CN1568903A - 接种哺乳动物细胞的复合支架 - Google Patents

接种哺乳动物细胞的复合支架 Download PDF

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CN1568903A
CN1568903A CNA2004100714807A CN200410071480A CN1568903A CN 1568903 A CN1568903 A CN 1568903A CN A2004100714807 A CNA2004100714807 A CN A2004100714807A CN 200410071480 A CN200410071480 A CN 200410071480A CN 1568903 A CN1568903 A CN 1568903A
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A·列扎尼亚
M·齐默曼
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Abstract

可植入的、生物相容的、包含生物相容的、多孔的、聚合物基质的支架，被包封和装在所述聚合物基质中的生物相容的、多孔的纤维垫和接种到所述组织支架上的多数哺乳动物细胞。本发明也涉及利用本发明支架治疗疾病或结构缺陷的方法。

Description

接种哺乳动物细胞的复合支架
技术领域
本发明涉及用于治疗软组织或硬组织中的疾病或结构缺陷的接种哺乳动物细胞的复合组织支架。
背景技术
存在用于治疗三种折磨病人疾病的临床需求，第一种疾病涉及例如：软骨、骨、半月板或肌肉的病患/损伤的肌骨骼组织。通常，修复例如：骨、软骨或肌肉等损伤或病患的肌骨骼组织的临床方法不能充分恢复这些组织的原始功能。假体关节/装置经常用于治疗带有由周围组织的松散、耐久力降低和功能丧失引起的混合缺陷的疾病。
第二种疾病涉及器官功能的丧失，例如：糖尿病(DM)。DM是由胰腺中β细胞被破坏或者肌肉或脂肪组织对胰岛素敏感而引起的。目前对糖尿病的治疗在防止例如失明、肾衰竭和溃烂主要的并发症方面仍然不足。
第三种疾病涉及中枢神经系统(CNS)的损伤或受损。脊髓的损伤可以导致除了血管之外的白质和灰质的破坏。外伤或变质过程往往引起脊髓的损伤。中枢神经系统不像其他许多组织那样拥有有限的自身修复能力，因为成熟的神经缺乏再生的能力。早先再生中枢神经系统中轴突的尝试包括：移植阻断抑制蛋白的抗体；移植神经胶质、巨噬细胞和干细胞；使用例如甲强龙等类固醇药来减少伴随中枢神经系统损伤的膨胀；和使用一种联合了细胞或生物活性信号的支撑结构来触发神经再生。这些方法没有给外伤或疾病后的中枢神经系统带来充足的修复。因此，仍然强烈需要一种可以避免目前临床方法常见问题的组织修复/再生的可供选择的方法。
新近出现的组织工程学可以提供可选择的修复和再生损伤/病患组织的方法。组织工程学方法已经探究了生物材料联合细胞和/或生长因子来发展可以极大恢复或改善组织功能的生物体代品的用法。支架材料已经在作为对组织修复有用的组织模板、导管、屏障和存储器等方面得到广泛的研究。尤其，以泡沫、海绵、凝胶、水凝胶、纺织品和无纺品形式的合成和天然材料已经应用于体外和体内来重建/再生生物组织，也用于传输引导组织生长的趋化剂。
不管支架和靶组织的成分是什么，支架必须拥有一些基础的特征。支架必须是生物相容的，拥有充足的抵抗手术期间经历负荷的机械性质；是柔韧的、高度多孔的以允许细胞的进入或生长，允许支架内细胞潴留的增加；易于消毒灭菌；可以通过渗入组织而重建，并且当新组织生成后是可以降解的。支架可以通过机械方式、固定装置、缝合或粘合等方式固定到周围组织。到目前为止，单独或联合应用组织支架的常规材料已经证实对植入后的接种细胞的潴留是无效的。
因此，存在一种能够解决常规材料局限性的接种细胞的支架的需求。
发明内容
本发明涉及可移植的、生物可相容的支架，该支架包含生物可相容的、多孔的聚合物基质，聚合物基质包封且布置其中的生物可相容的、多孔、纤维垫(mat)；以及，在将支架植入到哺乳动物缺陷部位或异位部位之前接种到所述组织支架上的多数哺乳动物细胞。本发明也涉及利用本发明的支架治疗哺乳动物疾病的方法。该纤维垫优选是无纺垫。包封了纤维垫的多孔的、生物相容的基质优选是多孔的聚合泡沫，优选使用冻干过程形成的聚合泡沫。
本发明可在复合支架内使得哺乳动物细胞的潴留增加以及期望的细胞外基质(ECM)的生成增多。
除此之外，接种了细胞的复合支架可以作为运载工具以运送细胞分泌生物因子。这样的生物因子可以直接正向调节或反向调节其他生长因子、蛋白质，细胞活素或其他细胞类型的增殖。许多细胞可以在复合支架植入缺陷部位或病变组织之前或之后接种于此复合支架上。
附图说明
图1是含有包封了90/10 PGA/PLA无纺垫的60/40 PGA/PCL泡沫的复合支架一部分的电子扫描显微照片。
图2是接种了小鼠支持细胞(Stertoli cells)的本发明组织支架的H&E部分。
图3是实施例12中所述复合支架的一部分的电子扫描显微照片。
图4是实施例13中所述复合支架的一部分的电子扫描显微照片。
图5是实施例14中所述复合支架的一部分的电子扫描显微照片。
图6是实施例15所述的接种了胰岛的复合支架的荧光图象。
本发明涉及生物相容的复合组织支架，该支架包含多孔的生物可相容的纤维垫，该纤维垫由多孔的、生物可相容的聚合物基质包封，并置于其中。哺乳动物细胞被给予方式可以是，即接种在该复合支架中，优选在复合支架植入哺乳动物缺陷部位和异位部位之前。
本发明的接种细胞的复合支架提供了一种环境，借此，给予的(即接种)细胞可以同时粘附到多孔纤维垫上，也可以粘附到包封纤维垫的多孔的聚合物基质的孔壁上。这种独特的设计，纤维垫和多孔的聚合物基质相联合，与单独使用多孔纤维垫或多孔聚合物基质相比，可增大所给予细胞在支架中的潴留。
