Testing drugs with the help of mathematical modelling

需要回答的一个重要问题是：是否有方法可以在限制使用动物进行测试的同时，更有效地开发新药？在一种新药被批准用于人类之前，它需要通过一系列的筛选测试。这些需要数年时间才能完成，当最终的筛选过程达到时，已经花费了数百万英镑用于新药的开发。通常使用的早期筛选技术是远远不现实的，这就是为什么许多药物通过这些早期测试，但大多数将在最后阶段失败。这是一个必须解决的问题，因为参与药物开发的制药公司正在损失大量的时间和金钱，并且在测试的最后阶段不必要地使用动物。在早期阶段，测试通常包括将细胞或组织暴露于体外环境中的化合物。传统上，这涉及在充满含有该化合物的液体的培养皿底部的单层细胞。然而，越来越多的人认识到，需要更多的生理相关的体外模型[1]。因此，已经转向2D和3D系统，其包括多层细胞;细胞簇;包含在基质和支架内的细胞以及使用先进的细胞培养设备连接在一起的这些的不同组合。在市售生物反应器系统中，包含流动变得越来越普遍[1，2]。虽然这些进步为微调药物检测系统提供了巨大的机会，但迄今为止尚未实现。一个重要的问题出现了：什么是最好的模拟现实的最佳实验条件？当然，这将取决于手头的系统，但是数学建模可以提供有助于回答这个重要问题的见解。该项目将对体外药物测试系统进行数学建模。这些模型将用于定义一组最佳实验条件，这些条件将产生最具临床相关性的结果。回顾文献并确定最需要新数学建模方法的系统子集。在受控条件下，通过细胞的3D配置开发流体流动和营养/药物运输的数学模型。根据文献和/或与合作者的互动中的实验数据对模型进行验证。开发环境对细胞/组织行为和健康影响的数学模型。使用数学模型为确定的区域的药物毒性测试的最佳实验设置提供指导。方法数学模型可用于确定测试药物的最佳条件，因为它提供了一个框架，帮助我们了解药物和营养物质如何渗透通过细胞和细胞簇（球状体）[3];生物标志物的暴露和释放;细胞空间排列和密度变化的影响;培养基内营养物质和化合物的流动和交换的影响[1，2]。这将允许开发更真实的测试系统，这将更能指示临床体内测试的结果。本项目将开发的模型将是新的，并将以开发系统的目标为驱动力，该系统将更早地识别注定失败的药物。将与相关实验人员和公司（例如Kirkstall Ltd）进行定期对话，以确保研究保持相关性和信息灵通。该模型的开发有可能导致新的设计工具，并使新的和更现实的药物测试系统的合理设计成为可能。

An important question that needs to be answered is: are there ways in which new drugs can be developed more time and cost efficiently while limiting the use of animals for testing? Before a new drug can be authorised for human usage, it needs to pass a series of screening tests. These take years to complete and by the time the final screening processes are reached, millions of pounds have already been spent in the development of the new drug. Often the early screening techniques which are used are far from realistic which is why many drugs pass these early tests, however most will fail in the final stages. This is a problem that must be solved as the pharmaceutical companies involved in the development of drugs are losing a lot of time and money, and animals are being used unnecessarily in the final stages of testing. In the early stages, testing usually consists of exposing cells or tissues to compounds in an in-vitro environment. Traditionally this involved a single layer of cells at the bottom of a petri dish filled with some fluid containing the compound. However, it is increasingly being recognised that more physiologically relevant in-vitro models are required [1]. There has therefore been a move to 2D and 3D systems which include multiple layers of cells; clusters of cells; cells contained within matrices and scaffolds and different combinations of these linked together using advanced cell culture apparatus. The inclusion of flow is becoming common in commercially available bioreactor systems [1,2]. Whilst these advances have provided enormous opportunity to fine-tune drug testing systems, to date this has not been achieved. An important question arises: what are the optimal experimental conditions which best mimic reality? Of course this will depend on the system at hand, however mathematical modelling can provide insights which can help to answer this important question. This project will mathematically model in-vitro drug testing systems. These models will be used to define an optimal set of experimental conditions that will give rise to the most clinically-relevant results.Objectivesi. Review the literature and identify a subset of systems where new mathematical modelling approaches are needed mostii. Develop mathematical models of fluid flow and nutrient/drug transport through 3D configurations of cells under controlled conditionsiii. Validate the models against experimental data from the literature and/or from interaction with collaboratorsiv. Develop mathematical models of the effect of the environment on the behaviour and health of the cells/tissuev. Use the mathematical models to provide guidance on the optimal experimental set-up for drug toxicity testing in the areas identified.MethodologyMathematical modelling can be used to identify the optimal conditions for testing drugs as it offers a framework which helps us understand how drugs and nutrients permeate through cells and clusters of cells (spheroids) [3]; the exposure and release of biomarkers; the effect of changes to the spatial arrangement and density of cells; the effect of flow and the exchange of nutrients and compounds within the media [1,2]. This will allow more realistic testing systems to be developed which will be more indicative of the outcome of the clinical in vivo tests.The models that will be developed in this project will be new and will be driven by the goal of developing systems which will identify drugs doomed to failure earlier. Regular conversations with relevant experimentalists and companies (e.g. Kirkstall Ltd) will be held to ensure the research remains relevant and well-informed. The models to be developed have the potential to lead to new design tools and to enable the rational design of new and more realistic drug testing systems.Alignment with EPSRC Strategies and Research AreasThis research sits broadly within the he