CN105992816B - 生物反应器中的细胞扩增 - Google Patents
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Abstract
本发明描述了用于在生物反应器中扩增细胞的实施方式。在一个实施方式中,提供了在生物反应器中分布细胞和使细胞附着至生物反应器的特定部分以改善细胞在生物反应器中的扩增的方法。可在被配置为加载、分布、附着和扩增细胞的细胞扩增系统上实施实施方式。
Description
相关专利申请的交叉引用
本申请要求于2013年11月16日递交的美国临时专利申请号61/905,182的名称为“在细胞扩增系统的生物反应器中加载并且分布细胞的方法(METHOD OF LOADING ANDDISTRIBUTING CELLS IN A BIOREACTOR OF A CELL EXPANSION SYSTEM)”的优先权,该美国临时专利申请通过引用整体并入本文中,就如其全文涵盖在本申请中一样。
背景技术
干细胞在各种治疗和疗法中的潜在应用已经取得了特别关注。细胞扩增系统可用于扩增(例如生长)干细胞以及其它类型的细胞,诸如骨髓细胞。从供体细胞扩增的干细胞可用于修复或替换受损的或有缺陷的组织,并且对于大量疾病都具有广泛的临床应用。再生医学领域中的最新进展证实了,干细胞具有很多特性,诸如增殖和自我更新能力、维持非特化状态以及在特定条件下分化成特化细胞的能力。
细胞扩增系统包括用于扩增细胞的一个或多个腔室,诸如细胞生长腔室(在本文中也被称为“生物反应器”)。为了扩增细胞,通常将初始体积的细胞加载并且分布在生物反应器中。因此,需要一种在与细胞扩增系统相连的生物反应器中加载并且分布细胞的方法。本发明解决了这种需要或其他需要。
鉴于这些和其它方面的考虑,进行了本发明的实施方式。但是,上述相对具体的问题并不限制本发明的实施方式对其它问题的适用性。
发明内容
提供该发明内容以介绍本发明的简化形式的一些实施方式的各个方面,并不用于确定本发明的关键或必要元素,也不用于限制权利要求的范围。
应理解本发明可包括多种不同的变体或实施方式,本发明内容并不是要进行限制或包括所有的变体或实施方式。本发明内容提供了对一些可被包括在实施方式中的特征的一些概括性描述,还包括了对可被包括在其他实施方式中的其他特征的一些更具体的描述。
一个或多个实施方式通常涉及用于在细胞扩增系统的生物反应器中加载和分布细胞的方法和系统。因此,实施方式包括可用于向流体中添加多个细胞的方法,该流体在细胞扩增系统的生物反应器内以第一速度循环。在实施方式中,生物反应器可包括具有多个独立中空纤维的中空纤维膜,细胞和其他流体穿过该具有多个独立中空纤维的中空纤维膜循环。最初,流体穿过生物反应器的中空纤维膜循环,并且将细胞添加到循环的流体中。流体以第一预定的循环速度进行循环。在循环过程中,生物反应器可处于水平位置。在通过添加至循环流体来加载细胞后,随着细胞流入和流出中空纤维膜的中空纤维,可允许细胞穿过系统循环并且均匀地分布在系统中。然后,可停止循环。随后,在重力的影响下,允许细胞沉淀,并且附着至生物反应器中的中空纤维的第一区上。在实施方式中,可允许细胞在第一预定时间段期间进行沉淀。在一些实施方式中,可对预定时间段进行选择,以允许细胞附着至中空纤维的第一区上。
在第一预定时间段之后,使生物反应器旋转180度。在生物反应器旋转之后,允许生物反应器内的细胞进行额外的沉淀。然后,细胞可在第二预定时间段期间沉淀在中空纤维的相对的部分上,可对该第二预定时间段进行选择,以允许细胞附着至该相对的部分。在第二预定时间段之后,使生物反应器旋转回到其初始的水平位置,然后细胞进行扩增程序。
在一些实施方式中,加载过程包括额外的步骤。在一些实施方式中,在生物反应器返回至其初始的水平位置之后,重新启动循环。可将循环速度设置为比第一预定循环速度慢的速度。一旦使还没有附着至表面的细胞进行额外的分布,则要进行循环。该循环应持续第三预定时间段,以允许未附着的细胞均匀分布在包括生物反应器的系统中。然后停止循环,以允许生物反应器中的细胞沉淀,并且在一些实施方式中再次附着至中空纤维的多个部分上
在允许细胞进行额外沉淀的第四预定时间段之后,使生物反应器旋转180度。在生物反应器旋转之后,允许生物反应器内的细胞进行额外的沉淀。然后,细胞可在第五预定时间段期间沉淀在中空纤维的相对部分上,可对该第五预定时间段进行选择,以允许细胞附着至中空纤维的相对部分。在第五预定时间段之后,使生物反应器旋转回到其初始的水平位置
通过使细胞在系统中循环,以再次重复上述程序,以使任何未附着的细胞进行均匀分布。但是,每次重新启动循环,都以比之前循环慢的速度重新启动。当停止循环时,允许细胞沉淀和附着。使生物反应器旋转180度,并且允许细胞沉淀和附着。然后,使生物反应器旋转回到其初始位置。可将循环、沉淀、旋转、沉淀和旋转的这些步骤重复预定的次数,之后,已经附着成层的附着的细胞在生物反应器中进行扩增。
其它实施方式还涉及用于在细胞扩增系统的生物反应器中加载和分布细胞的方法和系统。实施方式包括可用于向流体中添加多个细胞的方法,该流体在细胞扩增系统的生物反应器内以第一速度循环。在实施方式中,生物反应器可包括具有多个独立中空纤维的中空纤维膜,细胞和其他流体穿过该具有多个独立中空纤维的中空纤维膜循环。最初,流体穿过生物反应器的中空纤维膜循环,并且将细胞添加到循环的流体中。流体以第一预定的循环速度进行循环。在循环过程中,生物反应器可处于水平位置。在通过添加至循环流体来加载细胞后,随着细胞流入和流出中空纤维膜的中空纤维,可允许细胞穿过系统循环并且均匀地分布在系统中。然后,可停止循环。随后,在重力的影响下,允许细胞沉淀,并且附着至生物反应器中的中空纤维的第一区上。在实施方式中,可允许细胞在第一预定时间段期间进行沉淀。在一些实施方式中,可对预定时间段进行选择,以允许细胞附着至中空纤维的第一区上。
在第一预定时间段之后,使生物反应器旋转180度。在生物反应器旋转之后,细胞扩增程序。如可理解的,之前附着的细胞可以在中空纤维的顶部上。当细胞扩增时,细胞可受到重力影响,而重力可影响细胞朝中空纤维的底部生长。
在下面的讨论中,特别当与附图一起讨论时,本文中示出的实施方式的其他优点将变得非常明显。
附图说明
为了进一步阐明本发明的上述及其他优点和特征,将参考附图中示出的具体实施方式给出对本发明的更具体的描述。应理解,这些附图仅描绘了本发明的典型实施方式,因此不能认为限制了本发明的范围。通过使用附图,对本发明进行具体详细地描述和解释,在附图中:
图1A描绘了细胞扩增系统(CES)的一个是实施方式。
图1B描绘了CES的第二实施方式。
图1C描绘了CES的第三实施方式。
图1D描绘了在CES的运行过程中,旋转或侧向移动细胞生长腔室的摇动装置的实施方式。
图2A描绘了中空纤维细胞生长腔室的实施方式的侧视图。.
图2B描绘了在图2A中示出的中空纤维细胞生长腔室的实施方式的侧剖视图。
图3描绘了生物反应器的另一实施方式的侧剖视图,示出穿过生物反应器的循环路径。
图4示出根据实施方式的CES的一部分的透视图,该CES包括可拆卸地附接的生物反应器。
图5示出用于在根据实施方式的CES中扩增细胞的方法的流程图。
图6示出用于加载、分布、附着和扩增细胞的程序的流程图,在一些实施方式中,该程序包括可在图5示出的流程图的方法中使用的步骤。
图7是用于加载、分布、附着和扩增细胞的程序的流程图,在一些实施方式中,该程序包括可在图5示出的流程图的方法中使用的步骤
图8示出处于第一取向的生物反应器的实施方式的正视图。
图9示出图8的生物反应器的正视图,其中示出的生物反应器自图8的视图旋转了约90度。
图10是图8的生物反应器的正视图,其中示出的生物反应器自图8的视图旋转了约180度。
图11是图8的生物反应器的正视图,其中示出的生物反应器旋转回到图8示出的初始取向。
图12示出图8的生物反应器的正视图,其中示出的生物反应器自图8的视图旋转了约90度,并且自图9的视图旋转了约180度。
图13A至图13C示出随着执行在根据实施方式的生物反应器中分布、附着和扩增细胞的程序的步骤,可作为生物反应器的部件的中空纤维的(与中心轴线垂直的)横截面。
图13D和图13E示出随着执行在根据实施方式的生物反应器中分布、附着和扩增细胞的程序的步骤,可作为生物反应器的部件的中空纤维的横截面(与中心轴线平行)。
图14A至图14D示出随着执行在根据另一实施方式的生物反应器中分布、附着和扩增细胞的程序的步骤,可作为生物反应器的部件的中空纤维的横截面(与中心轴线垂直)。
图15A至图15F示出随着执行在根据又一实施方式的生物反应器中分布、附着和扩增细胞的程序的步骤,可作为生物反应器的部件的中空纤维的横截面(与中心轴线垂直)。
图16示出生物反应器的横截面,其中示出多个中空纤维和中空纤维区域,含细胞的液体可穿过该多个中空纤维和中空纤维区域以不同的流速循环。
图17示出可用于实施多个实施方式的基础计算机的框图。
具体实施方式
通过参考以下详细描述以及附图中描绘的实施方式,可进一步理解本发明的原理。应当理解的是,尽管相对于具体实施方式,下文示出并描述了具体特征,但是本发明并不限于下文所述的实施方式。总体来讲,本公开涉及在细胞扩增系统的生物反应器中分布多个细胞的方法。如下所述,在生物反应器中分布细胞的方法可包括:将细胞加载至生物反应器中;使生物反应器旋转,以及维持生物反应器静止在特定的取向处。
在图1A描绘了示例性细胞扩增系统(CES)的示意图。CES10包括第一流体循环路径12和第二流体循环路径14。第一流体流动路径16具有与中空纤维细胞生长腔室24(在本文中也被称为“生物反应器”)流体相连的至少相对端部18和20。具体地,相对端部18与细胞生长腔室24的第一入口22流体相连,而相对端部20与细胞生长腔室24的第一出口28流体相连。第一循环路径12中的流体流经布置在细胞生长腔室24中的中空纤维膜的中空纤维的内部(细胞生长腔室和中空纤维膜将在下文中进行更加详细地描述)。此外,第一流体流动控制器30与第一流体流动路径16可操作地相连,并且控制第一循环路径12中流体的流动。
第二流体循环路径14包括第二流体流动路径34、细胞生长腔室24以及第二流体流动控制器32。第二流体流动路径34具有至少相对端部36和38。第二流体流动路径34的相对端部36和38分别与细胞生长腔室24的进入端口40和排出端口42流体相连。流经细胞生长腔室24的流体与细胞生长腔室24中的中空纤维膜的外部相接触。第二流体循环路径14与第二流体流动控制器32可操作地相连。
因此,通过中空纤维膜,第一流体循环路径12和第二流体循环路径14在细胞生长腔室24中是分离的。第一流体循环路径12中的流体流经细胞生长腔室中的中空纤维的内毛细管(“IC”)空间。因此,第一循环路径12被称为“IC环路”。第二循环路径14中的流体流经细胞生长腔室中的外毛细管(“EC”)空间。因此,第二流体循环路径14被称为“EC环路”。第一流体循环路径12中的流体能以相对于第二流体循环路径14中的流体流动的顺流或逆流的方向流动。
流体进入路径44与第一流体循环路径12流体相连。流体进入路径44允许流体进入第一流体循环路径12,而流体排出路径46允许流体离开CES10。第三流体流动控制器48与流体进入路径44可操作地相联。或者,第三流体流动控制器48可与第一排出路径46可替代地相联。
本文中所使用的流体流动控制器可为泵、阀、夹具或它们的组合。多个泵、阀和夹具可以任何的组合来布置。在各个实施方式中,流体流动控制器是蠕动泵或包括蠕动泵。在其他实施方式中,流体循环路径、进入端口和排出端口可以由任意材料的管子构成。
各组件在本文中被称为“可操作地相联/相连”。如本文所使用的,“可操作地相联/相连”是指组件以可操作的方式连接在一起,并且涵盖其中组件直接连接的实施方式以及其中在两个连接的组件之间放置有额外的组件的实施方式。“可操作地相联/相连的”组件可为“流体相连”。“流体相连”是指将组件连接在一起,以使得能在它们之间运输流体。“流体相连”涵盖其中在两个流体相连的组件之间放置有额外的组件的实施方式,以及其中组件之间是直接相连的实施方式。流体相连的组件可包括不与流体相接触,而与其它组件相接触以操控系统的组件(例如,通过压缩管的外部来泵送流体穿过柔性管子的蠕动泵)。
通常来讲,任何类型的流体(包括缓冲液、含蛋白的流体以及含细胞的流体)都可流经各循环路径、进入路径以及排出路径。如本文所使用的,“流体”、“介质”以及“流体介质”是可互换使用的。