图1中显示了本发明的一个多孔复合支架的实施方案。该图显示复合支架10，该支架含有置于多孔聚合物基质30中并由多孔聚合物基质30包封的纤维垫20。支架10包含大孔25和微孔35。此处所说的微孔包括平均直径小于约50μm的孔。此处所说的大孔包括平均直径大于约50μm的孔。
制备好支架10以后，哺乳动物细胞在植入前或植入当时被给予或接种到支架中。根据预期的应用或正在治疗的疾病的状况，哺乳动物细胞可分离自无血管和有血管的组织。这些细胞在接种到支架之前要在本领域技术人员所熟知的标准条件下培养，以增加细胞的数量或诱导其分化成所需的表型。可供选择地，分离的哺乳动物细胞可以直接注射到支架10中然后在植入前在促进适宜的生物基质增殖和沉积的条件下进行体外培养。有了本发明所带来的启示本领域的技术人员可以容易的发现这种条件。在优选的实施方案中，在植入体内前被分离的细胞被直接注射到支架10中而没有进行进一步的体外培养。
本发明的支架可以是非-生物可降解的，即不能在体内轻易降解，由此降解的成分被吸收或被排除体外，其中所述的纤维垫的纤维20和/或多孔的、聚合物基质30都可以包含非-生物可降解的材料。在其他实施方案中，本发明的支架可以是生物可降解的，即能够被身体轻易降解，其中生物降解的成分被身体吸收或排出体外，其中的纤维垫和聚合物基质都包含生物可降解材料。
纤维垫可以包含生物可相容金属的非生物可降解纤维，包括但不限于，不锈钢、钴铬、钛和钛合金；或生物惰性的陶瓷，包括但不限于氧化铝、氧化锆和硫酸钙；或生物可降解的玻璃或陶瓷包括磷酸钙；或生物可降解的自体移植物、同种异体移植物或异体移植骨组织。
多孔的、聚合物基质或纤维垫可以含有非-生物可降解聚合物，包括但不限于聚乙烯、聚乙烯醇(PVA)、聚甲基丙烯酸甲酯(PMMA)、硅树脂、聚环氧乙烷(PEO)、聚乙二醇(PEG)、和聚氨酯。
聚合物基质可以包含生物可降解的生物聚合物。此处所用的术语“生物聚合物”应理解为包括了天然存在的聚合物和它们的合成改性物或衍生物。这样的生物聚合物包括但不限于透明质酸、胶原质、重组胶原质、纤维素、弹性蛋白、藻酸盐、硫酸软骨素、壳聚糖、壳多糖、角蛋白、丝、小肠粘膜下层(SIS)和它们的混合。这些生物聚合物可以通过引入交联剂或改变侧链残基的疏水性被进一步改性来增强其机械或降解性质。
在一个优选的实施方案中，纤维20和多孔的基质30优选包含生物可降解的聚合物。由此得到一个可完全被身体所降解的复合支架植入装置。
在这样的生物可降解支架中，各种生物降解聚合物可以用来制作纤维垫和多孔的聚合物基质，这些纤维垫和多孔的聚合物基质包括根据本发明的复合支架植入装置并用哺乳动物的细胞进行接种。合适的生物可相容的、生物可降解的聚合物的实例包括选自下述聚合物：脂族聚酯、聚亚烷基草酸酯、聚酰胺、聚碳酸酯、聚原酸酯、聚草酸酯(polyoxaester)、聚酰胺酯(polyamidoester)、聚酐和聚膦腈。
通常，脂族聚酯是用于制备本发明复合支架的优选的生物可降解聚合物。脂族聚酯可以是具有直链、支链或星型结构的均聚物和共聚物(无规、嵌段、多嵌段(segmented)、递变嵌段、接枝、三嵌段等)。合成脂族均聚物和共聚物的合适的单体可选自包括但不限于，乳酸、丙交酯(包括L-、D-、内消旋和L，D混合物)、羟基乙酸、乙交酯、ε-己内酯、p-二噁烷酮、三亚甲基碳酸酯、δ-戊内酯、β-丁内酯、ε-癸内酯(ε-decalactone)、2，5-二酮基吗呤、新戊内酯，α，α-二乙基丙内酯、碳酸亚乙酯、草酸亚乙酯、3-甲基-1，4-二噁烷-2，5-二酮、3，3-二乙基-1，4-二噁烷-2，5-二酮、γ-丁内酯，1，4-dioxepan-2-酮、1，5-dioxepan-2-酮、6，6-二甲基-dioxepan-2-酮和6，8-二氧杂二环辛烷-7-酮。
弹性共聚物也特别适用于本发明。合适的弹性共聚物包括那些具有特性粘度在大约1.2dL/g到大约4dL/g的范围内的弹性共聚物。更优选大约1.2dL/g到大约2dL/g，最优选大约1.4dL/g到大约2dL/g，这些数据均在25℃下将0.1g/dL聚合物的六氟异丙醇(HFIP)中测定。而且，合适的弹性体显示出高的延长百分率和低的模量，拥有好的抗张强度和好的回复特性。在本发明优选的实施方案中，形成复合支架的弹性体显示出超过大约200％的延长百分率且优选超过大约500％。除了这些延长和模量性质之外，合适的弹性体也应当具有超过大约500psi的抗张强度，优选超过大约1000psi，和超过大约50磅/英寸的撕裂强度，优选超过大约80磅/英寸。
示例性的生物可降解、生物可相容的弹性体包括但不限于，带有ε-己内酯和乙交酯摩尔比率在大约35/65到大约65/35范围的ε-己内酯和乙交酯的弹性共聚物，更优选35/65到45/55；ε-己内酯和丙交酯的摩尔比率在大约35/65到65/35的范围，且更优选35/65到45/55的ε-己内酯和丙交酯的弹性共聚物；丙交酯和乙交酯的摩尔比率在大约95/5到大约85/15的丙交酯和乙交酯的弹性共聚物；对-二噁烷酮和丙交酯的摩尔比率在大约40/60到大约60/40的对-二噁烷酮和丙交酯的弹性共聚物；ε-己内酯和对-二噁烷酮的摩尔比率是大约30/70到大约70/30的ε-己内酯和对-二噁烷酮的弹性共聚物；对-二噁烷酮和三亚甲基碳酸酯的摩尔比率是大约30/70到大约70/30的对-二噁烷酮和三亚甲基碳酸酯的弹性共聚物；三亚甲基碳酸酯和乙交酯的摩尔比率是大约30/70到大约70/30的三亚甲基碳酸酯和乙交酯的弹性共聚物；三亚甲基碳酸酯和丙交酯的摩尔比率是大约30/70到大约70/30的三亚甲基碳酸酯和丙交酯的弹性共聚物，或者它们的混合物。
脂族聚酯是典型地以开环聚合合成的。单体通常是高温下在有机金属催化剂和引发剂的存在下进行聚合。有机金属催化剂优选基于锡，即辛酸亚锡，以单体对催化剂的摩尔比率为从约10000/1到约100000/1的范围内存在于单体混合物中。引发剂通常为链烷醇(包括二元醇和多元醇)、乙二醇、羟基酸、或者胺，以单体对引发剂的摩尔比率从约100/1到约5000/1的范围内存在于单体混合物中。聚合反应典型地在大约80℃到大约240℃，优选约100℃至约220℃的温度下进行，直到得到了所需的分子量和粘度。
