CN106232800A - 介质的被动替代 - Google Patents
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Abstract
本文所描述的各实施方式总体涉及在封闭型细胞扩增系统中被动替代介质,以降低或防止化学信号转导的稀释,该化学信号转导用于抑制将细胞群保持在细胞生长停滞期的信号转导通路。为了防止上述稀释,可停止流入系统的主动输入流体流。为了替代系统损失的流体,可将容纳介质的袋子附接至废物管线,以替代与其连接的废物袋或输出袋。通过关停一个或多个泵,将来自替代袋的介质以蒸发速率添加至系统。可防止化学信号转导的稀释,同时使系统资源保持恒定。可通过从直接来源向系统添加诸如化学信号转导蛋白的分子,进一步增强化学信号转导来缩短细胞生长的停滞期。
Description
相关文献的交叉引用
本申请要求于2014年3月25日递交的名称为“介质的被动替代”的美国临时申请系列号61/970,274的权益。通过引用将该美国临时申请整体并入本文中,就如全文阐述用于其所有教导和所有目的。
背景技术
细胞扩增系统(CES)用于扩增细胞和使细胞分化。细胞扩增系统可用于扩增(例如生长)干细胞,诸如间充质干细胞、人类间充质干细胞等。细胞扩增系统还可扩增其它类型的细胞,诸如骨髓细胞。可从供体细胞扩增的干细胞可用于修复或替代受损的或有缺陷的组织,并且对于大量疾病具有广泛的临床应用。贴壁和非贴壁类型的细胞都可在细胞扩增系统中的生物反应器中生长。
发明内容
本公开的各实施方式总体涉及使用细胞扩增系统中介质的被动替代,以使介质保持不变,并且提供有助于支持细胞生长的环境。细胞(诸如人类间充质干细胞)的扩增例如使用细胞间的外部化学信号转导,以通过抑制细胞内部的停滞期的信号转导途径来引发细胞扩增。根据各实施方式,例如其他类型的细胞(诸如中国仓鼠卵巢(CHO)细胞)的扩增可能尤其对细胞间的化学信号转导敏感。例如,CHO细胞分泌胆囊收缩素(CCK),一种经由化学信号转导部分负责细胞培养维持和增殖的调节激素。在实施方式中,CCK可足够小至能穿过中空纤维生物反应器的多微孔膜。由于这种穿过膜的能力,不管输入介质被添加至细胞扩增系统的内毛细管回路还是外毛细管回路,都可发生化学信号转导的稀释。为了降低或防止封闭的自动化细胞扩增系统中的外部化学信号转导的稀释,从而缩短细胞停滞期,具体实施方式的多个方面通过中断正在执行的方案程序,并且用介质袋替代细胞扩增系统所使用的废物袋或输出袋,而为被动替代介质作好了准备。在实施方式中,容纳基础培养基的袋子可被附接至细胞扩增系统的废物管线,其中这样的配置允许基础培养基以无主动输入流体流的条件过程中的蒸发速率添加至所述系统。在实施方式中,其它类型的替代流体用于介质袋中,诸如完全介质或细胞因子或其它细胞信号转导蛋白分子。在其它实施方式中,可通过中断正在执行的方案程序,并且允许废物袋或输出袋中的任意流体(假设废物袋或输出袋中没有对细胞生长有毒性的成分)以在没有主动输入流体流的条件下的蒸发速率被动添加至所述系统,来被动替代流体。流体的被动添加避免添加过量的流体,其中过量的流体会稀释用于引发细胞扩增的化学信号转导。进一步地,介质成分自身最终可保持恒定,从而提高了系统效率并且节省了资源。
本公开的实施方式进一步涉及通过向生物反应器中的扩增的细胞群添加根据实施方式的分子,例如信号转导蛋白分子(诸如细胞因子),来增强化学信号转导。在一个实施方式中,例如,可通过将与细胞因子源连接的管线或其它材料,或预填充有细胞因子或其它期望成分的管线或其它材料,焊接至细胞扩增系统的取样线圈或样品线圈,向生物反应器中添加细胞因子或其它类型的细胞信号转导蛋白分子。因此,在该样品线圈处可将细胞因子添加至生物反应器。这样的直接添加能显著节省可能昂贵的细胞因子,因为与仅细胞因子源自身补充生物反应器时所需的量相比,添加至介质袋以补偿介质对细胞因子的稀释所需要的细胞因子的量大得多。进一步地,细胞因子易于随时间或者通过暴露于紫外(UV)光而快速降解,其中,可通过在更接近于扩增的细胞群处,例如在与UV光源隔离的生物反应器自身的样品线圈处,添加细胞因子,而使这样的降解最小化。在这样的实施方式中,生物反应器中的细胞因子可由此维持在特定的水平,同时保持资源恒定。
如本文所使用的,“至少一种”、“一种或多种”和“和/或”是在实施中既可结合又可分离的开放式表述。例如,“A、B和C中的至少一种”、“A、B或C中的至少一种”、“A、B和C中的一种或多种”、“A、B或C中的一种或多种”以及“A、B和/或C”表示单独的A,单独的B,单独的C,A和B一起,A和C一起,B和C一起,或者A、B和C一起。
该发明内容用于以简化的方式提供概念的选择,其中,这样的概念将在下面的具体实施方式中作进一步的描述。该发明内容不旨于以任何方式来限制所要求保护的主题的范围。除了本文所提供的之外,还可包括含其等同物和变体的特征。
附图说明
通过参照附图来描述本公开的实施方式。在附图中,相似的数字表示相似的项目。
图1描绘了根据本公开的实施方式的中空纤维生物反应器的透视图。
图2示出了根据本公开的实施方式的细胞扩增系统的透视图,该细胞扩增系统具有预安装的流体输送装置。
图3描绘了根据本公开的实施方式的细胞扩增系统的壳体的透视图。
图4示出了根据本公开的实施方式的预安装的流体输送装置的透视图。
图5描绘了根据本公开的实施方式的细胞扩增系统的示意图。
图6示出了细胞扩增系统的另一实施方式的示意图。
图7描绘了根据本公开的实施方式的图6的细胞扩增系统的实施方式,其中的废物袋被介质袋替代。
图8示出了根据本公开的实施方式的图5的细胞扩增系统的实施方式,其中的废物袋被介质袋替代。
图9描绘了根据本公开的实施方式的图6的细胞扩增系统的实施方式,其中包括分子源作为预安装的流体输送装置的一部分。
图10示出了一流程图,描绘了根据本公开的实施方式,用于被动替代细胞扩增系统中的介质的方法的操作特征。
图11描绘了一流程图,示出了根据本公开的实施方式,用于从分子源添加分子的方法的操作特征,该分子源作为细胞扩增系统自身的一部分实施。
图12示出了一流程图,描绘了用于被动替代细胞扩增系统中介质的方法的另一实施方式的操作特征。
图13描绘了细胞扩增系统的示例性处理系统,在该细胞扩增系统上可实施本公开的实施方式。
具体实施方式
参照附图,以下的详细描述提供了对说明性实施方式的讨论。本文所包含的具体实施方式不能被解释为限制或约束本发明。进一步地,在本文描述实施方式中使用了对特征、动作和/或结构特定的语言,但是权利要求并不受限于所述的特征、动作和/或结构。本领域技术人员应理解,包括改进的其它实施方式也在本公开的精神和范围内。
本公开的实施方式总体涉及用于被动替代细胞扩增系统中的介质的系统和方法。可通过中断对该系统正在执行的一个或多个方案程序,例如细胞加载、细胞供养等,并且用介质袋替代系统所使用的废物袋或输出袋,来实现介质的被动替代。通过中断或停止细胞扩增系统正在执行的方案的操作原理,可中止向系统的主动输入流体流,以降低或防止化学信号转导的稀释,该化学信号转导用于抑制使封闭系统的生物反应器中的细胞群保持在停滞期的内部信号转导通路。因此,降低或防止这样的稀释可缩短细胞生长的停滞期。因此,根据本公开的实施方式,可出现更有效且增加的细胞扩增,其中在较短的时间内可扩增出更大量的细胞。
当进入细胞扩增系统的输入流体流过度补偿流体从系统中的蒸发时,可能发生化学信号转导的稀释。例如,氧合器或气体转移组件可用于封闭型细胞扩增系统中,以维持生物反应器中的纤维中的介质,该生物反应器具有期望的气体浓度,例如5%CO2、20%O2、75%N2。作为实例,气体转移组件中的蒸发可以14mL/天发生。在没有任何输入流动的情况下,在例如废物管线是系统(其不被泵封闭)仅有的流体来源的实施方式中,这样的蒸发可导致系统中的空气聚集,或流体从废物或输出管线的回流。但是使用输入流动来引起这样的蒸发,可能导致过度补偿由于蒸发所造成的实际量的流体损失。例如,在实施方式中,进入细胞扩增系统的输入流动速率可具有最小流动速率。作为实例,输入流动速率可被设置为0.1mL/min或144mL/天的最小速率。当气体转移组件中的蒸发以14mL/天发生时,通过上述实施方式中的130mL/天的速率会过度补偿由于蒸发所造成的流体损失。该过量的130mL/天稀释了用于引发细胞扩增的化学信号转导。例如,这样的稀释可发生在如下实施方式中:化学信号转导分子能从内毛细管侧,跨越或穿过中空纤维膜,至外毛细管侧。结果是,通过向系统持续添加流体,来防止或降低化学信号转导分子的聚集,使得向内毛细管侧或外毛细管侧添加替代流体都会导致该化学信号转导分子的稀释。当发生这样的稀释时,会显著影响化学信号转导细胞之间的通讯,从而使得细胞不能扩增或甚至存活。与其它细胞类型相比,这样的稀释可能对一些细胞类型具有特别显著的影响。例如,根据实施方式,降低或防止化学信号转导分子的稀释可对中国仓鼠卵巢(CHO)细胞的扩增具有显著影响
在实施方式中,不使用可能不适当地过度补偿流体从系统中的蒸发的主动输入流体流,而是可停止向系统的主动输入流体流,以防止或最小化化学信号转导的稀释,该化学信号转导用于抑制使生物反应器中的细胞群持续处于停滞期的信号转导通路。例如,可通过中断或停止系统机构按照正在执行的方案进行操作,来停止上述主动输入流体流。不使用过度补偿的主动输入流体流,而是由此可停止上述主动输入流体流,同时使用介质的被动替代,因此不会导致空气的聚集或废物的回流。为了实现上述被动的介质替代,可通过使用一个或多个介质袋来替代系统中正常使用的一个或多个废物袋或输出袋,以与从系统蒸发的速率(例如从气体转移组件蒸发的速率)相等的速率,将流体(例如基础培养基)添加至上述系统。因此,可停止主动输入流体流,同时,来自替代(或取代)介质袋的介质替代因蒸发而从系统中损失的任意流体。上述流体的被动添加避免添加过量的流体,其中,过量的流体会稀释用于引发细胞扩增的化学信号转导。由此,损失的流体可通过以接近蒸发的速率添加介质而被替代,并且不稀释化学信号转导,该化学信号转导用于抑制使细胞群保持为停滞期的信号转导通路。因此,可显著缩短细胞生长的停滞期。进一步地,介质成分自身最终可保持恒定,从而增加了系统效率并且节省了资源。
在其它实施方式中,可通过中断正在执行的方案程序,并且在没有主动输入流体流的条件下,允许废物袋或输出袋中的任意流体(假设在废物袋或输出袋中没有对细胞生长有毒的成分)以蒸发的速率被动添加至系统,来被动替代流体。
当细胞介质包括昂贵的添加剂时,化学信号转导的稀释的成本会是特别高的。例如,细胞信号转导蛋白,例如细胞因子,可用于生物反应器中以刺激细胞生长。因此,稀释细胞因子可产生显著的浪费。相应地,节约过量的介质,例如130mL/天,可比其它细胞扩增方法显著节约成本。因此,根据本公开的实施方式,可使用介质的被动替代,来代替使用过度补偿主动输入流体流,以维持介质成分的浓度并且使介质保持基本恒定。进一步地,在实施方式中,其它类型的替代流体用于介质袋中,诸如包括细胞因子或其它细胞信号转导蛋白分子的介质袋。
