CN101897724A - 制备软组织填充物的方法和制备脂肪组织移植物的方法 - Google Patents
制备软组织填充物的方法和制备脂肪组织移植物的方法 Download PDFInfo
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Abstract
本发明提供了一种制备软组织填充物的方法，其包括将加工的脂肪抽吸物和完整的、未解聚的脂肪组织片段混合以得到所述软组织填充物。本发明还提供了一种制备脂肪组织移植物的方法，其包括将浓缩的含有脂肪衍生干细胞的细胞群体和完整的脂肪组织的第二部分混合以得到所述脂肪组织移植物。由本发明的方法制得的软组织填充物可以用来矫正外形缺陷；由本发明的方法制得的脂肪组织移植物中脂肪组织衍生细胞可提供支持移植物延长的存活和功能的环境。
Description
本申请是申请日为2002年12月9日，国际申请号PCT/US2002/39465，国家申请号为02827968.9，发明名称为“用加工的脂肪抽吸细胞来治疗患者的系统和方法”的申请的分案申请。
相关领域的交叉参考
本申请要求于2001年12月7日提交的发明名称为“加工的脂肪抽吸细胞以及脂肪衍生干细胞的临床装置、系统和应用”的第60/338,856号U.S.临时申请的优先权，该申请的整个内容引入本文以供参考。
发明背景
1.发明领域
本发明一般涉及衍生自脂肪组织的细胞，更具体来说，涉及脂肪衍生干细胞，使用脂肪衍生干细胞的方法，含有脂肪衍生干细胞的组合物，以及制备和使用脂肪衍生干细胞的系统。
2.相关技术的描述
再生医疗可定义为以临床目标方式利用身体的再生机制，以不是正常痊愈机制的一部分的方式使用它们，或者人工放大正常机制。该过程的一个经典实例是在骨髓移植中发现的过程，其中从供体收获造血干细胞和祖细胞，置于其中正常造血机制已经被切除或基本上排除或损害的接受者内，由此代替或再生接受者的造血能力(Thomas 1994)。在最近的临床和临床前研究中，该方法已经延伸到了骨髓的非造血干细胞组分，试验了再生(或试图再生)组织，包括骨(Connolly 1998；Horwitz，Prockop等人，1999；Horwitz，Prockop等人，2001)、心脏(Fukuda 2001；Orlic，Kajstura等人，2001；Orlic，Kajstura等人，2001；Strauer，Brehm等人，2002)和肝脏(Avital，Inderbitzin等人，2001)。这些研究是基于检测骨髓中非造血干细胞与内皮前体细胞的存在(Prockop，Azizi等人，2000)(Pittenger，Mackay等人，1999)(Shi，Rafii等人1998；Carmeliet和Luttun 2001)。
这些研究使用的是骨髓移植物接受动物，其中供体和宿主细胞可通过遗传标记区别开，以表明接受者中的某些新血管发育是衍生自供体骨髓细胞(Carmeliet和Luttun 2001)(Takahashi，Kalka等人，1999；Murayama，Tepper等人，2002)。虽然该研究确定性地证实了骨髓含有这样的细胞，但是通常将其意思延伸为骨髓是含有相应数目的这样的细胞的唯一组织，以至于当研究人员检测循环中的内皮前体细胞(EPC)或骨髓干细胞(MSC)时，自动假定这些细胞必然是骨髓衍生的。因此，没有人提出这样的观点，即其它组织的细胞群体可能代表另一或者也许是更好的治疗相关细胞群体来源。
已经有人证实了脂肪组织含有多能干细胞群体(Huang，Beanes等人，2002；Mizuno，Zuk等人，2002)(Zuk，Zhu等人，2001).Zuk等人，(Zuk等人，(In Press)Human Adipose Tissue Is A Source Of MultipotentStem Cells，Molecular Biology of the Cell)，并且其它人已表明该组织是内皮细胞来源(Kern，Knedler等人，1983；Hutley，Herington等人，2001)[U.S.专利5,372,945 Alchas等人，1994]，但是后面这些文献没有检验以及没有以任何方式提及内皮前体细胞。
干细胞是身体的主要细胞。已知得自胚胎的干细胞或胚胎干细胞(ESC)变成身体的很多—如果不是全部的话—细胞和组织类型。这些早期胎儿细胞不仅含有个体的所有遗传信息，而且具有变成200+细胞和身体组织的新生能力。正在进行的研究表明，这些细胞具有非常大的科学和临床价值。
然而，ESC的应用具有理论上的有限性。如果在临床上使用，它们必须衍生自另一个体、胚胎。当衍生自他们的干细胞或组织被移植到另一个人体内时，细胞接受者可能需要毒性免疫抑制药物来防止排斥反应。此外，另一个体的细胞可能携带可被传染给接受者的病毒或其它少见但显著的疾病。而且，已知ESC样细胞(例如畸胎瘤)会形成肿瘤。
最近，已经鉴定了非胚胎或成人干细胞，并且它们是代替ESC临床应用的重要可能供选择对象。这些细胞静息地位于很多—如果不是全部的话—组织中，假定它们在等待对创伤或其它破坏性疾病过程作出反应，这样它们可愈合损伤的组织。出现的科学证据表明，每一个体携带一些这样的干细胞，它们可以与ESC共享变成很多—如果不是全部的话—类型细胞和组织的能力。
据表明，成人干细胞群体存在于皮肤、肌肉、骨髓、肝脏、脑和脂肪组织当中的一个或多个中。迄今为止所提出的这样的细胞在组织工程中的应用包括通过细胞纯化和细胞培养方法来提高细胞数目、纯度和成熟度。这些步骤是补偿大部分组织中干细胞稀少所必需的。例如，据估计骨髓中间充质干细胞的比例为1/100,000有核细胞-1/100,000,0有核细胞。类似地，从皮肤中提取干细胞包括需要数周的一系列复杂细胞培养步骤。在心脏病临床试验中使用骨骼肌衍生干细胞采用2-3周的培养期，其中细胞数目增加至临床相关数目，并且细胞分化成肌肉的过程也得到了促进。
这些扩展和分化步骤可提供提高的细胞数目、纯度和成熟度，但是达到这样需要付出代价。代价可包括一个或多个以下代价：由于细胞老化而损失细胞功能，损失可能有用的非干细胞的细胞群体，延迟可能的细胞在患者中的应用，经济成本增加，和在培养期间细胞被环境微生物污染的危险性增大。虽然现在通过未被加工过而是作为基本上全骨髓使用的骨髓衍生细胞可获得关于人的数据(Horwitz，Prockop等人，1999；Horwitz，Prockop等人，2001)(Strauer，Brehm等人，2002)，但是所带来的临床益处是次最佳的，这是几乎肯定与从骨髓获得的有限的细胞剂量和纯度有关的结果。
已经开发了多种用于从脂肪组织收获细胞的装置，但是这些装置具有一个或多个以下缺点，不能最佳地提供抽吸装置来取出脂肪组织：从脂肪组织收获阶段到所有组织加工阶段期间缺乏部分或完全的自动化，缺乏大于100ml脂肪组织的体积容量，从脂肪组织收获阶段到所有组织加工阶段期间缺乏部分或完全封闭的系统，不能一次性处理部件来减轻样本彼此之间交叉污染的伴发危险性。
需要这样的替代方法，其中可以迅速且可靠地以高收率、一致性和/或纯度获得活性细胞群体，和因此可降低或排除细胞的提取后操作。理想情况是，细胞群体以适于将它们直接置于接受者体内的方式获得。
发明概述
本发明涉及用以使用衍生自脂肪组织的细胞的组合物、方法和系统，所述细胞与提高、产生或支持治疗、结构或美容有益效果所需的添加剂一起被直接置于接受者体内。
在一个实施方案中，脂肪组织加工在保持封闭、无菌流体/组织路径的系统中进行。这是通过使用预先装配、连接的封闭无菌容器和管线装置组合，让组织和流体成分在封闭的路径内传递来实现的。可将该加工装置组合与插入到可控制试剂加入、温度和加工时间的装置内的一系列加工试剂(例如盐水、酶等)连接，由此省去对人工控制加工的操作人员的需求。在优选的实施方案中，从组织提取到加工再到放置到接受者的整个过程都在相同装置内，实际上甚至在经历该过程的患者的相同房间内进行。
根据本发明的一个方面，将原始脂肪组织加工以基本上除去成熟的脂肪细胞和结缔组织，由此获得适于放置在接受者体内的不均一的多种脂肪组织衍生细胞。可将所得细胞与其它细胞、组织、组织片段或其它细胞生长和/或分化刺激剂一起置于接受者体内。在优选的实施方案中，将细胞与任何上述添加剂一起置于在一次手术操作中由其获得它们的人体内，以给接受者带来治疗、结构或美容有益效果。
在一个实施方案中，治疗患者的方法包括以下步骤：a)提供组织取出系统；b)使用组织取出系统将脂肪组织从患者体内取出，所述脂肪组织具有一定浓度的干细胞；c)加工至少一部分脂肪组织以获得浓度与加工前脂肪组织的干细胞浓度不同的干细胞；和d)将干细胞施用给患者，其中在施用给患者之前不将干细胞从组织取出系统中取出。
在另一个实施方案中，治疗患者的方法包括以下步骤：a)提供组织取出系统；b)使用脂肪组织取出系统将脂肪组织从患者体内取出，所述脂肪组织具有一定浓度的干细胞；c)加工脂肪组织以提高脂肪组织中的干细胞浓度；d)将具有该浓缩的干细胞的脂肪组织与另一单位部分的脂肪组织混和；和e)将具有提高的干细胞浓度的该脂肪组织施用给患者。
本文中公开的本发明系统包括a)组织收集容器，其包括i)用以接收从患者中取出的脂肪组织的组织收集入口；和ii)安置在容器内，并且用以保持从患者中取出的脂肪组织和让从患者中取出的非脂肪组织通过的滤器；b)与组织收集容器连接的混和容器，该混和容器用以接收从脂肪组织获得的干细胞，而不将干细胞从组织取出系统中取出，并包括用于施用至少一种添加剂以与包含在其中的干细胞混和的添加口；和c)用以让混和容器中的干细胞离开组织收集系统以施用给患者的出口。
本发明组合物包括两部分脂肪组织，第一部分是具有一定浓度干细胞的从患者中取出的脂肪组织，第二部分是干细胞浓度大于第一部分脂肪组织的从患者中取出的脂肪组织。
本文所描述的任何特征或特征组合都包括在本发明范围内，只要包括在任何这样的组合中的特征不互相矛盾即可，这可从上下文、本说明书和本领域技术人员的知识中显而易见地看出。通过以下详细描述，本发明的其它优点和方面将变得显而易见。
附图简述
附图1描绘了用于加工脂肪组织的组织取出系统。
附图2描绘了附图1的组织取出系统的组织收集容器。
附图3是附图2的组织收集容器的部分横截面视图。
附图4描绘了用于自动操作组织取出系统的加工装置。
附图5是描绘移植物重量与细胞剂量的关系的图。
附图6是描绘加工的脂肪抽吸物对于酒精处理的小鼠的影响的图。
附图7是接受加工的脂肪抽吸物的酒精处理的小鼠的肝脏组织的显微照片。
本发明优选实施方案的详细描述
下面详细描述本发明的优选实施方案，其实例在附图中说明。只要是可能的，在附图以及关于附图的说明或类似部分中使用相同或相似的参考编号。应当注意，附图是简化形式，而不是精确规模。在本文的公开内容中，仅为了方便和清楚起见，关于附图使用方向术语例如顶部、底部、左面、右面、向上、向下、在上面、在上方、在下面、在下方、后面和前面。这样的方向术语不应当理解为是以任何方式对本发明的限制。
虽然本文的公开提供了一些举例说明的实施方案，但是应当理解，提供这些实施方案只是为了举例说明，而不是限制性的。虽然讨论了示例性实施方案，但是应当理解，以下详细描述的目的是包括在如通过权利要求书所限定的本发明实质和范围内的所有变型、替代方案和等同实施方案。可以结合本领域常用的各种细胞或组织分离技术来实施本发明，将所有这样的常用加工步骤包括在本文中只是因为这是理解本发明所必需的。
本发明涉及存在于脂肪组织中的细胞群体，用于将所述细胞群体施用给人或动物患者的系统和方法。脂肪组织的细胞群体可用作治疗和美容应用的细胞来源。除了别的应用以外，这样的细胞还可用于再生医疗，例如用于可用再生细胞治疗的疾病。如本文所述，可在没有其它脂肪细胞或结缔组织的情况下将该细胞群体施用给患者，或者可将细胞群体以浓缩量与脂肪组织一起混和来施用。
