3D Collagen Vascular Tumor-on-a-Chip Mimetics for Dynamic Combinatorial Drug Screening.
3D Collagen Vascular Tumor-on-a-Chip Mimetics for Dynamic Combinatorial Drug Screening.
复制标题
3D胶原蛋白血管肿瘤在片上，用于动态组合药物筛查。
DOI：
10.1158/1535-7163.mct-20-0880
复制
发表时间：
2021-06
影响因子：
5.7
通讯作者：
Neumann CA
中科院分区：
文献类型：
--
作者：
Wan L;Yin J;Skoko J;Schwartz R;Zhang M;LeDuc PR;Neumann CA
疾病模型，包括体外细胞培养和动物模型，在过去几十年中为诊断和治疗的发展做出了重大贡献。传统药物筛选方法的成功通常受到不能充分模拟体内关键特征的阻碍，例如3D微环境和通过细胞外基质（ECM）的动态药物扩散。为了解决这些问题，我们开发了一种用于癌症药物筛选的3D动态药物递送系统，该系统通过创建胶原包埋的微流体通道来模拟药物通过肿瘤脉管系统和ECM的传播。使用这种新的3D ECM微系统，我们比较了肿瘤块的存活率与传统使用的2D方法，以响应3种不同的药物组合。通过模拟方法评估药物扩散曲线，并在3D ECM微系统和2D 96孔装置中进行测试。与2D对照相比，3D ECM微系统产生了关于活力、药物比率和组合指数的可靠数据。这种新方法能够实现更高的吞吐量，并为未来的应用奠定了基础，利用药物敏感性预测算法的基础上动态扩散配置文件，只需要最少的患者组织。我们的研究结果使药物敏感性筛查更接近临床意义，重点是测试组合药物效应-这一选择通常受到可用患者组织数量的限制。
Disease models, including in vitro cell culture and animal models, have contributed significantly to developing diagnostics and treatments over the past several decades. The successes of traditional drug screening methods were generally hampered by not adequately mimicking critical in vivo features, such as a 3D microenvironment and dynamic drug diffusion through the extracellular matrix (ECM). To address these issues, we developed a 3D dynamic drug delivery system for cancer drug screening that mimicks drug dissemination through the tumor vasculature and the ECM by creating collagen-embedded microfluidic channels. Using this novel 3D ECM microsystem, we compared viability of tumor pieces to traditionally used 2D methods in response to 3 different drug combinations. Drug diffusion profiles were evaluated by simulation methods and tested in the 3D ECM microsystem and a 2D 96 well set up. Compared to the 2D control, the 3D ECM microsystem produced reliable data on viability, drug ratios and combination indeces. This novel approach enables higher throughput and sets the stage for future applications utilizing drug sensitivity predicting algorithms based on dynamic diffusion profiles requiring only minimal patient tissue. Our findings moved drug sensitivity screening closer to clinical implications with a focus on testing combinatorial drug effects – an option often limited by the amount of available patient tissues.