Mathematical modelling and optimisation of organ-on-a-chip in vitro systems

芯片器官体外系统的数学建模和优化

基本信息

  • 批准号:
    2269758
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Studentship
  • 财政年份:
    2019
  • 资助国家:
    英国
  • 起止时间:
    2019 至 无数据
  • 项目状态:
    已结题

项目摘要

An essential feature of adequate prediction of drug toxicity in preclinical pharmaceutical development is the use of cellular in vitro models that recapitulate the physiology of human tissues as closely as possible. 3D cellular systems that include physiologically realistic fluid flow are important in providing appropriate shear stresses required for mechanobiological responses and correct function of cells. They can also provide the transport and recirculation of drugs, nutrients and waste compounds, as well as signalling molecules such as cytokines and chemokines, which drive cell-cell communication that is critical for physiological functioning of cells in-vitro. The distribution of such solutes is relevant to understanding cellular function and can be used to enhance pharmacokinetic and cell-cell interaction and signalling models in toxicology studies. A specific focus is organ-on-a-chip models of liver cells, since hepatotoxicity is a major cause of clinical failure in drug development. These can be extended to include multiple cell types or multi organ systems (e.g. immune cells, gut cells) to incorporate further interactions relevant to the drug's mechanism of action. Mathematical modelling of such systems not only helps to understand and improve the physiological relevance of in vitro models, but will also enable the optimisation of relevant experimental settings, and most importantly, enable quantitative predictions regarding toxicity in the drug development process.Aims and ObjectivesConstruct mechanistic mathematical models for fluid flow and solute transport for a range of organ-on-a-chip systems, coupled to relevant models of cellular function (e.g. metabolism, immune mediated effector-target toxicity, cytokine release cell-cell communication).Obtain quantitative predictions of fluid flow, shear stresses, and concentration distributions, and compare with results obtained experimentally.Determine optimal design and operating conditions of the in vitro system (flow rates, scaffold properties, system geometry) in order to match the in vivo environment experienced by cells as closely as possible and/or optimise the performance of the systems as a tool for toxicity assessments. Inform and optimise experimental design and pharmacokinetic modelling through understanding of fluid flow.Understand impact of fluid dynamical load on cellular function.Obtain a general mathematical framework that can be applied and adapted to a variety of microfluidic systems, where advanced understanding of fluid mechanics can provide fundamental insights through the interaction between complex fluid flows and cell function, informing the drug discovery process.Novelty of Research MethodologyResearch methodology will include mechanistic mathematical modelling, analysis and in silico computation, in combination with experimental studies performed at Roche. The mathematical model will incorporate a combination of ideas from fluid dynamic modelling (Navier-Stokes, Darcy/Brinkman equations, multiphase flows, reaction-advection-diffusion equations) which apply to different components of the system.The model will be investigated through a combination of numerical techniques (e.g. finite-difference, finite element and spectral methods, use of commercial software) and analytical approaches on reduced models obtained by exploiting different time/length scales (e.g. linear and nonlinear stability theory, regular and singular perturbation theory, multiple-scales analysis, limiting cases in parameter space).Data will be obtained from experimental studies and imaging performed at Roche.
在临床前药物开发中充分预测药物毒性的一个基本特征是使用细胞体外模型,尽可能接近地概括人体组织的生理学。3D细胞系统包括生理上真实的流体流动,在提供机械生物学反应和细胞正确功能所需的适当剪应力方面非常重要。它们还可以提供药物、营养物质和废物化合物的运输和再循环,以及细胞因子和趋化因子等信号分子,这些分子驱动细胞与细胞之间的交流,这对细胞在体外的生理功能至关重要。这种溶质的分布与了解细胞功能有关,并可用于加强毒理学研究中的药代动力学和细胞-细胞相互作用和信号模型。一个特别的焦点是肝细胞的芯片上器官模型,因为肝脏毒性是药物开发临床失败的主要原因。这些可以扩展到包括多种细胞类型或多器官系统(例如免疫细胞、肠道细胞),以结合与药物作用机制相关的进一步相互作用。这种系统的数学建模不仅有助于理解和改进体外模型的生理相关性,而且还将使相关的实验设置得以优化,并且最重要的是,能够对药物开发过程中的毒性进行定量预测。目的和目的构建一系列芯片上器官系统的流体流动和溶质运输的机械数学模型,与细胞功能的相关模型(例如新陈代谢、免疫介导的效应-靶毒性、细胞因子释放细胞-细胞通讯)相结合。获得对流体流动、剪切力和浓度分布的定量预测,确定体外系统的最佳设计和操作条件(流速、支架性能、系统几何形状),以尽可能接近细胞所经历的体内环境和/或优化系统的性能,作为毒性评估的工具。通过了解流体流动,为实验设计和药代动力学建模提供信息和优化。了解流体动力负荷对细胞功能的影响。获得可应用于各种微流体系统并适用于各种微流体系统的一般数学框架,其中对流体力学的高级理解可以通过复杂的流体流动和细胞功能之间的相互作用提供基本的见解,为药物发现过程提供信息。研究方法的创新研究方法将包括机械数学建模、分析和计算机计算,结合罗氏进行的实验研究。数学模型将结合适用于系统不同组件的流体动力学建模(Navier-Stokes、Darcy/Brinkman方程、多相流动、反应-平流-扩散方程)的思想。模型将通过数值技术(例如有限差分法、有限元和谱方法、商业软件的使用)和通过利用不同时间/长度尺度获得的简化模型的分析方法(例如线性和非线性稳定性理论、规则和奇异摄动理论、多尺度分析、参数空间的极限情况)相结合来研究。数据将来自罗氏的实验研究和成像。

项目成果

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其他文献

吉治仁志 他: "トランスジェニックマウスによるTIMP-1の線維化促進機序"最新医学. 55. 1781-1787 (2000)
Hitoshi Yoshiji 等:“转基因小鼠中 TIMP-1 的促纤维化机制”现代医学 55. 1781-1787 (2000)。
  • DOI:
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    0
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LiDAR Implementations for Autonomous Vehicle Applications
  • DOI:
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
生命分子工学・海洋生命工学研究室
生物分子工程/海洋生物技术实验室
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吉治仁志 他: "イラスト医学&サイエンスシリーズ血管の分子医学"羊土社(渋谷正史編). 125 (2000)
Hitoshi Yoshiji 等人:“血管医学与科学系列分子医学图解”Yodosha(涉谷正志编辑)125(2000)。
  • DOI:
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Effect of manidipine hydrochloride,a calcium antagonist,on isoproterenol-induced left ventricular hypertrophy: "Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,K.,Teragaki,M.,Iwao,H.and Yoshikawa,J." Jpn Circ J. 62(1). 47-52 (1998)
钙拮抗剂盐酸马尼地平对异丙肾上腺素引起的左心室肥厚的影响:“Yoshiyama,M.,Takeuchi,K.,Kim,S.,Hanatani,A.,Omura,T.,Toda,I.,Akioka,
  • DOI:
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评估用于航空航天应用的新型抗疲劳钛合金
  • 批准号:
    2879438
  • 财政年份:
    2027
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