已经发现，脂肪组织是尤其富含干细胞的来源。该发现可至少是部分由于易于将脂肪组织的主要非干细胞组分—脂肪细胞除去。因此，在人和动物试验中，加工的脂肪抽吸物(PLA)含有浓度为至少0.1％，并且通常大于0.5％的干细胞。在本发明的一些实施方案中，已获得了含有约2-12％干细胞的PLA。在其它实施方案中，加工PLA以获得其中干细胞占细胞群体最高达100％的细胞群体。依据本文所公开的本发明获得的干细胞的数量显著大于以前公开的在骨髓中1/100,000(0.001％)的浓度(Castro-Malaspina，Ebell等人，1984)(Muschler，Nitto等人，2001)。此外，和脂肪组织收集品有关的发病率低于类似体积的骨髓(Nishimori，Yamada等人，2002)。另外，脂肪组织含有内皮前体细胞，它们能够给患者提供治疗(参见例如Masuda，H.，C.Kalka，和T.Asahara，Endothelial progenitor cells for regeneration.Hum Cell，2000.13(4)：p.153-60；Kaushal，S.，等人，Functional small-diameterneovessels created using endothelial progenitor cells expanded ex vivo.Nat Med，2001.7(9)：p.1035-40；和Kawamoto，A.，等人，Therapeuticpotential of ex vivo expanded endothelial progenitor cells for myocardialischemia.Circulation，2001.103(5)：p.634-7)。
本文所用的“脂肪组织”是指含有多种类型细胞，包括脂肪细胞和微血管细胞的组织。脂肪组织包括干细胞和内皮前体细胞。因此，脂肪细胞是指贮存脂肪的脂肪，包括结缔组织。
本文所用的“单位脂肪组织”是指分散的或可测定量的脂肪组织。一个单位脂肪组织可通过确定该单位的重量和/或体积来测定。根据上面确定的数据，一个单位从患者中取出的加工的脂肪抽吸物具有这样的细胞组成，其中至少0.1％的细胞组分是干细胞。根据本文的公开内容，一个单位脂肪组织可指从患者中取出的脂肪组织的全部量，或小于从患者中取出的脂肪组织的全部量的量。因此，可将一个单位脂肪组织与另一个单位脂肪组织合并，以形成重量或体积是各单位之和的一个单位脂肪组织。
本文所用的“部分”是指小于全部的材料的量。一小部分是指小于50％的量，一大部分是指大于50％的量。因此，小于从患者中取出的脂肪组织的全部量的一个单位脂肪组织是一部分取出的脂肪组织。
本文所用的“干细胞”是指多能细胞，其有分化成多种其它细胞类型的能力，具有一种或多种特殊功能，并且能够自我更新。某些本文所公开的干细胞可以是多能的。
本文所用的“加工的脂肪抽吸物”(PLA)是指已经被加工过以将活性细胞组分(例如含有干细胞的组分)与成熟脂肪细胞和结缔组织分离开的脂肪组织。PLA通常是指通过洗涤和将细胞与脂肪组织分离开而获得的细胞团。细胞团一般是通过将细胞悬浮液离心，以使细胞聚集在离心容器的底部而获得的。
在实施本发明公开的方法过程中，施用给患者的细胞是从脂肪组织获得的。脂肪组织可通过本领域技术人员已知的任何方法获得。例如，可通过抽吸辅助脂肪抽吸术、超声辅助脂肪抽吸术和脂肪切除术将脂肪组织从患者中取出。此外，操作可包括这些技术的组合，例如脂肪切除术与抽吸辅助的脂肪抽吸术的组合。因为打算将组织或某些其级份再植入到患者体内，所以应当以这样的方式收集脂肪组织，即保持细胞组分的活力，将组织被可能的传染性生物体例如细菌和/或病毒污染的可能性降至最低。因此，组织提取应当以灭菌或无菌方式进行，以把污染降至最低。对于将脂肪组织从患者中取出，抽吸辅助脂肪抽吸术是可取的，因为它提供了侵害性最轻的收集组织的方法，将可能与其它技术例如超声辅助脂肪抽吸术有关的干细胞损害的可能性降至最低。
对于抽吸辅助脂肪抽吸术，脂肪组织是这样收集的：将插管插入到患者中存在的脂肪组织贮库内或者插入到脂肪组织贮库附近，然后将脂肪抽吸到吸入装置内。在一个实施方案中，可将小插管与注射器连接，并且可用手工力抽吸出脂肪组织。为了收集相对中等量的脂肪组织(例如0.1ml至几百毫升脂肪组织)，使用注射器或其它类似装置是可取的。采用这些较小装置的操作的优点在于，操作仅用局部麻醉就可以进行，而不用全身麻醉。超出该范围的较大体积的脂肪组织(例如大于几百毫升)可能需要全身麻醉，这由供体以及进行收集操作的人决定。当希望取出较大体积的脂肪组织时，可在操作中使用较大的插管和自动抽吸装置。
脂肪切除术操作包括但不限于这样的操作，其中将含有脂肪组织的组织(例如皮肤)作为操作的附带部分取出；也就是说，手术的主要目的是除去组织(例如在肥胖或美容手术中的皮肤)，其中脂肪组织与主要想除去的组织一起被取出。
从患者中取出的脂肪组织被收集到用以进一步加工的装置内。如本文所公开的那样，在一个实施方案中，装置被设计成目的是专用于收集组织，以制备加工的脂肪组织细胞群体，包括干细胞和/或内皮前体细胞。在其它实施方案中，装置可以是一般用于通过医师进行提取操作来收集组织的任何常规装置。
收集的组织的量将取决于多个变量，包括但不限于供体的体重指数、可进入的脂肪组织收获位点的可用性、伴行和先前存在的药物治疗和病症(例如抗凝血治疗)和收集组织的临床目的。用造血干细胞移植物(用于再生接受者的血细胞形成能力的骨髓或脐带血液衍生的干细胞)进行的实验表明，植入物是细胞剂量依赖性的，并且具有阈值作用。因此，可能“越多越好”这一大体原则将在由其它变量所设定的限度内适用，并且可行的是，收获将收集尽可能多的组织。
已经发现，从体瘦个体中提取的100ml脂肪组织的干细胞百分比大于从肥胖供体中提取的100ml脂肪组织的干细胞百分比(表1)。这反映了在肥胖个体中的增加的脂肪含量的稀释效应。因此，根据本发明的一个方面，可取的是，与从体瘦患者中抽取的组织的量相比，从过重个体中获得更大量的组织。这一观察还意味着，本发明的应用不限于具有大量脂肪组织的个体。
表1：体重指数对组织和细胞收量的影响
| 体重指数状态 | 所获得的组织的量(g) | 总细胞收量(×107) |
| 正常 | 641±142 | 2.1±0.4 |
| 肥胖 | 1,225±173 | 2.4±0.5 |
| p值 | 0.03 | 0.6 |
根据本发明进行治疗的患者接受的干细胞浓度与采用脂肪组织或得自脂肪组织的干细胞的其它治疗不同。因此，将从患者中取出的脂肪组织加工以改变施用给患者的干细胞浓度。在优选的本发明实施方案中，患者接受其浓度高于通常存在于脂肪组织移植物和其它类似的基于干细胞的治疗中的干细胞浓度的干细胞。可将浓缩的干细胞在基本上不含成熟脂肪细胞和结缔组织的包含脂肪衍生干细胞和/或内皮前体细胞的组合物中施用，或者，作为另一实例，可将浓缩的干细胞在具有提高的量的干细胞的包含一个单位脂肪组织的组合物中施用。本发明组合物包含浓度大于在等单位未加工的脂肪组织中发现的干细胞浓度的干细胞。在一些实施方案中，组合物具有这样的细胞组成，其中至少0.1％的细胞是干细胞。在其它实施方案中，组合物具有这样的细胞组成，其中干细胞占细胞组分的约2％-12％。高浓度，例如最高达100％的干细胞也包含在不同组合物中。组合物可包含另外的组分，例如在本文中描述的细胞分化因子、生长促进剂、免疫抑制剂或医疗装置。为了获得其中组合物主要含有一种类型细胞(例如脂肪衍生干细胞或脂肪衍生内皮前体细胞)的组合物，可采用适于分离不同细胞类型的任何方法，例如使用能识别和结合存在于干细胞或内皮前体细胞上的抗原的细胞特异性抗体。
对于大部分应用，需要除去活性细胞群体制备物中的包含成熟脂肪的脂肪组织的脂肪细胞组分。这一般是通过一系列洗涤和解聚步骤实现的，其中首先洗涤组织以减少游离脂质(从破碎的脂肪细胞中释放出来)和周围血液成分(从在组织收获期间切断的血管中释放出来)，然后解聚以将完整的脂肪细胞和其它细胞群体从结缔组织基质中释放出来。在一些实施方案中，将整个脂肪细胞组分或非干细胞组分与脂肪组织的干细胞组分分离开。在其它实施方案中，仅将一部分或几部分脂肪细胞组分与干细胞分离开。因此，在一些实施方案中。可将干细胞与内皮前体细胞一起施用。
洗涤是任选、但优选的步骤，其中将组织与溶液混和以洗去游离脂肪和单细胞组分例如在血液中的单细胞组分，留下完整的脂肪组织片段。在一个实施方案中，将从患者中取出的脂肪组织与等渗盐水或其它生理溶液(例如Baxter Inc的Plasmalyte
或Abbott Labs的Normoso
)混合。可通过本领域技术人员已知的任何方法，包括但不限于过滤、倾析、沉降或离心将完整的脂脂肪组织片段与游离脂质和细胞分离开。在举例说明的本发明实施方案中，如本文所述，通过使用放置在组织收集容器内的滤器来将脂肪组织与非脂肪组织分离开。在其它实施方案中，使用组织收集容器来将脂肪组织与非脂肪组织分离开，其中所述容器使用倾析、沉积和/或离心技术来分离物质。
然后使用任何常规技术或方法将完整的组织片段解聚，这些技术或方法包括机械力(切碎力或剪切力)，用一种或组合的蛋白酶例如胶原酶、胰蛋白酶、脂肪酶、如U.S.专利5,952,215中公开的释放酶(liberase)H1和胃蛋白酶进行酶消化或机械和酶方法的组合。例如，可通过以下方法将完整组织片段的细胞组分解聚：使用胶原酶介导的脂肪组织离解的方法，该方法类似于如在U.S.专利5,372,945中公开的用于收集脂肪组织中的微血管内皮细胞的方法。可用于本发明的使用胶原酶的其它方法公开在U.S.专利5,830,714和5,952,215，以及Williams，S.K.，S.McKenney，等人，(1995).“Collagenase lot selection andpurification for adipose tissuedigestion.”Cell Transplant 4(3)：281-9中。类似地，可使用中性蛋白酶来代替胶原酶，如在Twentyman，P.R.和J.M.Yuhas(1980).“Use of bacterial neutralprotease fordisaggregation of mouse tumours and multicellular tumor spheroids.”Cancer Lett 9(3)：225-8中公开的方法。此外，方法可采用酶的组合，例如胶原酶与胰蛋白酶的组合，如在Russell，S.W.，W.F.Doe，等人，(1976).“Inflammatory cells in solid murine neoplasms.I.Tum ordisaggregation and identification of constituent inflammatory cells.”IntJ Cancer 18(3)：322-30中公开的方法；或酶例如胰蛋白酶与机械离解的组合，如在Engelholm，S.A.，M.Spang-Thomsen，等人(1985).“Disaggregation of human solid tumours by combined mechanical andenzymatic methods.”Br J Cancer 51(1)：93-8中公开的方法。
