Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Sci Transl Med. 2012 Nov 7;4(159):159ra147. doi: 10.1126/scitranslmed.3004249.
Preclinical drug development studies currently rely on costly and time-consuming animal testing because existing cell culture models fail to recapitulate complex, organ-level disease processes in humans. We provide the proof of principle for using a biomimetic microdevice that reconstitutes organ-level lung functions to create a human disease model-on-a-chip that mimics pulmonary edema. The microfluidic device, which reconstitutes the alveolar-capillary interface of the human lung, consists of channels lined by closely apposed layers of human pulmonary epithelial and endothelial cells that experience air and fluid flow, as well as cyclic mechanical strain to mimic normal breathing motions. This device was used to reproduce drug toxicity-induced pulmonary edema observed in human cancer patients treated with interleukin-2 (IL-2) at similar doses and over the same time frame. Studies using this on-chip disease model revealed that mechanical forces associated with physiological breathing motions play a crucial role in the development of increased vascular leakage that leads to pulmonary edema, and that circulating immune cells are not required for the development of this disease. These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future.
目前,临床前药物开发研究依赖于昂贵且耗时的动物测试,因为现有的细胞培养模型无法重现人类复杂的器官水平疾病过程。我们提供了使用仿生微设备的原理证明,该设备可重建器官水平的肺功能,从而创建模拟肺水肿的人类疾病芯片模型。该微流控设备重建了人肺的肺泡-毛细血管界面,由紧密相邻的人肺上皮细胞和内皮细胞层组成,这些细胞层经历气流和液流以及周期性机械应变,以模拟正常呼吸运动。该设备用于复制在接受白细胞介素 2 (IL-2) 治疗的人类癌症患者中观察到的药物毒性引起的肺水肿,这些患者接受了类似剂量和相同时间框架的治疗。使用这种芯片疾病模型的研究表明,与生理呼吸运动相关的机械力在导致肺水肿的血管通透性增加的发展中起着至关重要的作用,并且循环免疫细胞不是这种疾病发展所必需的。这些研究还确定了潜在的新疗法,包括血管生成素 1 (Ang-1) 和一种新的瞬时受体电位香草醛 4 (TRPV4) 离子通道抑制剂 (GSK2193874),它们可能在未来预防 IL-2 的这种危及生命的毒性。