了应该需要的通过凝固浴的固定路径长度。以确定的速度将纤维抽出凝固浴。在实验室中,本发明使用了附着于可以精确保持其角速度的改良变速车床的量筒。然后根据所加载的生物分子的推荐储存条件,将抽出和挤出的纤维从量筒中移出并冻干、冷冻或烘干转移并放置于desecrator或冷冻机。
通过改变将聚合物乳状液注入凝固浴的速度与车床线性缠绕速度之比,可以发现纤维机械特征的许多令人惊讶的改变,如图9A和9B所示。纤维的机械特征作为下列变量的函数而改变:聚合物溶剂、凝固浴溶剂、溶剂系统的中间可混性、缠绕速度与注入速度之比、凝固浴中的总时间、乳状液中水相与聚合物溶液相聚合物溶液相之比,以及表面活性剂质量。作为一些变量的函数的机械特征的改变如图10A和10B所示。
另一种令人惊奇的发现是已经完成的纤维的表面质地也可以由溶剂和聚合物系统的适当选择而控制。本发明者制造了表面质地从光滑到绒面到有纵沟的纤维,如图11A-11C所示。这些表面质地的改变对细胞生长有实际应用,绒面质地提供了更大的粘附特征,有纵沟的纤维提供了更好的接触引导。所有这些机械特征和表面质地的改变显著影响了治疗剂的释放动力学。
纤维直径由处理条件控制,如图12所示。因为控制机械特征、表面质地、直径和释放动力学的处理参数是已知的,可以特制有特定特征用于特定用途的纤维。
在构造过程中保持生物活性的生物治疗剂可以用三明治ELISA表示,其中加载到纤维的试剂是鼠IgG的Fab片段。为使ELISA检测Fab的存在,必需保持两个结合表位的生物活性。
在构造过程的另一种实施方案中,将聚合物的不良溶剂加入聚合物溶液如甲苯。不良溶剂的加入改变了纤维的机械特征。
在另一种构造实施方案中,将最多20%v/v的聚合物溶剂加入凝固浴溶剂。聚合物溶剂的加入减小了纤维内到纤维外的浓度梯度。这改变了扩散率并因此改变了形成纤维外鞘的速度。外鞘的形成速度对于纤维表面质地和纤维的机械特性以及生物分子的释放动力学是关键的。
在另一种构造实施方案中,将增稠溶液如甘油加入凝固浴。这增加了凝固浴的粘度并改变了凝固浴的特异性比重。这两个变量都可导致形成加载纤维的能力显著增加。甘油的浓度从8到20%v/v。
另外,可以通过挤出领域的技术人员所公知的方法构造同轴纤维。通过使用这些技术,可以在同轴纤维的每层加入各种聚合物和生物分子。
实施例2
构造含有各种浓度治疗剂的聚合物纤维
在另一种构造实施方案中,过程与实施例1中的描述相似,除沿纤维长度应用了浓度梯度。这是通过采用两种溶液而实现的。一种是含有感兴趣的治疗剂的聚合物乳状液,另一种不含治疗剂或含有不同生物分子。通过在挤出过程中不断改变两种溶液的比例而实现梯度。这可以通过许多途径实现,包括如图13所示在“Y”连接处的蝶形阀或用图14所示的有或无混合室的独立泵。以这种方式,建立了每厘米长度有已知浓度改变的控制良好的梯度。本发明的另一种实施方案是建立了“有条带的纤维”。在有条带的纤维中,有一些可能的构象;在一种实施方案中,两种聚合物溶液都是含不同生物分子的乳状液。这通过与梯度相同的方式实现,梯度是一系列跃阶函数,从乳状液A交替转换为乳状液B。
在第二种实施方案中,从聚合物乳状液得到的一条带含有这里描述的其它实施方案中的一种或更多生物分子。另一条带是作为密封材料的聚合物节段,使得完成的纤维可以被切割为特定长度,而完成的纤维每端的两个末端可以被密封。在每一种实施方案中,带的长度是独立可调整的。这些梯度和有条带的纤维可以在有或无下一实施例中描述的同心包膜的情况下使用。
实施例3
构造有同心包膜的聚合物纤维
而在另一种构造实施方案中,将初步存在的纤维加入喷丝嘴并通过凝固浴。将液体聚合物乳状液加入“T”或“Y”连接并在进入凝固浴前包被纤维。这样将同心包膜应用于纤维,每个包膜具有含有不同治疗剂的能力,如图4所示。包膜聚合物可以与核心聚合物相同或不同。可以有分子附着在核心纤维上而增加包膜聚合物的粘合。例如,一薄层BSA可以改变脱乙酰壳多糖与聚(L-乳酸)的粘合。通过精密的喷丝嘴,可以将含有不同分子的两种或更多乳状液放在包膜内。这是通过将所有的包膜物质放入喷丝嘴,用阀门分开每个包膜聚合物流。这允许纤维以围绕纤维的角度位置的函数释放不同分子。在某些实施方案中,喷丝嘴可能是非圆形的,所以形成任何需要的截面形状。对核心纤维和包膜聚合物都是如此。
另一种构造技术是用特别设计的多腔喷丝嘴建立本领域中公知的标准纤维结构,如核心和鞘、海岛型复合纤维等。
实施例4
构造环境反应性聚合物凝胶纤维
在不同的构造实施方案中,通过聚合或其它方法形成纳球体(nanosphere)大小的环境反应性聚合物水凝胶。然后将这种纳球体掺入纤维。“环境反应性凝胶”表示当凝胶周围的环境进行相对小的改变时物理特征显示出很大改变的聚合物凝胶。发现在本发明中有用的聚合物水凝胶包括聚(N-异丙基丙烯酰胺)(NIPA)和聚(丙烯酸)(PAA)凝胶。例如,NIPA凝胶具有进行反应于小的温度改变(2-3C)而进行100倍的剧烈体积改变的能力。可以通过将这些纳球体浸入生物分子水溶液而给其加载生物分子。然后将这些加载的纳球体干燥并加入聚合物溶液,形成或不形成乳状液。所有其它的构造过程都相同。这一过程建立温度敏感性纤维。NIPA的相变可以由本领域的技术人员控制在38-39C发生。这提供了反应于病人生理状态的纤维。如果病人开始发热,它的释放动力学有剧烈增加,并且由于这是可逆现象,当体温恢复正常时,释放动力学又减慢。