然后，通过减少成熟脂肪细胞的存在，可由解聚的组织片段获得活性细胞群体(加工的脂肪细胞抽吸物)。让其中脂肪组织被解聚的加工的脂肪抽吸物与液体的悬浮液流到另一容器例如细胞收集容器中。通过使用泵，例如蠕动泵，悬浮液可流经一个或多个导管以到达细胞收集容器，其中泵将悬浮液从组织收集容器中抽吸出来，并驱动悬浮液到达细胞收集容器。其它实施方案可使用重力或真空，同时保持封闭的系统。分离悬浮液中的细胞可通过以下技术来实现：浮力密度沉降、离心、淘析、有差别的与固相的粘着和从固相上洗脱、抗体介导的选择、电荷的不同；免疫磁性珠、荧光激活细胞分选(FACS)或其它技术。这些不同技术以及进行这些技术的装置的实例可参见emstreet，G.P.，3rd，P.G.Enoch，等人，(1980).“Tissue disaggregation of human renalcell carcinoma with further isopyknic and isokinetic gradientpurification.”Cancer Res 40(4)：1043-9；Schweitzer，C.M.，van，等人，(1995).“Isolation and culture of human bone marrow endothelial cells.”Exp Hematol 23(1)：41-8；Gryn，J.，R.K.Shadduck，等人，(2002).“Factorsaffecting purification of CD34(+)peripheral blood stem cells using theBaxter Isolex 300i.”J Hematother Stem Cell Res 11(4)：719-30；Prince，H.M.，J.Bashford，等人，(2002).“Isolex 300i CD34-selected cells tosupport multiple cycles of high-dose therapy.”Cytotherapy 4(2)：137-45；Watts，M.J.，T.C.Somervaille，等人，(2002).“Variable product purityand functional capacity after CD34 selection：a direct comparison of theCliniMACS(v2.1)and Isolex 300i(v2.5)clinical scale devices.”Br JHaematol 118(1)：117-23；Mainwaring，G.和A.F.Rowley(1985).“Separation of leucocytes in the dogfish(Scyliorhinus canicula)usingdensity gradient centrifugation and differential adhesion to glasscoverslips.”Cell Tissue Res 241(2)：283-90；Greenberg，A.W.和D.A.Hammer (2001).“Cell separation mediated by differential rollingadhesion.”Biotechnol Bioeng 73(2)：111-24；和U.S.专利6,277,060；6,221,315；6,043,066；6,451,207；5,641,622；和6,251,295。在举例说明的实施方案中，使用旋转膜滤器将悬浮液中的细胞与悬浮液的其它细胞组分分离开。在其它实施方案中，使用离心机将悬浮液中的细胞与细胞组分分离开。在一个这样的示例性实施方案中，细胞收集容器可以是其结构适于放置在离心机内(例如用手放置或者采用自动系统放置)的柔性袋。在其它实施方案中，不使用柔性袋。如本文所述，离心后，细胞组分形成团，然后可用缓冲溶液将细胞团重新悬浮，这样可让细胞通过一个或多个导管到达混和容器。可通过任何合适的技术提供重悬液体。例如，可将缓冲液注射到细胞收集容器的端口中，或者细胞收集容器可包括缓冲液的储备物，可通过破坏储备物来将缓冲液与细胞团混和。当使用旋转膜滤器时，重悬是任选的，因为分离操作之后，细胞保留在液体中。
虽然一些本发明实施方案涉及将脂肪组织完全解聚以将活性细胞与成熟脂肪细胞和结缔组织分离开的方法，但是另外一些本发明实施方案涉及其中脂肪组织仅部分解聚的方法。例如，部分解聚可用一种或多种酶来进行，其中在酶把组织完全解聚的时间之前，将酶从至少一部分脂肪组织中取出。这样的方法可需要较少的加工时间。
在一个具体实施方案中，将组织用无菌缓冲等渗盐水洗涤，与胶原酶以足以提供充分解聚的胶原酶浓度、温度和时间培养。在优选的实施方案中，所用的胶原酶应当得到相关机构(例如美国食品和药品监督管理局)的批准应用于人。合适的胶原酶制剂包括重组和非重组胶原酶。非重组胶原酶可得自F.Hoffmann-La Roche Ltd，Indianapolis，IN和/或Advance Biofactures Corp.，Lynbrook，NY。重组胶原酶还可以按照U.S.专利6,475,764中公开的方法获得。
在一个实施方案中，溶液含有浓度为约10μg/ml-约50μg/ml的胶原酶，并且在约30℃-约38℃培养约20分钟-约60分钟。这些参数将根据胶原酶的来源而改变，通过经验实验优化，以确证该系统在合适的时间框架中提取所需细胞群体方面是有效的。特别优选的浓度、时间和温度是将20μg/ml胶原酶(Blendzyme 1，Roche)在约37℃培养45分钟。在特别优选的实施方案中，所用的胶原酶得到了相关机构(例如美国食品和药品监督管理局)的批准应用于人。所用的胶原酶应当不含微生物和污染物例如内毒素。
解聚后，可将活性细胞群体洗涤/冲洗以除去添加剂和/或解聚加工的副产物(例如胶原酶和新释放出的游离脂质)。然后可通过离心或上述本领域技术人员已知的其它方法将活性细胞群体浓缩。这些加工后洗涤/浓缩步骤可单独或同时施行。
在一个实施方案中，通过让细胞群体连续流过旋转膜系统或类似系统例如在U.S.专利5,034,135和5,234,608中公开的系统来将细胞浓缩和除去胶原酶。
除了上述方法以外，还有很多洗涤后方法可用于进一步纯化活性细胞群体。这些包括正选择(选择目标细胞)、负选择(选择性地除去不需要的细胞)或其组合。
在一个实施方案中，在所有细胞洗涤步骤之后，将具有所选粘着性质的固相材料插入到系统内，这种粘着性质使得对于加工的脂肪抽吸物内的细胞亚群体的粘着和/或洗脱能力有差别。该一般方法已经在临床输血中使用过，其中使用具有不同捕获白细胞能力的滤器来除去掺杂在白血病中的输入的红细胞(Soli，M.，等人，A multicentre evaluationof a new filtration protocol for leucocyte depletion ot high-haematocritred blood cells collected by an automated blood collection system.VoxSang，2001.81(2)：p.108-12；Smith，J.W.，Apheresis techniques andcellular immunomodulation.Ther Apher，1997.1(3)：p.203-6)。该类型滤器是通过Pall Bedieal(Leukogard RS and Purecell RCQ)和Asahi(RS2000)分配。差别粘着还已用于单核细胞的正选择(Berdel，W.E.，等人.Purification of human monocytes by adherence to polymericfluorocarbon.Characterization of the monocyte-enriched cell fraction.Immunobiology，1982.163(5)：p.511-20)和表皮干细胞的正选择(Bickenbach，J.R.和E.Chism，Selection and extended growth of murineepidermal stem cells in culture.Exp Cell Res，1998.244(1)：p.184-95)。在该实施方案中，让加工的脂肪抽吸物在预先确定的流动和缓冲条件下通过滤器，以提高目标细胞与不需要的细胞群体的差别粘着。对于正选择，滤器材料和条件将使得目标细胞优先粘着，而不需要的材料能自由地通过滤器，并且可用过量缓冲液洗去。通过改变条件例如流速、pH、离子强度和/或粘着所需的阳离子存在，可将目标细胞从滤器上洗脱下来。滤器材料可呈三维网状物、小颗粒填充盒、中空纤维或具有高表面积的其它构造形式。在优选的实施方案中，该滤器装置可以是如附图1所示的一次性整体部分，并且将插到附图4所示的装置内。设置和装置都必须根据具体附图所示的实例进行轻微改变；附图1包括滤器和遮盖物，附图4使得插入保持封闭、无菌流动线路所需的滤器遮盖物和管线(包括阀)。或者，可分别用装置配件和滤器/遮盖物代替混和室(附图4的部件108；附图1的部件30)。
差别粘着方法的另一个实施方案包括使用能够识别在目标和不需要的细胞上差别表达的表面分子的抗体和/或抗体组合。基于特异细胞表面标志物(或其组合)的表达而做的选择是另一种常用技术，其中抗体附着(直接或间接)在固相载体结构上(Geiselhart，A.，等人，Positiveselection of CD56+lymphocytes by magnetic cell sorting.Nat Immun，1996.15(5)：p.227-33；Formanek，M.，等人，Magnetic cell separation forpurification of human oral keratinocytes：an effective method forfunctional studies without prior cell subcultivation.Eur ArchOtorhinolaryngol，1998.255(4)：p.211-5；Graepler，F.，U.Lauer和M.Gregor，Magnetic cell sorting for parietal cell purification using a newmonoclonal antibody without influence on cell function.J BiochemBiophys Methods，1998.36(2-3)：p.143-55；Kobari，L.，等人，CD133+cellselection is an alternative to CD34+cell selection for ex vivo expansionof hematopoieticstem cells.J Hematother Stem Cell Res，2001.10(2)：p.273-81；Mohr，M.，等人，，Simultaneous immunomagnetic CD34+cellselection and B-cell depletion in peripheral blood progenitor cell samplesof patients suffering from B-cell non-Hodgkin′s lymphoma.Clin CancerRes，2001.7(1)：p.51-7；和Pugh，R.E.，等人，CD19selection improves thesensitivity of B cell lymphom detection.J Hematother，1998.7(2)：p.159-68)。该方法在其中例如残余白细胞可通过使用CD45抗体来除去的正和负选择中都有明显应用。类似地，Reyes等人已使用抗体的复杂混合物来从人骨髓中选择多能成熟祖细胞(Reyes，M.，等人，Purificationand ex vivo expansion of postnatal human marrow mesodermalprogenitor cells.Blood，2001.98(9)：p.2615-25)。例如，可特异性地与脂肪细胞结合的抗体例如AP2(Joyner，C.J.，等人，Development of amonoclonal antibody to the aP2 protein to identify adipocyte precursorsin tumours of adipose differentiation.Pathol Res Pract，1999.195(7)：p.461-6)可用于优先除去残余的脂肪细胞(包括不成熟的脂肪细胞和脂肪母细胞)。正选择可通过使用对目标细胞群体有特异性的抗体来应用。例如，Quirici等人已使用抗神经生长因子受体的抗体来富集骨髓衍生的间充质干细胞(Quirici，N.，等人，Isolation of bone marrowmesenchymal stem cells by anti-nerve growth factor receptor antibodies.Exp Hematol，2002.30(7)：p.783-91)。
在基于抗体的方法的一个实施方案中，将抗体(例如AP2)或抗体混合物(例如AP2、CD3、CD19、CD11b)加到加工的脂肪抽吸物中。本领域技术人员知道很多其它抗体和抗体组合，并且提供这些抗体只是为了举例说明。培养后，在预先确定以让这些抗体与其相应抗原最佳结合的条件下，让细胞通过旋转膜滤器或细胞洗涤室的其它实施方案来洗涤细胞，以除去未结合的过量抗体。然后让细胞通过固相结构，该固相结构类似于上面的实施方案中描述的结构，但是固相已附着了二级抗体，该二级抗体能够以高亲和力与结合在细胞表面上的初级抗体附着。目标细胞，例如脂肪组织衍生的干细胞将自由地通过该滤器，这是因为没有表达被所选抗体(抗体混合物)识别的细胞表面抗原，由此产生负选择系统所致。在该实施方案中，对一次性设置(附图3)和装置(附图4)进行非常类似于上面实施方案所述的较小改变。