在实施方式中,可将分子(诸如细胞信号转导蛋白分子)从这些分子源添加到生物反应器中。例如,可将与分子源(诸如细胞因子源)连接的管道或其它材料无菌焊接至细胞扩增系统中的样品线圈,并且可通过这种直接的细胞因子源补充生物反应器中的细胞因子。在实施方式中,所述管道或其它材料包括添加至取样线圈的额外的容积。在另一实施方式中,所述管道或其它材料包括用于替代取样线圈的对应段或部分的管道或其它材料段。在实施方式中,所述管道或其它材料可预填充有期望成分,例如细胞因子。在另一实施方式中,所述管道或其它材料可连接至包括所述期望成分的容器或袋子。细胞因子源使所使用的细胞因子的量保持恒定,因为细胞因子不被添加至IC介质袋,例如该IC介质袋会稀释细胞因子并且使用更大量的细胞因子来实现相同的补充浓度。进一步地,可在更靠近扩增细胞群处添加细胞因子,以使细胞因子的降解最小化。细胞因子的降解随着暴露于它们可被储存的介质袋和UV光的时间而增加。当更靠近扩增细胞群处添加细胞因子时,可降低所述降解,因为细胞因子在避免有任何UV光源的环境中以更短的时间到达正在扩增的细胞群。根据实施方式,所述细胞因子可被动或主动地被添加至生物反应器,以增强化学信号转导的能力。例如,所述细胞因子的被动添加可在以下情况中发生:根据实施方式,以在没有主动输入流体流的条件下的蒸发速率,将细胞因子从用于替代废物袋的介质袋添加至系统。
因此,在实施方式中,化学信号转导可通过在样品线圈处添加细胞因子来控制。在另一实施方式中,可通过在样品线圈处添加细胞因子与用介质袋替代废物袋结合,来控制化学信号转导。如上所述,通过使用介质袋替代废物袋,可显著降低生物反应器中的稀释。当细胞因子用于生物反应器中的细胞群扩增时,所述稀释的成本会是特别高的。因此,根据实施方式,通过使用介质袋替代来防止或降低所述稀释可得到显著节省。
在实施方式中,方法提供了在封闭型细胞扩增系统的生物反应器中控制化学信号转导,该封闭型细胞扩增系统包括一次性管道套件。在这样的实施方式中,所述方法可包括以下步骤:涂敷生物反应器,并且将细胞从细胞输入袋加载到生物反应器中。例如,根据实施方式,可通过循环分布来进行加载细胞的步骤。在另一实施方式中,例如可进行涉及通过均匀悬浮加载细胞的步骤。然后,例如可通过启动内毛细管循环泵,使细胞分布在生物反应器的整个膜上。在实施方式中,在加载和分布之后,可用介质袋替代附接至细胞扩增系统的废物袋。根据实施方式,在替代了废物袋之后,可将一个或多个泵,例如内毛细管循环泵、外毛细管输入泵和内毛细管输入泵,转为“关停”或以其它方式不启动。在另一实施方式中,可在替代输出袋或废物袋之前,将一个或多个泵转为“关停”或以其它方式不启动。例如,在扩增贴壁细胞的实施方式中,可在用介质袋替代了废物袋或输出袋之后,使内毛细管循环泵不启动。在另一扩增贴壁细胞的实施方式中,例如,可在用介质袋替代废物袋或输出袋之前,使内毛细管循环泵不启动。在又一扩增非贴壁细胞的实施方式中,例如,可使内毛细管循环泵保持启动,而使一个或多个其它泵不启动。
在至少一个实施方式中,来自介质袋的介质通过外毛细管废物阀流至外毛细管循环回路,以补充从外毛细管循环回路中的气体转移组件蒸发掉的流体。在实施方式中,在用介质袋替代废物袋之后,所述方法进一步包括使内毛细管输入泵不启动,使外毛细管输入泵不启动,维持外毛细管循环泵处于启动状态,并且维持外毛细管废物阀处于打开位置。
在一些实施方式中,所述细胞包括贴壁细胞,并且所述方法可包括以下额外的步骤:使贴壁细胞能附着至生物反应器膜,并且通过使外毛细管循环泵维持在启动状态,维持在外毛细管循环回路上的流动。在一些实施方式中,允许贴壁细胞附着至生物反应器膜一段时间,例如约十八(18)小时至约二十四(24)小时的第一时间段。在其它实施方式中,所述细胞包括非贴壁细胞或悬浮细胞,诸如CHO细胞。
在一些实施方式中,所述方法可进一步包括供养在封闭型细胞扩增系统的生物反应器中的细胞,同时维持介质袋替代废物袋,并且同时降低内毛细管输入速率。在这些实施方式中,供养可包括启动内毛细管循环泵。在实施方式中,可在供养约四十五(45)小时至约五十(50)小时的第二时间段之后,停止细胞的供养。在其它实施方式中,可在供养约四十八(48)小时的第二时间段之后,停止细胞的供养。
在实施方式中,所述方法进一步涉及测量细胞生成的乳酸盐的浓度,并且当乳酸盐的浓度等于或大于约6mmol/L时,停止细胞的供养。在一些实施方式中,所述方法包括移除介质袋,插入废物袋,启动内毛细管输入泵,启动内毛细管循环泵,并且维持外毛细管循环泵处于启动状态。在一些实施方式中,所述内毛细管输入泵可以约0.1mL/min的内毛细管输入速率运行。在一些实施方式中,所述内毛细管循环泵可以约20mL/min的内毛细管循环速率运行。根据实施方式,所述外毛细管循环泵可以约30mL/min的外毛细管循环速率运行。在实施方式中,根据其它实施方式,所述方法可额外涉及使内毛细管输入速率加倍,或以其它方式增加,直至可收获期望数量的细胞。当可收获期望数量的细胞时,实施方式包括以下额外的步骤:从生物反应器的膜释放细胞,使细胞悬浮在内毛细管循环回路中,并且将悬浮的细胞转移至收获袋。
在一些实施方式中,诸如通过执行储存在存储器中的预编程任务的处理器,可自动进行一些步骤,这些步骤例如包括:涂敷生物反应器,加载细胞,以及分布细胞。在一些实施方式中,可手动进行用介质袋替代废物袋;而在其它实施方式中,可自动进行用介质袋替代废物袋。在实施方式中,废物袋的自动替代可包括通过处理器接收执行替代废物袋的任务的指令,该任务储存在存储器中。在实施方式中,例如,当接收到上述袋子替代的指令时,处理器可发送信号来关闭例如废物袋的阀,并且打开附接的介质袋的另一阀。在另一实施方式中,一个阀,或其它类型的机构,可控制流体从废物袋或附接的介质袋流出。
介质袋可储存基础培养基,并且在一些实施方式中,例如储存约500mL的基础培养基。根据实施方式,所述基础培养基可包括许多不同的组分,例如包括葡萄糖以为细胞生长提供能量来源。根据本公开的实施方式,介质袋可包括其它流体和/或成分。
所述方法的其它实施方式提供了额外的步骤,其中一些步骤包括:将细胞信号转导蛋白分子加载到内毛细管循环回路的样品线圈中,并且启动内毛细管循环泵,以将细胞信号转导蛋白分子转移至生物反应器。在一些实施方式中,样品线圈和内毛细管循环回路是一次性管道套件的一部分。
在实施方式中,所述方法可进一步包括,在将细胞加载到生物反应器中之前,使用来自内毛细管介质袋的介质替代内毛细管循环回路和外毛细管循环回路上的流体,并且允许来自内毛细管介质袋的介质与气体供应达到平衡。
如上所述,一些实施方式关注于细胞扩增系统。在实施方式中,所述细胞扩增系统是封闭的,其中封闭型细胞扩增系统包括不直接暴露于大气的内容物。所述细胞扩增系统可以是自动化的。在实施方式中,贴壁细胞和非贴壁细胞都可在细胞扩增系统的生物反应器中生长。根据实施方式,所述细胞扩增系统可包括基础培养基。提供补充介质的方法,用于在封闭型细胞扩增系统的生物反应器中发生细胞生长。在实施方式中,用于所述系统的生物反应器可以是中空纤维生物反应器。根据本公开的实施方式,可使用很多类型的生物反应器。
在实施方式中,所述系统可包括生物反应器,该生物反应器进一步包括至少具有相对两个端部的第一流体流动路径,所述第一流体流动路径的第一相对端部与中空纤维膜的第一端口流体相连,并且所述第一流体流动路径的第二端部与所述中空纤维膜的第二端口流体相连,其中所述第一流体流动路径包括所述中空纤维膜的内毛细管部分。所述系统可进一步包括与所述第一流体流动路径流体相连的流体输入路径,其中多个细胞通过第一流体输入路径被引入到所述第一流体流动路径。所述系统还可包括第一泵,该第一泵用于使流体在所述生物反应器的第一流体流动路径中循环。在实施方式中,所述系统包括控制器,例如第一控制器,用于控制所述第一泵的运行。在实施方式中,所述控制器可为计算系统,例如包括处理器。在实施方式中,所述控制器被配置为控制泵,以使流体以第一速率在所述第一流体流动路径内循环,并且当用介质袋替代细胞扩增系统中的废物袋时,所述控制器在多个细胞被加载到生物反应器中之后,停止流体在所述第一流体流动路径内的循环。在一些实施方式中,所述系统包括:第二泵,用于将内毛细管输入流体从内毛细管介质袋转移至第一流体流动路径;和,控制器,例如第二控制器,用于控制该第二泵的运行。在实施方式中,所述第二控制器控制所述第二泵,以将细胞从细胞输入袋转移至第一流体流动路径,并且当用介质袋替代细胞扩增系统中的废物袋时,所述第二控制器在多个细胞被加载到生物反应器中之后,停止从细胞输入袋转移细胞。根据实施方式,可使用额外的控制器,例如第三控制器、第四控制器、第五控制器、第六控制器等。进一步地,根据本公开的实施方式,可使用额外的泵,例如第三泵、第四泵、第五泵、第六泵等。此外,虽然本公开提及介质袋、废物袋、细胞输入袋等,但在实施方式中可使用多个袋,例如第一介质袋、第二介质袋、第三介质袋、第一废物袋、第二废物袋、第三废物袋、第一细胞输入袋、第二细胞输入袋、第三细胞输入袋等,或其它类型的容器。在其它实施方式中,可使用一个介质袋、一个废物袋、一个细胞输入袋等。
在实施方式中,所述系统可例如受到以下装置的控制:与细胞扩增系统连接的处理器;显示装置,该显示装置与处理器通讯,并且可操作该显示装置以显示数据;以及存储器,该存储器与处理器通讯并且可被处理器读出,并且包含一系列指令。在实施方式中,例如当处理器执行指令时,所述处理器接收到涂敷生物反应器的指令。响应于涂敷生物反应器的指令,所述处理器可执行一系列步骤来涂敷生物反应器,并且例如,可接着接收到将细胞加载到生物反应器中的指令。响应于加载细胞的指令,所述处理器可执行一系列步骤,将细胞从细胞输入袋加载到生物反应器中。在将细胞加载到生物反应器中之后,所述处理器可接收到停止内毛细管输入泵、内毛细管循环泵和外毛细管输入泵的指令。可操作上述细胞扩增系统,以允许介质从介质袋流过外毛细管废物阀,其中外毛细管废物阀处于打开位置。所述处理器可接收到以下指令:将介质泵送到外毛细管循环回路中,以替代从位于外毛细管循环回路中的气体转移组件蒸发掉的流体。
参照图1,示出了本公开可使用的中空纤维细胞生长腔室100的实例的正面立视图。细胞生长腔室100具有纵轴LA-LA,并且包括细胞生长腔室壳体104。在至少一个实施方式中,细胞生长腔室壳体104包括四个开口或端口:IC输入端口108、IC输出端口120、EC输入端口128和EC输出端口132。
根据本公开的实施方式,在第一循环路径中的流体在细胞生长腔室100的第一纵向端部112处通过IC输入端口108进入细胞生长腔室100,进入并且通过多根中空纤维116的内毛细管侧(在多个实施方式中被称为中空纤维膜的内毛细管(“IC”)侧或“IC空间”),并且通过位于细胞生长腔室100的第二纵向端部124处的IC输出端口120流出细胞生长腔室100。在IC输入端口108和IC输出端口120之间的流体路径限定了细胞生长腔室100的IC部分126。第二循环路径中的流体通过EC输入端口128流入细胞生长腔室100,与中空纤维116的外毛细管侧或外侧(被称为“EC侧”或“EC空间”)接触,并且经由EC输出端口132离开细胞生长腔室100。在EC输入端口128和EC输出端口132之间的流体路径包括细胞生长腔室100的EC部分136。经由EC输入端口128进入细胞生长腔室100的流体可与中空纤维116的外侧接触。小分子(例如离子、水、氧、乳酸盐等)可通过中空纤维116,从中空纤维的内部或IC空间扩散至外部或EC空间,或从EC空间扩散至IC空间。大分子量分子,诸如生长因子,通常太大而不能通过中空纤维膜,并且留在中空纤维116的IC空间中。在实施方式中,可根据需要替代介质。也可使介质循环通过氧合器或气体转移组件,以根据需要交换气体。如下所述,根据实施方式,细胞可被包含在第一循环路径和/或第二循环路径内,并且可在膜的IC侧和/或EC侧。