本领域的普通技术人员将认识到，形成复合支架的合适的聚合物或共聚物的选择依赖数个因素。选择合适的用于制造支架的一个或多个聚合物的多个相关因素包括：生物降解(或生物降解)动力学参数；体内机械性能；细胞对细胞附属物质的材料的反应，增殖、迁移和分化；以及生物相容性。在某种程度上指示聚合物体外和体内行为的其他相关因素包括化学组成、组成物的空间分布、聚合物分子量和结晶度。
材料基材具有能在体内环境中被及时再吸收的能力是很关键的。然而，体内条件下降解时间的差异也可以作为联合应用两种不同共聚物的基础。例如：比例为35/65的ε-己内酯和乙交酯的共聚物(一个降解相对快的聚合物)和一个比例为40/60的ε-己内酯和丙交酯共聚物(一个降解相对较慢的聚合物)相混合以形成复合支架。优选地，复合支架被机体再吸收的速度近似于组织替代复合支架的速度。就是说，与组织替代复合支架速度相关的复合支架的再吸收速度必须是这样的：在所需的时间内得以维持支架在结构上的完整性。因此，本发明的装置有利地平衡了生物降解能力、长时间的重吸收和结构完整性、促使组织生长的能力之间特性的关系，所有这些性质中的每一个在组织再生或修复中都是所希望的、有用的和必需的。
在另一个实施例中，希望通过使用聚合物混合物来形成能以梯度类(gradient-like)结构从一个组合物转变成另一个组合物的构造。有该梯度类结构的复合支架特别有利的在组织工程学应用中用于修复或再生自然存在的组织的结构，例如软骨，如关节、半月板、隔膜、气管等的软骨。例如：通过混合ε-己内酯和乙交酯的弹性共聚物和由ε-己内酯和丙交酯(即以大约5/95的摩尔比率)的弹性共聚物，可以形成可从较软的海绵样材料转化到较坚硬的硬质材料的复合支架，以与从软骨到骨的转化相似的方式。显然，本领域普通技术人员有了本发明的启示后可以预见聚合物混合物可用作相似的梯度效应、或者以提供不同的梯度，例如：不同降解、应力反应或不同弹性的分布图。
本发明被多孔基质30包封的纤维20包括了选自以线、纱、网、带、毡和无纺物形式的纤维。优选地，纤维20是无纺纤维垫的形式。已知的湿-铺(wet-lay)或干-铺(dry-lay)的制备技术可以用于制备本发明复合支架的无纺纤维垫。
在另一个实施方案中，用于形成复合支架的无纺纤维垫的纤维是由生物可降解的玻璃制成的。生物玻璃，一种含有磷酸钙玻璃的硅酸盐、或含有加入了不同量的铁颗粒以控制降解时间的磷酸钙玻璃，是可以被拉制成玻璃纤维并且用于制备纤维垫的例子。
优选地，形成复合支架无纺纤维垫的纤维包括生物可降解聚合物、共聚物、或它们的混合物。生物可降解的聚合物可以选自聚乳酸(PLA)、聚羟基乙酸(PGA)、ε-聚己内酯(PCL)、聚二噁烷酮(PDO)、或它们的共聚物和混合物。
采用一种加热过程将复合支架的无纺垫的纤维和另一个聚合物一同熔化，可进一步的增强复合支架的无纺垫的结构完整性。例如：生物可降解的热塑聚合物或共聚物，诸如粉末形式的ε-聚己内酯(PCL)，可以加入到无纺纤维垫中，然后在不影响纤维结构的情况下适度热处理熔化PCL颗粒。该粉末拥有低熔化温度且在随后的增加无纺纤维垫的抗张强度和切变强度的处理过程充当粘合剂的角色。优选的PCL颗粒粉末直径在10-500μm的范围内，并优选在10-150μm内。附加粘合剂包括生物可降解的聚合物粘合剂，其选自聚乳酸(PLA)、聚二噁烷酮(PDO)和聚羟基乙酸(PGA)。
可选择地，可以通过在另一生物可降解聚合物溶液中喷雾或浸渍涂布无纺纤维垫将纤维熔和到一起。
在一个实施方案中，形成无纺垫的细丝可以被共挤出以生成带有鞘/核构造的细丝。这些细丝包含生物可降解聚合物的鞘，这个鞘围绕在含有另一种生物可降解聚合物的一个或多个核的周围。围绕慢速降解核的快速降解鞘的细丝在例如组织生长需要额外支撑的情况下是需要的。
本发明的多孔基质30优选是聚合物泡沫的形式。复合支架植入装置的聚合泡沫可以由本领域普通技术人员熟知的多种方法制备。例如：聚合的起始材料可以通过冻干、超临界溶剂发泡、注气喷出、注气成型或采用可提取材料(例如：盐，糖或其适宜的相似物)铸模的方法形成。
在一个实施方案中，本发明复合支架装置的聚合泡沫基质可以由诸如冻干法的聚合物-溶剂相分离技术制得。然而，一种聚合物溶剂通常可以用以下四种技术中的任何一种分离为两相：(a)热诱导的凝胶/结晶作用；(b)非溶剂诱导的溶剂相和聚合物相分离；(c)化学诱导的相分离，和(d)热诱导的旋节线分解。聚合物溶液以控制的方式被分离成两个截然不同的相或者两个双连续相中。随后溶剂相的移除通常会留下密度低于本体且孔为μm级的聚合物的多孔基质。
制备这些泡沫所涉及的步骤包括：为用于冻干的聚合物选择适宜的溶剂，以及在溶液中制备均匀的聚合物溶液。然后将聚合物溶液进行冷冻和真空干燥循环处理。冷冻步骤对聚合物溶液进行相分离，而真空干燥步骤通过升华和/或干燥移除溶剂，这样就留下了多孔的聚合物基质，或者是相互连接的、开室的(open-cell)、多孔的泡沫。
可以用于制备泡沫支架组分的适宜的溶剂包括但不限于，六氟异丙醇(HFTP)、环醚(例如：四氢呋喃(THF)和二亚甲基氟化物(DMF))、丙酮、甲基乙基酮(MEK)、1，4-二噁烷、二甲基碳酸酯、苯、甲苯、N-甲基吡咯烷酮、二甲基甲酰胺、氯仿和它们的混合物。在这些溶剂当中，优选的溶剂是1，4-二噁烷。聚合物在溶剂中的均匀溶液是用标准方法制备的。
本领域技术人员可以知道，优选的溶剂系统仅仅溶解聚合物泡沫的生物可降解聚合物而不溶解复合支架无纺垫的纤维。
可实施的聚合物浓度和要用到的溶剂的量将根据每个系统而变化。通常，溶剂中聚合物的量以重量计算可以大约0.01％到大约90％变化，优选按重量计算从大约0.1％到到约30％，根据诸如聚合物在给定溶剂中的溶解度和泡沫支架所需的最终性质等因素而变化。