通过包括促进细胞与固相载体脱离的第三种添加剂，可以以非常类似的方式实现抗体介导的正选择实施方案。在该实施方案中，可加入酶木瓜蛋白酶或cymopapain以裂解掉抗体分子和将细胞从固相载体上释放下来(Civin，C.I.，等人，Positive stem cell selection--basic science.Prog Clin Biol Res，1990.333(387)：p.387-401；讨论402)。另一实施方案是如Tseng-Law等人在US专利6,017,719中所述，使用能与细胞表面抗原竞争结合抗体的特异性肽。
在另一个实施方案中，可将细胞团重悬，在液体材料上面(下面)分层以形成连续或不连续的密度梯度，并放置在离心机中以基于细胞密度来分离细胞群体。适于形成这样的梯度的介质的实例包括Percoll和Ficoll-Paque(Qian，X.，L.Jin，和R.V.Lloyd，Percoll Density Gradient-Enriched Populations of Rat Pituitary Cells：Interleukin 6Secretion，Proliferative Activity，and Nitric Oxide Synthase Expression.EndocrPathol，1998.9(1)：p.339-346；Smits，G.，W.Holzgreve，和S.Hahn，Anexamination of different Percoll density gradients and magneticactivated cell sorting(MACS)for the enrichment of fetal erythroblastsfrom maternal blood.Arch Gynecol Obstet，2000.263(4)：p.160-3)或Ficoll-Paq ue(Lehner，M.和W.Holter，Endotoxin-free purification ofmonocytes for dendritic cell generation via discontinuous densitygradient centrifugation based on diluted Ficoll-Paque Plus.Int ArchAllergy Immunol，2002.128(1)：p.73-6)。Van Merris等人(Van Merris，V.，等人，Separation of bovine bone marrow into maturation-relatedmyeloid cell fractions.Vet Immunol Immunopathol，2001.83(1-2)：p.11-7)采用不连续的三步Percoll梯度来根据其成熟度分离牛髓样细胞。该实施方案将能够把一些残余的血细胞群体和不成熟的脂肪细胞(原脂肪细胞)从细胞群体中分离出来。
在类似的实施方案中，还可以使用连续流动方法例如apheresis(Smith，J.W.，Apheresis techniq ues and cellular immunomodulation.Ther Apher，1997.1(3)：p.203-6)和淘析(采用或不采用反流)(Lasch，J.，G.Kullertz，和J.R.Opalka，Separation of erythrocytes into age-relatedfractions by density or size？Counterflow centrifugation.Clin Chem La bMed，2000.38(7)：p.629-32；Ito，Y.和K.Shinomiya，A new continuous-flow cell separation method based on cell density：principle，apparatus，and preliminary application to separation of human buffy coat.J ClinApheresis，2001.16(4)：p.186-91；Dlubek，D.，等人，Enrichment ofnormal progenitors in counter-flow centrifugal elutriation(CCE)fractions of fresh chronic myeloid leukemialeukapheresis products.EurJ Haematol，2002.68(5)：p.281-8)。这样的机制已用于分离血细胞，包括基于成熟度来分离红细胞(Lasch，J.，G.Kullertz，和J.R.Opalka，Separation of erythrocytes into age-related fractions by density or size？Counterflow centrifugation.Clin Chem Lab Med，2000.38(7)：p.629-32)，并且应用该一般方法来进一步从加工的脂肪抽吸物中纯化所需细胞对于本领域技术人员来说将是显而易见的。该实施方案可能需要改变附图4中的装置和一次性设置(附图3)，这样给该装置集成了能够提供apheresis或淘析能力的另一装置。
与塑料粘着，然后是一段短时间的细胞扩增也已用于骨髓衍生的成熟干细胞群体(Jaiswal，N.，等人，Osteogenic differentiation of purified，culture-expanded human mesenchymal stem cells in vitro.J CellBiochem，1997.64(2)：p.295-312；Hou，L.，等人，Study of in vitroexpansion and differentiation into neuron-like cells of human umbilicalcord blood mesenchymal stem cells.Zhonghua Xue Ye Xue Za Zhi，2002.23(8)：p.415-9)。该方法使用培养条件以优先扩增一个群体，同时其它群体由于缺乏所需生长条件而保持不变(并且由于被生长的所需细胞稀释而减少)或丧失。Sekiya等人已描述了可在这方面用于骨髓衍生干细胞的条件(Sekiya，I.，等人，Expansion of Human Adult Stem Cells fromBone Marrow Stroma：Conditions that Maximize the Yields of EarlyProgenitors and Evaluate Their Quality.Stem Cells，2002.20(6)：p.530-41)。该方法(采用或不采用与组织培养塑料的差别粘着)可用于本发明的另一个实施方案中。在该实施方案中，将细胞从附图4所示的装置中取出，置于提供细胞培养组分的另一装置内。该装置可呈常规实验室组织培养器或生物反应器型装置，例如Tsao等人在US专利6,001,642中描述的装置和Armstrong等人在US专利6,238,908中描述的装置形式。在另一个实施方案中，组合部件(附图4所示装置的部件108；附图3中的部件30)可用能够进行加工的脂肪抽吸物的短期粘着和/或细胞培养的生物反应器部件代替。该实施方案将容许给装置整合生物反应器部件，并且省去了将细胞从该装置中取出和置于另一装置内的需要。
在一个实施方案中，将活性细胞群体直接施用到患者体内。换句话说，将活性细胞群体(例如干细胞和/或内皮前体细胞)施用给患者，在施用给患者之前不用从系统中取出或暴露于系统的外部环境中。提供封闭的系统降低了施用给患者的生物材料被污染的可能性。因此，在封闭的系统中加工脂肪组织提供了优于现有方法的优点，因为活性细胞群体更有可能是无菌的。在这样的实施方案中，干细胞和/或内皮前体细胞暴露于外部环境或从系统中取出的唯一时间是，将细胞抽到施用装置内和施用给患者时。在一个实施方案中，施用装置也可以是封闭系统的一部分。因此，在这些实施方案中使用的细胞没有进行培养加工或冷冻保存。
已经如上所述浓缩过的活性细胞可不用进一步加工直接施用给患者，或者可在与其它组织或细胞混和后施用给患者。在一些实施方案中，将浓缩的活性细胞(例如干细胞或内皮前体细胞)与没有进行类似加工的一个或多个单位脂肪组织混和。因此，通过实施本发明方法，可将具有高浓度活性细胞的包含脂肪组织的组合物施用给患者。不同脂肪组织单位的体积可能不同。例如，一个单位脂肪组织体积可能比另一个单位脂肪组织的体积大至少25％。此外，一个单位脂肪组织体积可能比另一个单位脂肪组织的体积大至少50％，例如至少100％，甚至150％或更多。另外，所需组合物可通过将具有浓缩的活性细胞群体(其可以是含有活性细胞的细胞团)的第一个单位脂肪组织与一个或多个其它单位脂肪组织混和来获得。在一些实施方案中，这些其它单位不具有高浓度的干细胞，或者换句话说，它们的活性细胞浓度小于包含在第一个单位脂肪组织中的活性细胞浓度。在其它实施方案中，一个单位是含有例如高浓度活性细胞的冷冻保存材料。
在其它实施方案中，将至少一部分活性细胞群体贮存以用于以后植入/输入。可将细胞群体分成一个以上的等份试样，这样将一部分干细胞和/或内皮前体细胞群体保存以用于以后施用，而将一部分细胞群体立即施用给患者。将所有或一部分细胞在细胞库中进行中到长期贮存也在本发明范围内，发明名称为“得自非造血组织的非胚胎细胞的保存”的于2002年9月12日提交的第10/242,094号U.S.专利申请公开了有关内容，该申请要求属于同一申请人的于2001年9月14日提交的第60/322,070号U.S.临时专利申请的优先权，并且该申请引入本文以供参考。在这样的实施方案中，可将细胞与一个或多个单位的新鲜或保存的脂肪组织混和，以提供含有干细胞，并且干细胞的浓度高于加工前的单位脂肪组织的组合物。
在加工结束时，可将浓缩的细胞负载到递送装置例如注射器中，以通过皮下、静脉内、肌内或腹膜内技术放置在接受者体内。换句话说，可通过本领域技术人员已知的任何技术将细胞置于患者体内，例如可将细胞注射到血管内以全身或局部递送，注射到组织(例如心肌或骨骼肌)内，注射到真皮内(皮下)，注射到组织空间(例如心包或腹膜)内，或注射到多个组织(例如尿道周围区域)内或其它位置。优选的实施方案包括通过针头或导管来放置，或者通过与添加剂例如预先形成的基质有关的直接手术植入来放置。
可将活性细胞群体单独施用或者与其它细胞，组织，组织片段，去矿质的骨，生长因子例如胰岛素，或药物例如thiaglitazone类药物，生物活性或惰性化合物，可重吸收的塑料支架或其它用于提高细胞群体的递送、效力、耐受性或功能的添加剂。还可以通过以下方法修饰细胞群体：插入DNA，或放置在细胞培养物中以改变、提高或补充细胞功能，从而用于美容、结构或治疗目的。例如，用于干细胞的基因转移技术是本领域技术人员已知的，例如公开在Mosca，J.D.，J.K.Hendricks，等人，(2000).“Mesenchymal stem cells as vehicles for genedelivery.”Clin Orthop(379 Suppl)：S71-90中，并且可包括病毒转染技术，更具体来说，腺相关病毒基因转移技术，例如公开在Walther，W.和U.Stein(2000).“Viral vectors for gene transfer：a review of their usein the treatment of human diseases.”Drugs 60(2)：249-71，和Athanasopoulos，T.，S.Fabb，等人，(2000).“Gene therapy vectors basedon adeno-associated virus：characteristics and applications to acquiredand inherited diseases(review).”Int J Mol Med 6(4)：363-75中。也可以按照Muramatsu，T.，A.Nakamura，等人，(1998).“In vivo electroporation：a powerful and convenient means of nonviral gene transfer to tissues ofliving animals(Review).”Int J Mol Med 1(1)：55-62中公开的方法实施非基于病毒的技术。
