Cancer and cardiovascular disease remain the two leading causes of death in the United States. Progress in treatment to reduce morbidity and mortality will include the development of new drugs. Recent advances in induced pluripotent stem (iPS) cell technology, tissue engineering, and microfabrication techniques have created a unique opportunity to develop 3-D microphysiological systems that more accurately reflect in vivo human biology when compared to 2-D "flat" systems or animal models. The primary goal of this project is to create 3-D micro-organ systems using iPS technology that simulate 1) the microcirculation, 2) cardiac muscle, and 3) solid tumor during the UH2 phase, and then combine these micro-organs into three integrated micro- organ systems that simulate 1) perfused cardiac muscle, 2) perfused solid tumor, and 3) perfused cardiac muscle and solid tumor during the UH3 phase. The platform will be initially validated to predict anti-cancer efficacy while minimizing cardiac muscle toxicity. The broader implication of this project is the creation of a platform technology that can accurately and affordably simulate the complex interplay between the major human organ systems, including the response to new and existing drugs. A critical feature will be blood flow through a human microcirculation (capillaries and larger microvessels), which is necessary to overcome diffusion limitations of nutrients and waste products in realistic 3-D cultures, and serves to integrate multiple organ systems. This is a necessary and critical feature of any platform that seeks to simulate integrated human organ systems, and our preliminary studies demonstrate this capability. Secondary goals of the project include achieving: 1) flexibility in the design such that alternate organ functions (e.g., liver) can be eaily inserted, removed, or rearranged (i.e., "plug-n-play");2) reproducibility in the manufacturing process and the biological response;3) portable design that is palm-sized;4) the use of iPS cell technology to create patient-specific (or "personalized") drug screening, and 5) non-invasive and non-destructive optical imaging methods to rapidly assess the metabolic state of a cell. The results should produce a new paradigm for efficient and accurate drug and toxicity screening, initially for anti-cancer drugs with minimal cardiac side effects, and a platform technology that can be eventually used to integrate all of the major organs of the human body.
The central objective of our proposal is to develop an integrated 3-D in vitro high-throughput system that mimics the major physiologic and biologic features of cardiac muscle and solid tumor. The system can be used to identify new anti-cancer drugs while minimizing potential harmful toxicity to cardiac muscle.
|Kurokawa, Yosuke K; George, Steven C (2016) Tissue engineering the cardiac microenvironment: Multicellular microphysiological systems for drug screening. Adv Drug Deliv Rev 96:225-33|
|Datta, Rupsa; Heylman, Christopher; George, Steven C et al. (2016) Label-free imaging of metabolism and oxidative stress in human induced pluripotent stem cell-derived cardiomyocytes. Biomed Opt Express 7:1690-701|
|Sobrino, Agua; Phan, Duc T T; Datta, Rupsa et al. (2016) 3D microtumors in vitro supported by perfused vascular networks. Sci Rep 6:31589|
|Wang, Xiaolin; Phan, Duc T T; Sobrino, Agua et al. (2016) Engineering anastomosis between living capillary networks and endothelial cell-lined microfluidic channels. Lab Chip 16:282-90|
|Ehsan, Seema M; George, Steven C (2015) Vessel network formation in response to intermittent hypoxia is frequency dependent. J Biosci Bioeng 120:347-50|
|Heylman, Christopher; Datta, Rupsa; Sobrino, Agua et al. (2015) Supervised Machine Learning for Classification of the Electrophysiological Effects of Chronotropic Drugs on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. PLoS One 10:e0144572|
|Merna, Nick; Fung, Kelsey M; Wang, Jean J et al. (2015) Differential Î²3 Integrin Expression Regulates the Response of Human Lung and Cardiac Fibroblasts to Extracellular Matrix and Its Components. Tissue Eng Part A 21:2195-205|
|Alonzo, Luis F; Moya, Monica L; Shirure, Venktesh S et al. (2015) Microfluidic device to control interstitial flow-mediated homotypic and heterotypic cellular communication. Lab Chip 15:3521-9|
|Lee, Eugene K; Kurokawa, Yosuke K; Tu, Robin et al. (2015) Machine learning plus optical flow: a simple and sensitive method to detect cardioactive drugs. Sci Rep 5:11817|