图1B描绘了更详细的细胞扩增系统800。CES800包括第一流体循环路径802(也被称为“内毛细管环路”或“IC环路”),以及第二流体循环路径804(也被称为“外毛细管环路”或“EC环路”)。第一流体流动路径806通过第一流体循环路径802与细胞生长腔室801流体相连。流体通过IC进入端口801A流入细胞生长腔室801,流经细胞生长腔室801中的中空纤维,并且经由IC排出端口801B流出。压力传感器810测量离开细胞生长腔室801的介质的压力。除了压力以外,传感器810在实施方式中也可为在运行期间检测介质压力和温度的温度传感器。介质流经可用于控制介质流速(例如在IC环路中的循环速度)的IC循环泵812。IC循环泵812可沿第一方向泵送流体,或沿与第一方向相对的第二方向泵送流体。排出端口801B可用作相反方向上的入口。进入IC环路802的介质可经过阀814进入。如本领域技术人员所知晓的,可将额外的阀和/或其他装置放置在各位置,以沿流体路径的多个部分隔离和/或测量介质的特性。因此,应当理解的是,示出的示意图代表CES800的各元件的一种可能的配置,而且对示出的示意图的修改在一个或多个所示的实施方式的范围内。
对于IC环路802,可在运行期间从样品线圈818中获得介质样品。随后介质返回至IC进入端口801A,以完成流体循环路径802。可将在细胞生长腔室801中生长/扩增的细胞冲出细胞生长腔室801,通过阀898和管线897进入收获袋899。或者,当阀898关闭时,细胞可在腔室801内重新分布以用于进一步的生长或加载。
第二流体循环路径804中的流体经由EC进入端口801C进入细胞生长腔室801,并且经由EC排出端口801D离开细胞生长腔室801。在EC环路804中的介质与在细胞生长腔室801中的中空纤维的外部相接触,从而允许小分子分散进入中空纤维内或分散出中空纤维,该中空纤维可在腔室801内。
在介质进入细胞生长腔室801的EC空间之前,布置在第二流体循环路径804中的压力/温度传感器824允许测量介质的压力和温度。在介质离开细胞生长腔室801之后,传感器826允许测量在第二流体循环路径804中的介质的压力和温度。对于EC环路804,可在运行期间从样品端口830或样品线圈中获得介质样品。
在离开细胞生长腔室801的EC排出端口801D之后,在第二流体循环路径804中的流体穿过EC循环泵828到达气体运输模块832。EC循环泵828也可沿相对方向泵送流体。第二流体流动路径822经由气体运输模块832的进入端口832A和排出端口832B与气体运输模块832流体相连。在运行中,流体介质经由进入端口832A流入气体运输模块832中,并且经由排出端口832B离开气体运输模块832。气体运输模块832将氧加入到CES800的介质中并且去除CES800的介质中的气泡。在各实施方式中,在第二流体循环路径804中的介质与进入气体运输模块832中的气体相平衡。气体运输模块832可为本领域已知的任意合适尺寸的装置,并且用于氧合或气体运输。空气或气体经由过滤器838流入气体运输模块832,并且通过过滤器840流出氧合器或气体运输装置832。过滤器838和过滤器840降低或防止氧合器832和相关介质的污染。在启动顺序的多个部分期间,从CES800排出的空气或气体可经由气体运输模块832排放到大气中。
在描绘的CES800的配置中,在第一流体循环路径802和第二流体循环路径804中的流体介质沿相同的方向(顺流配置)流经细胞生长腔室801。还可将CES800配置成以逆流构造流动。
根据至少一个实施方式,包括细胞(来自诸如细胞容器(例如袋子)的源)的介质可附接在附接点862处,并且来自介质源的流体介质可附接在附接点846处。可经由第一流体流动路径806,将细胞和介质引入到第一流体循环路径802中。附接点862经由阀864与第一流体流动路径806流体相连,附接点846经由阀850与第一流体流动路径806流体相连。试剂源可与点844流体连接,并且经由阀848与流体进入路径842相关联,或经由阀848和阀872与第二流体进入路径874相关联。
空气去除腔室(ARC)856与第一循环路径802流体相连。空气去除腔室856可包括一个或多个传感器(包括上传感器和下传感器),以在空气去除腔室856内的特定测量位置处检测空气、流体的缺乏,和/或气体/流体界面(例如空气/流体界面)。例如,超声波传感器可用在靠近空气去除腔室856的底部和/或顶部处,以检测这些位置处的空气、流体,和/或气体/流体界面。在不脱离本公开的精神和范围的情况下,实施方式提供了多种其它类型的传感器的应用。例如,根据本公开的实施方式,可使用光学传感器。在启动顺序的多个部分期间或其它方案中,从CES800中排出的空气或气体能够经由管线858从空气阀860排出进入大气,其中管线858与空气去除腔室856流体相连。
EC介质源可附接至EC介质附接点868,冲洗液源可附接至冲洗液附接点866,以将EC介质和/或冲洗液添加到第一流体流动路径或第二流体流动路径中。附接点866可与阀870流体相连,其中阀870经由阀872和第一流体进入路径842与第一流体循环路径802流体相连。或者,通过打开阀870和闭合阀872,附接点866可经由第二流体进入路径874和EC进入路径884与第二流体循环路径804流体相连。同样地,附接点868与阀876流体相连,其中阀876可经由第一流体进入路径842和阀872与第一流体循环路径802流体相连。或者,通过打开阀876和闭合阀分配器872,流体容器868可与第二流体进入路径874流体相连。
在IC环路802中,最初可通过IC进入泵854向前推动流体。在EC环路804中,最初可通过EC进入泵878向前推动流体。空气检测器880(诸如超声波传感器)也可与EC进入路径884相关联。
在至少一个实施方式中,第一流体循环路径802和第二流体循环路径804与废物管线888连接。当阀890打开时,IC介质可流经废物管线888,到达废物袋886。同样地,当阀892打开时,EC介质可流至废物袋886。
在细胞已经在细胞生长腔室801中生长后,可经由细胞收获路径897来收获生长的细胞。此时,在阀898是打开的情况下,可通过泵送含细胞的IC介质,使其经过细胞收获路径897进入细胞收获袋899,收获来自细胞生长腔室801的细胞。
CES800的各组件也可被包含或封装在机器或壳体899(诸如细胞扩增器)内,其中,该机器将细胞和介质维持在预定温度。进一步需要注意的是,在实施方式中,CES 800的组件可与其它CES(诸如CES10(图1A)或CES900(图1C))的组件组合。在其它实施方式中,CES可包括比图1A至图1C中所示出少的部件,而且这样的实施方式仍然在本公开的范围内。
图1C描绘了CES的另一实施方式。CES900包括第一流体循环路径902(也被称为“内毛细管(IC)环路”)以及第二流体循环路径904(也被称为“外毛细管环路”或“EC环路”)。
第一流体流动路径906通过第一流体循环路径902与细胞生长腔室908流体相连。流体通过进入端口910流入细胞生长腔室908中,流经细胞生长腔室908中的中空纤维,并且经由排出端口907离开。压力计917测量离开细胞生长腔室908的介质的压力。介质流经可用于控制介质流速的阀913和泵911。在运行期间,可从样品端口905或样品线圈909获得介质样品。布置在第一流体循环路径902中的压力/温度计915允许在运行期间检测介质的压力和温度。随后,介质返回至进入端口910,以完成流体循环路径902。可将在细胞生长腔室908中扩增的细胞冲出细胞生长腔室908或重新分布在中空纤维中,以用于进一步的生长。
第二流体循环路径904包括第二流体流动路径912,该第二流体流动路径912与环路中的细胞生长腔室908流体相连。第二流体循环路径904中的流体经由进入端口914进入细胞生长腔室908,并且经由排出端口916离开细胞生长腔室908。介质与细胞生长腔室908中的中空纤维的外部相接触,允许小分子扩散进入中空纤维和从中空纤维扩散出来。
在介质进入细胞生长腔室908的EC空间之前,布置在第二循环路径904中的压力/温度计919允许测量介质的压力和温度。在介质离开细胞生长腔室908之后,压力计921允许测量在第二循环路径904中的介质的压力。
在离开细胞生长腔室908的排出端口916之后,第二流体循环路径904中的流体穿过泵920和阀922到达氧合器918。第二流体流动路径912经由氧合器进入端口924和氧合器排出端口926与氧合器918流体相连。在运行中,流体介质经由氧合器进入端口924流入氧合器918中,并且经由氧合器排出端口926离开氧合器918。
氧合器918将氧加入到CES900中的介质中。在各实施方式中,第二流体循环路径904中的介质与进入氧合器918的气体相平衡。氧合器可为本领域已知的任意氧合器。气体经由过滤器928流入氧合器918中,并且通过过滤器930流出氧合器918。过滤器928和过滤器930降低或防止氧合器918和相关介质的污染。
在描绘的CES900的配置中,第一循环路径902和第二循环路径904中的流体介质沿相同的方向(顺流配置)流经细胞生长腔室908。本领域技术人员应认识到,CES900也可配置为逆流构造。本领域技术人员应认识到,相应的进入端口和排出端口可布置在细胞生长腔室908中的任何位置处。
可经由第一流体进入路径932,将细胞和流体介质引入至流体循环路径902中。流体容器934和流体容器936分别经由阀938和阀940与第一流体进入路径932流体相连。同样地,细胞容器942经由阀943与第一流体循环路径902流体相连。在一些实施方式中,细胞和流体可经过热交换器944、泵946,进入滴注腔室(drip chamber)948中。在来自容器942的细胞经过热交换器944的实施方式中,要使用额外的管线(未示出)来连接容器942和热交换器944。滴注腔室948与第一流体循环路径902流体相连。来自滴注腔室948的溢出物可经由阀952从溢出物管线950流出滴注腔室948。
可从流体容器954和流体容器956,将额外流体添加到第一流体循环路径902或第二流体循环路径904中。流体容器954与阀958流体相连,其中,阀958经由阀964、路径960和路径932与第一流体循环路径902流体相连。或者,流体容器954与第二流体进入路径962流体相连。同样地,流体容器956与阀966流体相连,其中阀966经由第一流体进入路径960与第一流体循环路径902流体相连。或者,流体容器956与第二流体进入路径962流体相连。
第二流体进入路径962被配置为,允许流体在进入滴注腔室970前流经热交换器944、泵968。第二流体进入路径962延续至第二流体循环路径904。溢出的流体可经由溢出物管线972通过阀974流出,到达废物容器976。
可经由细胞收获路径978收获细胞。当阀982打开时,可通过泵送含细胞的介质穿过细胞收获路径978到达细胞收获袋980,收获来自细胞生长腔室908的细胞。
第一流体循环路径902和第二流体循环路径904通过连接器路径984相连。当阀986打开时,介质可流经在第一循环路径902和第二循环路径904之间的连接器路径984。同样地,泵990可将介质泵送穿过在第一流体循环路径902和第二流体循环路径904之间的另一连接器路径988。
CES900的各组件可被容纳在培养箱999内。培养箱999将细胞和介质维持在恒定温度。
本领域技术人员应认识到,任意数目的流体容器(例如介质袋)能够以任意组合与CES900流体相连。还应注意到的是,滴注腔室948的位置或独立于滴注腔室948的传感器可位于CES900中进入端口910之前的任意位置处。
CES800和CES900可包括额外的组件。例如,可在CES上的蠕动泵的位置处增加一个或多个泵环路(未示出)。泵环路可由聚氨酯(PU)(可获自Tygothane C-210A)制成。或者,也可包括作为一次性部件的盒子(cassette),该盒子用于组织管线并且也可包括蠕动泵的管道环路。
在一些实施方式中还可提供可拆卸的流动线路(本文中也可称为“可拆卸的循环模块”)。可拆卸的流动线路可为细胞扩增模块的一部分,该细胞扩增模块被配置为附接至CES的更永久的固定部件。通常来讲,CES的固定部件包括蠕动泵。在各实施方式中,CES的固定部件可包括阀和/或夹具。
可拆卸的流动线路可包括具有至少两个端部的第一流体流动路径。第一端部被配置为与细胞生长腔室的第一端部流体相连,第一流体流动路径的第二端部被配置为与细胞生长腔室的第二端部流体相连。
同样地,可拆卸的流动线路可包括具有至少两个端部的第二流体流动路径。可拆卸的流动线路的一部分可被配置为与氧合器和/或生物反应器流体相连。可拆卸的流动线路可包括被配置为与氧合器和细胞生长腔室流体相连的第二流体流动路径。