在一个方面，可将细胞与脂肪组织的未加工片段混和，并使用大号针头或脂肪抽吸插管将其放回接受者体内。转移自体固有脂肪，并且不补充加工的细胞是整形和整复手术中的常用操作。然而，结果可能是不可预知的，因为转移的材料往往会迅速重吸收，导致不稳定的移植物。例如基本上不含成熟脂肪细胞的本发明脂肪组织衍生细胞可提供支持移植物延长的存活和功能的环境。
在另一个方面，可将细胞群体放置在接受者体内，并由可重吸收的塑料护套例如由MacroPore Biosurgery，Inc.生产的护套环绕(U.S.专利6,269,716和5,919,234)。在该设置中，护套可防止肌肉和其它软组织脱出到骨折区域内，由此安放了加工的脂肪组织衍生细胞以促进骨折的修复。在这方面，通过补充另外的组分例如原成骨蛋白生长因子或生物或人工支架，可提高有益作用。
在另一个方面，可将细胞与编码原成骨蛋白生长因子的基因结合，其中所述原成骨蛋白生长因子使得细胞能够在骨愈合或融合期间起它们自己的生长因子源的作用。基因的加入可通过本领域已知的任何技术来进行，包括但不限于腺病毒转导、“基因枪”、脂质体介导的转导和逆转录病毒或慢病毒属病毒介导的转导。
特别是，当把细胞和/或含有细胞的组织施用给不是由其获得该细胞和/或组织的患者的患者时，可给接受该细胞和/或组织的患者施用一种或多种免疫抑制剂，以减轻，优选防止移植物排斥作用。适用于本发明方法的免疫抑制剂的实例包括能抑制T-细胞/B-细胞共同刺激途径的活性剂，例如在U.S.专利出版物20020182211中公开的干扰T-细胞和B-细胞经由CTLA4和B7途径的偶联的活性剂。其它实例包括环孢菌素、myophenylate mofetil、雷帕霉素和抗胸腺细胞球蛋白。
在本发明的一些实施方案中，将细胞与一种或多种细胞分化剂例如细胞因子和生长因子一起施用给患者。不同细胞分化剂的实例公开在以下文献中：Gimble，J.M.，C.Morgan，等人，(1995).“Bonemorphogenetic proteins inhibit adipocyte differentiation by bonemarrow stromal cells.”J Cell Biochem 58(3)：393-402；Lennon，D.P.，S.E.Haynesworth，等人，(1995).“A chemically defined medium supports invitro proliferation and maintains the osteochondral potential of ratmarrow-derived mesenchymal stem cells.”Exp Cell Res 219(1)：211-22；Majumdar，M.K.，M.A.Thiede，等人，(1998).“Phenotypic and functionalcomparison of cultures of marrow-derived mesenchymal stem cells(MSCs)and stromal cells.”J Cell Physiol 176(1)：57-66；Caplan，A.I.和V.M.Goldberg(1999).“Principles of tissue engineered regeneration ofskeletal tissues.”Clin Orthop(367Suppl)：S12-6；Ohgushi，H.和A.I.Caplan(1999).“Stem cell technology and bioceramics：from cell to geneengineering.”J Biomed MaterRes 48(6)：913-27；Pittenger，M.F.，A.M.Mackay，等人，(1999).“Multilineage potential of adult humanmesenchymal stem cells.”Science 284(5411)：143-7；Caplan，A.I.和S.P.Bruder(2001).“Mesenchymal stem cells：buil ding blocks for molecularmedicine in the 21st century.”Trends Mol Med 7(6)：259-64；Fukuda，K.(2001).“Development of regenerative cardiomyocytes from mesenchymalstem cells for cardiovascular tissue engineering.”Artif Organs 25(3)：187-93；Worster，A.A.，B.D.Brower-Toland，等人，(2001).“Chondrocyticdifferentiation of mesenchymal stem cells sequentially exposed totransforming growth factor-betal in monolayer and ins ulin-like growthfactor-I in a three-dimensional matrix.”J Orthop Res 19(4)：738-49；Zuk，P.A.，M.Zhu，等人，(2001).“Multilineage cells from human adiposetissue：implications for cell-based therapies.”Tissue Eng 7(2)：211-28；和Mizuno，H.，P.A.Zuk，等人，(2002).“Myogenic differentiation byhuman processed lipoaspirate cells.”Plast Reconstr Surg 109(1)：199-209；讨论210-1。
通过给患者施用干细胞和/或内皮前体细胞，可治疗多种疾病，包括但不限于骨相关病症、疾病或损伤，包括慢性/未愈合骨折、骨质疏松(与年龄有关或者化疗引起的)、遗传骨疾病(成骨不全)；与脂肪有关的病症或疾病；肝脏相关疾病、病症或损伤，包括肝脏衰竭、乙型肝炎和丙型肝炎；心肌梗塞，包括心脏病发作或慢性心力衰竭；肾疾病或肾损伤；视网膜疾病或损伤或坏死；伤口愈合(例如手术后伤口愈合或糖尿病性溃疡愈合)；创伤性和遗传性骨骼肌病症；创伤性和自身免疫性软骨和关节修复；肺损伤；糖尿病；肠病症；神经系统病症、疾病或损伤，例如中枢神经系统病症、疾病或损伤，包括脊柱损伤、帕金森病、阿尔茨海默氏病和中风。
还可以出于美容原因将干细胞施用给患者，例如提高或改善身体特征，包括减少皱纹、提高器官质量等。
附图1显示了用于将脂肪组织从患者中取出的组织取出系统。在宽范围的实施方案中，组织取出系统10包括组织收集容器12和与组织收集容器12连接的混和容器30。在混和容器30与组织收集容器12直接的连接优选限定了封闭系统，其中从组织收集容器12传递到混和容器30的组织没有暴露于外部环境。系统10还包括出口32，出口32的结构使得浓缩的干细胞能从组织收集系统10中取出以施用给患者。组织收集容器12包括组织收集入口14和滤器16。滤器16安放在容器内，并且其结构使得在例如将组织从患者中取出时，保留脂肪组织和让非脂肪组织通过。更具体来说，在开始收获脂肪组织期间或者—在另一个实施方案中—在收获脂肪组织之后，滤器16让游离脂质、血液和盐水通过，而保留脂肪组织片段。在这方面，滤器16包括多个孔，这些孔具有相同或不同的孔径，并且孔径为约20μm-5mm。在优选的实施方案中，滤器是医用级的聚酯网状物，其厚度约为200μm，孔径约为265μm，并且约有47％的开放面积。该材料在洗涤期间保留组织，但是在组织解聚之后让细胞通过网孔。因此，当从患者中抽吸出组织时，可将非脂肪组织与脂肪组织分离开。混和容器30包括添加口31，添加口31的结构使得使用者能够将添加剂施加到混和容器30中以与包含在混和容器30中的干细胞混和。在优选的实施方案中，组织收集容器12的容量应当是这样的，其能够在滤器内保留约1升组织片段。在其它实施方案中，组织收集容器12可具有保留更大或更小体积的组织片段的容量；例如，组织收集容器可具有贮存至少100mL脂肪组织片段，最高达约2L脂肪组织片段的容量。
参见附图1的系统10中存在的其它特征，组织入口14经由管线22与插管24连接以限定组织取出线。在该举例说明的实施方案中，插管24是集成的、一次性使用的脂肪抽吸导管，并且管线是柔性管线。插管具有能够插入到患者体内以将脂肪组织从患者中取出的大小。在该系统中使用的管线22应当能够经得起与抽吸辅助脂肪抽吸术有关的负压以减小塌陷的可能性。组织收集容器12还包括安放在滤器16的组织入口14对面一侧上的抽吸口18。抽吸口18的结构使得其与可手动或自动操作的抽吸装置20连接。抽吸装置20可以是注射器，或者可以是电动真空等。抽吸装置20应当能够提供足够的负压以使容器12和插管24从患者中抽吸出组织。如附图所示，抽吸装置20经由管线22与抽吸口18连接。
如附图所示，组织取出系统10还包括位于组织收集容器12与混和容器30之间的细胞收集容器26。细胞收集容器26位于系统10内部，这样细胞例如干细胞从组织收集容器12流到细胞收集容器26中，然后再流到混和容器30中。在该举例说明的实施方案中，细胞收集容器26经由细胞收集口48与组织收集容器12。在系统10的一个实施方案中，细胞收集容器26包括促进细胞在悬浮液中分离的细胞浓缩器(未显示)。细胞浓缩器的一个实例是离心机装置，该装置可根据例如细胞的大小和密度来将细胞与其它材料分离开。另一实例是如上所述的旋转膜滤器，如附图所示，系统10还包括滤器28，滤器28的结构使得细胞能从细胞收集容器26到达混和容器30，和防止例如比细胞大的材料通过。细胞收集容器26还包括通向废弃物容器36的出口。包含在细胞收集容器26中的材料的流动方向由一个或多个阀的位置决定，阀可控制材料是流向废弃物容器36还是流向混和容器30。
在该举例说明的实施方案中，细胞滤器28包括直径或长度小于200μm的多个孔。在一些实施方案中，孔可具有小于200μm的直径。在其它实施方案中，孔具有20-200μm的直径。细胞滤器28可与细胞收集容器26隔开，或者可包含在细胞收集容器26内。细胞滤器28还可以在细胞收集容器26中集成形成。系统10的另外的实施方案不包括滤器28。细胞收集容器可由任何合适的材料制成。例如，细胞收集容器26可以是塑料袋，例如在血库中常用于加工血液的塑料袋；或者在其它实施方案中，其可以是在结构上刚性的。在一些实施方案中，细胞收集容器26可包括组分制备室和细胞洗涤/分离室。
在一些实施方案中，组分制备室包括一个或多个用于加入下述物质的口：可促进用于施用给患者的干细胞分离过程的物质，例如如上所述的生长因子或用于重悬细胞的缓冲液。在这些实施方案中，组分制备室优选包括混和装置，以将细胞和添加剂在容器中混和或搅拌。组分制备室还包括一个或多个用于将收集在其中的细胞取出的口。一个口可用于让细胞朝着混和容器30流动。其它口可用于让细胞或一部分细胞流向其它目标物例如植入材料，包括骨片，或流向培养或纯化装置。在一个实施方案中，细胞洗涤/分离室包括旋转膜滤器部件，其可用作除离心机装置以外的细胞浓缩器，或优选用作用以替代离心机装置的细胞浓缩器。
如附图所示，系统10还包括组织挽回管线34，其提供了从组织收集容器12到混和容器30的导管。因此，组织挽回管线34让包含在组织收集容器12中的组织流向或将其导向混和容器30，在混和容器30中，可将组织与得自细胞收集容器26的细胞混和。在该举例说明的实施方案中，组织挽回管线34延伸到组织容器12内以将包含在滤器16中的脂肪组织取出。使用一个或多个泵或抽吸装置，经由组织挽回管线34让组织通过或流过，以让已经洗涤过，但是无需解聚的脂肪组织通过。
