Open microfluidics platforms for the in vitro assessment of drug transport in microtumour samples

如何为晚期癌症患者找到正确的治疗方法？在基因组学的世纪里，临床医生越来越意识到肿瘤具有高度的患者特异性，并且可能对不同类型的抗癌药物具有不同的敏感性。考虑到大多数药物的治疗效果只能在几周后才能感受到，在治疗的早期识别无反应应该会大大减少副作用，并节省与无临床益处相关的成本。为了给病人开正确的药，今天的临床医生使用生物标志物来统计治疗结果与病人的遗传/表观遗传特征之间的关系。在过去的几年里，另一种有希望的针对患者的治疗方法出现了：直接在体外评估药物对患者自身肿瘤样本的反应，这些样本被捕获或生长在直径仅为一毫米的微型通道网络中。在这些微流体系统或芯片实验室中，微观肿瘤样本可以被捕获或在3D中进行组织工程，以恢复体内组织的一些特征。许多人认为，在这个意义上，它们比培养皿中的二维培养更适合研究细胞对药物的反应，因为后者忽略了肿瘤的一个重要方面：在复杂的三维细胞结构中，药物、氧气、营养物质、细胞因子和其他分析物的生化运输限制。

How to find the right treatment for a patient suffering from advanced cancer? In the century of genomics, there has been a growing awareness among clinicians that tumors are highly patient-specific and likely to have different sensitivities to different types of anti-cancer drugs. Given that the therapeutic effects of most drugs can only be felt after several weeks, identifying non-responders early in a treatment should greatly reduce side-effects and save costs associated with no clinical benefit. To prescribe the right drugs to a given patient, clinicians today use biomarkers to statistically correlate the outcome of a treatment with the patient’s genetic/epigenetic profile. Over the past years another promising approach to tailor treatments to patients has emerged: the direct in vitro assessment of drug response on samples from the patient’s own tumor trapped or grown in a network of miniature channels only fractions of a millimeter in diameter. In these microfluidic systems, or lab-on-a-chip, microscopic tumor samples can be trapped or tissue-engineered in 3D to recover some of the features of in vivo tissues. Many argue that they are in this sense superior to 2D cultures in petri dishes to study the response of cells to drugs as the latter neglect an important aspect of tumors: the biochemical transport limitations of drugs, oxygen, nutrients, cytokines and other analytes in complex 3D cellular architectures. Biochemical transport science in microfluidic systems is our primary scientific expertise. It deals with the study of advection, diffusion, and reactions of particles and molecules submitted to various forces in miniature channels. The solution to many technological challenges in lab-on-a-chip applications, including kinetics measurements in surface-based sensors and efficient separation in protein or DNA analysis, has been made possible through systematic understanding of mass transfer properties at the microscale. Since microfluidics allow for the precise control of the tumor microenvironment, it is poised to play a major role in the development of drug discovery platforms employing 3D in vitro models as efficient surrogates for in vivo testing in mouse models. It is the very challenge of bringing this vision to reality that we are describing in this proposal. The long term research goals of this research program is two-fold. On a fundamental level, we will seek to develop a detailed understanding of mass transport in lab-on-a-chip systems, with a focus on transport inside an around 3D biological samples trapped in microfluidics systems to understand how tumors respond to drugs. On a more applied, engineering level, we will use advanced transport concepts, numerical simulations, microfabrication and cell and tissue culture techniques to design fast analytical tools to speed up biological and medical data acquisition by integrating all steps of tumor analysis onto a chip. To achieve this goal, we will propose to break down the problem in three main objectives to be pursued as three parallel independent projects for Ph. D. students: i) Systematic exploration of advective/diffusive transport in open microfluidic geometries; ii) Modeling of analyte transport in and around spheroids and cancer tissue microsections and its effect on tumor chemoresponse ; iii) Systematic investigation of the effect of growth conditions on spheroid sizes. Through the proposed projects, we will train outstanding students at the interface between engineering and cancer biology, we will collaborate with clinicians to develop our technologies with the end user in mind, and, above all, we will strive to have a lasting impact in the way cancer patients are being treated to improve their general quality of life.