用于制作中空纤维膜的材料可以是能制成中空纤维的任何生物相容性聚合材料。根据本公开的实施方式,可使用的一种材料是合成的聚砜类材料。为了使细胞附着至中空纤维的表面,可采用一些方式,使用蛋白(诸如纤连蛋白或胶原蛋白)至少涂敷细胞生长表面,或使该表面暴露于辐射,对表面进行修饰。处理膜表面的伽马射线允许贴壁细胞的附着,且不需使用纤连蛋白等对膜进行额外的涂敷。由伽马射线处理的膜制成的生物反应器可重复使用。根据本公开的实施方式,为了细胞附着,可使用其它涂层和/或处理。
转向图2,示出了根据本公开的实施方式的具有预安装的流体运输组件的细胞扩增系统200的实施方式。CES 200包括细胞扩增器202,细胞扩增器202包括舱口(hatch)或可关闭的门204,用于与细胞扩增器202的后部206接合。在细胞扩增器202内的内部空间208包括适于接收并且啮合预安装的流体运输组件210的特征。预安装的流体运输组件210可拆卸地连接至细胞扩增器202,以促进细胞扩增器202处的新的或未使用的预安装的流体运输组件210相对快速地替代在同一细胞扩增器202处的使用过的预安装的流体运输组件210。可运行一个细胞扩增器202,以使用第一预安装的流体运输组件210使第一组细胞生长或扩增,之后,该细胞扩增器202可用于使用第二预安装的流体运输组件210使第二组细胞生长或扩增,且不需要在第一预安装的流体运输组件210交换第二预安装的流体运输组件210之间进行消毒。所述预安装的流体运输组件包括生物反应器100和氧合器或气体转移组件212。根据实施方式,管道导向槽被示为214,用于接收与预安装的流体运输组件210连接的多个介质管道。
接着,图3示出了根据本公开的实施方式,在可拆卸地连接预安装的流体运输组件210(图2)之前,细胞扩增器202的后部206。图3中省略了可关闭的门204(示于图2中)。细胞扩增器202的后部206包括很多不同的结构,这些结构用于与预安装的流体运输组件210的各个元件组合进行工作。更具体的,细胞扩增器202的后部206包括多个蠕动泵,用于与预安装的流体运输组件210上的泵回路合作,该多个蠕动泵包括IC循环泵218、EC循环泵220、IC输入泵222和EC输入泵224。此外,细胞扩增器202的后部206包括多个阀,该多个阀包括IC循环阀226、试剂阀228、IC介质阀230、排气阀232、细胞输入阀234、冲洗阀236、分配阀238、EC介质阀240、IC废物阀242、EC废物阀244和收获阀246。几个传感器也与细胞扩增器202的后部206联接,包括IC输出压力传感器248、IC输入压力和温度组合传感器250、EC输入压力和温度组合传感器252和EC输出压力传感器254。还示出了用于排气腔室的光学传感器256。
根据实施方式,示出了用于旋转生物反应器100的轴或摇动控制器258。与轴或摇动控制器258联接的轴承(shaft fitting)260允许轴进入孔,例如参见管道组织器的424(图4),例如参见预安装的运输组件210或400的300(图4),与细胞扩增器202的后部206的适当对齐。轴或摇动控制器258的旋转使轴承260和生物反应器100进行旋转运动。因此,当CES200的操作者或使用者将新的或未使用的预安装的流体运输组件400(图4)附接至细胞扩增器202时,上述对齐使预安装的流体运输组件210或400的轴进入孔424(图4)适当朝向轴承260成为相对简单的事情。
转向图4,示出了可拆卸地连接预安装的流体运输组件400的透视图。预安装的流体运输组件400可拆卸地连接至细胞扩增器202,以促进细胞扩增器202处的新的或未使用的预安装的流体运输组件400快速替代在同一细胞扩增器202处的使用过的预安装的流体运输组件400。如图4中所示,生物反应器100可附接至生物反应器联轴器,该生物反应器联轴器包括轴承402。轴承402包括一个或多个轴紧固机构,诸如偏压臂或弹簧构件404,用于啮合轴,例如细胞扩增器202的258(示于图3中)。
根据实施方式,如下所述,预安装的流体运输组件400包括管道408A、408B、408C、408D、408E等和多个管道配件,以提供图5~图9中示出的流体路径。还为泵提供了泵回路406A和泵回路406B。在实施方式中,尽管可在设置细胞扩增器202的位点处提供多种介质,但根据实施方式,预安装的流体运输组件400可包括足够的管道长度,以延伸至细胞扩增器202的外部,并且能焊接连接至与介质袋联接的管道。
图5示出了细胞扩增系统500的实施方式的示意图,并且图6示出了细胞扩增系统600的另一实施方式的简图。在图5和图6中示出的实施方式中,并且如下所述,细胞生长在IC空间中。但是,本公开并不受限于这些实施例,在其他实施方式中可提供在EC空间中生长的细胞。
图5示出了CES 500,根据实施方式,CES 500包括第一流体循环路径502(也被称为“内毛细管回路”或“IC回路”)和第二流体循环路径504(也被称为“外毛细管回路”或“EC回路”)。第一流体流动路径506可与细胞生长腔室501流体相连,以形成第一流体循环路径502。流体通过IC输入端口501A流入细胞生长腔室501中,通过细胞生长腔室501中的中空纤维,并且经由IC输出端口501B流出。压力计510测量离开细胞生长腔室501的介质的压力。介质流过IC循环泵512,该IC循环泵512可用于控制介质流动的速率。IC循环泵512可以第一方向或与第一方向相反的第二方向泵送流体。流出端口501B可用作反向的入口。进入IC回路502的介质可通过阀514进入。如本领域技术人员应当理解的,可将额外的阀和/或其他装置放置在多个位置,以沿流体路径的各部分隔离和/或测量介质的特征。相应地,应理解所示示意图代表CES 500各元件的一种可能配置,对所示示意图的修改在本发明的一个或多个实施方式的范围内。
对于IC回路502,在运行过程中,可从样品端口516或样品线圈518获得介质的样品。被设置在第一流体循环路径502中的压力计/温度计520能在运行过程中检测介质的压力和温度。然后,介质返回至IC输入端口501A,以完成流体循环路径502。在细胞生长腔室501中生长/扩增的细胞可被冲出细胞生长腔室501,通过阀598进入收获袋599,或者被重新分布在中空纤维内用于进一步的生长。下面将对此进行更详细的描述。
第二流体循环路径504中的流体经由EC输入端口501C进入细胞生长腔室501,并且经由EC输出端口501D离开细胞生长腔室501。EC回路504中的介质可与细胞生长腔室501中的中空纤维的外侧接触,从而使小分子能扩散至中空纤维中或扩散出中空纤维。
被设置在第二流体循环路径504中的压力/温度计524能在介质进入细胞生长腔室501的EC空间之前,测量介质的压力和温度。压力计526能在介质离开细胞生长腔室501之后,测量第二流体循环路径504中的介质的压力。对于EC回路,在运行过程中,可从样品端口530或样品线圈获得介质的样品。
在实施方式中,在离开细胞生长腔室501的EC输出端口501D之后,第二流体循环路径504中的流体流过EC循环泵528,到达氧合器或气体转移组件532。EC循环泵528也可以相反方向泵送流体。第二流体流动路径522可经由氧合器输入端口534和氧合器输出端口536与氧合器或气体转移组件532流体相连。在运行中,流体介质经由氧合器输入端口534流入氧合器或气体转移组件532中,并且经由氧合器输出端口536流出氧合器或气体转移组件532。氧合器或气体转移组件532向CES 500中的介质添加氧,并且从CES 500中的介质去除气泡。在多个实施方式中,第二流体循环路径504中的介质可与进入氧合器或气体转移组件532的气体保持平衡。氧合器或气体转移组件532可以是任意适当尺寸的氧合器或气体转移装置。空气或气体经由过滤器538流入氧合器或气体转移组件532中,并且通过过滤器540流出氧合器或气体转移组件532。过滤器538和过滤器540降低或防止氧合器或气体转移组件532及相关介质的污染。在启动顺序(priming sequence)的各个部分中,从CES 500中排出的空气或气体可经由氧合器或气体转移组件532被排放到大气中。
在CES 500的配置中,第一流体循环路径502和第二流体循环路径504中的流体介质以相同方向(平行流配置)流过细胞生长腔室501。CES 500也可被配置为以反向流构造流动。
根据至少一个实施方式,可经由第一流体流动路径506,将含细胞(来自袋子562)的介质和来自袋子546的流体介质引入到第一流体循环路径502中。流体容器562(例如细胞输入袋或用于启动空气排出系统的盐水启动流体)可经由阀564与第一流体流动路径506和第一流体循环路径502流体联接。
流体容器,或介质袋544(例如试剂)和546(例如IC介质)可分别经由阀548和阀550与第一流体输入路径542流体联接,或分别经由阀570和阀576与第二流体输入路径574流体联接。还提供了可封闭的第一无菌输入启动路径508和可封闭的第二无菌输入启动路径509。排气腔室(ARC)556可与第一循环路径502流体联接。排气腔室556可包括一个或多个超声传感器,包括上传感器和下传感器,以检测在排气腔室556内的特定测量位置处的空气、流体的缺乏和/或气体/流体界面,例如空气/流体界面。例如,超声传感器可在接近排气腔室556的底部和/或顶部处使用,以检测这些位置处的空气、流体和/或空气/流体界面。在不偏离本公开的精神和范围的情况下,实施方式提供了多种其他类型的传感器的使用。例如,根据本公开的实施方式,可使用光学传感器。在启动顺序的各部分或其他方案中,从CES500中排出的空气或气体可经由管线558排放至排气阀560外的大气,其中管线558可与排气腔室556流体联接。
将EC介质(来自袋子568)或冲洗液(来自袋子566)可被添加至第一流体流动路径或第二流体流动路径。流体容器566可与阀570流体联接,其中阀570可经由分布阀572和第一流体输入路径542与第一流体循环路径502流体联接。可替代的,通过打开阀570并且关闭分布阀572,流体容器566可经由第二流体输入路径574和EC输入路径584与第二流体循环路径504流体联接。同样地,流体容器568可与阀576流体联接,其中阀576经由第一流体输入路径542和分布阀572与第一流体循环路径502流体相连。可替代的,通过打开阀576并且关闭分布阀572,流体容器568可与第二流体输入路径574流体相连。
可提供可选的热交换器552,用于介质试剂或冲洗液的引入。
在IC回路中,可首先通过IC输入泵554使流体推进。在EC回路中,可首先通过EC输入泵578使流体推进。空气检测器580,诸如超声传感器也可与EC输入路径584联接。
在至少一个实施方式中,第一流体循环路径502和第二流体循环路径504与废物管线588连接。当打开阀590时,IC介质可流过废物管线588,达到废物袋或输出袋586。同样的,当打开阀582时,EC介质可流过废物管线588,到达废物袋或输出袋586。
在实施方式中,细胞可经由细胞收获路径596收获。在此,可通过将含细胞的IC介质通过细胞收获路径596和阀598泵送至细胞收获袋599,来收获来自细胞生长腔室501的细胞。
