Microfluidics for drug discovery and healthcare

我建议通过构建模仿人类细胞的人造细胞，在药物发现过程的早期测试方式上创造一个范式转变。我的研究提出了一种自下而上构建定制人造细胞的方法，其中包含主要的基于膜的细胞组件和细胞器。我们可以利用这些系统同时研究药物的主动和被动转运。这有可能为我们与疾病的斗争创造一个令人兴奋的新方向，并导致未来医学科学的突破性进步。新药的开发需要10-15年，每种药物的成本约为26亿美元。即使在发现过程的后期阶段，失败率也很高，因为候选药物在人体试验时可能会产生意想不到的效果。总体而言，只有14%的药物获得了监管部门的批准，而且越来越多的人担心，动物研究无法准确预测药物在人体内的行为。从广义上讲，当前的科学研究范式与疾病的生物学基础以及治疗疾病的新药开发有关，遵循传统步骤。最初使用的是体外研究，其中候选药物使用无细胞测试，然后是基于细胞的测试。接下来是动物体内试验，最后是人体临床试验。此外，从医学角度来看，医生研究这些疾病在人类身上的进展。在过去的五年里，我的研究小组进行了基础研究，开发了一种独特的新方法，通过在芯片上构建定制的模仿人类的人造细胞膜来量化分子如何进入细胞。在这里，我将把剩余的基于膜的细胞成分添加到我的人造细胞中。我们将利用这些系统对不同的膜成分对药物被动膜通透性的影响进行基础研究。这些包括脂域的形成，以及疾病和性别对通透性的影响。然后，我们将插入人类摄取和外排膜转运蛋白，以能够量化主动转运。第三，由于细胞中的每个隔室由膜划定，我们将使用脂质体在基于液滴界面双层(DIB)的人工细胞内模拟这些隔膜。最后，我们将开发检测方法，使我们能够准确地量化药物在分隔的人工细胞的每个位置的转运动力学。

I propose to create a paradigm shift in the way that drugs are tested early in the discovery process by building artificial cells that mimic human cells. My research proposes a way to build bespoke artificial cells from the bottom up that contain the major membrane-based cellular components and organelles. We can use these systems to study both active and passive transport of drugs at the same time. This has the potential to create an exciting new direction in our fight against disease and cause ground-breaking advances in the medicinal sciences of the future.New drugs take 10-15 years to be developed and cost around US $2.6 billion each. Even at the later stages of the discovery process, there is a high failure rate since drug candidates can have unexpected effects when tested in humans. Overall, only ~14% of drugs gain regulatory approval, and there is increasing concern that animal studies do not accurately predict drug behaviour in the human body. In broad terms, the current paradigm for scientific research concerned with the biology underpinning diseases and the development of new drugs to cure them follows conventional steps. Initially in vitro studies are used, where drug candidates are tested using cell-free and then cell-based assays. This is followed by in vivo studies in animals, and finally clinical trials in humans. Alongside, from a medical perspective doctors study these diseases as they progress in humans. Over the last five years my research group have performed the fundamental research to develop a unique new method to quantify how molecules enter cells by building custom-made human-mimetic artificial cell membranes on a chip. Here, I will add the remaining membrane-based cellular components to my artificial cells. We will use these systems to perform fundamental studies into the effect that different membrane components have on drug passive membrane permeability. These include lipid domain formation, and the effect of disease and sex on permeability. Then, we will insert human uptake and efflux membrane transport proteins to be able to quantify active transport. Thirdly, since each compartment in a cell is delineated by a membrane, we will mimic these inside our droplet interface bilayer (DIB)-based artificial cells using liposomes. Finally, we will develop detection methods that allow us to quantify the kinetics of drug transport accurately in each location of the compartmentalised artificial cells.