Institute of Biomedical Engineering and Department of Engineering Science, University of Oxford, Oxford, United Kingdom.
PLoS One. 2013;8(3):e59671. doi: 10.1371/journal.pone.0059671. Epub 2013 Mar 29.
Despite numerous technology advances, bioreactors are still mostly utilized as functional black-boxes where trial and error eventually leads to the desirable cellular outcome. Investigators have applied various computational approaches to understand the impact the internal dynamics of such devices has on overall cell growth, but such models cannot provide a comprehensive perspective regarding the system dynamics, due to limitations inherent to the underlying approaches. In this study, a novel multi-paradigm modeling platform capable of simulating the dynamic bidirectional relationship between cells and their microenvironment is presented. Designing the modeling platform entailed combining and coupling fully an agent-based modeling platform with a transport phenomena computational modeling framework. To demonstrate capability, the platform was used to study the impact of bioreactor parameters on the overall cell population behavior and vice versa. In order to achieve this, virtual bioreactors were constructed and seeded. The virtual cells, guided by a set of rules involving the simulated mass transport inside the bioreactor, as well as cell-related probabilistic parameters, were capable of displaying an array of behaviors such as proliferation, migration, chemotaxis and apoptosis. In this way the platform was shown to capture not only the impact of bioreactor transport processes on cellular behavior but also the influence that cellular activity wields on that very same local mass transport, thereby influencing overall cell growth. The platform was validated by simulating cellular chemotaxis in a virtual direct visualization chamber and comparing the simulation with its experimental analogue. The results presented in this paper are in agreement with published models of similar flavor. The modeling platform can be used as a concept selection tool to optimize bioreactor design specifications.
尽管技术取得了众多进步，但生物反应器仍主要被当作功能黑箱使用，在这个黑箱中，反复尝试最终会得到理想的细胞结果。研究人员已经应用了各种计算方法来了解这些设备的内部动态对整体细胞生长的影响，但由于基础方法固有的局限性，这些模型无法提供关于系统动态的全面视角。在本研究中，提出了一种新颖的多范式建模平台，该平台能够模拟细胞与其微环境之间的动态双向关系。设计建模平台需要将基于代理的建模平台与传输现象计算建模框架完全结合和耦合。为了展示其能力，该平台被用于研究生物反应器参数对整个细胞群体行为的影响，反之亦然。为了实现这一目标，构建并播种了虚拟生物反应器。虚拟细胞在一组规则的指导下，这些规则涉及到生物反应器内模拟的质量传输以及与细胞相关的概率参数，能够表现出多种行为，如增殖、迁移、趋化和凋亡。通过这种方式，该平台不仅能够捕捉生物反应器传输过程对细胞行为的影响，还能够捕捉细胞活动对局部质量传输的影响，从而影响整体细胞生长。通过在虚拟直接可视化室中模拟细胞趋化作用并将模拟与其实验模拟进行比较，对该平台进行了验证。本文提出的结果与类似风味的已发表模型一致。该建模平台可用作概念选择工具，以优化生物反应器设计规格。