在一个实施方案中，可以向聚合物-溶剂系统中加入一些固体以改变所得泡沫表面的组成。因为加入的颗粒没有在溶剂中而到了底部表面，就产生了含有加入固体成分但不含有泡沫聚合物材料的的区域。可选择地，在所得复合支架中，所需区域(即临近顶端、侧面或者底部)中的加入固体的浓度可以更高，这样，引起所有这些区域组成的改变。例如：在选定位置固体物质的浓度可以通过向装在由磁性材料制成的模子中的溶剂中加入金属固体来完成(或反过来)。
许多类型的固体可以加入到该聚合物-溶剂系统中来。优选地，固体是一种不与聚合物或溶剂发生反应的类型。通常地，加入的固体平均直径小于约1mm，优选在约50到500微米之间。优选地固体以占颗粒和聚合物-溶剂混合物总体积的大约1％到大约50％的百分体积的量存在(其中的总体积相当于100体积％)。
示例性的固体包括但不限于：用于骨修复的去除了矿物质的骨头颗粒、磷酸钙颗粒、生物玻璃颗粒或碳酸钙颗粒；用于产生孔的可滤去固体；和可以作为增强材料或者当降解时可以产生孔的不溶于溶剂系统的生物可降解的聚合物颗粒、非-生物可降解材料、和生物学衍生的生物可降解材料。
合适的可滤去的固体包括无毒的可滤去材料，诸如盐(例如：氯化钠、氯化钾、氯化钙、酒石酸钠、柠檬酸钠等等)、生物相容的单糖和二糖(例如：葡萄糖、果糖、右旋葡萄糖、麦芽糖、乳糖和蔗糖)、多糖(例如：淀粉、藻酸盐、壳聚糖)、水溶性蛋白质(例如胶和琼脂糖)。可滤去材料可以通过以下方法除去：将可滤去材料与泡沫一起浸泡在溶剂中足够长的时间以充分除去所有这些颗粒，该溶剂能够溶解该可滤去材料的颗粒，但不溶解或有害地改变泡沫。优选的萃取溶剂是水，最优选蒸馏-去离子水。优选地，除非期望加速泡沫的降解，一般在滤去过程结束后在低温和/或真空条件下干燥以使泡沫的水解降到最低。
合适的非-生物可降解材料包括生物可相容金属，诸如不锈钢、钴铬(coblaltchrome)、钛和钛合金；和生物惰性陶瓷颗粒(例如：氧化铝和氧化锆颗粒)。进而，非-生物可降解材料可以包括聚合物，诸如聚乙烯、聚乙烯醋酸酯、聚甲基丙烯酸甲酯、硅树脂、聚环氧乙烷、聚乙二醇、聚氨酯；和天然生物聚合物(例如：纤维素颗粒、壳多糖、角蛋白、丝和胶原质颗粒)；以及氟化聚合物和共聚物(例如：聚偏二氟乙烯)。
也可以加入能使复合支架对无线电不传导的固体(例如：硫酸钡)。这些可加入的固体还包括那些可以促进组织再生和再生长的固体，还包括那些充当缓冲剂、增强材料或孔隙改性剂的固体。
合适的生物材料包括小肠粘膜下层固体(SIS)颗粒、透明质酸、胶原质、藻酸盐、硫酸软骨素、壳聚糖和它们的混合物。这些固体可能包含生物材料的完整结构或存在于完整结构中的生物活性片段。
在植入到靶组织前，哺乳动物细胞被接种或培植到本发明的复合支架上。可在复合支架上接种或培养的细胞包括但不限于，骨髓细胞、平滑肌细胞、基质细胞、干细胞、间叶干细胞、滑膜衍生干细胞、胚胎干细胞、脐带血细胞、脐带沃顿胶质细胞(umbilical Wharton’sjelly cell)、血管细胞、软骨细胞、造骨细胞、源自脂肪组织的前体细胞、骨髓衍生祖细胞、肾细胞、肠细胞、胰岛、β细胞、胰管祖细胞、支持细胞(Sertoli cell)、外周血祖细胞、成纤维细胞、球细胞、角化细胞、髓核细胞、纤维环细胞、纤维软骨细胞(fibrochondrocyte)、成熟组织源干细胞、卵形细胞(oval cell)、神经原干细胞(neuronal stem cell)、神经胶质细胞、巨噬和遗传转移细胞或上述细胞的组合。在植入前，细胞可以接种到支架上经历较短的时间(＜1天)；或者培养较长时间(＞1天)以使得在植入之前，在接种了的支架内能完成细胞繁殖和细胞外基质的合成。
植入的部位依照需要治疗的病患/受损的组织而定。例如：为了治疗关节软骨、半月板和骨头的结构损伤，接种了细胞的复合支架被置于损伤部位以促进损伤组织的修复。
可选择地，为了治疗某种疾病，诸如糖尿病，接种细胞的支架可被置于便于临床的部位，诸如皮下、肠系膜或网膜。在这种特殊情况中，复合支架作为运载工具在体内移植到异位部位后截留给予的胰岛。
由于本发明的接种了细胞的复合支架在提供一种对于胰岛长期正常运作所必需的营养物质的转运和移植物血管的形成起作用的多孔结构的同时，推动了细胞—对—细胞的联系，因此所给予细胞的定位为糖尿病的治疗提供了很大的益处。
之前的在通过注射入门脉循环的直接的胰岛移植的努力被证实对长期治疗糖尿病是不够的。而且，多种包封有同基因的和异基因的胰岛的生物可降解和非可降解微球的方法没能长期控制血液葡萄糖水平。这些失败归咎于由于移植的胰岛的不充足的脉管和/或免疫排斥。
异基因的或同基因的胰岛与异基因或同基因的支持细胞相结合的给药可能可以避开上述失败。支持细胞可以帮助胰岛存活和阻止对移植胰岛的免疫应答。在肾脏内，异基因的、同基因的、或移植的支持细胞在免疫保护同基因的、异基因的胰岛的同时，也可以保护它们自己。本发明接种了细胞的复合支架，在与支持细胞和胰岛同时接种并进行皮下植入，避免了肾脏(一个非常难达到的临床部位)的使用。复合支架可以在提供形成血管生成床的条件的同时可共同定位两种细胞以便支持细胞可以免疫保护临近的胰岛。
可选择地，在植入异位部位之前，支持细胞可与复合支架一起培养，随后的某一时间点将胰岛给予到植入部位。在另一个实施方案中，在植入体内之前，胰岛和支持细胞可以同时注射到复合支架上。在另一个实施方案中，在注射到支架上之前，胰岛或支持细胞可以悬浮在生物聚合物之中，诸如透明质酸、胶原质、或藻酸盐、或以商品名MARIGEL出售的胶原质/层粘蛋白材料(Collaborative Biomedical Products，Inc.，Bedford，MA)；或者悬浮在合成的聚合物中，例如：聚乙二醇、聚乙二醇和聚赖氨酸的共聚物，醇酸树脂聚酯的水凝胶或者它们的联合。
对于中枢神经系统(CNS)损伤的情况，复合支架可以与成熟神经干细胞，胚胎干细胞、神经胶质细胞和支持细胞的结合体一同接种。在优选的实施方案中，复合支架可以与源自转细胞体系，异种或异源组织的支持细胞与神经干细胞结合进行接种。在加入神经干细胞并植入到损伤部位之前，支持细胞可以在复合支架中进行培养。这种方法可以避免细胞治疗中枢神经系统应用的一个主要障碍，也就是移植后干细胞的存活问题。带有大量支持细胞的复合支架可以提供一种更能适合于干细胞存活的环境。