在一个实施方案中，系统10包括温控装置，该温控装置位于系统10中以调节包含在组织收集容器12中的材料的温度。在一些实施方案中，温控装置是加热器，在其它实施方案中，温控装置是冷却器。在另外的实施方案中，温控装置能够在加热器与冷却器之间切换。温控装置可以是调节包含在组织收集容器12中的脂肪组织的温度的装置，或者可以是用于改变正在递送到组织收集容器12中的液体的温度的装置。已经发现，将脂肪组织加热有助于促进组织解聚，从而提高活性细胞组分的分离。此外，在一些实施方案中，希望将一部分组织，优选活性细胞组分冷却，以给细胞提供保护。即使将细胞轻微冷却，也可以提供合适的保护，从而提高在加工期间的细胞存活。
如附图所示，组织取出系统10的出口32是混和容器30的部件。在另外的实施方案中，出口32与混和容器30隔开。出口32优选包括维持组织取出系统10的密封结构的封闭部件，并且在一些实施方案中，出口32包括液体不能渗透的膜(例如液体和气体不能渗透的膜)。出口32的结构应当能让混和容器30中的组合物在合适的条件下到达患者。例如，如果使用注射器来抽出组合物，出口32应当能够容纳注射器的针头，并且不影响系统或组合物的无菌性。在另外的实施方案中，如果出口与用以施用组合物，但是不抽出组合物的装置，例如通过施加正压以经由插管转移组合物来施用组合物的插管连接时，出口32的配置应当能够让包含在混和容器30中的组合物流到插管内。在其它实施方案中，出口32可包括用以施用组合物的装置，例如注射器针头或用于通过施加正压来施用组合物的插管，或者以密封系统方式与这样的装置连接。
如附图所示，组织取出系统还包括废弃物容器36，该容器用于从组织收集容器12收集废弃物。在该举例说明的实施方案中，废弃物容器36的连接和位置还使得其能够从细胞收集容器26接受废弃物。还提供洗涤容器38，该洗涤容器38与洗涤管线39以流体能通过的方式连接，以将洗涤液体例如盐水或任何其它合适的缓冲液经由洗涤口46递送到组织收集容器12中。组织收集容器12还包括用于控制在组织收集容器12内的压力的气体入口40。在组织收集容器12上提供添加管线以容许将添加剂加到组织收集容器12中。根据本文所公开的方法，提供添加管线42以将一种或多种酶递送到组织收集容器12中，从而有助于将活性细胞组分与包含在滤器16中的其余脂肪组织分离开。如附图所示，添加管线42包括针头44。针头44可用于从合适的容器中接受酶。
附图2和3显示了组织取出系统10的部件的具体实施方案，其中同样的数字代表同样的部件。在附图2和3的具体实施方案中，组织收集容器12包括当给容器施加抽吸时能保持其形式的壳体。更具体来说，组织收集容器12包括刚性壳体，例如由医用级聚碳酸酯制成的壳体，其中含有由医用级聚酯制成的，筛孔尺寸为275μm的大体圆锥形滤器袋。该刚性组织收集容器的大小可以是高约8英寸，直径约5英寸；壁厚可以为约0.125英寸。圆柱体内部可具有以下入口：两个用于抽吸管线的口，两个用于经由无菌进入技术连接的具有管线的口，以及用于经由橡胶隔膜让针头刺入的两个口。可用不同材料、筛孔尺寸和口数目以及类型来实现相同功能。例如，小于100μm或大至几千微米的筛孔尺寸可实现让盐水和血细胞通过，而保留脂肪组织聚集物和片段的同一目的。类似地，装置目的可通过以下手段实现：使用另一种刚性塑料材料，用非一次性多用途无菌插管代替一次性插管，或本领域技术人员已知的其它改进。然而，在组织取出系统10的其它实施方案中，组织收集容器12可包括可收缩的壳体，例如组织收集袋。在这样的系统中，优选给这样的袋提供支持物例如内部或外部框架，这样的支持物有助于减小在给袋施加抽吸时袋塌陷的可能性。
为了减小在组织取出系统10中的污染，可在不同管线或导管上提供一个或多个夹子23，以控制材料经由管线向系统的不同部件的流动。夹子23使得使用者能有效地将组织取出系统10的不同区域密封。在优选的实施方案中，系统10的一个或多个部件是一次性的。在该实施方案中，避免重复使用部件有助于减小可能与反复使用不同部件有关的污染。此外，在一次性设置中提供部件具有能够将所有部件在单一时间灭菌的优点，这可以显著缩短实施本发明方法所需的时间。在全部或部分自动化的实施方案中，除了夹子23以外，或者作为夹子23的替代，可施用计算机控制的阀。
另外，组织取出系统10可包括另外的装置或部件，所述装置或部件使得能够测定保留在滤器16中的材料的体积，以记录关于提取或加工操作的书面信息，或执行其它补充功能例如在操作期间将装置附着在支架或基床上。
组织取出系统10的部件应当由这样的材料组成，它们不与生物液体或组织反应，并且不与加工生物液体和组织所用的物质反应。此外，制造各部件的材料应当能够经得起灭菌处理，例如高压灭菌和放射灭菌，包括但不限于β-或γ-放射。管线和插管柄可由任何合适的材料例如聚乙烯制成。插管可由不锈钢制成。
根据本发明，组织取出系统10提供了适于取出、加工和施用存在于脂肪组织中的干细胞的封闭系统。可将该系统放置在患者旁边以取出脂肪组织，并且可加工组织而无需将组织从该系统中取出来。因此，系统可给患者提供富含新鲜干细胞的组合物，并且降低了与培养或保存干细胞有关的危险性。
根据本文的公开内容，从患者中提取组织的方法可包括以下步骤：(i)给患者进行常规脂肪抽吸术的准备；(ii)将插管和组织取出系统从包装中取出来，放在无菌区域；(iii)将脂肪抽吸泵(具有常规捕集器和在线微生物滤器)与从组织收集容器引出的胶管接合器连接；(iv)确保管线螺旋夹子没有夹住组织收集容器的抽吸口；(v)使用插管作为常用的脂肪抽吸插管以取出不需要的脂肪组织；(vi)在手动操作实施方案中，用组织收集容器收集了所需量的脂肪组织之后，用两个管线螺旋夹子将组织收集容器密封；和(vii)确保用患者鉴别标签将组织收集容器适当标记，并根据标准惯例在标签上记录其它信息(日期和操作时间等)。
参照附图所示的组织取出系统10，通过把管线22与具有在线液体捕集器的抽吸源20连接，并且将插管24插到收获部位，组织被直接收集到加工部件中。然后将脂肪组织抽吸到组织收集容器12内，脂肪组织被保持在组织收集容器12内的滤器16保留。组织收集后，可用洗涤液体例如无菌等渗盐水将所收集的脂肪组织洗涤，其中洗涤液体包含在洗涤容器38中，并经由洗涤管线39加到组织收集容器12中。在该举例说明的实施方案中，当组织收集容器12是用刚性材料制成以支持在抽吸下的收集时，在加入盐水期间从壳体转移出的气体可经由空气入口40排放出去。或者，可将空气转移到废弃物容器36或类似保持位置内。一旦洗涤组织，即可让废弃物流到废弃物容器36内。
在一些实施方案中，在将脂肪组织在收集容器12中解聚之前，可将完整的脂肪组织单位从组织收集容器12中取出来。可让完整的脂肪组织单位沿着组织挽回管线34流动，这样这些单位可被递送到混和容器30内。在这些实施方案中，在施用给患者之前，可将完整的组织与干细胞混和。
收集了组织之后，可将针头44插到含有胶原酶的酶溶液的无菌瓶中，然后让酶溶液流到组织收集容器12内，在该容器内其与脂肪组织在37℃或约37℃混和30-60分钟。可按照需要重复进行洗涤步骤，并且可洗涤解聚的组织，然后洗脱活性细胞群体以获得最大收率。在组织解聚结束时，将组织收集容器12垂直放置以让脂肪细胞漂浮。然后让活性细胞群体流到细胞收集容器26内，在该容器中将细胞与残余游离脂质分离开。可通过本领域技术人员已知的任何方法将细胞洗涤和/或浓缩，包括但不限于依次离心/再悬浮洗涤或连续流动机械装置。然后让浓缩、洗涤的细胞流到混和容器30内，在混和容器30内可将它们与得自组织挽回管线的完整组织和/或任何添加剂混和，然后经由出口32取出以施用给患者。可使用细胞滤器28将包含在细胞收集容器26中的材料过滤，然后洗涤以促进除去不需要的残余细胞以及在施用时可导致栓塞的组织聚集体。
在加工期间，可按照需要将一种或多种添加剂加到不同容器中以提高结果。添加剂的某些实例包括能优化洗涤和解聚的添加剂，能提高加工期间活性细胞群体存活力的添加剂，抗微生物剂(例如抗生素)，裂解脂肪细胞和/或红细胞的添加剂，或富集所需细胞群体的添加剂(通过与固相部分的差别粘着或促进细胞群体的显著减少或富集)。
在上述实施方案中，组织收集容器12是组织取出系统10的内部固有部件。或者，可全部或部分使用单独的组织收集容器，例如在发明名称为“得自非造血组织的非胚胎细胞的保存”的于2002年9月12日提交的第10/242,094号专利申请中描述的组织收集容器，该申请共同转让的于2001年9月14日提交的第60/322,070号U.S.临时专利申请的优先权，并且该申请的内容明确引入本文以供参考，之后将解聚的材料转移到加工部件中，其它可能的组织收集容器公开在U.S.专利6,316,247和5,372,945中。
如上所述，在本发明的一些实施方案中，这些方法可通过提供一个或多个能够自动进行方法步骤的附加装置而自动进行。在这样的实施方案中，加工装置(例如微处理器或个人电脑)是让上述步骤部分或完全自动进行的装置。可施用这种自动化的步骤的实例包括但不限于，通过控制系统或加工装置的泵和阀门来控制液体和组织沿着特定管线的进入和排出；用压力传感器检测阻塞；混和机械装置，使用容量机械装置测定欲沿着特定路径移动的组织和/或液体的量；使用热控装置保持不同组分的温度；洗涤和浓缩细胞，以及用定时和软件设备使过程成为整体。在一个实施方案中，软件可控制加工参数，以产生根据特定操作者规定的的参数制得的细胞群体。因此，自动装置改善了操作的性能，提供了自动进行的脂肪组织的收获和加工以施用给患者。
附图4显示了一个具体的自动装置。组织取出容器(未显示)安放在装置100内，使用颜色编码的导向标记112-118来适当地排列和将管线插入到合适的途径中。装置100包括多个阀105和110，以及多个泵104和109。将管线放置在一系列阀105、110和泵104、109中，它们是由集成的微处理器系统控制的，以根据使用者规定的程序协调液体和组织流动。程序选择是经由使用者接触面板106进行的。将盐水容器放置在结构101上，并与组织收集容器连接。将胶原酶或其它组织离解介质或混合物的瓶或管(未显示)在点103插到组织收集容器内。将废弃物袋(未显示)插到保持结构111内，将细胞分离室/细胞收集容器放置在保持结构107内，将组织/细胞混和容器放置在保持结构108内。将组织收集容器放置在搅拌/培养室102内。
可在将容器放置在装置内的同时或者放置在装置内之前将脂肪组织收集到组织收集容器内。装置可含有任选透明插入物119或决定包含在组织收集容器内的组织体积的其它装置。或者，可通过测定包含在搅拌/培养室102(相当于组织收集容器12)中的材料的重量来确定体积。该体积可在使用者接触面板106上显示。
然后微处理器打开管线114和115上的阀，并启动管线114上的泵104以将盐水输入到收集室102内，和取出废弃物115递送到废弃物袋111中。在加工期间，通过摇动搅拌收集室，通过温热整合到室102内的装置来保持在程序设定的温度。在一些实施方案中，组织加工可使用预温热的盐水，在这种情况下，将搅拌/培养室的装置温热的作用是把温度保持在预先程序设定的点，而不是提高温度。
一旦将组织洗涤，即可以通过启动在管线116上的泵109和阀110来将0％-100％的完整洗涤的脂肪组织从培养室102中取出。将在该时间抽出的材料保持在混和室108中。通过打开在管线113上的阀105，关闭其它阀，和启动在管线113上的泵104来将离解介质103加到保留在室102中的材料内。加入离解介质之后，将室102搅拌并保持在如上所述的温度。在程序设定的时间结束时，停止搅拌，让脂肪细胞漂浮。可再加入盐水以辅助该加工。脂肪细胞漂浮之后，将管线112和115上的阀打开，让目标细胞群体从室102转移到细胞洗涤室107内。将洗涤过的细胞经由管线117转移到混和室108内，将上清液和洗涤溶液经由管线118转移到废弃物室111内。让另外的盐水经由管线114流到该系统内，以完成洗涤加工。将细胞在室108中与在该加工早期经由管线116取出的任何完整组织混和。混和可通过本领域技术人员已知的任何手段来进行，包括但不限于搅拌摇动/反转室，压缩脉冲或移动滚筒。然后经由该一次性设置的混和室中的口取出混和的材料。