实施例5
基于脱乙酰壳多糖的纤维
在另一种构造实施方案中,不使用前面所述的基于酯的合成聚合物,可以用天然存在的多糖如脱乙酰壳多糖作为聚合物系统。在本领域中熟知可以将脱乙酰壳多糖溶于3%乙酸,并用5%氢氧化钠作为凝固浴来制造脱乙酰壳多糖纤维。本发明者发现可以用1%盐酸溶解脱乙酰壳多糖,脱乙酰壳多糖的浓度可以低至2.5wt%,如果凝固浴由浓度为5到15%的Tris碱组成,可以获得优质纤维(图1)。这是关于在这些条件下挤出的脱乙酰壳多糖纤维的第一次报道。
脱乙酰壳多糖是一种生物可降解聚合物。脱乙酰壳多糖可以被存在于胞浆中、细胞间液和细胞内的溶菌酶酶促降解。由于溶菌酶对脱乙酰壳多糖的作用依赖于聚合物主链上的乙酰基的存在,因此可以在特定环境下以两种其它的方式调节前面所描述的纤维的释放速度:a)从由不同脱乙酰程度的脱乙酰壳多糖聚合物组成的非均质混合物按前面所述挤出纤维。以这种方式,可以维持需要时间段的最优范围内的药物释放水平;b)另一种可能性是挤出脱乙酰壳多糖分段纤维,其中每段由不同脱乙酰程度的脱乙酰壳多糖产生,如图2所示。后一种方法可以通过沿纤维建立时间梯度应用于迁移细胞。
本发明者也将重构基膜提取物(matrigel,Becton Dickinson,Bedford,MA)与溶解在盐酸中的脱乙酰壳多糖混合,并证明了用浓度从10-15%的Tris碱组成的凝固浴挤出优质纤维的能力。在这种情况下,发现轴突伸展比脱乙酰壳多糖单独时有所改进。ELISA证明了matigel的两种主要蛋白(层粘连蛋白和IV型胶原)在纤维中的出现。通过体外神经元附着实验和轴突伸展证明了这些蛋白也保持了生物活性。另一种可能性是用matrigel包被同样的Tris碱挤出的脱乙酰壳多糖纤维。
在一项惊人的发现中,如果本发明者在加入matrigel之前磺化脱乙酰壳多糖,与matrigel和未处理脱乙酰壳多糖的情况相比,神经元附着和轴突伸展显著改进(图3,图4)。采用同样的化学挤出条件,本发明者可以在有或没有matrigel作为共同挤出物质的情况下挤出由0.2%磺化脱乙酰壳多糖和3.2%未修饰脱乙酰壳多糖组成的聚合物纤维。
在本领域中熟知,由于相似的化学结构,磺化脱乙酰壳多糖有类肝素样抗凝特征。可以用磺化脱乙酰壳多糖或matrigel和磺化脱乙酰壳多糖包被溶解于盐酸并在Tris碱中挤出的由未修饰脱乙酰壳多糖组成的纤维。这可以产生有固有抗凝特征并可以加载活性药物的纤维。这可以在构造血管支架和其它与血液直接接触并要求机械强度和/或运送药物的能力的医学设备中有大量的临床应用。
按上述方法挤出脱乙酰壳多糖纤维的相对强烈的酸性和碱性环境很大程度将可以掺入纤维的生物分子限制为可以承受很大pH变化的生物分子。所以,为克服这种固有的限制,本发明者开发了一种保持加载到脱乙酰壳多糖纤维的甚至是最敏感生物分子的生物活性的新方法。在这种实施方案中,用溶剂蒸发和其它药物运送文献中熟知的技术将感兴趣的敏感生物分子加载到PLLA微球体。然后将PLLA微球体与3.5wt%的脱乙酰壳多糖溶液混合并按前面所述方法挤出。当用乙酸和氢氧化钠或1.2%盐酸和10-15%Tris碱挤出混合物时将形成加载了PLLA微球体的脱乙酰壳多糖纤维。PLLA微球体可以保护敏感生物分子不受脱乙酰壳多糖纤维的剧烈处理条件的影响。
实施例6
神经组织工程
在本发明的这方面,如图15所示将平行排列的纤维装入硅胶或其它适当物质的管中并加载神经营养蛋白以便轴突生长。将这些纤维束放置于切断的外周或中枢神经。可以将神经生长蛋白以线性或其它一些适当的梯度加载。植入这种设备可以将神经残端之间的缺口连接起来。当纤维释放神经营养蛋白时,轴突迁移到近端之外,跨过纤维束并进入神经远端。当在远端时,由存在的施旺细胞或胶质细胞提供引导线索然后可以进行再连接。以前已经发现轴突通过这些纤维束接收接触引导并且在使用未加载纤维时可以在大鼠坐骨神经切除术中穿过至少1.8cm。管中未加载纤维对于大鼠坐骨神经生长的最优密度为在直径1.5mm的管中约有32条纤维。
实施例7
制备和使用聚合物纤维支架
在另一种实施方案中,可以给纤维加载感兴趣的药物并用于支架或其它需要机械强度的医疗设备。如果需要机械特征,支架可以以将加载纤维与未加载纤维混合的方式编织。
可以将纤维与可买到的支架结合使用从而在放置位点运送药物。在这种情况下,纤维不提供任何机械支持,只作为药物运送储存器。
实施例8
制备和使用伤口敷料
在另一种实施方案中,可以用这些纤维制作纱布或敷料。这种敷料可以有两面,上表面释放用于表皮再生的分子并为这些分子提供培养基。下表面将促进真皮组织再生。这种敷料是为皮肤伤口愈合而设计的,包括烧伤、全皮肤厚度伤口和慢性或不愈合伤口及疼痛。可以包被每条纤维以提供与皮肤伤口愈合的三个阶段相对应的药物或因子的时间释放。
例如,在为创伤病人设计的敷料中,首先释放的化学物质将是止血的促凝因子。下一层然后可以释放帮助募集进行伤口愈合下一阶段的中性粒细胞和巨噬细胞的细胞因子。最后,释放帮助减少多余疤痕组织并抑制尤其对烧伤病人致残的收缩。
实施例9
构造人工动脉