在本发明的另一个实施方案中，接种了细胞的复合支架可以通过物理或化学的方法改性，以使其含有可以促进靶细胞类型的粘附、增殖、分化和细胞外基质合成的生物或人造因子。而且，生物因子也可以包含部分复合支架来控制这些因子的释放，以诱导所需的生物学功能。另一个实施方案包括对可影响内源性生长因子正向调节的小分子的传送。可以和当前发明基质一起使用的生长因子、细胞外基质蛋白质、和生物活性相关的肽片断，包括但不限于，TGF-β族成员，包括TGF-β1、2和3；骨形成蛋白质(BMP-2、-4、6、-12和-13)；纤维原细胞生长因子1和2、血小板衍生的生长因子-AA和-BB；富含血小板的血浆；胰岛素生长因子(IGF-I、II)；生长分化因子(GDF-5、-6、-8、-10)；血管内皮细胞衍生的生长因子(VEGF)；多效蛋白(pleiotrophin)；内皮素；烟碱；胰高血糖素样肽-I和II；Exendin-4；视黄酸；甲状旁腺激素；替拿素(tenascin)-C；弹性蛋白原；凝血酶衍生肽；层粘蛋白；包含粘附性细胞外基质蛋白的细胞连接区域和肝磷脂连接区域的生物肽，诸如纤维蛋白和玻连蛋白；和它们的组合。
生物活性因子可以通过商业途径或从组织分离和纯化得到。
而且，接种细胞的复合支架的聚合物和混合物可以当作治疗剂，或者药物，释放槽使用。可以与本发明联合使用的治疗剂的种类是多种的。通常，可以通过本发明组合物给药的治疗剂包括但不限于：抗排斥药；止痛剂；抗氧化剂；抗凋亡剂(anti-apoptotic agent)，例如促红细胞生成素；抗炎药，例如抗肿瘤坏疽因子α；抗-CD44；抗-CD3；抗-CD154；p38激酶抑制剂；JAK-STAT抑制剂；抗-CD28；acetoaminophen；曲尼斯特；细胞生长抑制剂，例如雷帕霉素；抗-IL2剂和它们的组合。
为了制得释放槽，在形成复合物前，聚合物可以与一种治疗剂混合。可选择地，治疗剂包衣到聚合物上，优选使用药用可接受的载体一起包衣。任何不溶解聚合物的药用载体都可以使用。治疗剂可以是液体、细分散固体或其他任一合适的物理形态。典型地，但不是任选地，释放槽包括一种或多种添加剂，诸如稀释液、载体、赋形剂、稳定剂等等。
治疗剂的量依据具体使用的特定试剂和正在治疗的医学条件而定。有代表性的，治疗剂的量占槽重量百分比的大约0.001％到大约70％，更典型地大约0.001％到大约50％，最典型地大约0.001％到大约20％。治疗剂递送槽使用的聚合物的量和类型根据期望的释放性质和使用治疗剂的量而变化。
在另一个实施方案中，本发明细胞接种的复合支架可以经受住在持续期和延长期伴随着治疗剂释放的逐渐降解(主要通过水解)。这将导致治疗剂的传送时间延长，例如：1到5000小时，优选2到800小时，传送的有效量为，例如0.0001毫克/千克/小时到10毫克/千克/小时。根据治疗的病人、病情的严重程度、医生的判断等，如有需要可以给予这样的剂型。根据相同或相似的方法，所属领域技术人员可以制备多种剂型。
移植物的结构必须是对促进组织生长有效的。优选的促进组织生长的结构是这样的一种结构，复合支架组分的孔是开放且具有足够大的尺寸以允许细胞在此生长。有效的孔尺寸是大约50到大约1000μm的平均直径，更优选大约50到大约500μm。
下面的实施例都是为了演示本发明的原理和实践，但不限定本发明的范围。许多本发明范围和精神之内的实施方案对所述领域技术人员来说是显而易见的。
在实施例中，使用常规分析技术，聚合物和单体都按照化学组成、纯度(NMR，FTIR)、热量分析(DSC)和分子量予以定性。
聚合物或共聚物的固有粘度(I.V.，dL/g)的测定，是在30℃恒温水浴中，使用0.1g/dL浓度的氯仿或六氟异丙醇作溶剂，将50孔的Cannon-Ubbelhode稀释粘度计浸泡于其中而测定的。
在这些实施例中使用了某些缩写。包括用PCL代表聚ε-己内酯；PGA代表聚乙交酯；PLA代表聚合的(L)丙交酯；PDO代表聚对-二噁烷酮。此外，共聚物前面的比率代表各个组成的摩尔百分率。
具体实施方式
实施例1：制备复合支架
按照下述方法制备由90/10PGA/PLA纤维组成的针孔无纺垫(2mm厚)。90/10的PGA/PLA共聚物以纺纱的常规方法熔化—挤压成连续的多丝纱，然后增加使其断裂需要的力度、延长性和能量。这些包含丝的纱的直径大约是20μm。然后将纱剪断并卷成均匀的的2英寸的长度以形成2英寸的定长纤维。
然后使用90/10的PGA/PLA共聚物定长纤维制备一个干铺的针孔无纺垫。这些定长纤维都经过标准的无纺机器打开和梳毛处理。所得的垫子是蜘蛛网状的定长纤维的形式。这些蜘蛛网状的定长纤维都用针打孔来形成干铺针孔无纺纤维垫。
垫子用乙酸乙酯冲洗60分钟，然后在真空下干燥。
制备一种用以冻干成泡沫的聚合物溶液。用以制造泡沫组成的聚合物是由Birmingham Polymers Inc(Birminghan，AL)生产的35/65的PCL/PGA共聚物，固有粘度为1.45dL/g。称出35/65的PCL/PGA，以5/95重量比存在于1，4-二氧杂环乙烷溶剂中。将聚合物和溶剂都放到一个烧杯中，将烧杯放到70℃的水浴中搅拌5小时形成溶液。然后使用抽提套管(特别粗糙、多孔的，ASTM170-220(EC)型号)过滤溶液，保存滤液到烧杯中。
使用实验室级别的冷冻干燥机，或冻干机(Model Duradry，FTS Kinetics，StoneRidge，NY)来制备复合支架。针孔无纺垫通过4英寸的铝模制成4英寸长。将聚合物溶液加入到模子中一时溶液覆盖无纺垫，并在模子中达到2mm的。
组合模子放到冻干机器的架子上然后开始冷冻干燥。本实施例使用的冷冻干燥的顺序是：1)-17℃下60分钟，2)100mT真空下-5℃60分钟，3)20mT真空下5℃60分钟，4)20mT真空下20℃60分钟。
