CN102834503A - 连续培养装置 - Google Patents
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Abstract
描述了一种用于在三维结构中培养哺乳动物细胞的连续培养装置,所述三维结构用于体内移植或植入。所述培养装置包括(a)由以有规律的间距间隔的相互连接的生长面矩阵形成的支架,和(b)在生长区域的入口和出口的流体分配装置。所述装置对于培养用于牙科植入物或骨重建的骨细胞尤其有用。
Description
发明领域
本发明涉及在用于体内移植或植入的三维结构中培养哺乳动物细胞的装置。更特别地,本发明涉及用于培养牙科植入物或骨重建的骨细胞的连续培养装置。
背景技术
对于在三维(3D)环境比如3D结构或支架上培养细胞受到越来越多的关注。在3D支架上进行细胞培养对于生产可移植的组织结构的组织工程是有用的。在3D支架上进行3D培养内在的困难是:(i)贯穿支架孔的统一、高效的细胞接种,和(ii)向支架中央部分细胞的物质转移受限。
过去三十年来在组织工程领域取得了巨大的进步,但是与在深的或厚的结构的中心培养细胞所遇到的困难相关的问题仍然存在。
美国专利6,194,210描述了在聚合微载体细胞中培养A型肝炎病毒的过程。
美国专利6,218,182描述了在生物反应器中培养3D组织,尤其是用作体外肝脏辅助装置的肝脏组织的方法,细胞接种于生物反应器中,并提供两股培养基流,每一股与细胞不同的侧面相接触。
US 2009/0186412描述多孔细胞支架和其生产方法。
所有的现有技术文献提出了高细胞密度的培养系统遇到不规律的液体流时出现的一些问题。
在厚的结构中或培养密度高时,已知的生物反应器不能有效地模拟体内营养机制。
在哺乳动物体内,流量的调节、营养物质和气体的传递、废物的清除是包括体内许多复杂功能的自动化过程。血液是复杂的系统,维持大量的气体和营养物质进入和排出遍布体内的细胞的能力。流量通过复杂的系统进行管理,其自动改变体积和压力以重新分配血流量到高需求的区域。所述分配系统包括数千分支,每个分支可以具有更小的内径,直到最后达到滋养细胞的维度水平。利用计算流体力学(CFD)软件能够进行复杂结构和其容器中的流动分析。当合适的特征的组合被确定,可以研究代谢参数,以保证物质的利用率和生产的废物的产率保持在典型的安全区域。一个例子是计算最大细胞密度和氧消耗率,以确保所有的细胞维持有氧。
现在我们找到了连续培养装置,其解决了在深或厚的结构的中心培养细胞时的问题。
发明内容
本发明的目的是连续培养装置,包括(a)由以规律的间距间隔的相互连接的生长面的矩阵形成的支架,和(b)位于生长区域的入口和出口的流体分配装置。
配置间距和界限,使通过和环绕生长面的定向流均一。
流量分配是指允许生长区域的入口和出口到每个生长面的足够的流量。所述流量分配利用计算流体动力学和主要代谢物利用分析进行分析,以保证细胞免于不利的生长条件。
优选地,流量分配是指分配新鲜营养物和气体的进入流到生长面。可以根据生长面的形状和生长面支持的细胞的总数量,调整分配装置通道的截面积和通道的数量,以方便到生长面的均匀分布。
优选地,培养装置包括相互连接的生长面的矩阵,其由多种纤维或三维结构的有组织和重复式的相互连接来限定,其可以加入任意数量的用于促进或加强细胞生长和附着的平面或表面物体。
形成矩阵的三维结构可以是圆柱形、长方形、六角形,或其他任何形状或形状的组合,并且表面可以是光滑的或有纹理的。
在本发明实际优选的实施方式中,支架是由围绕着中心支持物的以有规律的间距间隔的相互连接的生长面的矩阵形成。