该装置包括用于根据预先程序设定的参数自动进行该加工的微处理器控制的机械装置106。该系统还应当包括使用用于检测阻塞的压力传感器和类似的安全和质量控制装置。在优选的实施方案中，该系统的软件部件应当包括自动收集“运行数据”，包括例如一次性部件的批号、温度和体积测定值、组织体积和细胞数目参数、施用的酶剂量、培养时间、操作者身份、日期和时间、患者身份等。在该装置的优选实施方案中，整合入条形码读取系统，以让这些变量(例如一次性设置的批号和有效期限、胶原酶的批号和有效期限、患者/样本标识等)的数据作为加工文件编制的一部分输入到装置控制器内。这将减少数据输入差错的机会。使用USB或本领域已知的其它界面接口和系统，可很容易将该装置引入到控制器系统内。这样，该装置将提供对数据输入和加工文件编制的集中控制。这些参数的打印报告将是装置程序设定操作的用户定义参数的一部分。自然这将需要一体化的打印机部件(硬件和驱动器)或在软件中的打印机驱动器加上在装置硬件中的用于打印机的界面输出接口(例如USB接口)。
在另一个实施方案中，引入到控制器内的软件将在所需步骤期间提示使用者正确地将管线和其它部件插入到装置内。软件还将启动自动检验以确保管线被正确插入、没有堵塞等等。
在该装置中进行加工的一般方法将使用与在本申请其它部分描述的关于手动细胞加工的参数相同的参数。
用于细胞加工的分阶段机械装置的很多其它配置对于本领域技术人员来说是显而易见的，本发明的描述仅是作为一个实例包括在内。例如，在洗涤和解聚期间，组织与盐水的混和可通过如本文实例中描述的搅拌或通过流体循环来进行。细胞洗涤可通过连续流动方法，例如旋转膜方法、差别粘着、差别离心(包括但不限于差别沉降、速度或梯度分离)或通过组合的方法来进行。类似地，可使用另外的组分以进一步处理细胞，包括加入生长因子或其它生物反应调节剂(Lind，M.，Growth factor stimulation of bone healing.Effects on osteoblasts，osteomies，and implants fixation.Acta Orthop Scand Suppl，1998.283：p.2-37；Hanada，K.，J.E.Dennis，和A.I.Caplan，Stimulatory effects ofbasic fibroblast growth factor and bone morphogenetic protein-2 onosteogenic differentiation of rat bone marrow-derived mesenchymalstemcells.J Bone Miner Res，1997.12(10)：p.1606-14；Lieberman，J.R.，等人，Regional gene therapy with a BMP-2-producing murine stromal cell lineinduces heterotopic and orthotopic bone formation in rodents.J OrthopRes，1998.16(3)：p.330-9)，将细胞与其它结构组分混和(例如骨片(Jean，J.L.，S.J.Wang，和M.K.Au，Treatment of a large segmental bone defectwith allograft and autogenous bone marrow graft.J Formos Med Assoc，1997.96(7)：p.553-7)、胶原(Saadeh，P.B.，等人，Repair of a Critical SizeDefect in the Rat Mandible Using Allogenic Type I Collagen.JCraniofac Surg，2001.12(6)：p.573-579)和/或用于和细胞一起植入到接收者体内的合成组分(Petite，H.，等人，Tissue-engineered boneregeneration.Nat Biotechnol，2000.18(9)：p.959-63.taf/dynapage.taf？file＝/nob/biotech/v18/n9/full/nbt0900_959.htmltaf/dynapage.taf？file＝/ncb/biotech/v18/n9/abs/nbt0900_959.html；Gao，J.，等人，Tissue-Engineered Fabrication of an Osteochondral CompositeGraft Using Rat Bone Marrow-Derived Mesenchymal Stem Cells.TissueEng，2001.7(4)：p.363-71；Ohgushi，H.和A.I.Caplan，Stem celltechnology and bioceramics：from cell to gene engineering.J BiomedMater Res，1999.48(6)：p.913-27；Caplan，A.I.和V.M.Goldberg，Principles of tissue engineered regeneration of skeletal tissues.ClinOrthop，1999(367 Suppl)：p.S12-6)。加工后处理还可以包括细胞培养(Caplan，A.I.和S.P.Bruder，Mesenchymal stem cells：building blocksfor molecular medicine in the 21st century.Trends Mol Med，2001.7(6)：p.259-64；Petite，supra；Zuk，P.A.，等人，Multilineage cells from humanadipose tissue：implications for cellbased therapies.Tissue Eng，2001.7(2)：p.211-28)、基因转移(Luskey，B.D.，等人，Gene transfer into murinehematopoietic stem cells and bone marrow stromal cells.Ann N Y AcadSci，1990.612(398)：p.398-406；Grompe，M.，等人，Therapeutic trials inthe murine model of hereditary tyrosinaemia type I：a progress report.JInherit Metab Dis，1998.21(5)：p.518-31；Gazit，D.，等人，Engineeredpluripotent mesenchymal cells integrate and differentiate inregenerating bone：a novel cell-mediated gene therapy.J Gene Med，1999.1(2)：p.121-33；Mosca，J.D.，等人，Mesenchymal stem cells asvehicles for gene delivery.Clin Orthop，2000(379Suppl)：p.S71-90)或进一步细胞纯化(Greenberg，A.W.和D.A.Hammer，Cell separationmediatedby differential rolling adhesion.Biotechnol Bioeng，2001.73(2)：p.111-24；Mainwaring，G.和A.F.Rowley，Separation of leucocytes inthe dogfish(Scyliorhinus canicula)using density gradient centrifugationand differential adhesion to glass coverslips.Cell Tissue Res，1985.241(2)：p.283-90；Schweitzer，C.M.，等人，Isolation and culture ofhuman bone marrow endothelial cells.Exp Hematol，1995.23(1)：p.41-8)。可将用于实现这些功能的机械装置集成到附图4所示装置内，或者可引入到单独的装置内。
在本发明的其它实施方案中，可将收集到常规脂肪组织捕集器中的组织转移到设计用于加工其它组织的加工装置内。例如，Baxter Inc.生产和销售的一系列用于在骨髓移植物收获设置中使用的塑料袋和滤器(“Bone Marrow Collection Kit with Flexible Pre-Filters and InlineFilters”，Product Code，4R2107，U.S.专利4,346,703和5,724,988)。这种袋装置含有大的圆锥形袋，该圆锥形袋具有可用于洗涤所收集的脂肪组织的整合的800μm滤器。在该实例中，大于800μm的脂肪组织片段将保留在袋中。然后可通过反复加入盐水(或其它洗涤溶液)来洗涤这些片段，之后将废弃物经由滤器下面的口排出。混和可用手进行，或使用台式摇动装置进行，温热可通过施用加热垫来进行。解聚可在该袋的腔内进行。解聚后，让细胞经过整合的800μm滤器(并任选经过与该成套装置一起提供的一个或多个小筛孔尺寸滤器)和收集到收集袋(也提供的)中。可将该袋放置在可把细胞系列洗涤和浓缩的离心机(例如Sorval RC-3C)内。还可以使用现有的细胞洗涤装置(大部分是为了洗涤人血液制品而开发的)，例如Baxter Inc(Cytomate或BaxterCS3000)或Cobe Inc.(Cobe Spectra)销售的那些来洗涤细胞。可使用生产商提供的契合装置来整合这些一次性部件，或者可使用无菌连接装置例如由Terumo Inc生产的那些将它们连接。类似地，可将在该一体化程度较低的方法中描述的装置与中央控制器连接，并作为一体化程度更高的装置的部件进行装配。提供使用手动或自动夹子来打开或关闭流动路径，可使用蠕动泵或泵组来让液体自动流动。
在优选的本发明实施方案中，组织取出系统和加工装置可位于接受治疗的患者附近，例如在手术室或门诊操作室中(有效地在患者床边)。这使得能迅速、高效率地收获组织和加工，排除了样本操作/标记出差错的机会，由此使得整个加工能在一个手术操作期间进行。
提供下列实施例是为了举例说明可施用该技术的情形和设置，而不是为了限制本发明的范围，并且本申请包括权利要求书。
实施例1：自体固有脂肪转移
自体固有脂肪转移是较常见的美容和结构手术，其涉及从一个部位收获脂肪组织(组织)，并再植入到同一个体的另一个部位内(Coleman，S.R.(1995).“Long-term survival of fattransplants：controlleddemonstrations.”Aesthetic Plast Surg 19(5)：421-5；Coleman，S.R.(2001).“Structural fat grafts：the ideal filler？”Clin Plast Surg 28(1)：111-9；Coleman，W.P.，3rd(1991).“Autologous fat transplantation.”Plast
Reconstr Surg 88(4)：736)。然而，如上所述，该手术经常受到不一致植入效果的危害，这样植入的材料完全或部分被再吸收或者被瘢痕组织替代(Eremia，S.和N.Newman(2000).“Long-term follow-up afterautologous fat grafting：analysis of results from 116patients followed atleast 12 months after receiving the last of a minimum oftwotreatments.”Dermatol Surg 26(12)：1150-8)。至少一部分功能损失是由于植入的脂肪组织在其形成新血管和给植入物提供养分时坏死所致。因此，与植入到血液灌注不佳的组织内细胞，植入到高血管区域例如肌肉床内的组织表现出更好的植入效果(Guerrerosantos，J.，A.Gonzalez-Mendoza，等人，(1996).“Long-term survival of free fat graftsin muscle：an experimental study in rats.”Aesthetic Plast Surg 20(5)：403-8)。