在各实施方式中,可拆卸的流动线路可拆卸地且一次性地安装至流体流动控制器。可拆卸的流动线路可包括与CES的多个部件连接的可拆卸的流体导管(例如柔性管子)。
在其他实施方式中,可拆卸的流动线路可包括细胞生长腔室、氧合器以及用于容纳介质和细胞的袋子。在各实施方式中,多个组件可连接在一起,或是相互隔开的。或者,可拆卸的流动线路可包括被配置为与流体流通控制器(诸如阀、泵及其组合)附接的一个或多个部分。在使用蠕动泵的变形中,可拆卸的线路模块可包括蠕动环路,该蠕动环路被配置为环绕管道的蠕动部分安装。在各实施方式中,蠕动环路可被配置为与循环路径、进入路径和排出路径流体相连。可拆卸的流动线路也可组合在套件(kit)中,该套件具有将它组装或附接至流体流动控制器(诸如泵和阀)的说明书。
实施方式提供了使用许多不同的方法将细胞引入至CES的生物反应器中。如下文中进行的更详细地描述,实施方式包括在生物反应器中分布细胞以促进细胞一致扩增的方法和系统。
根据实施方式,细胞可在IC环路或EC环路中生长(“扩增”)。贴壁细胞和非贴壁的悬浮细胞都可进行扩增。在一个实施方式中,细胞生长腔室纤维的管腔可涂覆有纤连蛋白。将无二价阳离子(例如,无钙和镁)的PBS加入至CES系统中。在将贴壁细胞引入至细胞生长腔室,例如腔室24、801或908中之后,将它们孵育足够长的时间以使它们附着至中空纤维。循环IC介质和EC介质,以确保为细胞供应足够的营养。
可将IC环路和EC环路的流速调节至特定值。在各实施方式中,可将IC环路和EC环路的流速独立地设置为约2mL/分钟、约4mL/分钟、约6mL/分钟、约8mL/分钟、约10mL/分钟、约15mL/分钟、约20mL/分钟、约25mL/分钟、约30mL/分钟、约35mL/分钟、约40mL/分钟、约45mL/分钟、约50mL/分钟、约60mL/分钟、约70mL/分钟、约80mL/分钟、约90mL/分钟、约100mL/分钟、约200mL/分钟、约300mL/分钟、约400mL/分钟或约500mL/分钟。在各实施方式中,可将IC线路环路的流速设置为约10mL/分钟至约20mL/分钟,可将EC线路环路的流速设置为20mL/分钟至约30mL/分钟(允许介质流经氧合器并且重建氧的水平)。可以较低的流速(例如,在一些实施方式中为0.1mL/分钟)将额外的介质泵入至CES中,以更换通过气体交换模块(诸如,气体交换器/氧合器832和918)蒸发的介质。在各实施方式中,EC环路去除细胞废物,并且IC环路在介质中包含生长因子。
CES在不同的生长条件和标准中可提供很大的灵活性。通过使介质持续循环,可以使细胞在IC环路中保持悬浮。或者,可停止介质的循环,以使细胞沉淀。通过超滤可将新鲜的介质加入至IC环路中,以在不去除细胞的情况下容纳超额体积。EC介质的循环允许气体、营养物、废弃产物进行交换,并且允许在不去除细胞的情况下添加新介质。
扩增的细胞可包括贴壁细胞、非贴壁细胞或现有技术中的细胞的任意组合的共培养。可在CES的实施方式中生长的细胞的非限制性实例包括(非限制性的)干细胞(例如间充质细胞、造血细胞等)、成纤维细胞、角质细胞、祖细胞、其他完全分化的细胞,以及它们的组合。
在实施方式中,为了收获贴壁细胞,可将IC介质和EC介质替换成无二价阳离子的介质(例如,无二价阳离子的PBS)。在一个实施方式中,可将胰蛋白酶加载至第一循环路径中,并且与贴壁细胞一起孵育一段时间(在一些实施方式中,一起孵育约5分钟至约10分钟)。随后,可从系统中冲洗掉胰蛋白酶。通过增加流过细胞生长腔室的流速向细胞施加剪切力,并且可将从细胞生长腔室中释放的贴壁细胞泵入至细胞收获袋中。
当扩增非贴壁细胞时,可从循环IC线路冲洗出细胞。贴壁细胞保持在细胞生长腔室中,而去除了非贴壁细胞。
CES可用于进行各种细胞扩增方法。在一个实施方式中,可扩增接种的细胞群。将细胞引入或接种至CES中。在某些情况下,可使中空纤维的管腔处于允许细胞附着的适当条件。随后,将细胞加入至细胞生长腔室中,并且贴壁细胞附着至中空纤维,而非贴壁细胞(例如造血干细胞或HSC)并不附着。可从系统中冲洗出非贴壁细胞。在孵育一段时间之后,贴壁细胞可被释放并收获。
在实施方式中,细胞扩增系统的细胞生长腔室包括中空纤维膜,中空纤维膜由将第一流体循环路径和第二流体循环路径隔开的多个半通透的中空纤维组成。
CES可包括一装置,该装置通过将其附接至旋转和/或侧向摇动的装置,被配置为相对于细胞扩增系统的其它组件移动或“摇动”细胞生长腔室。图1D示出了这样的一个装置,其中,生物反应器400与两个旋转摇动组件和一个侧向摇动组件旋转相连。
第一旋转摇动装置组件402使生物反应器400绕生物反应器的中心轴线410旋转。生物反应器400还与侧向摇动装置404连接。旋转摇动装置组件402与生物反应器400旋转相联。旋转摇动装置402随后使生物反应器400绕生物反应器的中心轴线410旋转。旋转可沿顺时针方向进行或沿逆时针方向进行。生物反应器400可沿单一方向绕中心轴线410以顺时针方向或逆时针方向连续地旋转。或者,生物反应器400可以交替的方式旋转,绕中心轴线410首先顺时针旋转,随后逆时针旋转。
CES还可包括第二旋转摇动组件,该第二旋转摇动组件使生物反应器400绕旋转轴线412旋转。旋转轴线412穿过生物反应器400的中心点并且与中心轴线410正交。生物反应器400可沿单一方向绕旋转轴线412以顺时针方向或逆时针方向连续地旋转。或者,生物反应器400可以交替的方式旋转,绕旋转轴线412首先顺时针旋转,随后逆时针旋转。在各实施方式中,生物反应器400也可绕旋转轴线412旋转,并且位于相对于重力的水平取向或竖直取向上。
侧向摇动组件404与生物反应器400侧向相联。侧向摇动组件404的平面沿-x方向和-y方向侧向移动。因此,随着含细胞的介质在中空纤维中的运动,降低了细胞在生物反应器400中的沉淀。
摇动装置的旋转运动和/或侧向移动可降低装置内细胞的沉淀并且降低细胞被捕获在生物反应器400的一部分内的可能性。根据斯托克(Stoke)定律,细胞在细胞生长腔室(例如生物反应器400)中的沉淀速度与细胞和悬浮液介质之间的密度差异成比例。在某些实施方式中,进行如上所述的重复的具有暂停的180°旋转(快)(具有30秒的总组合时间)使非贴壁的血红细胞保持悬浮。在一些实施方式中,进行约180°的最小旋转;然而,在其它实施方式中,可利用高达360°或更大角度的旋转。可独立地或以任意组合使用不同的摇动组件。例如,使生物反应器400绕中心轴线410旋转的摇动部件可与使生物反应器400绕轴线412旋转的摇动组件相组合。同样地,也可以以任意组合,独立地进行绕不同轴线的顺时针旋转和逆时针旋转。
应注意,上述摇动装置和它们的组件可应用在使用任意适当结构的实施方式中。例如,在实施方式中,一个或多个马达可用作摇动装置,或摇动装置的组件(例如402和404)。在一个实施方式中,摇动装置可使用于2013年3月19日递交的美国专利8,339,245,名称为《细胞扩增系统的细胞生长腔室的旋转系统及其使用方法(ROTATION SYSTEM FORCELL GROWTH CHAMBER OF A CELL EXPANSION SYSTEM AND METHOD OF USE THEREFOR)》中示出和描述的实施方式中的摇动装置,该专利通过引用而整体并入本文中,就如其全文呈现在本申请中一样。
图2B和图2A中描绘了细胞生长腔室的实施方式,其中描绘了中空纤维细胞生长腔室200(可被称为“生物反应器”)的侧剖视图和侧视图。细胞生长腔室200被装在细胞生长腔室壳体202中。细胞生长腔室壳体202进一步包括四个开口或端口:进入端口204、排出端口206、进入端口208和排出端口210。
第一循环路径中的流体通过进入端口204进入细胞生长腔室200,进入且穿过多个中空纤维212的内毛细管侧(在各实施方式中被称为,中空纤维膜的内毛细管(“IC”)侧或“IC空间”),并且通过排出端口206流出细胞生长腔室200。术语“中空纤维”、“中空纤维毛细管”以及“毛细管”可互换使用。多个中空纤维212一起被称为“膜”。第二循环路径中的流体通过进入端口208流入细胞生长腔室中,与中空纤维212的外部(也被称为膜的“EC侧”或“EC空间”)相接触,并经由排出端口210离开细胞生长腔室200。细胞可被包含在第一循环路径或第二循环路径内,并且可在膜的IC侧或EC侧。
尽管细胞生长腔室壳体202的形状被描绘为圆柱形,但是它可具有本领域已知的任意形状。细胞生长腔室壳体202可由任意类型的生物相容性聚合物材料制成。其它各种细胞生长腔室壳体可具有不同的形状和尺寸。
本领域技术人员应知晓的是,术语“细胞生长腔室”并不意味着在CES中生长或扩增的所有细胞都生长在细胞生长腔室中。在许多实施方式中,贴壁细胞可附着至布置在生长腔室中的膜,或可生长在相关联的管道内。非贴壁细胞(也被称为“悬浮细胞”)也可生长。细胞可在第一流体循环路径或第二流体循环路径内的其它区域中生长。
例如,中空纤维212的端部可通过连接材料(在本文也被称为“灌封”或“灌封材料”)在细胞生长腔室200的侧面被灌封。灌封可为用于粘合中空纤维212的任意合适的材料,只要不阻塞介质和细胞进入中空纤维中的流动,并且穿过IC进入端口流入细胞生长腔室200中的液体仅流入中空纤维212中。示例性的灌封材料包括但并不限于聚氨酯以及其它合适的粘合或粘着组分。在各实施方式中,也可在每一端部通过垂直于中空纤维212的中心轴线切割中空纤维212和灌封,以使流体流入和流出IC侧。端部帽214和端部帽216被布置在细胞生长腔室的端部。
经由进入端口208进入细胞生长腔室200的流体与中空纤维212的外部相接触。中空纤维细胞生长腔室的这一部分也被称为“外毛细管(EC)空间”。小分子(例如水、氧、乳酸盐等)可穿过中空纤维212从中空纤维的内部扩散至EC空间,或从EC空间扩散至IC空间。大分子量的分子诸如生长因子通常太大而不能穿过中空纤维212,从而保持在中空纤维的IC空间中。在细胞生长在IC空间中的实施方式中,EC空间用作介质储存器,以为细胞供应营养物并且除去细胞代谢的副产物。根据需要可更换介质。介质也可穿过氧合器循环,以交换所需的气体。
在各实施方式中,可通过各种方法(包括注射)将细胞加载至中空纤维212中。也可从流体容器(例如袋子),将细胞引入到细胞生长腔室中,其中该流体容器可与细胞生长腔室流体相连。
中空纤维212被配置为允许细胞生长在纤维的内毛细管空间(即,中空纤维管腔的内部)中。中空纤维212足够大,能允许细胞附着在管腔上,而基本上不阻碍介质穿过中空纤维管腔的流动。在各实施方式中,中空纤维的内直径可大于或等于约10000微米、约9000微米、约8000微米、约7000微米、约6000微米、约5000微米、约4000微米、约3000微米、约2000微米、约1000微米、约900微米、约800微米、约700微米、约650微米、约600微米、约550微米、约500微米、约450微米、约400微米、约350微米、约300微米、约250微米、约200微米、约150微米或甚至约100微米。同样地,中空纤维的外直径可小于或等于约10000微米、约9000微米、约8000微米、约7000微米、约6000微米、约5000微米、约4000微米、约3000微米、约2000微米、约1000微米、约900微米、约800微米、约700微米、约650微米、约700微米、约650微米、约600微米、约550微米、约500微米、约450微米、约400微米、约350微米、约300微米、约250微米、约200微米、约150微米或甚至约100微米。在一些实施方式中,中空纤维壁的厚度应当足以允许小分子进行扩散。
只要中空纤维能与细胞生长腔室的进入端口和排出端口流体相连,则可在细胞生长腔室中使用任意数目的中空纤维。在各实施方式中,细胞生长腔室可包括数目大于或等于约1000、约2000、约3000、约4000、约5000、约6000、约7000、约8000、约9000、约10000、约11000或约12000个中空纤维。在其它实施方式中,细胞生长腔室可包括数目小于或等于约12000、约11000、约10000、约9000、约8000、约7000、约6000、约5000、约4000、约3000或甚至约2000个中空纤维。在其它各实施方式中,中空纤维的长度可大于或等于约100毫米、约200毫米、约300毫米、约400毫米、约500毫米、约600毫米、约700毫米、约800毫米或约900毫米。在实施方式中,细胞生长腔室含有约9000个中空纤维,这些中空纤维具有约295mm的平均长度、215微米的平均内直径以及315微米的平均外直径。