CES 500的多种组件可被包含或封装在机器或壳体内,诸如细胞扩增器202(图2和图3),其中该机器使细胞和介质维持在预定的温度。
转向图6,示出了细胞扩增系统600的另一实施方式的示意图。CES 600包括第一流体循环路径602(也被称为“内毛细管回路”或“IC回路”)和第二流体循环路径604(也被称为“外毛细管回路”或“EC回路”)。第一流体流动路径606可与细胞生长腔室601流体联接,以形成第一流体循环路径602。流体通过IC输入端口601A流入细胞生长腔室601中,通过细胞生长腔室601中的中空纤维,并且经由IC输出端口601B流出。压力传感器610测量离开细胞生长腔室601的介质的压力。在实施方式中,除了压力之外,传感器610还可以是温度传感器,在运行过程中检测介质的压力和温度。介质流过IC循环泵612,该IC循环泵612可用于控制介质流的速率。IC循环泵612可以第一方向或与第一方向相反的第二方向泵送流体。流出端口601B可用作反向的入口。进入IC回路的介质可通过阀614进入。如本领域技术人员应当理解的,可将额外的阀和/或其他装置放置在多个位置,以沿流体路径的各部分隔离和/或测量介质的特征。相应地,应理解所示示意图代表CES 600各元件的一种可能配置,对所示示意图的修改在本发明的一个或多个实施方式的范围内。
对于IC回路,在运行过程中,可从样品线圈618获得介质的样品。然后,介质返回至IC输入端口601A,以完成流体循环路径602。在细胞生长腔室601中生长/扩增的细胞可被冲出细胞生长腔室601,通过阀698和管线697进入收获袋699。可替代的,当关闭阀698时,细胞可被重新分布在腔室601内用于进一步的生长。
第二流体循环路径604中的流体经由EC输入端口601C进入细胞生长腔室601,并且经由EC输出端口601D离开细胞生长腔室601。根据实施方式,EC回路中的介质可与细胞生长腔室601中的中空纤维的外侧接触,从而使小分子能扩散至中空纤维中或扩散出中空纤维,其中中空纤维可在腔室601内。
被设置在第二流体循环路径604中的压力/温度传感器624能在介质进入细胞生长腔室601的EC空间之前,测量介质的压力和温度。传感器626能在介质离开细胞生长腔室601之后,测量第二流体循环路径604中的介质的压力和/或温度。对于EC回路,在运行过程中,可从样品端口630或样品线圈获得介质的样品。
在离开细胞生长腔室601的EC输出端口601D之后,第二流体循环路径604中的流体流过EC循环泵628,到达氧合器或气体转移组件632。根据实施方式,EC循环泵628也可以相反方向泵送流体。第二流体流动路径622可经由氧合器或气体转移组件632的输入端口632A和输出端口632B与氧合器或气体转移组件632流体联接。在运行中,流体介质经由输入端口632A流入氧合器或气体转移组件632中,并且经由输出端口632B流出氧合器或气体转移组件632。氧合器或气体转移组件632向CES 600中的介质添加氧,并且从CES 600中的介质去除气泡。在多个实施方式中,第二流体循环路径604中的介质可与进入氧合器或气体转移组件632的气体保持平衡。氧合器或气体转移组件632可以是用于氧合或气体转移的任意适当尺寸的装置。空气或气体经由过滤器638流入氧合器或气体转移组件632中,并且通过过滤器640流出氧合器或气体转移组件632。过滤器638和过滤器640降低或防止氧合器或气体转移组件632及联接的介质的污染。在启动顺序的部分中,从CES 600中排出的空气或气体可经由氧合器或气体转移组件632被排放到大气中。
在CES 600的配置中,第一流体循环路径602和第二流体循环路径604中的流体介质以相同方向(平行流配置)流过细胞生长腔室601。根据实施方式,CES 600也可被配置为以反向流构造流动。
根据至少一个实施方式,含细胞(来自诸如细胞容器的源,例如袋子)的介质可被附接至附接点662处,并且来自介质源的流体介质可被附接至附接点646处。细胞和介质可经由第一流体流动路径606被引入到第一流体循环路径602中。附接点662可经由阀664与第一流体流动路径606流体联接,并且附接点646可经由阀650与第一流体流动路径606流体联接。试剂源可流体连接至点644并且经由阀648与流体输入路径642联接,或经由阀648和阀672与第二流体输入路径674联接。
排气腔室(ARC)656可与第一循环路径602流体相连。排气腔室656可包括一个或多个超声传感器,包括上传感器和下传感器,以检测在排气腔室656内的特定测量位置处的空气、流体的缺乏和/或气体/流体界面,例如空气/流体界面。例如,超声传感器可在接近排气腔室656的底部和/或顶部处使用,以检测这些位置处的空气、流体和/或空气/流体界面。在不偏离本公开的精神和范围的情况下,实施方式提供了多种其他类型的传感器的使用。例如,根据本公开的实施方式,可使用光学传感器。在启动顺序的部分或其他方案中,从CES600中排出的空气或气体可经由管线658被排放至排气阀660外的大气,其中管线658可与排气腔室656流体联接。
EC介质源可被附接至EC介质附接点668,并且冲洗液源可被附接至冲洗液附接点666,以将EC介质和/或冲洗液添加至第一流体流动路径或第二流体流动路径。附接点666可与阀670流体联接,其中阀670经由阀672和第一流体输入路径642与第一流体循环路径602流体联接。可替代地,通过打开阀670并且关闭阀672,附接点666可经由第二流体输入路径674和第二流体流动路径684与第二流体循环路径604流体联接。同样地,附接点668可与阀676流体联接,其中阀676经由第一流体输入路径642和阀672与第一流体循环路径602流体联接。可替代地,通过打开阀676并且关闭阀分布672,流体容器668可与第二流体输入路径674流体联接。
在IC回路中,可首先通过IC输入泵654使流体推进。在EC回路中,可首先通过EC输入泵678使流体推进。空气检测器680,诸如超声传感器也可与EC输入路径684联接。
在至少一个实施方式中,第一流体循环路径602和第二流体循环路径604与废物管线688连接。当打开阀690时,IC介质可流过废物管线688,达到废物袋或输出袋686。同样的,当打开阀692时,EC介质可流至废物袋或输出袋686。
在细胞已经在细胞生长腔室601中生长后,它们可经由细胞收获路径697来收获。在此,在打开阀698的情况下,能够通过泵送含细胞的IC介质穿过细胞收获路径697进入细胞收获袋699,收获来自细胞生长腔室601的细胞。
CES 600的多种组件可被包含或封装在机器或壳体内,诸如细胞扩增器202(图2和图3),其中该机器使细胞和介质维持在预定的温度。进一步要注意的是,在实施方式中,CES600和CES 500(图5)的组件可进行组合。在其他实施方式中,CES可包括比图5和图6所示组件少的或额外的组件,但仍然在本公开的范围内。
在图5和图6示出了细胞扩增系统的不同实施方式的示意图,图7和图8描绘了这些相同的细胞扩增系统,其中根据本公开的实施方式废物袋或输出袋(586和686)被替代为介质袋。例如,如图7所描绘的,CES 600(图6)中的废物袋或输出袋686已经被介质(例如基础培养基)袋700替代。进一步地,根据实施方式,一个或多个泵,例如IC循环泵612、EC输入泵678和IC输入泵654已经被转为“关停”。因此,没有主动输入流体流入细胞生长腔室601中。为了补偿由于氧合器或气体转移组件632处的蒸发所造成的流体损失,使EC循环泵628处于“开动”状态,并且EC废物阀692处于“打开”状态。这种配置使得流体能以,与从氧合器或气体转移组件632蒸发的速率相等的速率,从介质袋700回流至CES 600系统中。从而可替代由于蒸发所造成的系统中的流体损失,且不会在细胞在其中生长的过程中,稀释在生物反应器601中发生的化学信号转导。在实施方式中,因此可显著缩短生物反应器601中的细胞生长的停滞期,并且可发生更有效的细胞扩增。进一步地,通过使输入泵转为“关停”或以其他方式不启动,可使系统源恒定,因为没有不必要地引入主动的输入流体到系统中。虽然图7示出了其中IC循环泵612、EC输入泵678和IC输入泵654已经被转为“关停”的实施方式,但是其他实施方式提供了这些泵中的一个或多个,例如IC循环泵612维持“开动”或启动(图7中未示出)。例如,在实施方式中,取决于根据实施方式的扩增的细胞类型,例如非贴壁细胞,可能需要在内毛细管侧中进行持续循环。
在一些实施方式中,介质袋(例如700)的位置物理学上可比EC回路604的至少一部分更高,以允许重力有助于流体从介质袋排放至EC回路604中。在一些实施方式中,废物袋686(图6)的位置可低于EC回路604,以允许重力有助于废物介质排放至废物袋686中。根据实施方式,当介质袋700替代废物袋686时,取代或替代的介质袋700的位置可比废物袋686的初始位置在物理学上来说更高。
转向图8,示出了类似的配置,其中例如,废物袋586已经被介质(例如基础培养基)袋800替代。进一步地,根据实施方式,一个或多个泵,例如IC循环泵512、EC输入泵578和IC输入泵554已经被转为“关停”。因此,没有主动输入流体流入细胞生长腔室501中。为了补偿由于气体转移组件或氧合器532处的蒸发所造成的流体损失,可使EC循环泵528处于“开动”状态,并且EC废物阀582处于“打开”状态。在实施方式中,这种配置使得流体能以,与从气体转移组件或氧合器532蒸发的速率相等的速率,从取代或替代的介质袋800回流至系统中。从而可替代由于蒸发所造成的系统中的流体损失,且不会在细胞在其中生长的过程中,稀释在生物反应器501中发生的化学信号转导。在实施方式中,因此可显著缩短生物反应器501中的细胞生长的停滞期,并且可发生更有效的细胞扩增。进一步地,通过使一个或多个输入泵转为“关停”,可使系统源恒定,因为没有将主动输入流体不必要地引入到系统中。虽然图8示出了其中IC循环泵512、EC输入泵578和IC输入泵554已经被转为“关停”的实施方式,但是其他实施方式提供了这些泵中的一个或多个,例如IC循环泵512维持“开动”或启动(图8中未示出)。例如,在实施方式中,取决于根据实施方式的扩增的细胞类型,例如非贴壁细胞,可能需要在内毛细管侧中进行持续循环。
在一些实施方式中,当废物袋586被介质袋800替代时,取代或替代的介质袋的位置可比废物袋586的初始位置在物理学上来更高,以允许重力有助于介质排放至EC回路504中。
废物袋被介质袋替代允许被动替代由于蒸发所造成的流体损失。流体的这种被动替代可提供在细胞扩增方法中的流体的显著恒定。在包括主动介质替代的方法中,介质可在细胞附着过程中被添加至IC回路和在IC回路中循环,以替代由于蒸发所造成的流体损失。如上所述,根据实施方式,例如如果以0.1ml/min添加介质(可能发生在一些方法中),这可能产生系统中高达130mL/天的过量的(超过蒸发掉的量)流体。使用介质袋替代废物袋所进行的流体的被动添加可避免过量添加。能够理解的是,介质可包括昂贵的添加剂。例如,与其他细胞扩增方法相比,节省约130mL/天可提供显著的成本节约。