按照本发明所述方法制得的加工的脂肪抽吸物通过给植入物补充另外的内皮前体和干细胞而解决了该问题。按照本发明公开的方法，将从近亲交配的Wistar大鼠中提取的脂肪组织片段与加工的脂肪抽吸物混和。然后将该组合物皮下植入到接收大鼠的股腿和头皮下。作为对照，让相同数目的大鼠在头皮下接受单独的脂肪组织(未加工的脂肪抽吸物)，而在腿内接受植入物的大鼠在对侧腿内植入单独的脂肪组织。植入后一个月收获移植物。
结果(附图5)表明，随着加工的脂肪抽吸物剂量的增加，腿内植入物的移植物重量有增加的趋势。植入物的组织学检查表明补充加工的脂肪抽吸物的移植物的血管供应改善了。对头皮植入物观察到了类似结果，虽然由于这些大鼠背侧头颅的低血管供应而使得整个保留较低。
在该技术的临床应用中，制备本发明加工的脂肪抽吸物，并如上所述，与完整的(未解聚的)脂肪组织混和。可将包含脂肪组织与干细胞的混合物的组合物植入到接收者体内，以提供自体软组织填充物来矫正外形缺陷(皱纹、“草皮”、痘痕和较大缺陷)(Coleman，S.R.(2001).“Structural fat grafts：the ideal filler？”Clin Plast Surg 28(1)：111-9)或给损伤的结构例如尿道提供支持(Palma，P.C.，C.L.Riccetto，等人，(1997).“Repeated lipoinjections for stress urinary incontinence.”JEndourol 11(1)：67-70；Lee，P.E.，R.C.Kung，等人，(2001).“Periurethralautologous fat injection as treatment for female stress urinaryincontinence：a randomized double-blind controlled trial.”J Urol 165(1)：153-8)。
实施例2：急性肝损伤
通过腹膜内注射烯丙醇而引起的肝损伤是常用的门静脉周急性肝损伤模型(Lee，J.H.，Z.Ilic，等人，(1996).“Cell kinetics of repair afterallyl alcohol-induced liver necrosis in mice.”Int J Exp Pathol 77(2)：63-72；Werlich，T.，K.J.Stiller，等人，(1999).“Experimental studies on thestem cell concept of liver regeneration.II.”Exp Toxicol Pathol 51(1)：93-8.；Yin，L.，D.Lynch，等人，(1999).“Participation of different celltypes in the restitutive response of the rat liver to periportal injuryinduced by allyl alcohol.”J Hepatol 31(3)：497-507)。该模型已经用于证实对肝再生至关重要的干细胞群体存在(Yavorkovsky，L.，E.Lai，等人，(1995).“Participation of small intraportal stem cells in the restitutiveresponse of the liver to periportal necrosis induced by allyl alcohol.”Hepatology 21(6)：1702-12；Werlich，T.，K.J.Stiller，等人，(1999).“Experimental studies on the stem cell concept of liver regeneration.II.”Exp Toxicol Pathol 51(1)：93-8)。我们在Swiss Webster小鼠中修饰了该模型，其中在该小鼠中产生醇引起的损伤，然后注射加工的脂肪抽吸物。一周后将动物处死，取出肝脏，称重，并准备组织学检查。结果(附图6和7)表明，在接受加工的脂肪抽吸物的动物中，肝脏重量得到了显著提高。组织学分析表明在治疗的动物中有正常组织学，没有白细胞渗入或可能异常提高肝脏重量的任何其它机制的任何证据。
在临床设置中，肝损伤患者将接受根据本发明方法提取和加工的脂肪组织。然后可将加工的脂肪抽吸物静脉内注射，以经由肝脏循环系统全身或靶向递送到肝脏中。
实施例3：急性心脏损伤
急性心肌梗塞(心脏病发作)导致心肌的缺血性损伤。组织损伤可通过再灌注损伤组织和心肌组织再生来减轻(Murry，C.E.，R.W.Wiseman，等人，(1996).“Skeletal myoblast transplantation for repair of myocardialnecrosis.”J Clin Invest 98(11)：2512-23；Orlic，D.，J.Kajstura，等人，(2001).“Bone marrow cells regenerate infarcted myocardium.”Nature410(6829)：701-5；Rajnoch，C.，J.C.Chachques，等人，(2001).“Cellulartherapy reverses myocardial dysfunction.”J Thorac Cardiovasc Surg121(5)：871-8；Strauer，B.E.，M。Brehm，等人，(2002).“″Repair ofinfarcted myocardium by autologous intracoronary mononuclear bonemarrow cell transplantation in humans.”Circulation 106(15)：1913-8)。在本申请中描述的临床方法将提供可能优良的再生细胞源，因为可以以更大的数量和纯度提供细胞，同时没有与骨髓收获有关的发病。实施例4：用于遗传性疾病的同种异体应用
Horwitz等人已经证实了得自骨髓的干细胞可给患有非造血性病症，具体来说是成骨不全的患者提供临床益处(Horwitz，E.M.，D.J.Prockop，等人，(1999).“Trans plantability and therapeutic effects of bonemarrow-derived mesench ymal cells in children with osteogenesisimperfecta.”Nat Med 5(3)：309-13；Horwitz，E.M.，D.J.Prockop，等人，(2001).“Clinical responses to bone marrow transplantation in childrenwith severe osteogenesis imperfecta.”Blood 97(5)：1227-31)。在这些研究中，作者尝试通过让细胞在培养物中生长以扩展和纯化MSC组分来补偿骨髓中非造血干细胞的低数目和频数。然而，如上所述，在培养物中生长细胞会带来大量技术和临床上的问题，而依据本发明加工的脂肪组织可提供高数目干细胞来源，而无需细胞培养，这代表着患者养护的显著改善。在该模型中，未患有遗传疾病(正常基因型或无症状的携带者)的适当匹配的供体，优选同胞或其他最直系亲戚可以是供体细胞来源，尽管使用无亲缘关系的供体也在本发明范围内。可从脂肪组织中提取出细胞，以输入到患有导致组织功能或再生受到损害的遗传性疾病的患者中。实例包括但不限于成骨不全、Duschenes肌肉营养障碍(和其它肌肉营养障碍)、遗传性视网膜变性疾病、遗传性酪氨酸血症和多种其它遗传性疾病。
结论是，应用其中通过把基因插到干细胞隔室内来调节自体(自身)加工的脂肪抽吸物的基因治疗方法将省去对同种异体(非自身)供体的需要。这样的方法还可用于治疗感染性疾病，其中是将新的基因插到干细胞内。例如，可使用反义或核酶构建物来产生能提供抗-HIV作用的细胞。该方法还可用于产生能够起药物递送载体作用的干细胞。
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本文描述的任何特征或特征组合都包括在本发明范围内，只要在任何这样的组合中包括的特征不互相矛盾即可，这在上下文、本说明书和本领域技术人员的知识中是显而易见的。为了总结本发明，在本文中已经描述了本发明的一些方面、优点和新特征。当然，应当理解，不需要将所有这样的方面、优点或特征都在本发明的任何特定实施方案中体现。本发明的其它优点和方面将从详细描述和权利要求书中显而易见地看出。
提供上述实施方案只是为了举例说明，本发明不限于这些实施例。对于本领域技术人员，通过考虑上面的描述，可在不互相排他的程度上做很多改变和改进。此外，对于本领域技术人员，通过阅读本文的公开内容，其它组合、省略、替代和改变将是显而易见的。因此，本发明不受所公开的实施方案的限制，而由权利要求书限定。
上文中已经引用了很多出版物和专利。每一所引用的出版物和专利都全文引入本文以供参考。
Claims (20)
1.一种制备软组织填充物的方法，该方法包括：
提供加工的脂肪抽吸物，该加工的脂肪抽吸物含有脂肪衍生干细胞；
提供完整的、未解聚的脂肪组织片段；以及
将所述加工的脂肪抽吸物和所述完整的、未解聚的脂肪组织片段混合以得到所述软组织填充物。
2.根据权利要求1所述的方法，其中，通过酶解聚悬浮液中的脂肪组织并减少成熟脂肪细胞的存在，获得所述加工的脂肪抽吸物。
3.根据权利要求2所述的方法，其中，所述方法还包括通过离心分离悬浮液中的细胞。
4.根据权利要求1-3中任意一项所述的方法，其中，所述方法还包括提供添加剂。
5.根据权利要求1-4中任意一项所述的方法，其中，所述软组织填充物适于矫正外形缺陷。
6.根据权利要求5所述的方法，其中，所述外形缺陷为皱纹、草皮、痘痕或较大缺陷。
7.根据权利要求1-4中任意一项所述的方法，其中，所述软组织填充物适于给损伤的结构提供支持。
8.根据权利要求7所述的方法，其中，所述损伤的结构是尿道。
9.根据权利要求1-8中任意一项所述的方法，其中，冷冻保存所述加工的脂肪抽吸物，该加工的脂肪抽吸物含有脂肪衍生干细胞。
10.根据权利要求1-9中任意一项所述的方法，其中，冷冻保存所述脂肪组织。
11.一种制备脂肪组织移植物的方法，该方法包括：
提供第一部分的完整的脂肪组织；
酶解聚所述第一部分的脂肪组织以产生被解聚的细胞悬浮液；
减少所述被解聚的细胞悬浮液中成熟脂肪细胞的存在；
分离细胞群体，该细胞群体含有来自所述被解聚的细胞悬浮液中的细胞组分的脂肪衍生干细胞；
浓缩含有脂肪衍生干细胞的所述细胞群体；
提供第二部分的完整的脂肪组织；以及
将所述浓缩的含有脂肪衍生干细胞的细胞群体和所述第二部分的完整的脂肪组织混合以得到所述脂肪组织移植物。
12.根据权利要求11所述的方法，其中，所述酶解聚包括胶原酶。
13.根据权利要求11所述的方法，其中，所述细胞群体通过离心得到浓缩。
14.根据权利要求11-13中任意一项所述的方法，其中，所述方法还包括提供添加剂。
15.根据权利要求11-14中任意一项所述的方法，其中，所述脂肪组织移植物适于矫正外形缺陷。
16.根据权利要求15所述的方法，其中，所述外形缺陷为皱纹、草皮、痘痕或较大缺陷。
17.根据权利要求11-14中任意一项所述的方法，其中，所述脂肪组织移植物适于给损伤的结构提供支持。
18.根据权利要求17所述的方法，其中，所述损伤的结构是尿道。
19.根据权利要求11-18中任意一项所述的方法，其中，冷冻保存所述浓缩的含有脂肪衍生干细胞的细胞群体。
20.根据权利要求11-19中任意一项所述的方法，其中，冷冻保存所述第二部分的完整的脂肪组织。
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