A microfluidic platform for personalized throughput drug screening using cancer spheroids

癌症仍然是全球主要的死亡原因。对于许多患者来说，标准护理治疗包括手术切除原发肿瘤，但手术后往往伴随着远处继发微肿瘤的生长。需要的治疗方法要么对微转移瘤有毒，要么将它们锁定在休眠状态，然而，评估药物对生长在不同环境中、具有不同保护属性的微肿瘤的有效性是一个挑战。**目前，缺乏用于评价治疗药物的重建微转移的工具。动物模型昂贵、耗费人力和时间；通常只提供终点分析，可以说与人类无关。二维细胞培养产生的微肿瘤模型在性质和表型上与在生理三维环境中生长的模型有很大的不同，因此可能不是一种有效的药物筛选模型。多细胞癌球(MCS)架起了2D细胞培养和动物模型的桥梁，在药物筛选中有着非常有前途的应用。然而，目前用于药物筛选的MCS模型受到一些限制。**这项建议旨在开发一个微流控(MF)平台，用于筛选新药和优化用于治疗癌症的现有药物配方。这项技术利用了大量大小均匀的MCS，这些MCS来自患者来源的细胞，这些细胞在MF设备中的仿生水凝胶中生长，在接近生理流动的条件下向这些MCS输送药物，并对MCS治疗的药效进行吞吐量筛选。MF-MCS平台包括多排平行的微孔，每行最多有100个MCS。该平台允许在不同行之间系统地改变特定因素，从而能够筛选在特定环境中从特定细胞类型生长的MCS的药效，以及药物剂量和组合的影响，仅举几例，所有这些都是在单个MF设备中进行的一系列实验中的。**************

Cancer remains the leading cause of death worldwide. For many patients, standard-of-care therapy involves surgical removal of the primary tumour, however the surgery is often followed by the growth of secondary microtumours at distant locations. Therapies are required that are either toxic toward micrometastases or that lock them in the dormant state, yet there is a challenge to assess the effectiveness of drugs for microtumors grown in different environments with varying protective properties. ** Currently, there is lack of tools that recreate micrometastasis for the evaluation of therapeutic agents. Animal models are expensive, labor- and time-consuming; generally, provide only endpoint analyses and arguably, are not relevant for humans. Two-dimensional cell culture yields microtumor models that differ considerably in their properties and phenotype from those grown in physiological 3D environments, and thus may not serve as an efficient model for drug screening. Multicellular cancer spheroids (MCS) bridge 2D cell culture and animal models, and have very promising applications in drug screening however presently used MCS models for drug screening suffer from a number of limitations. ** This proposal aims at the development of a microfluidic (MF) platform for screening of new drugs and optimization of existing drug formulations for therapeutic cancer treatment. The technology utilizes large arrays of uniformly-sized MCSs derived from patient-derived cells that are grown in a biomimetic hydrogel in a MF device, the delivery of drugs to these MCSs under close-to-physiological flow conditions, and throughput screening of drug efficacy for MCS treatment. The MF-MCS platform includes multiple parallel rows of microwells, with up to 100 MCSs in each row. The platform enables systematic variation of a particular factor between different rows, thus enabling screening of drug efficacy for MCSs grown from a particular cell type in a specific environment, and the effect of drug dosages and combinations, to name just a few, all in one series of experiments conducted in a single MF device. **************