图7和图8允许通过使用介质袋替代废物袋,以在封闭型细胞扩增系统中进行介质的被动替代,同时图9示出了一个实施方式,其中分子源,例如细胞信号转导蛋白分子源,可被添加至细胞扩增系统,诸如CES 600(图6)(或CES 500(图5))。在一个实施方式中,分子源900可以是被焊接在样品线圈或取样线圈618中的细胞因子源,其中该细胞因子源包括被焊接在取样线圈618中的一段管道或其它材料。通过这样的源,即直接源,可将细胞因子添加至IC回路602,且不会稀释这些蛋白,其中例如细胞因子在IC介质袋处添加时会发生稀释。在实施方式中,分子被直接添加至IC回路602。根据实施方式,例如这样的直接添加也可发生在样品端口。因此,细胞生长腔室601中的细胞因子可由上述细胞因子源被动或主动补充。在这样的实施方式中,IC循环泵612转为“启动”位置,以允许在取样线圈618处进入IC回路602,从而被泵送至生物反应器601中的扩增细胞群。当在生物反应器中使用的化学信号转导蛋白特别昂贵(例如细胞因子)时,这样的细胞源可最终节省显著量的资源。
已经描述了用于被动替代介质的细胞扩增系统和方法的多个示例性实施方式,图10示出了根据本公开的实施方式的,用于被动替代流体以控制封闭型细胞扩增系统中的化学信号转导的示例性操作步骤1000。起始START(开始)操作1002,并且过程1000进行至将一次性管道套件1004加载到细胞扩增系统上。接着,使系统操作1006,诸如通过使用者或操作者通过选择操作任务命令系统来运行。在另一实施方式中,自动使系统操作1006,而无需使用者或操作者进行任务或指令的任何选择。在使装置运行之后,方法1000进行至涂敷生物反应器1008,其中使用试剂涂敷生物反应器。例如,可将试剂加载到IC回路中,直至试剂袋清空。试剂从排气腔室被赶至IC回路中,然后试剂在IC回路中循环。一旦生物反应器被涂敷,就执行IC/EC洗出任务1010,其中替代IC循环回路和EC循环回路上的流体。根据实施方式,通过交换的IC体积和EC体积的数量,来决定替代的体积。接着,为了维持生物反应器的膜中的整个纤维的适当或期望的气体浓度,执行条件介质任务1012,以在细胞被加载到生物反应器中之前,使介质能与所提供的气体供应达到平衡。例如,通过使用高EC循环速率,提供介质与由气体转移组件或氧合器所提供的气体供应之间的快速接触。在实施方式中,将上述系统维持在适当状态,直至使用者或操作者准备好将细胞加载到生物反应器中。在其他实施方式中,使用者或操作者不需要进行上述步骤/操作;而是由细胞扩增系统自动进行上述步骤/操作。
过程1000接着进行通过循环分布,将细胞从细胞输入袋加载到生物反应器中1014。在实施方式中,将细胞从细胞输入袋加载到生物反应器中,直至细胞输入袋清空。然后,细胞从排气腔室被赶至生物反应器。更大的驱赶体积使细胞扩散,并且使细胞朝IC出口移动。经由IC循环,诸如通过IC循环泵,没有IC输入,促进细胞在整个膜上的分布。
在通过循环分布任务1014完成加载细胞之后,使用介质袋替代废物袋或输出袋1016。在实施方式中,介质袋包括约500mL基础培养基。根据实施方式,介质袋可包括其他流体和/或成分。在实施方式中,使用介质袋替代输出或废物袋1016是可选的,其中可通过中断正在执行的方案程序,并且允许输出袋或废物袋中的任意流体(假设输出或废物袋中没有对细胞生长有毒的成分)以在没有主动输入流体流的条件下的蒸发速率,被动添加至系统,来被动替代流体。流体的这样的被动添加避免添加过量的流体,从而避免稀释化学信号转导分子。
转向图10,然后可将一个或多个泵,例如IC输入泵、IC循环泵和EC输入泵转为“关停”,或以其他方式指示停止或不启动1018。然后,根据本公开的实施方式,允许生物反应器中的任意贴壁细胞附着至生物反应器膜1020一段时间,诸如约十八(18)小时至约二十四(24)小时。在这一时间段中,流动在EC循环回路上继续,其中根据实施方式,EC循环速率维持在约30mL/min。非零的EC循环速率有助于继续通过气体转移组件或氧合器将流体泵送至EC回路中,在生物反应器膜的整个纤维上维持适当或期望的气体浓度。通过使用气体转移组件来维持适当或期望的气体浓度的同时,还在气体转移组件处发生流体的蒸发。但是,通过保持EC废物阀处于打开状态,来自介质袋(替代废物袋)的介质可回流至系统中,并且通过EC循环泵经EC回路进行泵送。因此,介质可以蒸发速率替代由于从气体转移组件的蒸发所造成的流体损失。因此,生物反应器中的膜纤维不会被过量流体稀释,并且不抑制细胞生长脱离停滞期的转变。
根据实施方式,在任意贴壁细胞附着约十八(18)小时至约二十四(24)小时之后,持续的细胞附着期1022继续进行,直至约四十八(48)小时。在操作1022过程中,IC循环泵可被启动或转为“开动”,以甚至为生物反应器膜的最远的纤维提供介质。例如,根据本公开的实施方式,可启动IC循环泵,以将IC循环速率调节至约20mL/min。但是,在通过启动IC循环泵进行修改的供养时段1022中,IC输入速率维持在0mL/min。取代的介质袋(替代废物袋)继续向系统提供所需的任意流体替代,同时不稀释膜或抑制化学信号转导。因此,使用经修改的细胞供养所进行的操作1022允许细胞附着继续进行,且不破坏在生物反应器中发生的化学信号转导。根据实施方式,该持续的细胞附着期继续,长达约额外的四十八(48)小时,和/或在实施方式中,直至细胞的乳酸盐生成大于或等于约6mmol/L。在实施方式中,测量乳酸盐的浓度。在另一实施方式中,例如测量乳酸盐生成率。在实施方式中,在操作1024处检查乳酸盐生成,以确定乳酸盐浓度是否等于或高于6mmol/L。在其他实施方式中,在操作1024处检查乳酸盐生成,以确定相对于另一预定量的乳酸盐浓度。
方法1000接着进行询问1026,其中确定自启动IC循环泵是否过去了多于四十八小时,或者确定乳酸盐浓度是否等于或高于约6mmol/L。如果过去了少于四十八(48)小时,或者如果乳酸盐浓度不等于或未超过约6mmol/L,则过程1000进行NO(否),以检查乳酸盐生成操作1024,然后再次询问1026。要注意的是,本公开不受限于确定是否过去了四十八(48)小时,或乳酸盐浓度是否等于或高于6mmol/L。在其他实施方式中,方法1000可包括不同的预定时间段。例如,在询问1026处,可确定是否过去了约12小时、约24小时、约36小时或约40小时。在其他实施方式中,预定时间段可以是约50小时或约60小时。在实施方式中,可确定是否过去了多于约12小时、多于约24小时、多于约36小时或多于约40小时。在其他实施方式中,可确定是否过去了少于约60小时或少于约50小时。在其他实施方式中,方法1000可包括确定乳酸盐浓度是否等于或大于另一预定量,诸如约3mmol/L、约4mmol/L、约5mmol/L、约7mmol/L或约8mmol/L。在实施方式中,可确定乳酸盐浓度是否高于约3mmol/L、高于约4mmol/L或高于约5mmol/L。在其他实施方式中,可确定乳酸盐浓度是否小于约8mmol/L或小于约7mmol/L。
如果在询问1026处,确定自启动IC循环泵已经过去了多于约四十八(48)小时,或乳酸盐浓度等于或高于6mmol/L,则方法1000进行YES(是),至供养细胞的操作1028,其中IC输入泵被启动或转为“开动”,以维持0.1mL/min的IC输入速率。接着,方法1000进行测量葡萄糖消耗1030。在实施方式中,测量葡萄糖的浓度。在另一实施方式中,测量例如葡萄糖消耗速率。在实施方式中,在询问1032处,确定所测量的葡萄糖消耗是否小于约70mg/L。如果葡萄糖消耗小于约70mg/L(或根据其他实施方式,小于另一预定量),方法1000进行YES(是),以使IC输入速率加倍1034。然后,方法1000进行操作1030,以继续测量细胞的葡萄糖消耗并且回到询问1032。
本公开不受限于确定葡萄糖消耗是否小于约70mg/L。在其他实施方式中,方法1000可包括不同的预定量。例如,在实施方式中,方法1000可包括确定葡萄糖消耗是否小于另一预定量,诸如约65mg/L,约60mg/L或约55mg/L。在其他实施方式中,方法1000可包括确定葡萄糖消耗是否小于另一预定量,诸如约85mg/L,约80mg/L或约75mg/L。在实施方式中,可确定葡萄糖消耗是否高于约55mg/L,高于约60mg/L或高于约65mg/L。在其他实施方式中,可确定葡萄糖消耗是否小于约85mg/L,小于约80mg/L或小于约75mg/L。
在询问1032处,如果确定葡萄糖消耗大于70mg/L,方法1000进行NO(否),至释放细胞的操作1036,其中细胞从生物反应器的膜释放出来并且悬浮在IC回路中。在实施方式中,在用于添加试剂的准备中,进行IC/EC洗出任务。例如,在用于添加胰蛋白酶或另一化学释放试剂以释放所有贴壁细胞的准备中,可将IC/EC介质替代为磷酸盐缓冲液(PBS)以去除蛋白、钙(Ca2+)和镁(Mg2+)。将试剂加载到系统中,直至试剂袋清空。试剂可被赶至IC回路中,并且试剂可在IC回路内进行混合。在释放所有贴壁细胞之后,收获操作1038将悬浮的细胞(包括在生物反应器中剩余的所有细胞)从IC循环回路转移至收获袋。然后,方法1000在END(结束)操作1040处终止。
接着,图11描绘了流程图,示出了根据本公开的实施方式,用于添加来自分子源的分子的方法1100的操作特征,该分子源作为细胞扩增系统自身的一部分使用。在已经描述了细胞扩增系统和用于向细胞扩增系统添加分子的方法的多个示例性实施方式的同时,图11示出了根据本公开的实施方式,示例性的操作步骤1100,用于添加影响封闭型细胞扩增系统中的化学信号转导的分子。一些实施方式提供了来自分子源的分子的被动添加。起始START(开始)操作1102,并且方法1100进行至将一次性管道套件加载到细胞扩增系统上1104。接着,例如启动系统1106,诸如使操作者或使用者通过选择启动任务,向系统提供指令,来进行启动。在另一实施方式中,自动启动系统1106,不需要操作者或使用者进行任何任务或指令的选择。
在启动装置之后,方法1100进行至涂敷生物反应器1108,其中可使用试剂涂敷生物反应器。例如,在实施方式中,将试剂加载到IC回路中,直至试剂容器清空。可将试剂从排气腔室赶至IC回路中,然后试剂可在IC回路中进行循环。一旦生物反应器被涂敷,就可执行IC/EC洗出任务1110,其中根据实施方式,可替代IC循环回路和EC循环回路上的流体。在实施方式中,可通过交换的IC体积和EC体积的数量,来确定替代体积。
接着,为了在生物反应器膜中的整个纤维上维持适当或期望的气体浓度,执行条件介质任务1112,以在细胞被加载到生物反应器中之前,使介质能与所提供的气体供应达到平衡。例如,通过使用高EC循环速率,提供介质与由气体转移组件或氧合器所提供的气体供应之间的快速接触。在实施方式中,然后可将系统维持在适当或期望的状态,直至使用者或操作者准备好将细胞加载到生物反应器中。在实施方式中,可自动进行这样的细胞加载。
方法1100接着进行通过循环分布1114,将细胞从细胞输入袋加载到生物反应器中。在实施方式中,将细胞从细胞输入袋加载到生物反应器中,直至细胞输入袋清空。然后,细胞从排气腔室被赶至生物反应器。在利用更大的驱赶体积的实施方式中,使细胞扩散并且朝IC出口移动。例如经由IC循环,诸如通过IC循环泵,没有IC输入,可促进细胞在整个膜上的分布。