由所述结构相互连接形成的开放空间,等于或大于0.7mm,小于3mm,优选的等于或大于0.9mm,小于3mm。在优选的实施方式中,间距大于1.0mm,但是需要时可以根据支架的物理强度作出改变。在本发明的另一个更优选的实施方式中,相互连接的生长面以等于或大于1.0mm,小于2.0mm的规律间距间隔。
间距是本发明的特征性特性。围绕上述范围内的参数变化可以优化整个支架中的培养基流,并同时独立于它们最终的形状和维度,赋予根据本发明的所有装置的3D结构的足够坚固性。由生长面相互连接形成的开放空间,形成了根据本发明的装置的有组织的特征结构,其区别于现有技术中已知装置的多孔结构。
支架的形状优选是立方体,但它可以是另一种形状,例如圆柱形的或解剖学上正确的。
优选地,培养装置包括大量均一安排的相互连接的生长面,形成限制每立方体积最大数量细胞的大的开放区域,便于生长区域容易地进行血管生成。
培养装置可以由任何生物相容性材料制成。
生物相容性材料是任何生物相容性的有机聚合物或其混合物以及生物相容性的有机多聚体和生物相容性的有机或无机非聚合化合物的掺合物或混合物。
用于本发明的生物相容性材料成分的非限制性的特定例子是聚己内酯、聚氧化乙烯-对苯二甲酸乙二醇酯、聚酰胺、聚L-乳酸、聚乙醇酸、胶原蛋白、纤维连接蛋白、羟基磷灰石等。
在实际优选实施方式中,所述培养装置还包括无菌密封罩,其可以在培养期完成时拆卸。所述无菌罩可以包括密封的可拆卸盖、入口分配装置、可选的出口分配装置,和用于定位和固定培养装置中的生长面的必要的支持物。
所述罩可以是长方形、圆柱体或其他的保持培养装置以及提供无菌除去支架的额外特征所需的其他任何形状。
本发明提供了超过以前的培养装置的几个优势,在于营养输送使得组织在厚(>1mm)的基质上产生并保持活力。
可以在单个步骤的过程中生产本发明的3D培养装置。
可选择地,首先可以生产2D层,所述的单个2D层可以通过一个覆盖另外一些的方式组装形成根据本发明的3D培养装置。
3D培养装置的最终尺寸的将取决于组装的2D层的数目。
本发明的培养装置,可以有效地用于培养任何类型的细胞成3D组织。优选培养用于牙科植入物或骨重建的细胞。一旦细胞生长成3D组织,可以停止培养基流,可以使用或保存组织供将来使用。本发明的培养装置也可以有效地用来培养直接进入人体的细胞。事实上,所述装置可以植入需要组织重建的病人,可以在体内实现所述培养。
使用根据本发明的培养装置,细胞可以在受控制的环境中在可生物降解的支架上生长。生长面相互连接形成大的开放的区域,使它们能够接触到均匀的培养基流,并防止在生长过程中的污染。特别是,防止了在生长过程中由于气泡形成的生长面的污染或阻塞。
此外,使用本发明的培养装置,培养条件被连续监测,对所需条件的任何偏离,进行自动校正和报警。这提供了维持细胞未分化状态,以尽量减少最大细胞密度和相关的毒性坏死的必要条件,并提供了对关键的营养物质和气体非扩散限制的环境。
另外,根据本发明提供的培养装置,如对兔子进行的实验显示在没有细胞存在的情况下也提供了组织的生长。
实施例
实验方案
根据本发明的两层支架(11mm×11mm×5mm),切成等尺寸的四件,用于小鼠上的细胞生长实验。
组织学分析和结果
四个连续培养装置植入免疫缺陷的NOD/SCID小鼠。
从植入起一周后的炎症反应分析表明,没有典型的炎症反应迹象,即肿胀、发红、分泌物等。
对照材料HA(羟基磷灰石),即市售的生物医用材料作为标准样品的组织学分析,没有显示炎症(如淋巴细胞浸润),相反地,它显示了多孔陶瓷材料与组织的整合(成纤维细胞进入材料的孔隙)。
从含有本发明目标的连续培养装置的所有的样品中去除聚己内酯,并用石蜡代替。它导致阴性的或空的显微图像。
样品P(聚己内酯)、PC(有细胞的聚己内酯)、PD(三钙磷酸盐浸渍的聚己内酯)(图7)、PDC(三钙磷酸盐浸渍的有细胞的聚己内酯)(图8)的组织学分析没有显示组织的任何炎症过程。所以,在体内植入本发明的的连续培养装置,提供了细胞的生长而没有组织的炎症过程。
