Heylman Christopher, Sobrino Agua, Shirure Venktesh S, Hughes Christopher Cw, George Steven C
Department of Biomedical Engineering, University of California, Irvine, CA 92697, USA The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, CA 92697, USA.
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
Exp Biol Med (Maywood). 2014 Sep;239(9):1240-54. doi: 10.1177/1535370214525295. Epub 2014 Apr 16.
Cancer is one of the leading causes of morbidity and mortality around the world. Despite some success, traditional anticancer drugs developed to reduce tumor growth face important limitations primarily due to undesirable bone marrow and cardiovascular toxicity. Many drugs fail in clinical development after showing promise in preclinical trials, suggesting that the available in vitro and animal models are poor predictors of drug efficacy and toxicity in humans. Thus, novel models that more accurately mimic the biology of human organs are necessary for high-throughput drug screening. Three-dimensional (3D) microphysiological systems can utilize induced pluripotent stem cell technology, tissue engineering, and microfabrication techniques to develop tissue models of human tumors, cardiac muscle, and bone marrow on the order of 1 mm(3) in size. A functional network of human capillaries and microvessels to overcome diffusion limitations in nutrient delivery and waste removal can also nourish the 3D microphysiological tissues. Importantly, the 3D microphysiological tissues are grown on optically clear platforms that offer non-invasive and non-destructive image acquisition with subcellular resolution in real time. Such systems offer a new paradigm for high-throughput drug screening and will significantly improve the efficiency of identifying new drugs for cancer treatment that minimize cardiac and bone marrow toxicity.
癌症是全球发病和死亡的主要原因之一。尽管取得了一些成功，但为减少肿瘤生长而研发的传统抗癌药物面临着重要局限性，主要是由于不良的骨髓和心血管毒性。许多药物在临床前试验中显示出前景后却在临床开发中失败，这表明现有的体外和动物模型对人类药物疗效和毒性的预测能力较差。因此，需要更准确模拟人体器官生物学的新型模型用于高通量药物筛选。三维（3D）微生理系统可以利用诱导多能干细胞技术、组织工程和微制造技术来开发尺寸约为1立方毫米的人类肿瘤、心肌和骨髓组织模型。一个由人类毛细血管和微血管组成的功能网络，可克服营养物质输送和废物清除中的扩散限制，也能滋养3D微生理组织。重要的是，3D微生理组织生长在光学透明的平台上，能够实时进行具有亚细胞分辨率的非侵入性和非破坏性图像采集。此类系统为高通量药物筛选提供了一种新范式，并将显著提高识别新的癌症治疗药物的效率，这些药物可将心脏和骨髓毒性降至最低。