循环结束后，从冻干机器中取出组合模子在真空条件下脱气3到3小时。然后在氮气条件下保存该复合支架。
所得含无纺垫的复合支架被包封在聚合泡沫基质中，并分布在其中。支架的厚度大约是1.5mm。
实施例2：制备复合支架
除冻干成泡沫的聚合物是购自Birmingham Polymers Inc.，Birmingham，AL，固有粘度为1.45 dL/g的60/40PLA/PCL共聚物外，其余均依照实施例1的过程制造生物可降解的复合支架。。复合支架孔的大小通过水银测孔计分析确定。孔大小为1-300μm，平均大小为45μm。图1是复合支架横截面的电子扫描显微照片(SEM)。此扫描显微照片清楚的显示冻干泡沫支架环绕并包封着无纺垫。
实施例3：制备复合支架
除冻干成泡沫的聚合物是购自Birmingham Polymers Inc.Birmingham，AL，的固有粘度1.50dL/g的60/40PLA/PCL共聚物和固有粘度为1.45dL/g的35/65PLA/PGA共聚物的50∶50的混合物外，其余均依照实施例1的过程制造生物可降解的复合支架。
实施例4：制备复合支架
除冻干成泡沫的聚合物是固有粘度为1.50dL/g的60/40PLA/PCL的共聚物(购自Birmingham Polymers Inc Birmingham，AL)，和固有粘度1.78dL/g的85/15PLA/PGA的共聚物(购自Purac，lincolshine，IL)以70∶30混合的混合物外，其余均依照实施例1的过程制备生物可降解的复合支架。
实施例5：制备复合支架
除冻干成泡沫的聚合物是固有粘度为1.50dL/g的60/40PLA/PCL的共聚物(购自Birmingham Polymers Inc Birmingham，AL)，和固有粘度为1.78dL/g的85/15PLA/PGA的共聚物(购自Purac，lincolshine，IL)以30∶70混合的混合物外，其余均依照实施例1的过程制备生物可降解的复合支架。
实施例6：制备复合支架
除冻干成泡沫的聚合物是固有粘度为1.5dL的60/40PLA/PCL的共聚物(购自Birmingham Polymers Inc Birmingham，AL)，和固有粘度1.78dL/g的85/15PLA/PGA的共聚物(购自Purac，lincolshine，IL)以50∶50混合的混合物外，其余均依照实施例1的过程制备生物可降解的复合支架。
实施例7：制备复合支架
除干铺针孔无纺垫由PDO纤维组成外，其余均依照实施例1的过程制备生物可降解的复合支架。
实施例8：制备复合支架
除干铺针孔无纺垫由PGA纤维组成外，其余均依照实施例1的过程制备生物可降解的复合支架。
实施例9：制备复合支架
除干铺针孔无纺垫由PGA纤维组成外，其余均依照实施例4的过程制备生物可降解的复合支架。
实施例10：制备接种了细胞的复合支架
本实施例演示了复合支架中的聚合物泡沫或干铺针孔无纺垫对软骨细胞体外反应的影响。
如Buschmann等人在J.Orthop.Res.10，745，(1992)中叙述的那样，原始软骨细胞从牛肩分离制得。牛软骨细胞在用10％胎牛血清(FCS)、10mM HEPES、0.1mM非必需氨基酸、20μg/ml的脯氨酸、50μg/ml的抗坏血酸维生素C、100U/ml青霉素、100μg/ml链霉素和0.25μg/ml的两性霉素B(生长介质)进行补充供给的Dulbecoo′s改进的Eagle培养基(DMEM-高含量葡萄糖)中培养。每隔一天补充一半的介质。
如实施例1，4，8和9所述制备复合支架。直径长5mm，厚1.5mm的复合支架，在70％的乙醇溶液中消毒20分钟后用磷酸缓冲盐溶液(PBS)冲洗5次。
通过在每个支架上加入细胞悬浮液(15微升)，刚分离的牛软骨细胞以5×106细胞/支架的密度接种在24孔的低簇培养皿上。在加入1.5毫升的介质前允许细胞放在支架上3个小时。在将一半样品转移到旋转生物反应堆以及将剩余的支架在静态条件下培养之前，所有支架都在细胞培养器皿中培养7天。由NASA-所开发的模拟微重力状态的Slow Turning Lateral Vessel(STLV)旋转生物-反应器(Synthecon，Inc.，Houston，TX)在此项研究中应用。每个生物—反应器加载4个包含细胞的支架，且容器旋转速度调整到与接种了细胞的支架重量增加相适应。支架保持在一个连续的自由下落的阶段。支架在37℃、5％CO2和95％空气的气体条件下在增湿温育器中温育6周。为了生物-反应堆的培养，每隔一天更换一般的介质(～50毫升)。每隔一天给六孔器皿中的静置培养物添加介质(5毫升)。每个时间点对3个样品通过组织学染色进行评价。将不同时间点(第1、7、21和42天)所得到的支架都浸泡入10％的福尔马林溶液中、植入石蜡中和使用ZEISSMICROSTONE进行切面。聚合物支架中的细胞分布通过接种细胞24小时后的支架横界面的苏木精染色来测定。进而，在硫酸盐化的蛋白多糖存在下使用番红-O(SO；硫酸盐化的GAG’s)给截面染色，I型和II型胶原质进行免疫组织化学染色。对原生牛的软骨和皮肤也进行I型和II型胶原质染色以验证免疫染色的特异性。II型胶原质用作软骨-样基质的指针而I型胶原质用作纤维样基质的指示。使用带有Nikon CCD摄影机(Nikon，Japan)的Nikon Microphot-FXA显微镜得到电脑图象。
实施例1，4，8和9中形成的复合支架，在生物反应堆条件下培养了6周后得到其组织学切片(100X)。实施例4的包含了90/10的PGA/PLA无纺垫的复合支架，与实施例9的包含了100％PGA无纺垫的复合支架相比，显示了均匀的细胞分布和蛋白多糖构成。然而，在生物反应堆条件下培养了6周的实施例1和8的复合支架的在GAG产品和细胞分布上没有明显的分化。这就意味着泡沫的成分和复合支架无纺垫的组成可以影响细胞的分布和细胞外基质的组成。