中空纤维可由任何能形成如下尺寸的材料构成,该尺寸足以形成能够将液体从细胞生长腔室进入端口运输至细胞生长腔室排出端口的纤维。在各实施方式中,中空纤维可由塑料附着材料构成,该塑料附着材料能够粘合某些种类的细胞,诸如贴壁干细胞(例如MSC)。在各其它实施方式中,中空纤维可经诸如纤连蛋白的化合物进行处理,以形成附着表面。
在某些实施方式中,中空纤维可由半通透的生物相容性聚合材料制成。这样的一种可使用的聚合材料为聚酰胺、聚芳醚砜和聚乙烯吡咯烷酮的共混物(在本文中也被称为“PA/PAES/PVP”)。半通透膜允许营养物、废物和溶解的气体穿过在EC空间和IC空间之间的膜进行转移。在各实施方式中,选择中空纤维膜的分子转移特性,以最大限度地降低从中空纤维中丢失细胞生长所必需的昂贵试剂(诸如生长因子、细胞因子),同时允许代谢废弃产物穿过膜扩散进入中空纤维管腔侧而被去除。
在某些变型中,每一PA/PAES/PVP中空纤维的一个外层的特征在于,具有限定表面粗糙度的均匀且开孔的结构。孔的开口尺寸可在约0.5微米至3微米的范围内,并且在纤维外表面上的孔的数目可在约10000个孔/mm2至约150000个孔/mm2的范围内。该外层具有约1微米至约10微米的厚度。在每个中空纤维中的下一层为具有海绵结构形式的第二层,并且在实施方式中具有约1微米至约15微米的厚度。该第二层可用作外层的支撑。紧挨着第二层的第三层可具有指状结构的形式。该第三层提供了机械稳定性和高孔隙体积,使得膜在穿过膜运输分子时具有较低的阻力。在使用期间,指状孔隙充满流体,并且与具有较低空隙体积的海绵填充结构的基质相比,该流体为扩散和对流给出了较低的阻力。该第三层可具有约20微米至约60微米的厚度。
在进一步的实施方式中,中空纤维膜可包括在约65wt%至95wt%之间的至少一种疏水性聚合物,以及在约5wt%至约35wt%之间的至少一种亲水性聚合物。疏水性聚合物可选自由聚酰胺(PA)、聚芳酰胺(PAA)、聚芳醚砜(PAES)、聚醚砜(PES)、聚砜(PSU)、聚芳砜(PASU)、聚碳酸酯(PC)、聚醚、聚氨酯(PUR)、聚醚酰亚胺,以及任意上述聚合物的共聚物混合物(诸如聚醚砜,或聚芳醚砜和聚酰胺的混合物)所组成的组。在进一步的实施方式中,亲水性聚合物可选自由聚乙烯吡咯烷酮(PVP)、聚乙二醇(PEG)、聚乙二醇单酯、水溶性纤维衍生物、聚山梨醇酯和聚乙烯-聚丙烯氧化物共聚物所组成的组。
根据要在细胞生长腔室中扩增的细胞的类型,可使用诸如纤连蛋白的物质对聚合物纤维进行处理,以增强细胞生长和/或细胞对膜的附着。
现参考图3,示出了另一细胞生长腔室的实施例,生物反应器300的侧剖视图。生物反应器300具有纵轴线LA-LA,并且包括生物反应器壳体304。在至少一个实施方式中,生物反应器壳体304包括四个开口或端口:IC进入端口308、IC排出端口320、EC进入端口328以及EC排出端口332。
第一循环路径中的流体通过在生物反应器300的第一纵向端部312处的IC进入端口308进入生物反应器300,进入且穿过多个中空纤维316的内毛细管侧(在各种实施方式中被称为中空纤维膜的内毛细管(“IC”)侧或“IC空间”)并且通过位于生物反应器300的第二纵向端部324处的IC排出端口320流出生物反应器300。第二循环路径中的流体通过EC进入端口328流入生物反应器300中,与中空纤维316的外毛细管侧或外部(也被称为膜的“EC侧”或“EC空间”)相接触,并且经由EC排出端口332离开生物反应器300。经由EC进入端口328进入生物反应器的流体与中空纤维的外部相接触。小分子(例如水、氧、乳酸盐等)可穿过中空纤维从中空纤维的内部扩散至EC空间,或从EC空间扩散至IC空间。大分子量的分子诸如生长因子通常太大而不能穿过中空纤维,从而保持在中空纤维的IC空间内。可以根据需要更换介质。介质也可穿过氧合器循环,以交换所需的气体。细胞也可被包含在第一循环路径和/或第二循环路径中,并且可在膜的IC侧和/或EC侧。通过示例性且非限制性的方式,在一个实施方式中,生物反应器300可包括约11520个具有215×10-6m的内直径(ID)的纤维。
尽管生物反应器壳体304被描绘为圆柱形,但是其可具有各种形状,诸如长方体。生物反应器壳体304可由任意类型的生物相容性聚合物材料制成,包括基本透明的材料,以允许观察者观察多个中空纤维316中的一个或多个以及在生物反应器壳体304内的流体。各种其它的生物反应器壳体可具有不同的形状和尺寸。
现在参考图4,示出了CES430的一部分的透视图,该CES430的一部分包括CES430的主体408的后部434。为了清晰起见,主体408的前部未示出,然而,前部诸如通过铰链438附接至后部434,从而允许前部包括门或舱口,可打开该门或舱口以进入CES430的生物反应器300。管道和取样端口420的线管416可附接至生物反应器300。在生物反应器300附近的环境为温控的,以为细胞生长提供合适的条件。
现在参考图5,示出了描述与使用CES相关的细胞扩增程序的一个实施方式的流程图500,其中包括与在生物反应器(例如生物反应器300)中加载和分布细胞相关的步骤,下面将进行进一步描述。尽管CES(例如CES430)的特征被描述为执行流程图500的一些步骤,但是本发明并不限于此。事实上,一些实施方式中,可利用具有不同的特征的其它CES,这些特征未在本文中描述或在上面描述(例如CES10、CES800或CES900)。因此,参考CES430(诸如生物反应器300)的特征仅提供用于解释说明的目的,流程图500并不限于用于任何特定的CES。
流程图500起始于502并且转到504,其中生物反应器300和任意相关联的管道以及相关的结构与主体408连接,以提供可操作的CES430。一旦与主体408连接,在508处,利用合适的预补液(priming fluid)(诸如生理盐水)启动生物反应器300和其相关联的管道和相关的结构。在512处,将细胞加载到生物反应器300中,并且进行分布。
在实施方式中,细胞的加载和分布涉及许多子步骤,例如,在一些实施方式中,步骤512额外地包括可选子步骤:在可选子步骤516处,使生物反应器300定向在第一取向;随后,在可选子步骤520处,将细胞加载到生物反应器300中并且进行分布。在可选子步骤524处,可允许细胞附着至生物反应器。
将细胞加载到生物反应器300中并且进行分布之后,在528处细胞进行扩增。也就是说,允许生物反应器300中的细胞进行扩增,即生长和/或增殖。在532处,对是否需要将额外的细胞加入至生物反应器300中,和/或是否需要旋转生物反应器300以在生物反应器300内分布细胞进行评价。如果需要将额外的细胞加载至生物反应器300中,和/或如果需要在生物反应器300中进行细胞的分布,则随后流程图500返回至步骤512。如果不需要加入细胞和/或不需要旋转生物反应器300,则在536处对细胞扩增程序528是否完成进行评价。如本文所使用的,如果已经达到了足够数目的细胞和/或已经实现了细胞特性的改变,则确定细胞扩增程序完成。如果细胞扩增程序528完成,则在540处收获细胞。如果细胞扩增程序528没有完成,则随后允许在528处继续进行细胞扩增程序。流程图500终止于544。
现在将提供与程序有关的其他细节,该程序在一些实施方式中,可用于在生物反应器和CES中加载、分布和扩增细胞,例如步骤512和步骤528(图5)。图6和图7示出可用于加载、分布、附着和扩增细胞的一些程序的流程图。可作为流程图500的程序的一部分进行这些程序,例如上述步骤(例如步骤512和步骤528)的子步骤。在其他实施方式中,可在不考虑流程图500中所述步骤的情况下,执行流程图600和流程图700所述的程序。此外,下面可将流程图600和流程图700中的步骤描述为通过CES或其部分(例如CES10、CES800、CES900)来执行或关于CES或其部分(例如CES10、CES800、CES900)来执行,其中CES或其部分(例如CES10、CES800、CES900)包括多个组件(例如用作摇动组件402和摇动组件404的马达)、生物反应器(例如生物反应器24、生物反应器300、生物反应器400、生物反应器801或生物反应器908),或生物反应器的多个部件。本说明书并不在于限制流程图600和流程图700,在实施方式中,流程图600和流程图700的步骤可通过或关于其他系统、装置、组件或零件来执行。
流程图600起始于604,并且转到步骤608,在步骤608中含细胞的流体可穿过生物反应器(诸如生物反应器300)(参见图3和图8~图12)循环。在实施方式中,步骤608可涉及启动一个或多个泵,以使流体穿过生物反应器300循环。例如,可启动IC循环泵(例如812或911),以使流体以第一循环流速穿过生物反应器300的IC侧循环。在至少一个实施方式中,携带细胞的流体可从IC侧经过生物反应器300的中空纤维流至EC侧。在其他实施方式中,可将细胞加载到生物反应器300的EC侧中,并且使携带细胞的流体从EC侧流至IC侧。在这些实施方式中,可启动EC循环泵(例如828或974),以使流体以第一循环流速穿过生物反应器300的EC侧
在一些实施方式中,步骤608还可涉及使生物反应器300以特定顺序旋转,辅助细胞穿过生物反应器300和可与生物反应器300流体相连的CES的循环路径进行分布。在于2010年12月15日递交的美国专利申请序列号12/968,483,名称为“在细胞扩增系统的生物反应器中加载和分布细胞的方法(METHOD OF LOADING AND DISTRIBUTING CELLS IN ABIOREACTOR OF A CELL EXPANSION SYSTEM)”中描述了用于使生物反应器300以特定顺序旋转以在循环或加载过程中辅助细胞分布的实施方式的实例,该专利申请通过引用整体并入本文中,就如其全文呈现在本申请中一样。在其他实施方式中,循环步骤608可涉及在一些时间段中使生物反应器300旋转,而在其他时间段中使生物反应器300维持静止。
在步骤608之后,在步骤612降低流体循环速度。可将循环速度降低至约零(0)ml/min,或者在其他实施方式中,可将循环速度降低至高于零(0)ml/min,但仍然允许细胞沉淀并且附着至生物反应器300(例如生物反应器300的中空纤维316的内表面)的速度。在实施方式中,步骤612可涉及停止或关闭一个或多个在步骤608中使用以使流体循环的泵。
流程从步骤612转到可选步骤616,可执行可选步骤616以将生物反应器(例如生物反应器300)的方向调整至初始取向。在实施方式中,可能已经将生物反应器调整为初始取向,这样使得步骤616是不必要的。当执行时,可通过实施方式中的一个或多个马达执行步骤616。
现在参考图8~图12,图8中示出的生物反应器300位于初始取向。作为可选步骤616的一部分,可以使生物反应器300处于起始取向的纵向轴线LA-LA来定向,所述起始取向例如如图8中示出的第一水平取向。
流程从步骤616转到步骤620,在步骤620中,将生物反应器维持在第一取向以允许细胞沉淀,并且在一些实施方式中,允许细胞附着至生物反应器300的第一区。执行步骤620,持续第一预定时间段。
现在参考图13A~图13C,这些附图示出中空纤维1300的(取与中空纤维1300的中心轴线和生物反应器300的中心轴线垂直的)横截面,该中空纤维1300可以是生物反应器300的中空纤维316中的一个。这些附图示出在流程图600的一些步骤期间,细胞在中空纤维316内的可能的位置。如图13A所示,在实施方式中,在步骤612处降低循环速度之前,各中空纤维1300内的细胞可均匀分布在中空纤维1300容积的各个部分中。当降低循环速度时,细胞开始受到重力1304的影响,并且开始沉淀。
在实施方式中,随着生物反应器300处于第一水平取向(图8),允许生物反应器300内的细胞沉淀在生物反应器的第一区上。如图13B所示,生物反应器300的第一区可至少包括中空纤维1300的区1308。在实施方式中,允许细胞沉淀第一预定时间段(流程图600的步骤620),可对该第一预定时间段进行选择,使得不仅允许细胞沉淀,而且还允许细胞附着至中空纤维1300的区1308。
在一些实施方式中,第一预定时间段可以持续足够长的时间,以仅允许细胞沉淀和附着至区1308。在这些实施方式中,细胞可仅需要移动中空纤维1308的内径的距离。例如,在中空纤维具有约150微米至约300微米之间的内径的实施方式中,第一预定时间段可小于约20分钟、小于约15分钟或甚至小于约10分钟。在其他实施方式中,第一预定时间段可大于约1分钟、大于约2分钟、大于约3分钟或甚至大于约4分钟。在一个实施方式中,第一时间段可以在约3分钟至约8分钟之间,诸如约5分钟。