对小鼠进行的分析表明,连续培养装置是生物相容的,且没有局部毒性。此外,连续培养装置的典型的3D结构提供了组织的再生。
本发明将通过下面代表了本发明特定实施方式的附图进行更详细的说明,但不限于此。
附图的简要说明
图1支架的一个实施方式
图2流量分配装置的一个实施方式
图3两个流量分配装置间支架的一个实施方式
图4系统流程图
图5CFD流动分析
图6流量分析图片
图7样品PD的显微图片
图8样品PDC的显微图片
图9样品HA、PD和PDC的图片
附图的详细说明
图1是支架的一个实施方式。支架(1)由圆柱(3)结构的矩阵相互连接形成。支架(1)围绕着中心支持物(2)形成。
图2是流体分配装置(5)的一种实施方式。在该装置中,流体在连接到分流管(7)的共同的管道(6)呈送给所述装置(5)。支撑装置(8)显示与支架(1)的中心支持物(2)连接。
图3描述了位于两个分配装置(5)之间的支架(1)。在该实施方式中,所述的流体传递到入口共同管道(6),并进一步分配到分流管(7),之后被分配经过和围绕支架(1)的开放式结构(4)。然后收集所述流体,并送到位于出口装置(5B)的共同管道(7),在出口装置(5B),其被收集并送到分配装置(5B)的共同管道(6)。
图4是连接到中央循环系统(9)的培养装置(10)的略图。当培养装置(10)连接到系统(9),其被定位来接收由泵(12)所提供的营养物质和溶解气体的连续流。连接培养装置(10)的入口和泵的出口(12)形成中央循环环。培养装置(10)的出口和泵的入口(12)通过储液池(13)连接。在系统(12)中与所述流体保持持续通讯状态的是各种传感器(11)。传感器(11)与监视和控制系统(12)条件的控制装置(20)连接。提供了额外的泵(14,15),以供给新鲜的营养物质到系统的计量传递,以及将废弃物质排出所述系统。
图5举例说明计算流体动力学分析的例子,其中流体分配贯穿整个结构。
图6是流量分析的照片。
图7和图8分别表示没有炎症过程的样品PD和样品PDC的细胞生长。显微照片的放大倍率是20×,显微照片的顶部是表皮。
图9说明了对小鼠进行的细胞生长实验的样品HA、PD和PDC的应用和分析区域。样品的外部分析未表现出任何纤维化反应或炎症过程。
Claims (10)
1.一种连续培养装置,包括:(a)由以有规律的间距间隔的相互连接的生长面的矩阵形成的支架,和(b)在生长区域的入口和出口的流体分配装置。
2.根据权利要求1所述的装置,其中所述的支架是由围绕着中心支持物以有规律的间距间隔的相互连接的生长面的矩阵形成的。
3.根据权利要求1所述的装置,其中所述相互连接的生长面由相互连接的多种纤维或三维结构限定。
4.根据前述任一项权利要求所述的装置,其中所述相互连接的生长面以规律的等于或大于0.7mm且小于3.0mm的间距间隔。
5.根据前述任一项权利要求所述的装置,其中所述相互连接的生长面以规律的等于或大于0.9mm且小于3.0mm的间距间隔。
6.根据前述任一项权利要求所述的装置,其中所述相互连接的生长面以规律的等于或大于1.0mm且小于3.0mm的间距间隔。
7.根据前述任一项权利要求所述的装置,其中所述相互连接的生长面以规律的等于或大于1.0mm且小于2.0mm的间距间隔。
8.根据前述任一项权利要求所述的装置,进一步包括可以在培养期完成时拆卸的无菌密封罩。
9.根据权利要求4所述的装置,其中所述无菌罩包括密封的可拆卸盖、入口分配装置、可选的出口分配装置,和用于定位和固定培养装置中的生长面的必要的支撑装置。
10.前述任一项权利要求所述连续培养装置培养用于牙科植入物或骨重建的骨细胞的用途。
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