总之，包封了无纺纤维垫的泡沫支架的结构可支撑细胞迁移以及硫酸盐化的蛋白多糖基质的沉积。
实施例11：制备细胞接种的复合支架
本实施例演示了聚合物泡沫或复合支架的干铺针孔无纺垫的成分影响体外的支持细胞反应。
支持细胞获自于9-12天大的雄性Balb/c鼠的睾丸。所有的睾丸都被收集到Hank’s平衡盐溶液(HBSS)中，切成1mm的细片，然后37℃下在HBSS中使用胶原酶(2.5毫克/毫升；Sigma V型)消化10分钟。使用包含1mmol/l EDTA和0.5％牛血清蛋白(BSA)且不含Ca2+/Mg2+的HBSS冲洗3次。37℃下在HBSS中使用胰岛素(25μg/ml，Boehringer Mannheim)和脱氧核糖核酸酶Dnase(4μg/ml，BoehringerMannheim)消化10分钟，随后用HBSS冲洗四次。最后的细胞球重新悬浮在补充有10％热-钝化马血清的M199介质(Gibco Life Technologies，Rockville，MD)中，用500μm的过滤器过滤后在超低簇培养皿(Corning Inc，Corning，NY)中培养2天以允许支持细胞的聚集。
依照实施例1制备复合支架，接种120万小鼠支持细胞，在填充有10％热钝化马血清、青霉素和链霉素的M199介质中培养3周。3周后，装置都用10％的缓冲福尔马林浸泡，嵌入石蜡，使用Zeiss Microtome进行切片。通过苏木精和曙红(H & E)染色来评定构造中细胞的分布。图2显示了含有支持细胞复合支架的H & E切面。
实施例12：制备复合支架
依照下述制备由90/10的PGA/PLA纤维组成的针孔无纺垫(2mm厚)。使用常规纺纱方法将PGA/PLA(90/10)的共聚物熔化挤压成连续的复丝纱然后增加断裂所需的力度、延展性和能量。这些纱包含了直径大约20μm的细丝。然后剪断卷曲这些纱成均匀的2英寸长，以形成2英寸的定长纤维。
然后由90/10的PGA/PLA共聚物定长纤维制成一个干铺针孔无纺垫。定长纤维在标准的无纺机器上打开和梳毛处理。所得的垫子是蜘蛛网状的定长纤维。蜘蛛网状的定长纤维都用针打孔以形成干铺针孔、纤维性无纺垫。
用乙酸乙酯冲洗垫子60分钟，然后在真空下干燥。
然后制备用于冻干成泡沫的60毫升的聚合物溶液。用于制造泡沫组分的聚合物是Birmingham Polymer Inc(Birmingham，AL)生产的固有粘度为1.45dL/g的35/65的PCL/PGA的共聚物。称出重量比为0.25/99.25的35/65PCL/PGA在1，4-二氧杂环乙烷中的混合物。聚合物和溶液都放入烧杯中，然后将烧杯放入水浴中在70℃下搅拌5小时成溶液。然后使用抽提套管(特别粗糙、多孔的，ASTM170-220(EC)型号)过滤溶液，保存滤液到烧杯中。
实验用的冻干机器，或冷冻干燥机器(Model Duradry，FTS Kinetics，StoneRidge，NY)，用来制备复合支架。大约10毫升的聚合物溶液加入到4英寸见方的铝模中均匀地覆盖模子的表面。针孔无纺垫浸泡在盛有剩余溶液的烧杯中直到完全浸透，然后将其放到铝模中。剩余的聚合物溶液倒入模中以使溶液覆盖无纺垫，并在模子中深度达到2mm。
将组合模具放到冷冻干燥机的架子上开始冷冻干燥步骤。本实施例中使用的冷冻干燥步骤是：1)-17℃下60分钟，2)100mT真空-5℃下60分钟，3)20mT真空5℃下60分钟，4)20mT真空20℃下60分钟。
循环结束后，从冻干机器中取出组合模具，在真空条件下脱气2到3小时。复合支架然后在氮气条件下保存。图3是复合支架横界面的电子扫描显微照片(SEM)。SEM清晰显示了冻干泡沫支架围绕并包封着无纺纤维。
实施例13：
除了用于冻干制造复合支架泡沫部分的是重量比为0.5/99.50的35/65PCL/PGA(Birmingham，AL，固有粘度1.45dL/g)溶于1，4-二氧杂环乙烷溶液之外，其余均依照实施例12的过程制造一个生物可降解的复合支架。图4是复合支架的横界面的电子扫描显微照片(SEM)。SEM清晰地显示了冻干泡沫支架围绕和包封着无纺纤维。
实施例14：
除了用于冻干制造复合支架泡沫部分的是重量比为1/99的35/65PCL/PGA(Birmingham，AL，固有粘度1.45dL/g)溶于1，4-二氧杂环乙烷溶液之外，其余均依照实施例12的过程制造一个生物可降解的复合支架。图5是复合支架的横界面的电子扫描显微照片(SEM)。SEM清晰地显示了冻干了的泡沫支架围绕和包封着无纺纤维。
实施例15：制备细胞接种的复合支架
本实施例演示了接种鼠科动物胰岛到按照实施例12制备的复合支架上。
鼠科动物胰岛都是通过胶原酶消化胰岛和采摘胰岛后密度梯度离心方法分离自Balb/c小鼠。复合支架(直径8mm，厚2mm)放在包含多个直径大小为7.75mm孔的特制的聚四氟乙烯模具中。500个新鲜的胰岛作为覆盖支架表面的细胞悬浮液(100微升体积)加入。含有细胞接种结构的模子在300RPM下离心1分钟。将这些结构从孔中移除。置于规则的细胞培养平板上，在含有由牛血清蛋白(0.5％)、烟碱(10mM)、D-葡萄糖(10mM)、L-谷氨酸盐(2mM)、IBMX(3-异丁基-甲基黄嘌呤，50mM)和青霉素/链霉素补给的Hams-F10(Gibco LifeTechologies，Rockville，MD)的培养基中培养1天。使用Live/Dead化验工具(Molecular Probes，Oregon)对细胞接种的结构染色来促进生存能力。如图6所示，多数的胰岛存活并均匀地分布在整个支架中。

Claims (35)

1、可植入地，生物可相容的支架，包括：
生物相容的、多孔的聚合物基质；
被包封且装在所述聚合物基质中的生物相容的、多孔的纤维垫；和
植入到所述组织支架中的多数哺乳动物细胞。
2、权利要求1支架，其中所述支架是生物可降解的。
3、权利要求1的支架，其中所述的聚合物基质包含选自生物可降解的聚合物的聚合物，所述纤维垫包含选自包括生物可降解玻璃和含有磷酸钙的陶瓷和生物可降解聚合物的材料的纤维。