在通过循环分布任务1114完成加载细胞之后,使用介质袋替代废物袋1116。在实施方式中,介质袋包括约500mL基础培养基。在另一实施方式中,介质袋包括任意类型的替代流体。在又一实施方式中,步骤1116是可选的,其中输出袋或废物袋保持连接,并且不被另一袋子替代。还在又一实施方式中,步骤1116是可选的,其中输出袋或废物袋保持连接,并且将期望的成分或其他流体添加至输出袋或废物袋,用于向系统被动添加该成分/其他流体。
在实施方式中,然后可将一个或多个泵,例如IC输入泵、IC循环泵和EC输入泵转为“关停”,或以其他方式指示停止或不启动1118。然后,根据本公开的实施方式,允许生物反应器中的任意贴壁细胞附着至生物反应器膜1120一段时间,诸如约十八(18)小时至约二十四(24)小时。在这一时间段中,流动在EC循环回路上继续,其中根据实施方式,EC循环速率维持在约30mL/min。非零的EC循环速率有助于继续通过气体转移组件或氧合器将流体泵送至EC回路中,在生物反应器膜的整个纤维上维持适当或期望的气体浓度。通过使用气体转移组件来维持适当或期望的气体浓度的同时,还在气体转移组件处发生流体的蒸发。但是,通过保持EC废物阀处于打开状态,来自取代介质袋(替代废物袋)的介质可回流至系统中,并且通过EC循环泵经EC回路进行泵送。因此,介质可以蒸发速率,替代由于从气体转移组件的蒸发所造成的流体损失。因此,生物反应器中的膜纤维不会被过量流体稀释,并且不抑制细胞生长脱离停滞期的转变。
在所有贴壁细胞附着之后,进行添加分子期1122。该分子可以是蛋白分子,添加该蛋白分子以促进细胞的扩增。例如,该分子可以是信号转导分子,诸如参与细胞间通讯的一种或多种细胞因子或生长因子。所述分子可向细胞发送信号,使细胞进行扩增。在其他实施方式中,所述分子不直接参与信号转导,但可以帮助创建有益于细胞生长的环境,其中所述分子的实例包括载体蛋白、缓冲剂、pH调节剂等。在实施方式中,将所述分子添加至细胞正在生长的空间,例如IC空间或EC空间。在实施方式中,将所述分子从该分子的直接源直接添加至IC回路。例如,根据实施方式,所述直接添加可发生在取样线圈或样品端口处。例如,通过将与细胞因子源连接的管线或其他材料焊接至细胞扩增系统的取样线圈或样品线圈,向生物反应器中添加细胞因子或其它类型的细胞信号转导蛋白分子。因此,细胞因子可在样品线圈处被添加至生物反应器。这样的直接添加能显著节省可能昂贵的细胞因子,因为与根据实施方式的仅细胞因子源自身补充生物反应器时所需的量相比,需要量大得多的细胞因子添加至介质袋中,来补偿介质对细胞因子的稀释。进一步地,细胞因子倾向于快速降解,其中通过靠近扩增细胞群处添加细胞因子,例如在生物反应器自身的样品线圈处添加细胞因子,可使所述降解最小化。在这样的实施方式中,细胞反应器中的细胞因子可被维持在特定水平,同时使来源恒定。可通过这样的来源,即直接来源,将细胞因子添加至IC回路,且不会稀释这样的蛋白,其中在例如IC介质袋处添加细胞因子时,可能发生所述稀释。
如上所述,根据实施方式,在使用介质袋替代废物袋1116之后,可进行添加分子期1122。在一些实施方式中,在操作1122处添加的分子是可能是相对昂贵的,因此期望使用促进细胞生长所需的最小量。进行操作1116首先允许介质从介质袋(替代废物袋)回流至系统中,并且通过EC循环泵经EC回路进行泵送。根据实施方式,以蒸发速率,仅替代由于从气体转移组件蒸发所损失的介质。因此,所述分子不会被过量流体稀释。相应的,在实施方式中,在操作1122处,仅添加可有效促进生长的量的分子,因为不会出现被过量流体稀释。
在操作1122之后,在操作1124处使细胞生长。要注意的是,操作1124可包括许多子操作。在一些实施方式中,子操作包括在方法1000(图10)中进行的操作。可进行循环介质操作,以供养细胞。IC循环泵可被启动或转为“开动”,以为甚至生物反应器膜的最远的纤维提供介质。根据本公开的实施方式,可启动IC循环泵,以将IC循环速率调节至约20mL/min。在一些实施方式中,即使打开IC循环泵,IC输入速率也维持在0mL/min。介质袋(替代废物袋的取代的介质袋)继续向系统提供所需的任意流体替代,同时不稀释分子,或以其他方法抑制化学信号转导。在实施方式中,操作1124允许发生细胞附着和细胞生长,且不会通过稀释分子而破坏化学信号转导。根据实施方式,该持续的细胞附着和生长可继续某预定的时间段,或可基于细胞的乳酸盐生成,例如6mmol/L(在一个实施方式中)。在这些实施方式中,可进行额外的子操作,诸如确定乳酸盐浓度或确定过去了预定时间段。
操作1124可进一步涉及以下子操作:启动IC输入泵,以维持预定的IC输入速率,例如0.1mL/min。例如,可基于已经过去了预定时间段或基于测量,诸如乳酸盐浓度,来触发这一子操作。
在一些实施方式中,操作1124可涉及许多子操作,来确定何时停止细胞生长,并且开始释放和收获细胞。在一个实施方式中,这可包括测量参数,诸如葡萄糖消耗。在一些实施方式中,预定的葡萄糖浓度,例如高于70mg/L可触发后续操作,例如1126和1128。在其他实施方式中,其他参数或预定时间段的传代(passage)可触发后续操作。
在操作1126处,所有贴壁细胞从生物反应器的膜上释放出来,并且悬浮在例如IC回路中。在实施方式中,作为操作1126的一部分,在用于添加试剂以释放细胞的准备中,可进行IC/EC洗出任务。例如,在添加胰蛋白酶或其他化学释放试剂以释放所有贴壁细胞的准备中,可使用PBS替代IC/EC介质以去除蛋白、钙(Ca2+)和镁(Mg2+)。可将试剂加载到系统中,直至试剂袋清空。试剂可被赶至IC回路中,并且试剂可在IC回路内进行混合。在释放所有贴壁细胞之后,收获操作1128将悬浮的细胞(包括在生物反应器中剩余的所有细胞)从IC循环回路转移至收获袋。然后,方法1100在END(结束)操作1130处终止。
转向图12,示出了根据本公开的实施方式的,用于被动替代流体以控制封闭型细胞扩增系统中的化学信号转导的示例性操作步骤1200。起始START(开始)操作1202,并且方法1200进行至将一次性管道套件加载到细胞扩增系统上1204。接着,例如启动系统1206,诸如使使用者或操作者通过选择启动任务,向系统提供指令,来进行启动。在另一实施方式中,自动启动系统1206,不需要使用者或操作者进行任何任务或指令的选择。在启动装置之后,方法1200进行至IC/EC洗出1208,其中在用于细胞培养的准备中,可替代IC循环回路和EC循环回路上的流体。根据实施方式,可通过交换的IC体积和EC体积的数量,来确定替代的体积。接着,为了在细胞加载之前,使介质能与气体供应达到平衡,方法1200继续至条件介质任务1210。例如,通过使用高EC循环速率,提供介质与气体供应之间的快速接触。在实施方式中,然后使系统维持在适当状态,直至使用者或操作者准备好将细胞加载到生物反应器中。在实施方式中,使用者或操作者可能不需要进行上述步骤/操作;这些步骤/操作可由细胞扩增系统自动进行。
方法1200接着进行通过均匀悬浮来加载细胞1212。在实施方式中,细胞可从细胞输入袋记载。可使用IC循环来分布细胞。在实施方式中,将细胞从细胞输入袋加载到生物反应器中。然后,细胞从排气腔室被赶至IC回路。根据实施方式,例如经由IC循环,没有IC输入,从而也没有超滤,来促进细胞在整个膜上的分布。
接着,方法1200进行至可选(以虚线形式示出)步骤:使用介质袋(例如取代的介质袋)替代输出袋或废物袋1214。在实施方式中,取代的介质袋包括约0.2L没有蛋白的介质。根据本公开的实施方式,在取代的介质袋中可使用其他体积或类型的替代流体。方法1200接着进行至转为“关停”,或以其他方式使一个或多个泵不启动1216。在实施方式中,IC输入泵和EC输入泵转为“关停”,或以其他方式指示停止或不启动1216。所述泵的不活动通过使朝IC循环回路和EC循环回路的输入介质流速变成“关停”,而使化学信号,诸如CCK的浓度增加。在这样的实施方式中,来自取代袋的流体可以无主动输入流体流的条件下的蒸发速率,被动添加至系统中。在没有替代输出袋或废物袋的实施方式中,可通过中断正在执行的方案程序,并且,允许在输出袋或废物袋中的任意流体(假设输出袋或废物袋中没有对细胞生长有毒性的成分)以在没有主动输入流体流的条件下的蒸发速率被动添加至所述系统,来被动替代系统中的流体。流体的这种被动添加避免了添加过量的流体,从而避免了稀释化学信号转导。在实施方式中,EC循环泵可维持为“开动(ON)”状态。在其他实施方式中,IC循环泵和EC循环泵都维持启动或“开动(ON)”状态。
接着,方法1200进行至供养细胞1218。在实施方式中,可对细胞培养物进行取样,用于进行细胞计数,同样通过切割一段管道来提供IC回路的代表性细胞浓度样品。在其他实施方式中,例如可通过从取样线圈或样品端口取出样品,来对细胞进行计数。
方法1200接着进行至测量葡萄糖和/或乳酸盐浓度1220。在询问1222处,确定细胞培养条件是否达到最小耐受葡萄糖浓度或最大耐受乳酸盐浓度。根据实施方式,这样的耐受浓度可发生在第4天前后。如果还没有达到上述耐受浓度,方法1200进行NO(否),以继续测量葡萄糖/乳酸盐浓度1220。如果达到了上述耐受浓度,方法1200进行YES(是),至可选(以虚线方式示出)步骤:使用废物袋或输出袋替代取代的介质袋(来自可选步骤1214)1224。在实施方式中,在可选步骤1214中被移除的原废物袋或输出袋用于在可选步骤1224处替代取代的介质袋。在另一实施方式中,使用不同的废物袋或介质袋,在可选步骤1224处替代取代的介质袋。
在可选步骤1224之后,例如方法1200进行至一旦细胞培养条件达到了最小耐受葡萄糖浓度或最大耐受乳酸盐浓度,就通过向IC循环回路和/或EC循环回路以受控的流速添加1226,来供养细胞。在实施方式中,低流速被持续添加至IC循环回路和/或EC循环回路。根据实施方式,该使用低流速的持续添加的供养可在第4天前后发生。
收获操作1228接着将悬浮的细胞从IC循环回路(包括生物反应器中的细胞)转移至收获袋。然后,方法1200在END(结束)操作1230处终止。
根据本公开的实施方式,对于图10、图11和图12中示出的方法,用于例示的目的提供了所描绘的操作步骤,这些操作步骤可进行重新排列、组合成其他步骤、与其他步骤平行使用等。因此,尽管使用以特定顺序列出的步骤对上述方法进行了描述,但本公开并不受限于该顺序。在其他实施方式中,步骤可以不同顺序、平行或任意不同次数(例如在另一步骤之前和之后)进行。进一步地,在不偏离本公开的精神和范围的情况下,可在实施方式中使用较少或额外的步骤。例如,当仅存在悬浮细胞或非贴壁细胞时,一些步骤可能不与它们对于贴壁细胞那样使用,诸如涂敷生物反应器1008和1108,允许细胞附着1020和1120,和释放细胞1036和1126。例如根据实施方式,即使没有这些步骤,图10和图11例如仍然可以应用于扩增悬浮细胞或非贴壁细胞。作为进一步的实例,尽管没有在图10和图11中示出,额外的步骤可包括使用输出袋或废物袋替代取代的介质袋(之前用于替代输出袋或废物袋)。根据实施方式,上述输出袋或废物袋可以是系统所使用的原输出袋或废物袋。在另一实施方式中,可使用不同的输出袋或废物袋来替代取代的介质袋。另外,参数,诸如预定时间段的流逝、乳酸盐浓度、葡萄糖消耗和循环速率,例如也可以与上面所描述的不同,其中提供上面所描述的参数仅用于示例性目的。此外,如上所述,方法1200包括以虚线方式示出的一些可选步骤/子步骤。但是,没有指示为可选的上述任意步骤(在方法1000、方法1100和/或方法1200中的任一方法)都不应被认为对于一个或多个本发明是必须的,而是可以在一个或多个本发明的一些实施方式进行,而在其他实施方法中不进行。进一步地,根据实施方式,虽然参考操作者或使用者描述了一些步骤、操作和/或子操作,但这些步骤、操作和/或子操作也可自动进行。