在其他实施方式中,第一预定时间段可以持续足够长的时间,以不仅允许细胞沉淀而且还允许细胞附着至中空纤维,该第一预定时间段可持续足够长的时间以允许附着的细胞生长。在这些实施方式中,细胞可侧向生长。因为任一侧向可提供最小的阻力。换句话说,因为如果在区1308上的细胞在纤维壁上朝上生长的话,则这些细胞要对抗重力1304进行生长,因此相信在一些实施方式中,这些细胞至少最初是侧向生长的。在这些实施方式中,当允许细胞在附着之后进行生长时,第一预定时间段可大于约5小时、大于约10小时、大于约15小时、大于约20小时或甚至大于约24小时。在其他实施方式中,第一预定时间段可小于约60小时、小于约55小时、小于约50小时或甚至小于约45小时。在一个实施方式中,上述预定时间段可在约10小时至约48小时之间。
重新参考图6,在一些实施方式中,在步骤620之后,流程转到步骤640,在步骤640中,生物反应器300从第一水平取向旋转约180度至第二水平取向。如图8~图10所示,可通过首先从第一水平取向(图8)旋转至距第一水平取向约90度的第一竖直取向,例如轴线LA-LA处于竖直取向(图9),来旋转生物反应器。然后,将生物反应器300再旋转90度(图10),以完成到第二水平取向的旋转。
在实施方式中,在旋转到第二水平取向之后,流程600可转到步骤644,在步骤644中,在生物反应器300处于第二水平取向的同时,进行细胞扩增。图13C示出在第二水平取向时,附着至中空纤维1300的细胞现在位于中空纤维1300的内侧顶部。步骤644可涉及一些子步骤,诸如将流体循环到生物反应器中,以为附着在生物反应器中的细胞供给和提供营养。可以理解的是,步骤644还可涉及为细胞提供氧气,以便它们能够增殖。可控制生物反应器中的几种其他参数,以优化扩增,即细胞的生长。在一些实施方式中,步骤644可包括使流体持续循环约24小时、约36小时、约48小时、约60小时或甚至约72小时,以饲养细胞。在一些实施方式中,作为步骤644的一部分,细胞的饲养可持续小于约120小时、小于约108小时、小于约96小时、小于约84小时或甚至小于约72小时。然后,流程600可终止于648。
在不受到理论束缚的情况下,相信在实施方式中,如果细胞如图13C所示在重力影响下生长,则能改善细胞扩增。在实施方式中,细胞可在中空纤维1300中向下生长,朝中空纤维中还没有细胞的部分生长。相信细胞可朝纤维中提供最小阻力的部分(诸如在顶部1308下面的部分,参见图13C)生长。在实施方式中,与传统工艺相比,在重力影响下的生长改善了细胞产量,并且缩短了细胞倍增的时间。
在其他实施方式中,流程600可包括额外的步骤。例如,在一些实施方式中,在步骤620之后,流程600可转到步骤624,在步骤624中,可将生物反应器628旋转至竖直取向。例如,如图9所示,可将生物反应器300旋转至第一竖直取向。在步骤624之后,流程可转到步骤628,在步骤628中,可使生物反应器在第一竖直取向上维持第二预定时间段。
现在参考图13D和图13E,这些图示出中空纤维1300的(取与中空纤维1300的中心轴线和生物反应器300的中心轴线平行的)横截面,该中空纤维1300可以是生物反应器300的中空纤维316中的一个。图13D和图13E示出在步骤620之后的中空纤维1300,其中细胞已经沉淀且附着至纤维1300的一部分上。如图13D所示,当生物反应器300旋转至第一竖直取向时,中空纤维1300的第一端部1312位于第二端部1316的上面。
如上所述,在不受到理论束缚的情况下,相信附着至纤维1300的细胞将受到重力1304的影响,开始生长,即朝端部1316纵向扩增。因此,在实施方式中,持续第二预定时间段执行步骤628(维持第一竖直取向),该第二预定时间短可持续足够长的时间以允许细胞纵向生长。在一些实施方式中,第二预定时间段可大于约5小时、大于约10小时、大于约15小时、大于约20小时或甚至大于约24小时。在其他实施方式中,第二预定时间段可小于约60小时、小于约55小时、小于约50小时或甚至小于约45小时。在一个实施方式中,上述预定时间段可在约10小时至约48小时之间。
在步骤628之后,流程可转到步骤632,在步骤632中,可将生物反应器旋转至第二竖直取向。图12中示出处于第二竖直取向的生物反应器300的一个实例。在步骤624之后,流程可转到步骤636,在步骤636中,可使生物反应器在第二竖直取向上维持第三预定时间段。
参考图13E,该图示出在步骤632之后的中空纤维1300,其中细胞已经沉淀且附着至中空纤维1300的一部分上,并且已经使生物反应器300从第一竖直取向旋转至第二竖直取向并且维持在第二竖直取向上。如图13E所示,当使生物反应器300旋转至第二竖直取向时,中空纤维1300的第一端部1312位于第二端部1316的下面。
与步骤628(维持第一竖直取向)相似,执行步骤636(维持第二竖直取向),因为相信在实施方式中,附着至纤维1300的细胞将受到重力1304的影响,开始生长,即朝端部1312纵向扩增。在实施方式中,如图13E所示,可执行步骤636,持续第三预定时间段,该第三预定时间段可持续足够长的时间以允许细胞朝端部1312纵向生长。在一些实施方式中,第三预定时间段可大于约5小时、大于约10小时、大于约15小时、大于约20小时或甚至大于约24小时。在其他实施方式中,第二预定时间段可小于约60小时、小于约55小时、小于约50小时或甚至小于约45小时。在一个实施方式中,上述预定时间段可在约10小时至约48小时之间。
重新参考流程图600,在步骤636之后,流程可转到步骤640,在步骤640中,如上所述,可使生物反应器旋转到如图11所示的第二水平位置。如上所述,流程600从步骤640转到644,在644中,细胞进行扩增,即增殖。然后,流程终止于648。
现在转到图7,流程700在704开始,然后转到步骤708,在步骤708中,含细胞的流体可穿过生物反应器(诸如生物反应器300)进行循环(参见图3和图8~图12)。在实施方式中,步骤708可包括启动一个或多个泵,以使流体穿过生物反应器300循环。例如,可启动IC循环泵(例如812或911),以使流体以第一循环流速穿过生物反应器300的IC侧循环。在至少一个实施方式中,携带细胞的流体可经过生物反应器300的中空纤维从IC侧流到EC侧。在其他实施方式中,可将细胞加载到生物反应器300的EC侧中,并且使携带细胞的流体从EC侧流到IC侧。在这些实施方式中,可启动EC循环泵(例如828或974),以使流体以第一循环流速穿过生物反应器300的EC侧循环。
在实施方式中,第一循环流速可以是相对较高的流速。在实施方式中,第一循环流速可小于约500ml/min、小于约400ml/min或甚至小于约300ml/min。在其他实施方式中,第一循环速度可大于约50ml/min、大于约100ml/min或甚至大于约150ml/min。在一个实施方式中,第一循环流速在约100ml/min至约300ml/min之间,诸如约200ml/min。
在一些实施方式中,步骤708可还涉及使生物反应器300以特定顺序旋转,以促使细胞穿过生物反应器300和CES的循环路径进行分布,其中生物反应器300可与CES的循环路径流体相连。在其他实施方式中,循环步骤708可涉及使生物反应器300在一些时间段中旋转,但使生物反应器300在其他时间段中保持静止。
在步骤708之后,在步骤712处降低流体循环速度。可将循环速度降低至约零(0)ml/min,或者在其他实施方式中,可将循环速度降低至大于零(0)ml/min但仍允许细胞沉淀且附着至生物反应器300,例如生物反应器300的中空纤维316的内表面的速度。在实施方式中,步骤712可涉及停止或关闭在步骤708中用于使流体循环的一个或多个泵。
流程从步骤712转到可选步骤716,执行可选步骤716以将生物反应器(例如生物反应器300)的方向调整为初始取向。在实施方式中,生物反应器可能已经处于初始取向,这样就不需要执行步骤716。在一些实施方式中,当执行步骤716时,可通过一个或多个马达执行步骤716。
现在参考图8~图12,在图8中示出的生物反应器300位于初始取向。作为可选步骤716的一部分,可使生物反应器300的纵向轴线LA-LA处于起始取向,例如如图8所示的水平取向。
流程从716转到步骤720,在步骤720中,使生物反应器维持在第一取向上以允许细胞沉淀,并且在一些实施方式中附着至生物反应器300的第一部分。执行步骤820,持续第一预定时间段。
现在参考图14A~图14D和图15A~图15F,这些附图示出中空纤维1400的(取与中空纤维1400的中心轴线和生物反应器300的中心轴线垂直的)横截面,该中空纤维1400可以是生物反应器300的中空纤维316中的一个。这些附图示出在流程图700的一些步骤期间,细胞在中空纤维316内的可能的位置。如图14A所示,在实施方式中,在步骤712处降低循环速度之前,各中空纤维1400内的细胞可均匀分布在中空纤维1400的整个体积。当降低循环速度时,细胞开始受到重力1404的影响,开始沉淀。图15A也示出对于中空纤维1500和重力1504的类似的情况。
在实施方式中,随着生物反应器300处于第一水平取向(图8),允许生物反应器300内的细胞沉淀在生物反应器的第一区上。如图14B和图15B所示,生物反应器300的第一区可至少包括中空纤维1400的区1408和/或中空纤维1500中的区1508。在实施方式中,允许细胞沉淀第一预定时间段,可对该第一预定时间段进行选择,使得不仅允许细胞沉淀,而且还允许细胞附着至中空纤维1400的区1408(和中空纤维1500的区1508)。
在一些实施方式中,第一预定时间段可以持续足够长的时间,以允许细胞沉淀和附着至区1408和区1508。在这些实施方式中,细胞可仅需要移动中空纤维1400或中空纤维1500的内径的距离。例如,在中空纤维具有约150微米至约300微米之间的内径的实施方式中,第一预定时间段可小于约20分钟、小于约15分钟或甚至小于约10分钟。在其他实施方式中,第一预定时间段可大于约1分钟、大于约2分钟、大于约3分钟或甚至大于约4分钟。在一个实施方式中,第一时间段可以在约3分钟至约8分钟之间,诸如约5分钟。
在步骤720之后,流程转到步骤724,在步骤724中,可使生物反应器300自第一水平取向旋转约180度至第二水平取向。如图8~图10所示,可通过首先从其第一水平取向(图8)旋转至距第一水平取向约90度的第一竖直取向,例如轴线LA-LA处于竖直取向(图9),来旋转生物反应器。然后,将生物反应器300再旋转90度(图10),以完成到第二水平取向的旋转。在一些实施方式中,可通过与生物反应器300连接的一个或多个马达来执行步骤724。这些马达可以是摇动装置的一部分。
在一些实施方式中,流程700从步骤724转到步骤736,在步骤736中,将生物反应器300在第二水平取向(图10)上维持第二预定时间段,以允许细胞沉淀至生物反应器的第二区,诸如中空纤维1400的区1412(图14C)或中空纤维1500的区1512(图15C)。
在一些实施方式中,在步骤736之前,流程700可包括可选的步骤728和步骤732。与步骤708类似,步骤728使流体穿过生物反应器300循环。在实施方式中,步骤728可涉及启动一个或多个泵,以使流体穿过生物反应器300循环。如上所述,可启动IC循环泵(例如812或911),以使流体以第二循环流速穿过生物反应器300的IC侧循环。在至少一个实施方式中,携带细胞的流体可经过生物反应器300的中空纤维从IC侧流到EC侧。在其他实施方式中,可将细胞加载到生物反应器300的EC侧中,并且使携带细胞的流体从EC侧流到IC侧。在这些实施方式中,可启动EC循环泵(例如828或974),以使流体以第二循环流速穿过生物反应器300的EC侧循环。
在实施方式中,第二循环流速可小于第一循环速度。在实施方式中,第二循环流速可小于约400ml/min、小于约300ml/min或甚至小于约200ml/min。在其他实施方式中,第二循环速度可大于约25ml/min、大于约500ml/min或甚至大于约75ml/min。在一个实施方式中,第二循环流速在约50ml/min至约150ml/min之间,诸如约100ml/min。
在一些实施方式中,步骤728可还涉及以与步骤708中的循环方向不同的方向进行循环。换句话说,在一些实施方式中,步骤708可涉及使流体以逆时针方向循环(参见图8和图9中的IC环路)。在一些实施方式中,在步骤728处的循环可以是顺时针的。换句话说,上述循环可以与步骤708处的循环相反地流动。在其他实施方式中,步骤708中的循环可以与步骤708相同的方向,顺时针或逆时针流动。