4、权利要求3的支架，其中所述的聚合物基质和所述纤维垫包含生物可降解聚合物。
5、权利要求4的支架，其中所述生物可降解聚合物选自包含脂肪族聚酯、聚亚烷基草酸酯、聚酰胺、聚碳酸酯、聚原酸酯、聚草酸酯、聚酰胺酯、聚酐和聚膦腈的均聚物和共聚物。
6、权利要求5的支架，其中所述纤维垫包含90/10的聚乙交酯/聚丙交酯的共聚物。
7、权利要求5的支架，其中所述的纤维垫包含聚二噁烷酮，
必需对制备基质的聚合物溶液的重量百分比加以限定：0.1-10wt％，优选0.1-5wt％。
8、权利要求5的支架，其中所述的聚合物基质包含摩尔比率范围在大约95/5到大约85/15的聚丙交酯/聚乙交酯的共聚物。
9、权利要求6的支架，其中所述的多孔的、聚合物基质包含摩尔比率为大约35/65到大约45/55的聚己内酯/聚乙交酯的共聚物。
10、权利要求9的支架，其中所述的多孔的聚合物基质包含泡沫。
11、权利要求5的支架，其中所述的多孔的聚合物基质包含摩尔比率范围在大约35/65到大约65/35的聚丙交酯/聚己内酯的共聚物。
12、权利要求1的支架，其中所述的纤维垫包含以选自包括线、纱、网、带、毡和无纺品形式的纤维。
13、权利要求1的支架，其中所述的哺乳动物的细胞选自骨髓细胞、平滑肌细胞、基质细胞、干细胞、间叶干细胞、滑膜衍生干细胞、胚胎干细胞、血管细胞、软骨细胞、造骨细胞、源自脂肪组织的前体细胞、骨髓衍生祖细胞、肾细胞、肠细胞、胰岛、β细胞、支持细胞、外周血祖细胞、成纤维细胞、球细胞、角化细胞、髓核细胞、纤维环细胞、纤维软骨细胞、成熟组织源干细胞、卵形细胞、神经原干细胞、神经胶质细胞、巨噬和遗传转移细胞。
14、权利要求13的支架，其中所述的细胞选自胰岛和支持细胞。
15、权利要求13的支架，其中所述的细胞选自成熟的神经原干细胞、胚胎干细胞和神经胶质细胞。
16、权利要求1的支架，进一步包括生物因子。
17、权利要求16的支架，其中所述的生物因子是选自TGF-β1、TGF-β2和TGF-β3、BMP-2、BMP-4、BMP-6、BMP-12和BMP-13、成纤维细胞生长因子-1和成纤维细胞生长因子-2、血小板衍生的生长因子-AA、血小板衍生的生长因子-BB、富含血小板的血浆、IGF-I、IGF-II、GDF-5、GDF-6、GDF-8、GDF-10、血管内皮细胞衍生的生长因子、多效蛋白、内皮素、烟碱、胰高血糖素样肽-I和胰高血糖素样肽-II、Exendin-4、视黄酸、甲状旁腺激素、替拿素-C、弹性蛋白原、凝血酶衍生肽、层粘蛋白、包含细胞连接区域的生物肽和包含肝磷脂连接区域的生物肽。
18、权利要求1的支架，进一步包含治疗剂。
19、权利要求18的支架，其中所述的治疗剂选自抗排斥药、止痛剂、抗氧化剂、抗凋亡剂、促红细胞生成素、抗炎药、抗肿瘤坏疽因子α、抗-CD44、抗-CD3、抗-CD154、p38激酶抑制剂、JAK-STAT抑制剂、抗-CD28、acetoaminophen、细胞生长抑制剂、雷帕霉素和抗-IL2剂。
20、治疗哺乳动物疾病的方法，包括给所述动物植入生物可降解的支架，所述支架包括：
生物相容的、多孔的聚合物基质，
被包封和装在所述聚合物基质中的生物相容的、多孔的纤维垫；和
接种在所述组织支架上的多数的哺乳动物细胞。
21、权利要求20的方法，其中所述的支架是生物可降解的。
22、权利要求20的方法，其中所述的聚合物基质包含选自生物可降解的聚合物的聚合物，所述纤维垫包含选自含有生物可降解玻璃和含有磷酸钙的陶瓷和生物可降解聚合物的材料制成的纤维。
23、权利要求20的方法，其中所述的聚合物基质和纤维垫包含生物可降解聚合物。
24、权利要求23的方法，其中所述生物可降解聚合物选自包含脂肪族聚酯、聚亚烷基草酸酯、聚酰胺、聚碳酸酯、聚原酸酯、聚草酸酯、聚酰胺酯、聚酐和聚膦腈的均聚物和共聚物。
25、权利要求24的支架，其中所述纤维垫包含90/10的聚乙交酯/聚丙交酯的共聚物。
26、权利要求25的方法，其中所述聚合基质包含摩尔比率为大约35/65到大约45/55的聚己内酯/聚乙交酯的共聚物。
27、权利要求26的方法，其中所述的聚合物基质包含泡沫。
28、权利要求20的方法，其中所述的哺乳动物的细胞选自骨髓细胞、平滑肌细胞、基质细胞、干细胞、间叶干细胞、滑膜衍生干细胞、胚胎干细胞、脐带血细胞、脐带沃顿胶质细胞、血管细胞、软骨细胞、造骨细胞、源自脂肪组织的前体细胞、骨髓衍生祖细胞、肾细胞、肠细胞、胰岛、β细胞、胰管祖细胞、支持细胞、外周血祖细胞、成纤维细胞、球细胞、角化细胞、髓核细胞、纤维环细胞、纤维软骨细胞、成熟组织源干细胞、卵形细胞、神经原干细胞、神经胶质细胞、巨噬和遗传转移细胞。
29、权利要求20的方法，其中所述的疾病是糖尿病。
30、权利要求29的方法，其中所述的支架接种了支持细胞和胰岛。
31、权利要求29的方法，其中所述的装置进一步包含生物因子。
32、治疗哺乳动物结构缺陷的方法，包括给所述哺乳动物植入生物相容的支架，所述支架包括：
生物相容的多孔的聚合物基质，
被包封和装在所述聚合物基质中的生物相容的、多孔的纤维垫；和
接种在所述组织支架上的多数哺乳动物细胞。
33、权利要求32的方法，其中所述的支架是生物可降解的。
34、权利要求32的方法，其中所述的哺乳动物的细胞选自包括骨髓细胞、平滑肌细胞、基质细胞、干细胞、间叶干细胞、滑膜衍生干细胞、胚胎干细胞、脐带血细胞、脐带沃顿胶质细胞、血管细胞、软骨细胞、造骨细胞、源自脂肪组织的前体细胞、骨髓衍生祖细胞、肾细胞、肠细胞、胰岛、β细胞、胰管祖细胞、支持细胞、外周血祖细胞、成纤维细胞、球细胞、角化细胞、髓核细胞、纤维环细胞、纤维软骨细胞、成熟组织源干细胞、卵形细胞、神经原干细胞、神经胶质细胞、巨噬和遗传转移细胞。
35、权利要求32的方法，其中所述的结构缺陷是在选自包括关节软骨、半月板和骨的组织中的。
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