可以用这里描述的技术构建人工血管。可以用非编织技术将一系列中空的、圆柱形切面与加载了各种生物试剂的纤维接合、编织、编结或构造在一起。最内层圆柱体优选紧密编织并含有促进完整内皮细胞层迁移、扩散和起作用的试剂。下一层圆柱体由编织或接合结构组成,其纤维主要在外周缠绕在内层圆柱体周围。这一层将诱导平滑肌纤维的迁移和增生,并促进弹性蛋白的表达从而建立内部弹性介质。下一层圆柱体由接合或非编织纤维组成并将含有促进成纤维细胞、巨噬细胞的内向生长和细胞外基质的建立的药物。最后一层将由促进动脉细胞通过人工滋养血管形成血管的纵向纤维组成,由VEGF释放纤维或其它血管生成的启动子建立。
实施例10
药物运送支架
在另一种实施方案中,这些纤维可以在纤维形式优于微球体的位置用于药物运送支架。例如,对于直接运送到血流的药物,纤维可以附着在血管壁,并被整个包含在血管内。微球体不能流经循环系统,因为它们将在一定水平上被捕捉,潜在危害下游组织。然而,纤维可以释放药物并且只要纤维保持完整不会导致堵塞下游血管分支的问题。其它纤维比微球体更好的位置可以包括眼,在这里微球体可能更容易干扰受试者的视力。纤维可以被朝下粘住而不漂浮到视野中。纤维可以比微球体更好地停留在适当的位置,特别是在纤维可以盘绕的位置中。以这种方式,纤维中的机械张力将使它顶住组织空间的侧面并因此保持适当的位置。
实施例11
原位动脉形成
与实施例9的范围相似的是原位动脉形成。在这种实施方案中,将含VEGF或相似替代物的纤维束放置于体内,纤维束的两端接近或接触存在的血管。当纤维开始释放VEGF或相似替代物时,将诱导存在血管的内皮细胞迁移到存在血管外,遵循与正常血管生成相似的过程。先导上皮细胞将穿过纤维束路径,这样产生沿纤维束路径的新血管。此纤维束可以有几种形式,它可以存在只释放VEGF或它的替代物的单个或几条纤维,或它可以是管状,内部为趋化内皮细胞的VEGF或相似的生长因子,外部为针对平滑肌的不同因子。以这种方式,可以确定建立血管的大小。在这种应用中,细胞被细胞特异性生长因子引导入开始无细胞的支架。
实施例12
骨折愈合
在另一种创伤愈合的实施方案中,将已知促进骨折愈合的蛋白加载到纤维中。然后在骨折位点将纤维包裹在骨周围,释放生长因子并增加骨折修复速度。
这些纤维可以是螺旋结构(单或多螺旋),或它们可以编织为疏松、开放的织物。纤维可以以螺旋或编织形式围绕在骨碎片周围,当释放它们的生长因子时使其保持恰当的位置。
在由于失血或骨折位点供血不足而导致不愈合骨折的情况下,含VEGF或其等同物的一条或一系列纤维可以用于增加骨折区的血供。
在此实施方案中,与未治疗骨折相比,骨折可以以增加的速度愈合,在某些情况下不联合的位点可以愈合。
实施例13
皮肤溃疡愈合
与描述了一种皮肤伤口愈合形式的例8相似,本技术的另一种重要实施例是愈合各种起源的慢性皮肤溃疡,如糖尿病足溃疡,静脉曲张性溃疡和一般的褥疮的潜能。以创建释放抑制加速皮肤愈合的因子,如血小板源生长因子(PDGF)、转化生长因子β(TGF-β)和VEGF或相似蛋白的非编织网眼为基础可以治愈这些状况和其它潜在的相似状况。这种非编织网眼可以插入或直接包裹到溃疡或伤口,在这里生长因子可以帮助加速伤口愈合过程。这些敷料可以设计用于愈合皮肤疮和溃疡。在这种情况下,几乎不需要减少出血;而这些病人,特别是那些有糖尿病溃疡的病人的最大需要之一是缺少到伤口部位的血供。所以,诱导血管生成的因子可以增加循环并帮助疮和溃疡部位的组织再生。
每种敷料可以设计为通过改变释放的生物分子和它们的释放动力学而满足各种伤口和疮类型的特定需要。
实施例14
肌肉移植
在另一种实施方案中,可以将肌肉干细胞加载到平行列的纤维中。这些干细胞可以是心肌、平滑肌或骨骼肌起源。当这些干细胞被种植到纤维列中时,这些纤维可以在体外机械伸展从而帮助这些细胞恰当排列和分化。也可以用很小直径的纤维来完成排列。我们对于轴突的经验提示规格为直径50μm左右的纤维倾向于帮助细胞平行于纤维轴排列。在此束中的其它纤维可以释放血管生成因子从而建立肌肉细胞的血管供应。在骨骼肌或平滑肌组织的情况下,也可包括用于神经生长的纤维以便诱导神经肌肉连接的形成。各种用于收获、分离、繁殖和分化这些干细胞的实验条件是本领域技术人员公知的,不是本发明的一部分。
实施例15
纤维构造程序1的替代程序
为构造规格为100μl聚合物溶液的小量聚合物,开发了下面的方法。按实施例1建立乳状液。将此乳状液加入小容器,如通过在试管底部插入20-30号,最典型为23号的针头而改良的1ml FALCON试管。将此试管放入充满凝固浴溶剂的改良50ml试管。将此试管放入离心机并以500到1200rpm旋转,最典型为700rpm。离心力将推动小量聚合物乳状液通过针头进入凝固浴。通过与实施例1所描述的相似的溶剂交换,形成纤维。此方法使用非常少的聚合物乳状液,浪费很少的乳状液。
实施例16
纤维构造程序2的替代程序
作为替代构造程序,凝固溶剂以规定速度流过长的垂直试管,聚合物溶液被挤出到凝固浴溶剂流中。此液流从试管流出到凝固浴中。纤维经过一个或更多筒管并从凝固浴中取出并盘绕在轴上。溶剂流速、聚合物挤出速度、聚合物溶液/乳状液的组成、凝固浴溶剂的组成、纤维盘绕速度、在连续筒管之间发生的拉伸、以及其它额外的浴或处理将影响纤维的机械和化学特征以及被加载生物物质的释放动力学。
实施例17
青光眼的治疗