最后,图13示出了计算系统1300的示例性组件,本公开的实施方式可在计算系统1300上实施。计算系统1300可用于实施方式中,例如其中细胞扩增系统使用处理器来执行任务,诸如作为方法(诸如上述方法1000、方法1100和方法1200)的一部分进行的定制任务或预编程的任务。例如,预编程的任务可包括“供养细胞”。
计算系统1300可包括使用者界面1302、处理系统1304和/或存储装置1306。如本领域技术人员所理解的,用户界面1302可包括输出装置1308和/或输入装置1310。输出装置1308可包括一个或多个触摸屏,其中触摸屏可包括提供一个或多个应用窗口的显示区域。触摸屏也可以是输入装置1310,其中输入装置1310例如可接收和/或捕获来自使用者或操作者的物理触摸事件。如本领域技术人员所理解的,触摸屏可包括具有电容结构的液晶显示器(LCD),该电容结构允许处理系统1304演绎出触摸事件的位置。随后,处理系统1304可将触摸事件的位置映射到应用窗口预定位置中显示的使用者界面(UI)元件。根据实施方式,触摸屏也可通过一个或多个其它电子结构接收触摸事件。其它输出装置1308可包括打印机、扬声器等。如本领域技术人员所理解的,其它输入装置1310可包括键盘、其它触摸输入装置、鼠标、语音输入装置等。
根据本公开的实施方式,处理系统1304可包括处理单元1312和/或存储器1314。处理单元1312可为通用处理器,可操作地执行在存储器1314中存储的指令。根据实施方式,处理单元1312可包括单个处理或多个处理器。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。如本领域技术人员所理解的,处理器可包括通用处理器、专用集成电器(ASIC)、现场可编程门阵列(FPGA)、其它集成电路等。
根据实施方式,存储器1314可包括任意的用于数据的短期存储装置或长期存储装置,和/或可执行指令的处理器。如本领域技术人员所理解的,存储器1314可包括,例如随机存取存取卡(RAM)、只读存储器(ROM)或电可擦除可编程只读存储器(EEPROM)。如本领域技术人员所理解的,其它存储介质可以包括,例如,CD-ROM、磁带、数字多功能盘(DVD)或其它光存储装置、磁带、磁盘存储、磁带、其它磁存储装置等。
存储装置1306可为任意的长期数据存储装置或组件。根据实施方式,存储装置1306可包括一个或多个与存储器1314相关联的系统。存储装置1306可为永久的或可擦除的。在实施方式中,存储装置1306存储由处理系统1304产生或提供的数据。
实施例
下面是可用于细胞扩增系统,诸如CES 500(图5)、CES 600(图6)、CES 700(图7)、CES 800(图8)或CES 900(图9)的方案的实施例,例如该细胞扩增系统实施本公开的特征。要注意的是,提供下面的示例性方案用于例示目的,并不旨于限制可包括不同步骤、参数或其他特征的其他实施方式。在一些实施方式中,诸如通过执行在存储器中存储的预编程任务的处理器,例如可自动进行包括加载细胞和分布细胞的步骤(和任意子步骤)的示例性方案。在其他实施方式中,通过自动和手动执行操作的组合,来进行上述步骤(和任意子步骤)。在进一步的实施方式中,通过操作者或使用者,或通过其他手动方式,来进行上述步骤(和任意子步骤)。
实施例1:方案1
天:-1涂敷生物反应器
示例性方案的这一部分使用试剂涂敷生物反应器。该生物反应器可包括中空纤维膜。
步骤1:将试剂加载到IC回路中,直至袋子清空。
步骤2:将上述试剂从ARC赶至IC回路中。
步骤3:使上述试剂在IC回路中循环。
在开始这一任务之前,可满足以下前提:
细胞输入袋中包括最少40mL的空气。
表1描述了在进行该方案的涂敷生物反应器部分时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用如表2中所示的用于步骤1的各设置的值。
可使用表3中示出的用于步骤2的各设置的值。
可使用表4中示出的用于步骤3的各设置的值。
天:0 IC EC洗出
进行示例性方案的这一部分,以替代在IC循环回路和EC循环回路上的流体。可通过交换的IC体积和EC体积的数量来具体限定替代的体积。
表5描述了在进行该示例性方案的IC EC洗出时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表6中示出的用于IC EC洗出的值。
天:0条件介质
进行示例性方案的这一部分,以在加载细胞之前,允许介质与所提供的气体供应达到平衡。这一任务可包括两个独立步骤:
步骤1:通过使用高EC循环速率,提供介质和气体供应之间的快速接触。
步骤2:使系统维持在适当状态,直至操作者准备好加载细胞。
表7描述了在进行条件介质时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实施例。
可使用表8中示出的用于步骤1的值。
可使用表9中示出的用于步骤2的值。
天:0通过循环分布加载细胞
进行示例性方案的这一部分,以将细胞从细胞输入袋加载到生物反应器中。IC循环可用于分布细胞,并且可不尝试将细胞从管线赶至生物反应器中。这一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。更大的驱赶体积使细胞扩散,并且使细胞朝IC出口移动。
步骤3:经由IC循环并且没有IC输入,从而没有超滤,促进细胞在整个膜上的分布。
在开始这一任务之前,可满足以下前提:
细胞输入袋中包括最少40mL的空气。
表10描述了在进行通过循环分布加载细胞时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表11中示出的用于步骤1的值。
可使用表12中示出的用于步骤2的值。
可使用表13中示出的用于步骤3的值。
天:0使细胞附着
进行示例性方案的这一部分,以使贴壁细胞能附着至生物反应器膜,同时允许在EC循环回路上流动。将至IC回路的泵流速设置为近似零。
表14描述了在进行使细胞附着时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表15中示出的用于使细胞附着的值。
天:1供养细胞
进行示例性方案的这一部分,以低流速向IC循环回路和/或EC循环回路持续添加。存在几种输出设置,可用于移除添加至该系统的流体。
表16描述了在进行供养细胞时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表17中示出的用于步骤1的值。
可根据需要提高IC输入速率。作为一个实例,可如下提高IC输入速率:第1天~第2天:0.0mL/min;第2天~第3天:0.1mL/min;第3天~第4天:0.2mL/min;第4天~第5天:0.4mL/min;和,第5天~第6天:0.8mL/min。
释放贴壁细胞
进行示例性方案的这一部分,以从膜上释放细胞,并且使这些细胞留在IC回路中。
步骤1:在用于添加试剂的准备中,进行IC/EC洗出任务。例如,在用于添加胰蛋白酶的准备中,上述系统使用PBS替代IC/EC介质以去除蛋白、Ca++和Mg++。
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回路中。
步骤4:混合IC回路中的试剂。
在开始这一任务之前,可满足以下前提:
在细胞输入袋中包括最少40mL的空气。
表18描述了在进行释放贴壁细胞时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表19中示出的用于步骤1的值。
可使用表20中示出的用于步骤2的值。
可使用表21中示出的用于步骤3的值。
可使用表22中示出的用于步骤4的值。
可从样品线圈和/或样品端口采集样品,用于进行胰蛋白酶测定。
收获细胞
进行示例性方案的这一部分,以将悬浮的细胞从IC循环回路(包括生物反应器中的细胞)转移至收获袋。
表23描述了在进行收获细胞时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表24中示出的用于收获细胞的值。
实施例2:方案2
胆囊收缩素(CCK)是由细胞分泌的调节激素,并且很多情况中,可部分经由化学信号转导来用于细胞培养的维持和增殖。如果培养基中的CCK浓度没有达到阈值,可能危及细胞群。实施例2提供了细胞分泌的化学信号的实例,该化学信号用于在体外维持细胞群并且使细胞群增殖;在本实施例中,该细胞是CHO细胞。根据实施方式,CCK的近似4,000道尔顿的分子量使得它足够小至能容易地通过中空纤维生物反应器的多微孔膜。在实施方式中,不管输入介质添加至IC循环回路还是EC循环回路,都会由于自由通过该膜而发生化学信号的稀释。但是,根据实施方式,通过介质的被动替代,可使这样的化学信号转导的稀释最小化或完全消除。例如,根据实施方式,以下方案提供了在非贴壁细胞或悬浮细胞(诸如CHO细胞)的细胞扩增过程中的介质的被动替代。
天:0 IC EC洗出
进行示例性方案的这一部分,以在细胞培养的准备中,替代在IC循环回路和EC循环回路上的流体。可通过交换的IC体积和EC体积的数量来具体限定替代的体积。
表25描述了在进行该示例性方案的IC EC洗出时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表26中示出的用于IC EC洗出的值。
天:0条件介质
进行示例性方案的这一部分,以在加载细胞之前,允许介质与所提供的气体供应达到平衡。这一任务可包括两个独立步骤:
步骤1:通过使用高EC循环速率,提供介质和气体供应之间的快速接触。
步骤2:使系统维持在适当状态,直至操作者准备好加载细胞。
表27描述了在进行条件介质时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实施例。
可使用表28中示出的用于步骤1的值。
可使用表29中示出的用于步骤2的值。
天:0通过均匀悬浮加载细胞
进行示例性方案的这一部分,以将细胞从细胞输入袋加载到生物反应器中。例如,在实施方式中,所述细胞包括CHO细胞。IC循环可用于分布细胞,并且可不尝试将细胞从管线赶至生物反应器中。这一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IC回路中。
步骤3:经由IC循环并且没有IC输入(从而没有超滤),促进细胞在整个膜上的分布。
在开始这一任务之前,可满足以下前提:
细胞输入袋中包括最少40mL的空气。
表30描述了在进行通过均匀悬浮加载细胞时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表31中示出的用于步骤1的值。
可使用表32中示出的用于步骤2的值。
可使用表33中示出的用于步骤3的值。
天:0供养细胞