在一些实施方式中,可选步骤728还涉及使生物反应器300以特定顺序旋转,以促使细胞穿过生物反应器300和CES的循环路径进行分布,其中生物反应器300可与CES的循环路径流体相连。在其他实施方式中,循环步骤728可涉及使生物反应器300在一些时间段中旋转,但使生物反应器300在其他时间段中保持静止。
在可选步骤728之后,在步骤732处再一次降低流体循环速度。可将循环速度降低至约零(0)ml/min,或者在其他实施方式中,可将循环速度降低至大于零(0)ml/min但仍允许细胞沉淀且附着至生物反应器300,例如生物反应器300的中空纤维316的内表面的速度。在实施方式中,步骤732可涉及停止或关闭在步骤728中用于使流体循环的一个或多个泵。
再一次参考步骤736,使生物反应器维持在第二水平取向允许细胞沉淀在可与区1408相对的区1412(或图15C的1512)上,例如可将区1408(或1508)称为“底部”,而将区1412(或图15C中的1512)称为“顶部”。图14C和图15C示出细胞沉淀在区1412和区1512上,或者在一些实施方式中相反。在实施方式中,允许细胞沉淀第二预定时间段,可对第二预定时间段进行选择,以不仅允许细胞沉淀,而且还允许细胞附着至中空纤维1400的区1412(或纤维1500的1512)。
在一些实施方式中,第二预定时间段可以持续足够长的时间,以允许细胞沉淀且附着至区1412(或图15C中1512)。在这些实施方式中,细胞可仅需要移动中空纤维1400或中空纤维1500的内径的距离。例如,在中空纤维具有约150微米至约300微米之间的内径的实施方式中,第二预定时间段可小于约20分钟、小于约15分钟或甚至小于约10分钟。在其他实施方式中,第二预定时间段可大于约1分钟、大于约2分钟、大于约3分钟或甚至大于约4分钟。在一个实施方式中,第二时间段可以在约3分钟至约8分钟之间,诸如约5分钟。
在一些实施方式中,在步骤736之后,流程700可转到步骤772,在步骤772中,细胞进行扩增。步骤772可涉及许多子步骤,诸如使流体循环到生物反应器中,以为附着在生物反应器中的细胞供给和提供营养。可以理解的是,步骤772还可涉及为细胞提供氧气,以便它们能够增殖。可控制生物反应器中的几种其他参数,以优化扩增,即细胞的生长。在一些实施方式中,步骤772可包括使流体持续循环约24小时、约36小时、约48小时、约60小时或甚至约72小时以饲养细胞。在一些实施方式中,作为步骤772的一部分,细胞的饲养可持续小于约120小时、小于约108小时、小于约96小时、小于约84小时或甚至小于约72小时。然后,流程终止于776。
在其他实施方式中,流程700可转到步骤740,在步骤740中,生物反应器300旋转回到其初始的第一水平取向。图11示出已经旋转回到其第一水平取向的生物反应器300。可通过与生物反应器300连接的一个或多个马达执行步骤740。这些马达可以是摇动装置的一部分。在实施方式中,流程可从步骤740转到步骤772,在步骤772中,细胞进行扩增。然后,流程终止于776。
在其他实施方式中,流程700从步骤740转到步骤744,或在其他实施方式中,流程可直接从步骤736转到步骤744(当不执行额外旋转时),其中使流体以第三循环流速再次循环。与步骤708和步骤728类似,使流体穿过生物反应器300循环。在实施方式中,步骤744可涉及启动一个或多个泵,以使流体穿过生物反应器300循环。如上所述,可启动IC循环泵(例如812或911),以使流体以第三循环流速穿过生物反应器300的IC侧循环。在至少一个实施方式中,携带细胞的流体可经过生物反应器300的中空纤维从IC侧流到EC侧。在其他实施方式中,可将细胞加载到生物反应器300的EC侧中,并且使携带细胞的流体从EC侧流到IC侧。在这些实施方式中,可启动EC循环泵(例如828或974),以使流体以第三循环流速穿过生物反应器300的EC侧循环。
在实施方式中,第三循环流速可小于第二循环速度。在实施方式中,第三循环流速可小于约200ml/min、小于约150ml/min或甚至小于约100ml/min。在其他实施方式中,第三循环速度可大于约10ml/min、大于约20ml/min或甚至大于约30ml/min。在一个实施方式中,第三循环流速在约20ml/min至约100ml/min之间,诸如约50ml/min。
在一些实施方式中,步骤744可还涉及以与步骤728中的循环方向不同的方向进行循环。换句话说,在一些实施方式中,步骤728可涉及使流体以顺时针方向循环。在一些实施方式中,在步骤744处的循环可以与步骤708类似,并且是逆时针方向(参见图8和图9中的IC环路)。换句话说,步骤744处的循环可以与步骤728处的循环相反地流动,并且与步骤708的循环方向相同。在其他实施方式中,步骤708、步骤728、步骤744中的循环可以相同方向,顺时针或逆时针流动。
在一些实施方式中,可选步骤744还涉及使生物反应器300以特定顺序旋转,以促使细胞穿过生物反应器300和CES的循环路径进行分布,其中生物反应器300可与CES的循环路径流体相连。在其他实施方式中,循环步骤744可涉及使生物反应器300在一些时间段中旋转,但使生物反应器300在其他时间段中保持静止。
流程从744转到步骤748,在步骤748中,再一次降低流体循环速度。可将循环速度降低至约零(0)ml/min,或者在其他实施方式中,可将循环速度降低至大于零(0)ml/min但仍允许细胞沉淀且附着至生物反应器300,例如生物反应器300的中空纤维316的内表面的速度。在实施方式中,步骤748可涉及停止或关闭在步骤744中用于使流体循环的一个或多个泵。
流程从步骤748转到步骤752,在步骤752中,使生物反应器维持在水平取向。在包括步骤744(旋转到第一取向)的实施方式中,步骤752涉及维持第一水平取向。在不包括步骤740的旋转的实施方式中,步骤752涉及维持第二水平取向。在任何情况中,都执行步骤752以允许细胞再次沉淀在如区1508(参见图15D和图15E,如果执行旋转步骤740)上。在实施方式中,允许细胞沉淀第三预定时间段,可对该第三预定时间段进行选择,以不仅允许细胞沉淀,而且还允许细胞附着。
在一些实施方式中,第三预定时间段可以持续足够长的时间,以仅允许细胞沉淀和附着至区1508。在这些实施方式中,细胞可仅需要移动中空纤维1500的内径的距离。例如,在中空纤维1500具有约150微米至约300微米之间的内径的实施方式中,第三预定时间段可小于约20分钟、小于约15分钟或甚至小于约10分钟。在其他实施方式中,第三预定时间段可大于约1分钟、大于约2分钟、大于约3分钟或甚至大于约4分钟。在一个实施方式中,第三时间段可以在约3分钟至约8分钟之间,诸如约5分钟。
在一些实施方式中,流程700可从步骤752转到步骤772,在步骤772中,细胞进行扩增。图15F示出这些实施方式中的纤维1500。然后,流程终止于776。
在其他实施方式中,如下所述,在移动到扩增细胞的步骤772之前,流程700可包括额外的旋转(756)、循环(760)、降低循环(764)和维持取向(768)的步骤。在这些实施方式中,流程700可从步骤752转到步骤756,如果在步骤740旋转到第一水平取向的话,在步骤756中,使生物反应器300旋转回到第二水平取向。图10示出处于第二水平取向的生物反应器300。可通过与生物反应器300连接的一个或多个马达执行步骤756。这些马达可以是摇动装置的一部分。在一些实施方式中,如果没有执行步骤740以使生物反应器旋转到第一水平取向的话,则不需要执行这一步骤。
流程700转到步骤760,在步骤760中,流体以第四循环流速再次进行循环。与步骤708、步骤728和步骤744类似,流体穿过生物反应器300循环。在实施方式中,步骤744可涉及启动一个或多个泵以使流体穿过生物反应器300循环,如上所述,可启动IC循环泵(例如812或911),以使流体以第四循环流速穿过生物反应器300的IC侧循环。在至少一个实施方式中,携带细胞的流体可经过生物反应器300的中空纤维从IC侧流到EC侧。在其他实施方式中,可将细胞加载到生物反应器300的EC侧中,并且使携带细胞的流体从EC侧流到IC侧。在这些实施方式中,可启动EC循环泵(例如828或974),以使流体以第四循环流速穿过生物反应器300的EC侧循环。
在实施方式中,第四循环流速可小于第三循环速度。在实施方式中,第四循环流速可小于约100ml/min、小于约75ml/min或甚至小于约50ml/min。在其他实施方式中,第四循环速度可大于约5ml/min、大于约10ml/min或甚至大于约15ml/min。在一个实施方式中,第四循环流速在约15ml/min至约35ml/min之间,诸如约25ml/min。
在一些实施方式中,步骤760可还涉及以与步骤744中的循环方向不同的方向进行循环。换句话说,在一些实施方式中,步骤744可涉及使流体以逆时针方向循环。在一些实施方式中,在步骤760处的循环可以与步骤728类似,并且是顺时针方向。换句话说,步骤760处的循环可以与步骤744处的循环相反地流动,并且与步骤728的循环方向相同。在其他实施方式中,步骤708、步骤728、步骤744和步骤760中的循环可以相同方向,顺时针或逆时针流动。
在一些实施方式中,步骤760还可涉及使生物反应器300以特定顺序旋转,以促使细胞穿过生物反应器300和CES的循环路径进行分布,其中生物反应器300可与CES的循环路径流体相连。在其他实施方式中,循环步骤760可涉及使生物反应器300在一些时间段中旋转,但使生物反应器300在其他时间段中保持静止。
流程从760转到步骤764,在步骤764中,再一次降低流体循环速度。可将循环速度降低至约零(0)ml/min,或者在其他实施方式中,可将循环速度降低至大于零(0)ml/min但仍允许细胞沉淀且附着至生物反应器300,例如生物反应器300的中空纤维316的内表面的速度。在实施方式中,步骤764可涉及停止或关闭在步骤760中用于使流体循环的一个或多个泵。
流程从步骤764转到步骤768,在步骤768中,使生物反应器维持在第二水平取向上,以允许细胞再次沉淀在例如区1512上(参见图15F)。在实施方式中,允许细胞在第四预定时间段期间进行沉淀,可对第四预定时间段进行选择,以不仅允许细胞沉淀而且还允许细胞再次附着。
在一些实施方式中,第四预定时间段可以持续足够长的时间,以允许细胞沉淀和附着。在这些实施方式中,细胞可仅需要移动中空纤维(例如纤维1500)的内径的距离。例如,在中空纤维1500具有约150微米至约300微米之间的内径的实施方式中,第四预定时间段可小于约20分钟、小于约15分钟或甚至小于约10分钟。在其他实施方式中,第四预定时间段可大于约1分钟、大于约2分钟、大于约3分钟或甚至大于约4分钟。在一个实施方式中,第四时间段可以在约3分钟至约8分钟之间,诸如约5分钟。
在步骤768之后,流程700转到步骤772,在步骤772中,沉淀且附着至生物反应器300(例如生物反应器的中空纤维)的细胞进行扩增,即增殖。然后,流程700终止于776。
在不受到理论束缚的情况下,相信在实施方式中,如果执行流程700的步骤,则能改善细胞扩增。相信这些实施方式有助于在细胞扩增之前,在生物反应器的更多部分,例如生物反应器中的中空纤维的表面接种细胞。与传统工艺相比,这样可初始接种更多的细胞,并且最终改善细胞产量并且缩短细胞倍增的时间。
尽管流程700包括提供旋转、循环、降低循环和维持生物反应器的取向的特定数目的步骤,但是其他实施方式并不限于这些特定数目的步骤。在其他实施方式中,甚至在步骤768之后,也可使生物反应器再次旋转,再次启动循环,然后进行降低循环的另一阶段,以允许细胞沉淀,并且维持取向一段时间以允许细胞附着至生物反应器的一部分。可将这些步骤执行任意次数。在实施方式中,每次启动循环时,该循环的速度都小于之前的循环。在其他实施方式中,循环速度可以在每次启动的循环中都是相同的。在另外一些实施方式中,可以改变循环的方向,其中一循环为第一方向,然后终止该循环以允许细胞沉淀和附着,然后以与第一方向相反的方向(顺时针对逆时针)进行循环并且再次终止循环以允许细胞沉淀。
现在参考图16,示出了生物反应器(例如生物反应器300)的横截面1600(与中心轴线垂直)。横截面1600示出可在壳体1604内的多个中空纤维1608。横截面1600取自生物反应器的一个末端,除了中空纤维1608之外,横截面1600还示出将中空纤维1608保持在一起的基质材料1628(如上可被称为灌封材料)。