与例10所描述的将药物运送到眼,和例6中简要描述的神经支架相似,可以通过将眼内药物运送与应用于视神经的神经治疗相结合而治疗青光眼。视网膜神经节细胞进行凋亡导致视神经轴突的死亡。假设细胞可以在眼内和沿视神经路径得到支持,这些细胞可以存活。释放生长因子如NT-4,BDNF,CNTF的纤维束可以应用于视神经外部。同时,将释放凋亡抑制因子的纤维或支持视网膜神经节细胞的因子植入到眼内。这种结合的努力可以延长或保存青光眼患者的视力。
从前面的实施例中可以看到,当理解了基本生理结构时,可以编织其它组织、器官或结构。这可以扩展到消化系统、肌肉骨骼系统、泌尿系统、循环系统、神经系统的器官。
这里公开和要求的所有组合物和方法可以在没有不适当的实验的条件下根据本公开内容制造和执行。尽管以优选实施方案的形式描述了本发明的组合物和方法,对于本领域技术人员很明显的是,可以在不离开本发明的概念、精神和范围的前提下,对组合物和方法、这里描述的方法的步骤或步骤的顺序进行改变。更具体地说,很明显可以用化学和物理相关的某些试剂替代这里所描述的试剂而达到相同或相似的结果。对于本领域技术人员很明显的是,所有这些由从属权利要求定义的小的替代和修饰认为是在本发明的精神、范围和概念内。
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Claims (198)
1.一种植入组合物,包含一种支架,此支架包含生物可降解聚合物纤维,该纤维含有一种或更多随时间释放的治疗剂。
2.权利要求1的组合物,其中支架包含编织纤维。
3.权利要求1的组合物,其中支架包含非编织纤维。
4.权利要求1的组合物,其中支架包含接合纤维。
5.权利要求1的组合物,其中纤维包含两个或更多纤维亚型,纤维亚型的生物可降解聚合物含量不同。
6.权利要求1的组合物,其中纤维或纤维亚型包含一种或更多同轴或其它多成分生物可降解聚合物层。
7.权利要求1的组合物,其中纤维或纤维亚型包含含有一种或更多治疗剂的纤维,其中纤维或纤维亚型中的一种或更多治疗剂的含量沿纤维或纤维亚型的纵轴而改变。
8.权利要求7的组合物,其中一种或更多治疗剂作为沿纤维纵轴距离的函数以线性或指数改变,所以一种或更多治疗剂的含量从纤维或纤维亚型的第一端到纤维或纤维亚型的第二端逐渐减少。
9.权利要求7的组合物,其中一种或更多治疗剂以双向方式改变,所以一种或更多治疗剂的含量从纤维或纤维亚型的第一端增加到最大,然后向纤维或纤维亚型的第二端逐渐减少。
10.权利要求1的组合物,其中纤维亚型不含治疗剂。
11.权利要求1的组合物,其中一种或更多治疗剂选自生长因子、免疫调节剂、促进血管生成的化合物、抑制血管生成的化合物、抗炎化合物、抗生素、细胞因子、抗凝剂、促凝剂、趋化剂、促进凋亡的试剂、抑制凋亡的试剂和促有丝分裂剂。
12.权利要求1的组合物,其中一种或更多治疗剂包括放射性试剂或成像研究的造影剂。
13.权利要求1的组合物,其中一种或更多治疗剂选自病毒载体、多核苷酸、和多肽。
14.权利要求1的组合物,其中一种或更多治疗剂包含促进血管生成的试剂。
15.权利要求14的组合物,其中促进血管生成的试剂为血管内皮生长因子。
16.权利要求1的组合物,其中生物可降解聚合物为单聚合物或共聚物或聚合物的混合,其中聚合物选自聚(L-乳酸)、聚(DL-乳酸)、聚己酸内酯、聚(乙醇酸)、聚酐、脱乙酰壳多糖、或磺化脱乙酰壳多糖。
17.包含一种或更多生物可降解聚合物纤维的药物运送组合物,生物可降解聚合物纤维含一种或更多治疗剂,其中纤维内的一种或更多治疗剂沿纤维纵轴改变,所以一种或更多治疗剂的含量从纤维第一端到第二端逐渐减少。
18.权利要求17的组合物,其中纤维的至少一个亚型包含一个或更多同轴层或生物可降解纤维的其它多成分构型。
19.一种控制纤维支架植入物中的一种或更多治疗剂的空间和时间浓度的方法,包括将纤维支架植入宿主,其中纤维支架包含含有一种或更多治疗剂的生物可降解聚合物纤维,其中一种或更多治疗剂以确定的非均质模式分布于纤维支架中,纤维类型和分布可以是或不是均质的。
20.权利要求19的方法,其中支架包含编织纤维。
21.权利要求19的方法,其中支架包含非编织纤维。
22.权利要求19的方法,其中支架包含接合纤维。
23.权利要求19的方法,其中支架包含两种或更多纤维亚型,该纤维亚型的生物可降解聚合物含量不同。
24.权利要求19的方法,其中纤维或纤维亚型包含至少一个同轴层或其它由一种或更多生物可降解聚合物层组成的多成分构型的多样性。
25.权利要求19的方法,其中纤维或纤维亚型包含含有一种或更多治疗剂的纤维,其中纤维或纤维亚型中的一种或更多治疗剂的含量沿纤维或纤维亚型的纵轴而改变。
26.权利要求25的方法,其中一种或更多治疗剂作为沿纤维纵轴距离的函数以线性或指数改变,所以一种或更多治疗剂的含量从纤维或纤维亚型的第一端到纤维或纤维亚型的第二端逐渐减少。
27.权利要求25的方法,其中一种或更多治疗剂以双向方式改变,所以一种或更多治疗剂的含量从纤维或纤维亚型的第一端增加到最大,然后向纤维或纤维亚型的第二端逐渐减少。
28.权利要求19的方法,其中纤维亚型不含治疗剂。
29.权利要求19的方法,其中一种或更多治疗剂选自生长因子、免疫调节剂、促进血管生成的化合物、抑制血管生成的化合物、抗炎化合物、抗生素、细胞因子、抗凝剂、促凝剂、趋化剂、促进凋亡的试剂、抑制凋亡的试剂和促有丝分裂剂。