进行实验方案的这一部分,以通过对IC循环回路和EC循环回路将输入介质流式“关停”,允许提高诸如CCK的化学信号的浓度。在本配置中可使用IC出口或EC出口。
表34描述了在进行供养细胞时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表35中示出的用于步骤1的值。
在实施方式中,每一天都使用以下设置,对细胞培养物进行取样,以对细胞进行计数。
在实施方式中,在停止条件之后,立即切割出约六(6)英寸长(1mL)的管道长度。该样品中的体积提供了整个IC回路的代表性细胞浓度样品。这允许使用者在培养过程中自始至终对细胞进行监控。
天:4供养细胞
进行示例性方案的这一部分,一旦细胞培养条件达到了最小耐受葡萄糖浓度或最大耐受乳酸盐浓度,就持续以低流速向IC循环回路和/或EC循环回路添加。在实施方式中,这可发生在第4天前后。存在可用于移出添加至系统的流体的几种输出设置。
表37描述了在进行供养细胞时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表38中示出的用于步骤1的值。
在实施方式中,每一天都对细胞培养物进行取样,以对细胞进行计数(例如参见表36)。
天:7收获细胞
进行示例性方案的这一部分,以将悬浮的细胞从IC循环回路(包括生物反应器中的细胞)转移至收获袋。
表39描述了在进行收获细胞时,附接至各管线的溶液袋。提供了这些溶液和对应的体积,作为可使用的默认设置的一个实例。
可使用表40中示出的用于收获细胞的值。
对于本领域技术人员明显的是,可对本文所述的装置、系统、结构和方法进行各种修改和变化。因此,应当理解的是,各实施方式并不限制于本公开所讨论的主题。此外,本公开用于覆盖各种修改、变体和/或等价物。公开的作用、特征、结构和/或介质仅作为权利要求书实施的例示性实施方式。
Claims (39)
1.一种用于控制在封闭型细胞扩增系统的生物反应器中的化学信号转导的方法,所述方法包括:
涂敷所述生物反应器;
将细胞加载到所述生物反应器中,其中将所述细胞从细胞输入袋加载到所述生物反应器中;
启动内毛细管循环泵;
使用介质袋替代附接至所述细胞扩增系统的废物袋;并且
在使用所述介质袋替代了所述废物袋之后,关停所述内毛细管循环泵。
2.根据权利要求1所述的方法,其中,来自所述介质袋的介质流过外毛细管废物阀到达外毛细管循环回路,以补充从所述外毛细管循环回路中的气体转移组件蒸发掉的流体。
3.根据权利要求1所述的方法,进一步包括:
在使用所述介质袋替代了所述废物袋之后:
关停内毛细管输入泵;
关停外毛细管输入泵;
将外毛细管循环泵维持在启动状态;并且
将外毛细管废物阀维持在打开位置。
4.根据权利要求1所述的方法,其中,所述细胞是贴壁细胞。
5.根据权利要求4所述的方法,进一步包括:
使所述贴壁细胞能附着所述生物反应器的膜;并且
通过将外毛细管循环泵维持在启动状态,来维持外毛细管循环回路上的流动。
6.根据权利要求5所述的方法,其中,使所述贴壁细胞能附着至所述生物反应器的膜,持续约18小时至约24小时的时间段。
7.根据权利要求6所述的方法,进一步包括:
供养所述封闭型细胞扩增系统的生物反应器中的细胞,同时维持所述介质袋替代所述废物袋,并且同时停止内毛细管输入速率,其中所述供养包括:
启动所述内毛细管循环泵。
8.根据权利要求7所述的方法,进一步包括:
在供养约45小时至约50小时的第二时间段之后,停止所述细胞的供养。
9.根据权利要求7所述的方法,进一步包括:
在供养约48小时的第二时间段之后,停止所述细胞的供养。
10.根据权利要求7所述的方法,进一步包括:
测量由所述细胞生成的乳酸盐的浓度;并且
当乳酸盐的浓度等于或大于约6mmol/L时,停止所述细胞的供养。
11.根据权利要求10所述的方法,进一步包括:
移除所述介质袋;
插入所述废物袋;
启动所述内毛细管输入泵;
启动所述内毛细管循环泵;并且
将所述外毛细管循环泵维持在启动状态。
12.根据权利要求11所述的方法,其中:
所述内毛细管输入泵以约0.1mL/min的内毛细管输入速率运行;
所述内毛细管循环泵以约20mL/min的内毛细管循环速率运行;并且
所述外毛细管循环泵以约30mL/min的外毛细管循环速率运行。
13.根据权利要求12所述的方法,进一步包括:
使所述内毛细管输入速率加倍,直至能收获期望数量的细胞。
14.根据权利要求13所述的方法,进一步包括:
当能收获期望数量的细胞时:
从所述生物反应器的膜释放所述细胞;
使所述细胞悬浮在所述内毛细管循环回路中;并且
将悬浮的所述细胞转移至收获袋。
15.根据权利要求1所述的方法,其中,涂敷所述生物反应器的步骤和加载所述细胞的步骤由所述细胞扩增系统自动进行。
16.根据权利要求15所述的方法,其中,涂敷所述生物反应器的步骤和加载所述细胞的步骤由处理器进行,所述处理器执行储存在存储器中的预编程的任务。
17.根据权利要求1所述的方法,其中,手动进行将所述废物袋替代为所述介质袋。
18.根据权利要求1所述的方法,其中,将所述废物袋替代为所述介质袋由所述细胞扩增系统自动进行。
19.根据权利要求18所述的方法,其中,所述废物袋的自动替代包括:接收执行用于替代所述废物袋的任务的指令;并且其中,所述任务被储存在系统存储器中。
20.根据权利要求1所述的方法,其中,所述介质袋储存基础培养基。
21.根据权利要求20所述的方法,其中,所述介质袋储存约500mL的基础培养基。
22.根据权利要求1所述的方法,进一步包括:
将细胞信号转导蛋白分子从直接来源加载到内毛细管循环回路中;以及
启动所述内毛细管循环泵,以将所述细胞信号转导蛋白分子转移至所述生物反应器。
23.根据权利要求22所述的方法,其中,所述细胞信号转导蛋白分子被加载到所述内毛细管循环回路的取样线圈中。
24.根据权利要求22所述的方法,其中,所述细胞信号转导蛋白分子被加载到所述内毛细管循环回路的样品端口中。
25.根据权利要求23所述的方法,其中,所述取样线圈和所述内毛细管循环回路是一次性管道套件的一部分。
26.根据权利要求24所述的方法,其中,所述样品端口和所述内毛细管循环回路是一次性管道套件的一部分。
27.根据权利要求1所述的方法,进一步包括:
在将细胞加载到所述生物反应器中之前:
将内毛细管循环回路和外毛细管循环回路上的流体替代为来自内毛细管介质袋的介质;并且
允许来自所述内毛细管介质袋的介质,与气体供应达到平衡。
28.根据权利要求1所述的方法,进一步包括:
使所述细胞分布在所述生物反应器的整个膜上,其中所述细胞的分布通过启动所述内毛细管循环泵而发生。
29.一种细胞扩增系统,所述细胞扩增系统包括:
生物反应器,所述生物反应器包括至少具有两个相对端部的第一流体流动路径,所述第一流体流动路径的第一相对端部与中空纤维膜的第一端口流体相连,并且所述第一流体流动路径的第二端部与所述中空纤维膜的第二端口流体相连,其中,所述第一流体流动路径包括所述中空纤维膜的内毛细管部分;
流体输入路径,所述流体输入路径与所述第一流体流动路径流体相连,其中多个细胞通过所述第一流体输入路径被引入到所述第一流体流动路径中;
第一泵,所述第一泵用于使流体在所述生物反应器的第一流体流动路径中循环;
处理器,所述处理器与所述细胞扩增系统连接;
显示装置,所述显示装置与所述处理器通讯,并且能操作所述显示装置以显示数据;以及
存储器,所述存储器与所述处理器通讯并且能被所述处理器读取,并且所述存储器含有一系列指令,当所述处理器执行所述一系列指令时,使得所述处理器:
接收涂敷所述生物反应器的指令;
响应于涂敷所述生物反应器的指令,执行涂敷所述生物反应器的步骤;
接收将多个细胞加载到所述生物反应器中的指令;
响应于加载细胞的指令,执行将细胞从细胞输入袋加载到所述生物反应器中的步骤;
在将细胞加载到所述生物反应器中之后,接收停止内毛细管输入泵、内毛细管循环泵和外毛细管输入泵的指令;以及
允许介质从介质袋流动通过外毛细管废物阀,其中所述外毛细管废物阀处于打开位置。
30.根据权利要求29所述的细胞扩增系统,进一步包括:
接收泵送所述外毛细管循环回路中的介质的指令,以替代从位于所述外毛细管循环回路中的气体转移组件蒸发掉的流体。
31.根据权利要求30所述的细胞扩增系统,其中,所述介质袋中的介质包括基础培养基。
32.根据权利要求29所述的细胞扩增系统,其中,所述多个细胞包括贴壁细胞。
33.根据权利要求29所述的细胞扩增系统,其中,所述多个细胞包括非贴壁细胞。
34.一种细胞扩增系统,所述细胞扩增系统包括:
生物反应器,所述生物反应器包括至少具有相对两端部的第一流体流动路径,所述第一流体流动路径的第一相对端部与中空纤维膜的第一端口流体相连,并且所述第一流体流动路径的第二端部与所述中空纤维膜的第二端口流体相连,其中,所述第一流体流动路径包括所述中空纤维膜的内毛细管部分;
流体输入路径,所述流体输入路径与所述第一流体流动路径流体相连,其中多个细胞通过所述第一流体输入路径被引入到所述第一流体流动路径中;
第一泵,所述第一泵用于使流体在所述生物反应器的第一流体流动路径中循环;以及
控制器,所述控制器用于控制所述第一泵的运行,其中所述控制器被配置为控制所述第一泵,以:
使流体以第一速率在所述第一流体流动路径内循环;以及
当所述细胞扩增系统中的废物袋被介质袋替代时,在所述多个细胞被加载到所述生物反应器中之后,停止流体在所述第一流体流动路径内的循环。
35.根据权利要求34所述的细胞扩增系统,其中,所述介质袋包括基础培养基。
36.根据权利要求34所述的细胞扩增系统,其中,所述细胞扩增系统是封闭的。
37.根据权利要求34所述的细胞扩增系统,其中,所述多个细胞包括贴壁细胞。
38.根据权利要求34所述的细胞扩增系统,其中,所述多个细胞包括非贴壁细胞。
39.根据权利要求34所述的细胞扩增系统,进一步包括:
第二泵,所述第二泵用于将内毛细管输入流体从内毛细管介质袋转移至所述第一流体流动路径;
第二控制器,所述第二控制器用于控制所述第二泵的运行,其中所述第二控制器被配置为控制所述第二泵,以:
将所述多个细胞从细胞输入袋转移至所述第一流体流动路径;以及
当所述细胞扩增系统中的废物袋被介质袋替代时,在所述多个细胞被加载到所述生物反应器中之后,停止从所述细胞输入袋转移所述多个细胞。
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EP3122866A1 (en) | 2017-02-01 |
WO2015148704A1 (en) | 2015-10-01 |
CN106232800B (zh) | 2020-07-03 |
US11008547B2 (en) | 2021-05-18 |
EP3122866B1 (en) | 2019-11-20 |
EP3613841B1 (en) | 2022-04-20 |
JP6783143B2 (ja) | 2020-11-11 |
US20180119094A1 (en) | 2018-05-03 |
US20150275170A1 (en) | 2015-10-01 |
JP2017509344A (ja) | 2017-04-06 |
US11795432B2 (en) | 2023-10-24 |
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