图16还示出区域1612、1616、1620和1624。这些区域代表其中可能有流体以不同流速循环穿过其中的纤维。换句话说,在不受到理论束缚的情况下,相信处于相对较高流速的循环可主要流经纤维的区域1612,其中相对较高流速诸如可在循环步骤708或步骤728(图7)中使用的速度。在不受到理论束缚的情况下,相信较高流速不能使流体分散到足以允许均匀流到中空纤维的外区域中。随着流速降低(诸如在步骤744和步骤760中),相信流体可分散到中空纤维的外区域中,诸如区域1616、区域1620和区域区域1624。
相应地,在不受到理论束缚的情况下,相信通过步骤708、步骤728、步骤744和步骤752以不同流速进行循环,允许流体比仅使用一种流速要流经更多的中空纤维1608。在按照流程图700进行的工艺的一个实施方式中,在步骤708(处于上述流速)时,流体可流经中空纤维的区域1612。在步骤728(处于上述流速)时,因为速度较慢并且流体可更加分散,因此流体可流经中空纤维的区域1612和区域1616。在步骤744(处于上述流速)时,因为流速更慢并且流体甚至更加分散,因此流体可流经中空纤维的区域1612、区域1616和区域1620。在步骤752(处于上述流速)时,因为流速甚至更慢并且流体可分散至所有纤维的各个区域,因此流体可流经中空纤维的所有区域1612、区域1616、区域1620和区域1624。因此,相信与使用单一高流速循环相比,使用一系列的不同流速可使含细胞的流体流入更多的中空纤维中。
此外,还相信不同的流速还可影响细胞沿生物反应器(即沿中空纤维)的纵向分布。也就是说,较高的流速可允许细胞沿中空纤维内侧流动地更远。例如,在较高流速时,被流体携带的细胞可达到中空纤维长度的一半之外。在较低流速时,被流体携带的细胞可达到中空纤维长度的一半。在甚至更低的流速时,被流体携带的细胞可达到小于中空纤维长度一半。因此,在一些实施方式中,相信使用不同流速可在细胞沿生物反应器(例如中空纤维)的长度纵向分布上得到一些改善。
注意到,在参考流程图500、流程图600和流程图700描述的实施方式可用于扩增任意类型的细胞,该任意类型的细胞的一些非限制性实例包括干细胞(间充质细胞、造血细胞等)、成纤维细胞、角质细胞、祖细胞、内皮细胞、其他完全分化的细胞,以及它们的组合。可使用具有不同特征和特征的组合的工艺来扩增不同细胞,其中一些可包括参考流程图500、流程图600和/或流程图700所述的步骤。
尽管流程图500(图5)、流程图600(图6)和流程图7(图7)描述了以特定顺序列出的步骤,但本发明并不限于此。在其他实施方式中,例如在另一步骤之前和之后,可以不同顺序、平行或以任意不同的次数执行各步骤。另外,如上所述,流程图500、流程图600和流程图700可包括一些可选步骤或子步骤。但是,不应将上面不是作为可选步骤示出的那些步骤认为对于本发明是必需的,而是可以在本发明的一些实施方式中执行,而在其他实施方式中不执行。
最后,图17示出基础计算机系统1700的示例性组件,在该基础计算机系统1700上可执行本发明的实施方式。计算机系统1700可执行用于加载和分布细胞的方法中的一些步骤。系统1700可以是用于控制特征的控制器,所述特征例如为上述在其中加载且分布了细胞以进行扩增的CES系统10、430、800和900的流动控制装置、泵、阀、生物反应器的旋转、马达等。
计算机系统1700包括输出装置1704和/或输入装置1708。输出装置1704可包括一个或多个显示器,包括CRT、LCD和/或等离子体显示器。输出装置1704还可包括打印机、扬声器等。输入装置1708可包括键盘、触摸输入装置、鼠标、语音输入装置等。
根据本发明的实施方式,基础计算机系统1700还可包括处理元件1712和/或存储器(memory)1716。处理元件1712可为通用处理器,可操作地用于执行存储器1716中存储的指令。根据实施方式,处理元件1712可包括一个处理器或多个处理器。进一步地,在实施方式中,每个处理器都可为具有一个或多个核的多核处理器,以读取和执行独立的指令。上述处理器可包括通用处理器、专用集成电路(ASIC)、现场可编程门阵列(FPGA),其它集成电路。
根据实施方式,存储器1716可包括用于短期存储或长期存储数据和/或处理器可执行指令的任意有形介质。存储器1716可包括例如随机存取存储卡(RAM)、只读存储卡(ROM)或电可擦除可编程只读存储卡(EEPROM)。其它存储介质可以包括例如CD-ROM、磁带、数字多功能盘(DVD)或其它光学存储器,磁带、磁盘存储器、磁带、其它磁存储装置等等。在实施方式中,系统1700可用于控制生物反应器300的旋转和/或CES系统的各流动控制装置、泵、阀等。存储器1716可存储方案1720和程序1724,诸如将细胞加载和分布在生物反应器中的方案和程序,能够控制循环泵、阀、生物反应器的旋转等的运行。
贮存器(storage)1728可以上任意的长期数据存储装置或组件。根据实施方式,贮存器1220可包括连同存储器1716一起描述的一个或多个系统。贮存器1728可为永久的或可擦除的。在实施方式中,系统1700为CES的一部分,并且贮存器1728可存储利用CES系统加载、分布、附着、扩增和收获各种类型的细胞的各种方案。
实施例
下面,描述本发明的具体实施方式的一些实例。但是,应注意尽管下面根据一些实施方式,描述了例如用于为CES(即细胞扩增系统)提供程序的具体参数、特征和/或数值,但是提供这些具体参数、特征和/或数值仅为了示例目的,本发明并不限于下面提供的具体细节。
实施例1
本研究的目的是描绘使用两种独特的细胞接种方法,使来源于人类骨髓的间充质干细胞(hMSC)在细胞扩增系统中进行扩增。
目前,用于预先选定的hMSC的QUANTUM细胞扩增系统上使用的细胞加载程序经由均匀的细胞悬浮液将细胞分布在生物反应器中。将细胞加载到QUANTUM细胞扩增系统的IC循环环路中,然后以相对较高的流速(200mL/min)循环2分钟。该循环方法,同时伴随有目的的生物反应器运动,得到细胞的均匀悬浮液。一旦使细胞均匀悬浮,则循环和生物反应器的运动停止,从而使细胞沉淀在生物反应器的表面上。
该细胞加载程序的一个限制是,仅将细胞接种至生物反应器纤维的凹槽中。hMSC常常以特定细胞密度(例如500个细胞/cm2)进行接种。当确定要加载的细胞的适当数目时,为了实现特定的接种密度,只能考虑生物反应器表面积的约50%。在500个细胞/cm2时,QUANTUM细胞扩增系统生物反应器可接种10.5E+06个细胞(500个细胞/cm2x 21000cm2)。但是,由于现有细胞加载方案的上述机械性,仅可认为生物反应器表面积的50%是“能接种的”。此外,为了利用生物反应器的“不能接种的”表面,尝试迁移至该表面的扩增细胞必须要克服重力。本文建立的理论是,与在培养瓶对应部分中扩增的那些细胞群相比,迁移细胞可能采取阻力最小的路径,从而得到细胞群内的快速汇合。
总共七个无菌的具有生物反应器的Quantum CES一次性套件可经纤连蛋白包被(5mg)过夜。所有的Quantum系统都可接种预培养的hMSC。一个Quantum细胞扩增系统可使用现有的循环作业加载(Load with Circulation Task),并且用作实验对照。三个Quantum细胞扩增系统可使用“循环作业加载:改型1”(改型1),而且三个Quantum细胞扩增系统可使用循环作业加载:改型2”(改型2)。
一次性套件:所有生物反应器都整合在QUANTUM细胞扩增系统(CES)一次性套件中,并且经环氧乙烷进行消毒。
细胞来源和密度:可使用的生物反应器可具有2.1m2的内(IC)表面积。可能需要基于IC环路的生物反应器的体积分数,对对照培养瓶的接种密度进行调整。所有生物反应器可均匀接种来自直接重加载的相同细胞来源的最高20E+06预先选定的MSC(存在1~3次传代)。优选来自一个供体的细胞。作为用于对比目的的生物反应器,以每cm2相同密度的hMSC接种三(3)个T25对照培养瓶。
CES介质IC进入Q管理&收获:当葡萄糖水平低于70mg/dL时,介质供给速度(IC进入Q)可加倍;如果葡萄糖值继续低于70mg/dL,则IC进入Q可在一天期间再次加倍。可同时并且不晚于第8天,收获所有的一次性条件,以限制潜在的聚集。可根据细胞培养物显示的代谢特征,来决定细胞收获时间。目标收获时间可以是细胞的对数生长后期。
收获后的评估:可对每一收获产物进行评估。这些评估可包括细胞计数和存活力。
Quantum CES细胞加载改型1
可使用下面以粗体示出的改型,执行目前的细胞加载程序。在允许细胞附着5分钟之后,可使所有生物反应器旋转180度以允许细胞沉淀在中空纤维膜的顶部,持续额外的5分钟。然后,使生物反应器旋转回到初始的水平位置,并且进行扩增方案。该改型的基本原理是使细胞在生物反应器中空纤维的整个表面积上进行分布。
天:0使用一次(1)旋转使细胞附着
目的:使贴壁细胞能附着至生物反应器的膜上,同时允许在EC循环环路中进行流动。可将至IC环路的泵流速设置为零。
表1描述了当使细胞附着时,可与每一管线附接的溶液袋。这些溶液和对应的体积可基于该任务的默认设置。
表1:使细胞附着的改型1的溶液
表1:用于使细胞附着的溶液
细胞路径:任务>加载和附着>使细胞附着
输入在方案表2a~2c中示出使细胞附着的每一设置的数值。
表2a:任务>加载和附着>使细胞附着,步骤1改型1
表2b:任务>加载和附着>使细胞附着,步骤2改型1
表2c:任务>加载和附着>使细胞附着,步骤3改型1
Quantum CES细胞加载改型2
可使用下面以粗体示出的改型,执行目前的细胞加载程序、预先选定的MSC扩增方案。在细胞附着期间(18~24小时),通过使生物反应器旋转至180度位置,可使细胞附着至中空纤维的顶部。然后,使生物反应器旋转回到初始位置,并且进行扩增方案。该改型的基本原理是在细胞扩增期间,使重力影响细胞朝空的生长表面迁移的方向。
重力可用于“影响”扩增期间的细胞迁移。这可通过如在目前细胞加载程序中所述的接种细胞,然后在扩增期间可使生物反应器旋转180°来完成。在这种配置中,生物反应器的未被占据的生长表面在接种的细胞的下方。然后,细胞朝最小阻力方向(例如在重力的帮助下朝下)进行扩增。
天:0使用一次(1)旋转使细胞附着
目的:使贴壁细胞能附着至生物反应器的膜上,同时允许在EC循环环路中进行流动。可将至IC环路的泵流速设置为零。
表5描述了当使细胞附着时,可与每一管线附接的溶液袋。这些溶液和对应的体积可基于该任务的默认设置。
表5:使细胞附着的改型2的溶液
细胞路径:任务>加载和附着>使细胞附着
表6:任务>加载和附着>使细胞附着的改型2
结果可如下:
表7
表8
表9
实施例2
牛眼样细胞(Bull’s Eye cell)加载程序是一系列步骤,这些步骤被设计为通过允许细胞在细胞扩增系统的生物反应器内进行更均匀的分布,并且通过减少在接种过程中细胞丢失的数目,来增加细胞产量。
QUANTUM细胞扩增系统的牛眼样细胞加载技术提供了一系列步骤,包括并且加入通常用于加载生物反应器的“使用均匀悬浮液加载细胞(Load Cells with UniformSuspension)”的方案(软件版本2.0的Quantum细胞扩增系统操作者手册)。在使用均匀悬浮液加载细胞(LCWUS)中,在细胞悬浮液以200mL/min穿过IC环路循环之后,悬浮的细胞有一个时机进入并且附着至生物反应器的一个纤维的内表面。牛眼样细胞可允许在初始悬浮之后不附着的细胞和那些不是在生物反应器中而是留在IC环路中的细胞被重新悬浮,并且转运到生物反应器内的不同纤维中用于随后的附着。
可基于以下原理进行牛眼样细胞的加载:依赖于IC环路中的细胞悬浮液的循环速度,经由IC环路的循环引入到生物反应器中的细胞悬浮液可经过生物反应器纤维的不同组。
在使用均匀悬浮液(LCWUS)加载细胞的初始200mL/min悬浮循环之后,IC环路中的细胞悬浮液可选地以顺序较低的循环速度-100mL/min、50mL/min、-25mL/min,以正向和反向进行循环。IC环路的每一逐渐较慢的循环可允许,那些仍留在悬浮液中的细胞有额外的机会进入并且附着至生物反应器纤维的内表面上。
流体在IC环路中的每一次循环都可跟着7分钟的细胞附着时间,在这一时间段中,IC循环速度可以是零。已表明MSC细胞在5分钟内附着至在QUANTUM细胞扩增系统中使用的生物反应器中的纤维的内表面上。这样,7分钟的附着可允许5分钟用于细胞附着,额外的2分钟允许较慢的细胞附着。IC环路中的细胞悬浮液和细胞附着的总四次循环可跟着24小时附着期间,在该24小时附着时间之后,可根据需要输入适当的细胞饲养计划。
天:-1包被生物反应器
目的:使用试剂包被生物反应器的膜。
步骤1:在IC环路中加载试剂,直至袋子清空。
步骤2:将上述试剂从ARC赶至IC环路中。
步骤3:使上述试剂在IC环路中进行循环。
在启动这一任务之前,可满足下面的前提:
在细胞输入袋中包括至少40mL空气。
表10描述了在执行包被生物反应器时,可用于与每一管线附接的溶液袋。这些溶液和对应的体积可基于该任务的默认设置。
包被生物反应器的路径:任务>系统管理>包被生物反应器
输入在表11中示出的步骤1的每一设置的数值。
输入在表12中示出的步骤2的每一设置的数值。
输入在表13中示出的步骤3的每一设置的数值。
天:0 IC EC冲洗
目的:用于替换IC循环环路和EC循环环路中的流体。通过交换的IC体积和EC体积的数量来限定替换的体积。表14描述了当进行IC EC冲洗时,可与每一管线附接的溶液袋。这些溶液和对应的体积可基于该任务的默认设置。
IC EC冲洗路径:任务>冲洗>IC EC冲洗
确认表15中示出的用于IC EC冲洗的每一设置的数值。
天:0条件培养基(介质)
按照该任务的指令,在加载细胞之前,允许介质达到与提供的气体供应的平衡。该任务可包括两个独立步骤:
步骤1:通过使用高EC循环速度,提供介质和气体供应之间的快速接触。
步骤2:将系统维持在适当状态,直至操作者准备要加载细胞。
表16描述了当执行条件培养基时,可与每一管线附接的溶液袋。这些溶液和对应的体积可基于该任务的默认设置。
条件介质路径:任务>系统管理>条件介质
输入在表17中示出对步骤1的每一设置的数值。
输入在表18中示出对步骤2的每一设置的数值。
天:0使用均匀悬浮液加载细胞
目的:将细胞从细胞输入袋加载到生物反应器中,直至袋子清空。该任务仅使用IC循环来分布细胞,并且不尝试将细胞从管线赶至生物反应器中。该任务可包括三个独立步骤。
步骤1:将细胞从细胞输入袋加载到生物反应器中。
步骤2:将细胞从ARC赶至生物反应器中。更大驱赶体积(chase volume)扩散细胞并且使细胞朝IC出口移动。
步骤3:促使细胞经由IC循环跨越膜进行分布而不经由IC入口,因此没有超过滤。
在启动该任务之前,可满足下面的前提:
在细胞输入袋中包括至少40 mL的空气。
表19描述了在执行使用均匀悬浮液加载细胞时,可与每一管线附接的溶液袋。这些溶液和对应的体积可基于该任务的默认设置。
使用均匀悬浮液加载细胞的路径:任务>加载和附着>使用均匀悬浮液加载细胞
确认表20中示出的用于步骤1的每一设置的数值。
确认表21中示出的用于步骤2的每一设置的数值。
确认表22中示出的用于步骤3的每一设置的数值。
天:0牛眼样细胞的附着
目的:在允许在EC循环环路中进行流动时,允许贴壁细胞附着至生物反应器膜上。可将至IC环路的泵流速设置为零。
步骤1:允许细胞7分钟附着至处于180°的生物反应器的内表面。
步骤2:使IC流体和剩余的悬浮细胞以高速,与初始加载相反的方向循环。
步骤3:该步骤是第二个7.0分钟,允许进一步的细胞附着。使从IC环路或从生物反应器的不同区域重新定位的那些细胞有机会沉淀且贴壁到生物反应器上。
步骤4:再次使留在IC环路中的那些细胞和还没有附着至表面上的那些细胞重新循环。循环可以为正向,并且这一次的循环速度可较低,以避免移除已经附着的那些细胞,并且优选接种到生物反应器中在之前的步骤中还没有接种的区域上。
步骤5:该步骤是第三个7.0分钟,允许进一步的细胞附着。使从IC环路或从生物反应器的不同区域重新定位的那些细胞有机会沉淀且贴壁到生物反应器上。
步骤6:使留在IC环路中的那些细胞和还没有附着至表面的那些细胞重新循环。循环可以为反向,并且这一次的循环速度可较低,以避免移除已经附着的那些细胞。
步骤7:24小时附着细胞阶段。细胞可有24小时,以在饲养开始之前,牢固地锚固至生物反应器上
表23描述了在执行牛眼样细胞的附着时,可与每一管线附接的溶液袋。这些溶液和对应的体积可基于该任务的默认设置。
牛眼样细胞附着路径:任务>自定义>自定义
输入表24中示出的每一设置的数值。
输入表25中示出的每一设置的数值。
输入表26中示出的每一设置的数值。
输入表27中示出的每一设置的数值。
输入表28中示出的每一设置的数值。
输入表29中示出的每一设置的数值。
输入表30中示出的每一设置的数值。
天:1饲养细胞
目的:持续低流速向IC循环环路和/或EC循环环路进行添加。在该任务过程中,存在几种排出设置,可用于移除向系统添加的流体。
表31描述了在执行饲养细胞时,可与每一管线附接的溶液袋。这些溶液和对应的体积可基于该任务的默认设置。
饲养细胞的路径:任务>饲养和添加>饲养细胞
确认表32中示出的步骤1的每一设置的数值。
根据需要,增加IC进入速度。
释放贴壁细胞和收获
目的:从膜上释放细胞,是细胞离开IC环路并且将来自IC循环环路的细胞(包括在生物反应器中的细胞)以悬浮液的形式转移到收获袋中。
步骤1:在准备中,执行IC EC冲洗任务,以添加试剂。例如,在准备中,该系统将PBS替换成IC EC介质以去除蛋白、Ca++和Mg++,以添加胰蛋白酶。
步骤2:将试剂加载到系统中,直至袋子清空。
步骤3:将试剂赶至IC环路中。
步骤4:混合IC环路内的试剂。
步骤5:将来自IC循环环路的细胞(包括生物反应器中的细胞)以悬浮液的形式转移至收获袋中。
在启动该任务之前,可满足下面的前提:
在细胞输入袋上包括至少40mL的空气。
表33描述了在执行释放贴壁细胞和收获时,可与每一管线附接的溶液袋。这些溶液和对应的体积可基于该任务的默认设置。
释放贴壁细胞的路径:任务>释放和收获>释放贴壁细胞和收获
确认表34中示出的步骤1的每一设置的数值。
确认表35中示出的步骤2的每一设置的数值。
确认表36中示出的步骤3的每一设置的数值。
确认表37中示出的步骤4的每一设置的数值。
确认表38中示出的步骤5的每一设置的数值。
本研究的结果如下:
表39
可使用来自四个不同供体的MSC,来评估牛眼样细胞的加载。加载的牛眼样细胞的收获产量可相应高于使用LCWUS加载且在相同条件下培养的产量。使用牛眼样细胞(n=6)vs.LCWUS(n=4)得到的细胞平均产量增加可为25%。
在进行牛眼样细胞加载之后立即从IC环路中采集的MSC样品的存活力为100%。对于所有样品,来自牛眼样细胞收获物的MSC的存活力高于98%。来自牛眼样细胞收获物的MSC显示出培养物中的典型形态,并且通过流式细胞仪测量的所有MSC生物标记物都符合ISCT标准。
实施例3
可使用与上述实施例2相同的方案,来研究对牛眼样细胞附着方案的改型。对牛眼样细胞附着的改型(牛眼样细胞II)和对上述方案的改型包括去除在循环速度100ml/min、-50ml/min和25ml/min之后的附着阶段。也就是说,取代如上所述的7分钟停止条件,没有停止条件,以便下一个循环速度接着前一个循环速度。对照以及原牛眼样细胞运转(牛眼样细胞I)也实施作为对比。
本研究的结果如下:
表40
各组件在本文中被称为“可操作地相联/相连”。如本文所使用的,“可操作地相联/相连”是指组件以可操作的方式连接在一起,并且涵盖组件直接连接的实施方式以及在两个连接的组件之间放置有额外的组件的实施方式。
前面对本发明的一个或多个实施方式的讨论是用于解释和说明的目的并不要进行限制。例如在上文的具体实施方式中,一个或多个实施方式的各特征可组合在一起,以简化本公开。不能将本公开的方法理解为反映实施方式需要比在权利要求明确记载的更多的特征的发明。此外,如下文权利要求所反映的,创造性方面较小地依赖于在前述一个实施方式的所有特征。因此,将后附权利要求并入到该具体实施方式中,其中每个权利要求自身代表本发明的一个独立实施方式。
此外,尽管说明书包括对一个或多个实施方式的描述以及某些变型和改型,但其它变型和改型也在本发明的范围内(例如,在理解本公开之后,可在本领域技术人员的技能和知识的范围内)。在不用于向公众贡献任何可专利性的主题的情况下,本发明要获得在可允许范围内的替代实施方式的权利,包括要求权利的可替代地、可互换的和/或等价的结构、功能、范围或步骤,而不管这些可替代的、可互换的和/或等价的结构、功能、范围或步骤是否被本文所公开。
Claims (18)
1.一种将细胞加载到细胞扩增系统中的方法,所述方法包括:
使流体以第一流速穿过细胞扩增系统的生物反应器循环,其中所述流体包括多个细胞;
使流体的循环自所述第一流速降低至0ml/min;
使所述生物反应器在第一取向上维持第一预定时间段,以允许至少所述多个细胞的第一部分沉淀;
在所述第一预定时间段之后,使所述生物反应器旋转至距所述第一取向180度的第二取向;
使流体以第二流速穿过所述生物反应器循环,其中所述第二流速比所述第一流速慢;
使所述循环自所述第二流速降低至0ml/min;
使所述生物反应器在所述第二取向上维持第二预定时间段,以允许至少所述多个细胞的第二部分沉淀;以及
在所述生物反应器中,使至少所述细胞的第一部分和第二部分扩增。
2.根据权利要求1所述的方法,进一步包括:
在所述第二预定时间段之后:
使流体以第三流速穿过所述生物反应器循环,其中所述第三流速比所述第二流速慢;
使流体的循环速度自所述第三流速降低;以及
使所述生物反应器在所述第二取向上维持第三预定时间段,以允许至少所述多个细胞的第三部分沉淀。
3.根据权利要求2所述的方法,进一步包括:
在所述第三预定时间段之后:
使流体以第四流速穿过所述生物反应器循环,其中所述第四流速比所述第三流速慢;以及
使流体的循环自所述第四流速降低;以及
使所述生物反应器在所述第二取向上维持第四预定时间段,以允许至少所述多个细胞的第四部分沉淀。
4.根据权利要求3所述的方法,其中,所述第一时间段、所述第二时间段、所述第三时间段和所述第四时间段是相同的。
5.根据权利要求1所述的方法,其中,所述第一时间段和所述第二时间段的持续时间相等。
6.根据权利要求1所述的方法,其中,所述第一时间段小于10分钟。
7.根据权利要求6所述的方法,其中,所述第一时间段小于8分钟。
8.根据权利要求1所述的方法,其中,所述生物反应器包括中空纤维膜。
9.根据权利要求1所述的方法,进一步包括:
在所述第二预定时间段之后并且在扩增之前,将所述生物反应器旋转180度至所述第一取向。
10.一种用于扩增细胞的系统,所述系统包括:
生物反应器;
被配置为与所述生物反应器连接并且使所述生物反应器旋转的至少一个马达;
与所述生物反应器流体相连的至少一个流体循环路径;
用于使流体穿过所述至少一个流体循环路径和所述生物反应器循环的至少一个泵;
被配置为执行处理器可执行指令的处理器;以及
储存处理器可执行指令的存储器,其中当所述指令由所述处理器执行时,执行包括以下步骤的方法:
启动所述至少一个泵,以使流体以第一流速穿过所述生物反应器循环,其中所述流体包括多个细胞;
停止所述至少一个泵;
使所述生物反应器在第一取向上维持第一预定时间段,以允许至少所述多个细胞的第一部分沉淀;
在所述第一预定时间段之后,启动所述至少一个马达,以使所述生物反应器旋转至距所述第一取向180度的第二取向;
启动所述至少一个泵,以使流体以第二流速穿过所述生物反应器循环,其中所述第二流速比所述第一流速慢;
停止所述至少一个泵;
使所述生物反应器在所述第二取向上维持第二预定时间段,以允许至少所 述多个细胞的第二部分沉淀;以及
启动所述至少一个泵,以使流体穿过流体输送系统循环并且使细胞在所述生物反应器中扩增。
11.根据权利要求10所述的系统,其中,所述处理器可执行指令进一步包括用于以下各项的指令:
在所述第二预定时间段之后:
启动所述至少一个泵,以使流体以第三流速穿过所述生物反应器循环,其中所述第三流速比所述第二流速慢;
停止所述至少一个泵;以及
使所述生物反应器在所述第二取向上维持第三预定时间段,以允许所述多个细胞的至少第三部分沉淀。
12.根据权利要求11所述的系统,其中,所述处理器可执行指令进一步包括用于以下各项的指令:
在所述第三预定时间段之后:
启动所述至少一个泵,以使流体以第四流速穿过所述生物反应器循环,其中所述第四流速比所述第三流速慢;以及
停止所述至少一个泵;以及
使所述生物反应器在所述第二取向上维持第四预定时间段,以允许至少所述多个细胞的第四部分沉淀。
13.根据权利要求12所述的系统,其中,所述第一流速在150ml/min至250ml/min之间。
14.根据权利要求13所述的系统,其中,所述第二流速在50ml/min至150ml/min之间。
15.根据权利要求14所述的系统,其中,所述第三流速在25ml/min至100ml/min之间。
16.根据权利要求15所述的系统,其中,所述第四流速小于50ml/min。
17.根据权利要求10所述的系统,其中,所述生物反应器包括中空纤维膜。
18.根据权利要求17所述的系统,其中,所述中空纤维膜包括多个中空纤维。
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