30.权利要求19的方法,其中一种或更多治疗剂包括放射性试剂或成像研究的造影剂。
31.权利要求19的方法,其中一种或更多治疗剂选自病毒载体、多核苷酸、和多肽。
32.权利要求19的方法,其中一种或更多治疗剂包含促进血管生成的试剂。
33.权利要求32的方法,其中促进血管生成的试剂为血管内皮生长因子。
34.权利要求19的方法,其中生物可降解聚合物为单聚合物或共聚物或聚合物的混合,其中聚合物选自聚(L-乳酸)、聚(DL-乳酸)、聚己酸内酯、聚(乙醇酸)、聚酐、脱乙酰壳多糖、或磺化脱乙酰壳多糖。
35.一种制备纤维支架的方法,纤维支架是为制备可以控制一种或更多治疗剂的空间和时间浓度的植入物而制备,该方法包含提供含有一种或更多治疗剂的生物可降解聚合物纤维并使该生物可降解聚合物纤维形成在三维纤维支架内,其中一种或更多治疗剂以确定的非均质模式分布于纤维支架中,纤维类型或生物物质含量可以是或不是均质的。
36.权利要求35的方法,其中支架包含编织纤维。
37.权利要求35的方法,其中支架包含非编织纤维。
38.权利要求35的方法,其中支架包含接合纤维。
39.权利要求35的方法,其中支架包含两种或更多纤维亚型,该纤维亚型的生物可降解聚合物含量不同。
40.权利要求35的方法,其中纤维或纤维亚型包含至少一个同轴层或其它生物可降解聚合物层多成分构型的多样性。
41.权利要求35的方法,其中纤维或纤维亚型包含含有一种或更多治疗剂的纤维,其中纤维或纤维亚型中的一种或更多治疗剂的含量沿纤维或纤维亚型的纵轴而改变。
42.权利要求41的方法,其中一种或更多治疗剂作为沿纤维纵轴距离的函数以线性或指数改变,所以一种或更多治疗剂的含量从纤维或纤维亚型的第一端到纤维或纤维亚型的第二端逐渐减少。
43.权利要求41的方法,其中一种或更多治疗剂以双向方式改变,其中一种或更多治疗剂的含量从纤维或纤维亚型的第一端增加到最大,然后向纤维或纤维亚型的第二端逐渐减少。
44.权利要求35的方法,其中纤维亚型不含治疗剂。
45.权利要求35的方法,其中一种或更多治疗剂选自生长因子、免疫调节剂、促进血管生成的化合物、抑制血管生成的化合物、抗炎化合物、抗生素、细胞因子、抗凝剂、促凝剂、趋化剂、促进凋亡的试剂、抑制凋亡的试剂和促有丝分裂剂。
46.权利要求35的方法,其中一种或更多治疗剂包括放射性试剂或成像研究的造影剂。
47.权利要求35的方法,其中一种或更多治疗剂选自病毒载体、多核苷酸、和多肽。
48.权利要求35的方法,其中一种或更多治疗剂包含促进血管生成的试剂。
49.权利要求48的方法,其中促进血管生成的试剂为血管内皮生长因子。
50.权利要求35的方法,其中生物可降解聚合物为单聚合物或共聚物或聚合物的混合,其中聚合物选自聚(L-乳酸)、聚(DL-乳酸)、聚己酸内酯、聚(乙醇酸)、聚酐、脱乙酰壳多糖、或磺化脱乙酰壳多糖。
51.一种用脱乙酰壳多糖建立药物释放纤维的方法,包含将盐酸作为溶剂以及Tris碱作为凝固浴。
52.权利要求51的方法,其中盐酸浓度为约0.25%到约5%。
53.权利要求52的方法,其中盐酸浓度进一步规定为约1%到约2%。
54.权利要求51的方法,其中Tris碱浓度为约2%到约25%。
55.权利要求54的方法,其中Tris碱浓度为约4%到约17%。
56.权利要求55的方法,其中Tris碱浓度为约5%到约15%。
57.权利要求51的方法,包括使用含不同脱乙酰程度的脱乙酰壳多糖的非均质混合物。
58.权利要求51的方法,包括建立含不同脱乙酰程度的脱乙酰壳多糖片段的药物释放纤维。
59.权利要求51的方法,包括用脱乙酰壳多糖和细胞外基质建立药物释放纤维。
60.权利要求59的方法,其中脱乙酰壳多糖的浓度为约0.5wt.%到约10wt.%。
61.权利要求60的方法,其中脱乙酰壳多糖的浓度为约1wt.%到约7wt.%。
62.权利要求61的方法,其中脱乙酰壳多糖的浓度为约2wt.%到约5wt.%。
63.权利要求62的方法,其中脱乙酰壳多糖的浓度为约3wt.%到约4wt.%。
64.权利要求63的方法,其中脱乙酰壳多糖的浓度为约3.5wt.%。
65.权利要求59的方法,其中细胞外基质包含Matrigel。
66.权利要求59或65的方法,其中细胞外基质浓度为约1vol.%到约20vol.%。
67.权利要求65的方法,其中细胞外基质浓度为约2vol.%到约15vol.%。
68.权利要求67的方法,其中细胞外基质浓度为约3vol.%到约10vol.%。
69.权利要求68的方法,其中细胞外基质浓度为约4vol.%到约6vol.%。
70.权利要求69的方法,其中细胞外基质浓度为约5vol.%。
71.权利要求59的方法,包括用细胞外基质包被纤维。
72.权利要求59的方法,其中脱乙酰壳多糖为磺化脱乙酰壳多糖。
73.权利要求72的方法,其中磺化脱乙酰壳多糖的浓度为约0.025wt.%到约2wt.%。
74.权利要求73的方法,其中磺化脱乙酰壳多糖的浓度为约0.05wt.%到约1wt.%。
75.权利要求74的方法,其中磺化脱乙酰壳多糖的浓度为约0.1wt.%到约0.5wt.%。
76.权利要求75的方法,其中磺化脱乙酰壳多糖的浓度为约0.15wt.%到约0.3wt.%。
77.权利要求76的方法,其中磺化脱乙酰壳多糖的浓度为0.2wt.%。
78.权利要求71的方法,其中脱乙酰壳多糖和磺化脱乙酰壳多糖被挤出到纤维。
79.一种建立药物释放纤维的方法,包括将加载了药物或蛋白的作为药物运送储存器的聚(L-乳酸)微球体添加到酸中的脱乙酰壳多糖溶液以及使用氢氧化钠凝固浴。
80.权利要求79的方法,包括将约3.5wt.%的脱乙酰壳多糖加入约2vol.%的酸中并用5vol.%的氢氧化钠作为凝固浴。
81.权利要求79的方法,其中酸为乙酸。
82.权利要求79的方法,其中酸为盐酸。
83.权利要求82的方法,其中溶液中的酸包含从约1vol.%到约2vol.%的盐酸。
84.权利要求83的方法,包括将加载了药物的聚(L-乳酸)微球体添加到约1vol.%的盐酸到约2vol.%的盐酸中的约3.5wt.%的脱乙酰壳多糖溶液以及使用包括从约5vol.%的tris碱到约15vol.%的tris碱的凝固浴。
85.权利要求79的方法,进一步包含将表面活性剂添加到溶液。
86.权利要求85的方法,其中表面活性剂包含白蛋白。
87.权利要求86的方法,其中溶液包含约3wt.%的白蛋白。
88.权利要求87的方法,其中溶剂包含约1.2vol.%的盐酸。
89.一种组合物,包含含有脱乙酰壳多糖和细胞外基质的纤维。
90.权利要求89的组合物,进一步规定为包含磺化脱乙酰壳多糖。
91.包含三维支架的组合物,该支架包含编织、非编织、或接合、或编结的纤维,其中该纤维包含一种组合物,该组合物包含含有脱乙酰壳多糖和细胞外基质的纤维。
92.权利要求91的组合物,其中脱乙酰壳多糖为磺化脱乙酰壳多糖。
93.一种组合物,该组合物包含含有脱乙酰壳多糖、细胞外基质和生物分子的纤维。
94.权利要求93的组合物,其中脱乙酰壳多糖为磺化脱乙酰壳多糖。
95.根据权利要求89,90,92,93,94任意一项的含非均质纤维支架的组合物,其中生物分子对于支架的所有纤维不是相同的。
96.一种脱乙酰壳多糖纤维组合物,包含第二种聚合物的微球体,该微球体包含一种或更多生物分子。
97.权利要求96的组合物,进一步包含为生物分子的表面活性剂。
98.权利要求97的组合物,进一步包含细胞外基质。
99.权利要求97的组合物,其中脱乙酰壳多糖为磺化脱乙酰壳多糖。
100.权利要求96的组合物,其中第二种组合物为聚(L-乳酸)、聚(D-乳酸)、聚(乙醇酸)、聚(己酸内酯),或这些聚合物的共聚物。
101.一种构造纤维的方法,包括:
a)获得包括在生物可降解聚合物溶液中含有活性生物分子和表面活性剂的水相的油包水型乳状液;及
b)将该乳状液挤出到凝固浴。
102.权利要求101的方法,其中生物可降解聚合物可以是任何合成的生物可降解聚合物。
103.权利要求101的方法,其中聚合物溶液的聚合物溶剂是聚合物的良好溶剂,与水是基本不可混的,并且与凝固浴是高度可混的。
104.权利要求101的方法,其中表面活性剂选自于牛血清白蛋白(BSA),聚(乙烯醇),环氧乙烷与环氧丙烷的嵌段共聚物,或天然存在的表面活性剂。
105.权利要求104的方法,其中表面活性剂为天然存在的表面活性剂。
106.权利要求105的方法,其中天然存在的表面活性剂为磷脂。
107.权利要求101的方法,其中凝固浴溶剂为聚合物的非溶剂并与凝固浴溶剂高度可混。
108.权利要求102的方法,其中聚合物为至少一种选自聚(L-乳酸)、聚(DL-乳酸)、聚(乙醇酸)、聚己酸内酯和聚酐的聚合物。
109.权利要求108的方法,其中聚合物为选自聚(L-乳酸)、聚(DL-乳酸)、聚(乙醇酸)、聚己酸内酯和聚酐的共聚物或聚合物混合。
110.权利要求103的方法,其中聚合物溶剂为氯仿或二氯甲烷。
111.权利要求107的方法,其中凝固浴溶剂为己烷、乙醇或丙酮。
112.权利要求111的方法,其中凝固浴溶剂为乙醇。
113.权利要求112的方法,其中凝固浴溶剂为异丙醇。
114.权利要求101的方法,其中聚合物溶剂系统包含至少一种聚合物易溶的溶剂和至少一种聚合物难溶的溶剂。
115.权利要求114的方法,其中易溶的溶剂为氯仿或二氯甲烷,难溶的溶剂为甲苯。
116.权利要求101的方法,其中凝固浴系统进一步包含聚合物溶剂。
117.权利要求116的方法,其中凝固浴包含最多到20%v/v的聚合物溶剂。
118.权利要求101的方法,其中凝固浴溶剂系统进一步包含增稠溶剂。
119.权利要求118的方法,其中增稠溶剂为甘油。
120.权利要求119的方法,其中甘油浓度为约8%到约20%v/v。
121.一种用生物分子的线性梯度构造纤维的方法,该方法包含:
a)获得第一种聚合物溶液和第二种聚合物溶液;及
b)将第一种聚合物溶液与第二种聚合物溶液以不断改变的比例混合,获得第一种与第二种聚合物溶液的混合物,而将混合物挤出到凝固浴。
122.权利要求121的方法,其中第一种聚合物溶液和第二种聚合物溶液的至少一种为油包水乳状液,其水相在生物可降解聚合物溶液中包含感兴趣的活性生物分子和表面活性剂。
123.权利要求121的方法,其中第二种聚合物包含表面活性剂并缺乏活性生物分子,或包含不同的活性生物分子。
124.权利要求122的方法,其中用蝶形阀控制混合第一种聚合物溶液与第二种聚合物溶液的比例。
125.权利要求122的方法,其中第一种聚合物溶液与第二种聚合物溶液容纳在分开的泵中并在混合室中混合。
126.权利要求121的方法,其中聚合物为合成的生物可降解聚合物。
127.权利要求121的方法,其中聚合物溶液包含聚合物的良好溶剂,该溶剂与水基本不可混并与凝固浴高度可混。
128.权利要求121的方法,其中表面活性剂选自于牛血清白蛋白(BSA),聚(乙烯醇),环氧乙烷与环氧丙烷的嵌段共聚物,或天然存在的表面活性剂。
129.权利要求128的方法,其中表面活性剂为天然存在的表面活性剂。
130.权利要求129的方法,其中表面活性剂为磷脂。
131.权利要求127的方法,其中凝固浴溶剂为聚合物的非溶剂。
132.权利要求127的方法,其中聚合物为至少一种选自聚(L-乳酸)、聚(DL-乳酸)、聚(乙醇酸)、聚己酸内酯和聚酐的聚合物。
133.权利要求132的方法,其中聚合物为选自聚(L-乳酸)、聚(DL-乳酸)、聚(乙醇酸)、聚己酸内酯和聚酐的共聚物或聚合物混合。
134.权利要求127的方法,其中聚合物溶剂为氯仿或二氯甲烷。
135.权利要求127的方法,其中凝固浴溶剂为己烷、乙醇或丙酮。
136.权利要求135的方法,其中凝固浴溶剂为异丙醇。
137.权利要求121的方法,其中聚合物溶剂包含至少一种聚合物易溶的溶剂和至少一种聚合物难溶的溶剂的混合物。
138.权利要求137的方法,其中至少一种易溶的溶剂为氯仿或二氯甲烷,至少一种难溶的溶剂为甲苯。
139.权利要求127的方法,其中凝固浴溶剂进一步包含聚合物溶剂。
140.权利要求139的方法,其中凝固浴溶剂进一步包含最多到约20%v/v的聚合物溶剂。
141.权利要求127的方法,其中凝固浴溶剂包含粘性溶剂。
142.权利要求141的方法,其中粘性溶剂为甘油。
143.权利要求142的方法,其中甘油浓度为约8%到约20%v/v。
144.一种建立药物释放纤维的方法,该方法包含:
在溶剂中获得包含合成生物可降解聚合物的聚合物溶液;
将加载了生物分子的NIPA凝胶加入聚合物溶液;及
将聚合物溶液挤出到包含至少一种溶剂的凝固浴中其中聚合物溶剂与水基本不可混并与凝固浴溶剂高度可混。
145.权利要求144的方法,其中聚合物为至少一种选自聚(L-乳酸)、聚(DL-乳酸)、聚(乙醇酸)、聚己酸内酯和聚酐的聚合物。
146.权利要求145的方法,其中聚合物为一种以上选自聚(L-乳酸)、聚(DL-乳酸)、聚(乙醇酸)、聚己酸内酯和聚酐的聚合物的共聚物或混合物。
147.权利要求144的方法,其中聚合物溶剂为氯仿或二氯甲烷。
148.权利要求144的方法,其中凝固浴溶剂为己烷、乙醇或丙酮。
149.权利要求148的方法,其中凝固浴溶剂为异丙醇。
150.权利要求144的方法,其中聚合物溶剂包含至少一种聚合物易溶的溶剂和至少一种聚合物难溶的溶剂的混合物。
151.权利要求149的方法,其中至少一种易溶的溶剂为氯仿或二氯甲烷,至少一种难溶的溶剂为甲苯。
152.权利要求144的方法,其中凝固浴溶剂进一步包含聚合物溶剂。
153.权利要求152的方法,其中凝固浴溶剂包含最多到20%v/v的聚合物溶剂。
154.权利要求144的方法,其中凝固浴溶剂包含粘性溶剂。
155.权利要求154的方法,其中粘性溶剂为甘油。
156.权利要求155的方法,其中甘油浓度为约8%到约20%v/v。
157.一种从脱乙酰壳多糖建立药物释放纤维的方法,该方法包含:
a)获得包含脱乙酰壳多糖和盐酸的聚合物溶液;及
b)将聚合物溶液挤出到含tris碱的凝固浴。
158.权利要求157的方法,其中盐酸浓度为约1%。
159.权利要求157的方法,其中tris碱的浓度为约5%到约15%。
160.权利要求157的方法,进一步包含挤出前将包含至少一个生物分子的微球体加入脱乙酰壳多糖溶液。
161.权利要求160的方法,其中生物分子微球体由纯聚合物或选自聚(L-乳酸)、聚(DL-乳酸)、聚(乙醇酸)、聚己酸内酯和聚酐聚L-乳酸的共聚物或聚合物混合物而制造。
162.权利要求145的方法,进一步包括将至少一种含生物分子乳状液的聚合物包膜应用于纤维,从而产生可以时间上控制多种生物分子释放的纤维,其中该应用步骤是在挤出步骤之前。
163.权利要求162的方法,其中该应用包括将纤维通过含乳状液的喷丝嘴。
164.权利要求162的方法,进一步包含将多种纤维聚集到织物,该织物的一种或多种纤维含至少一种有某种细胞类型的特异活性的生物分子,其中该生物分子可以与织物中的其它纤维中的生物分子不同。
165.权利要求164的方法,其中纤维在一段时间内释放生物分子。
166.权利要求164的方法,其中纤维的至少一部分可以被包被而在一段时间中释放各种因子和化学物质。
167.权利要求164的方法,其中在纤维至少一部分的生物分子为VEGF。
168.权利要求166的方法,其中有包膜纤维的第一部分与皮肤伤口愈合的第一阶段相对应,有包膜纤维的第二部分与皮肤伤口愈合的第二阶段相对应,有包膜纤维的第三部分与皮肤伤口愈合的第三阶段相对应。
169.权利要求168的方法组合物,其中有包膜纤维的第一部分包含诱导血栓形成而达到迅速止血的包膜。
170.权利要求168的方法组合物,其中有包膜纤维的第二部分包含中性粒细胞和巨噬细胞动员剂。
171.权利要求170的方法组合物,其中中性粒细胞和巨噬细胞动员剂可以是选自PDGF,TGFβ,FGF,IL-1和TNF的一种或更多化合物。
172.权利要求164的方法组合物,其中纤维诱导细胞形成有功能的动脉。
173.权利要求172的方法组合物,其中织物包含诱导内皮细胞层、中层和外层的形成。
174.权利要求173的方法组合物,其中中层包含通过纤维缠绕而环形排列的平滑肌细胞。
175.权利要求173的方法组合物,其中外层包含有从纵向排列的VEGF纤维得到的血管滋养层成分的成纤维细胞。
176.一种环形横截面中的平行纤维束组合物,用于治疗神经系统病变,其中至少一些纤维加载了神经营养蛋白。
177.权利要求176的组合物,其中病变位于周围神经系统。
178.权利要求176的组合物,其中病变位于中枢神经系统。
179.一种用于治疗消化系统病变的组合物,包含加载了一种或更多诱导上皮细胞、平滑肌细胞等进入管状支架的生物分子的纤维。
180.一种用于治疗肌肉骨骼系统病变的组合物,包含含有平行排列的纤维的支架,用于诱导和排列肌肉骨骼细胞。
181.权利要求180的组合物,其中支架进一步包含含有促进血管生成的因子的纤维。
182.权利要求180的组合物,其中支架进一步包含含有神经营养蛋白的纤维。
183.权利要求181的组合物,其中支架进一步包含含有神经营养蛋白的纤维。
184.权利要求162的方法,其中有包膜的纤维通过同轴多成分挤出技术而构造。
185.权利要求121的方法,其中第一种聚合物溶液包含直接溶解于聚合物溶液中的有机可溶活性生物分子,而且没有水相。
186.权利要求121的方法,其中第一种聚合物溶液包含至少一种直接溶解于聚合物溶液中的有机可溶活性生物分子和水相。
187.权利要求186的方法,其中水乳状液进一步包含水溶生物分子和表面活性剂。
188.权利要求121的方法,其中第二种聚合物溶液不含乳状液或表面活性剂。
189.权利要求19的组合物,其中支架包含编织纤维。
190.一种同轴纤维组合物,包含第一节段和第二节段,其中第一节段包含一种惰性密封剂,第二节段含至少一种生物活性分子。
191.权利要求190的组合物,其中纤维用包含至少一种生物活性分子的组合物包被。
192.权利要求1的组合物,其中支架包含编织纤维。
193.权利要求1的组合物,其中纤维或纤维亚型包含含有一种或更多治疗剂的纤维,其中纤维或纤维亚型中的一种或更多治疗剂的含量围绕纤维或纤维亚型成环形改变。
194.权利要求1的组合物,其中支架含多种纤维类型,其中纤维类型由纤维内含有的生物分子而不同。
195.权利要求194的组合物,其中含不同治疗剂的纤维在支架中不均匀分布。
196.权利要求195的组合物,其中治疗剂的不均匀分布模式指导支架中特定三维位置中的生物过程。
197.权利要求196的组合物,其中指导的生物过程为细胞迁移。
198.一种纤维组合物,当放置在视神经附近时释放神经营养蛋白到视神经。
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CN109394399A (zh) * | 2018-10-22 | 2019-03-01 | 乐畅医疗器械(上海)有限公司 | 一种药物缓释支架 |
CN111870732A (zh) * | 2020-07-20 | 2020-11-03 | 卓阮医疗科技(苏州)有限公司 | 一种可诱导组织再生修复的止血颗粒及其制备方法和应用 |
CN111870732B (zh) * | 2020-07-20 | 2022-06-14 | 卓阮医疗科技(苏州)有限公司 | 一种可诱导组织再生修复的止血颗粒及其制备方法和应用 |
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CA2379909C (en) | 2011-01-04 |
JP2003506401A (ja) | 2003-02-18 |
WO2001010421A1 (en) | 2001-02-15 |
US20030203003A1 (en) | 2003-10-30 |
CA2379909A1 (en) | 2001-02-15 |
CN1378445B (zh) | 2013-02-06 |
US6858222B2 (en) | 2005-02-22 |
EP1206254A1 (en) | 2002-05-22 |
AU6526100A (en) | 2001-03-05 |
JP2011255197A (ja) | 2011-12-22 |
JP5383757B2 (ja) | 2014-01-08 |
US6596296B1 (en) | 2003-07-22 |
JP4859317B2 (ja) | 2012-01-25 |
US20050106211A1 (en) | 2005-05-19 |
US7514095B2 (en) | 2009-04-07 |
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