Abstract
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 cell technology, tissue engineering, and microfabrication techniques have created a unique opportunity to develop three-dimensional (3D) microphysiological systems that more accurately reflect in vivo human biology when compared with two-dimensional flat systems or animal models. Our group is working to develop 3D microphysiological systems using induced pluripotent stem cell technology that simulates the microcirculation, the cardiac muscle, and the solid tumor, and then to combine these systems into an integrated microphysiological system that simulates perfused cardiac muscle and solid tumor on a single platform. The platform will be initially validated to predict anti-cancer efficacy while minimizing cardiac muscle toxicity. 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 3D 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. The results of our project 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 multiple major organ systems of the human body.
Highlights
Cancer and heart disease are, by far, the two leading causes of mortality in the United States
We demonstrated the versatility of this platform to form robust capillary networks using various matrices such as type I collagen and porcine cardiac-derived extracellular matrix (ECM) [11] blended with fibrin (Figure 2a)
We demonstrate feasibility for using our proposed system to create a vascularized cardiac microtissue by first differentiating human induced pluripotent stem cell (iPSC) into cardiomyocytes following a matrix sandwich method [20]
Summary
Cancer and heart disease are, by far, the two leading causes of mortality in the United States. It is unrealistic to create 3D models of all NCI60 tumor cell lines; because anti-colon cancer drugs have known cardiac toxicity, our focus is on two colon cancer cells lines that are part of the NCI60 (SW620 and HCT116) This focus provides the opportunity to compare the response of our 3D system with a large body of data collected in simpler 2D systems, while focusing our efforts on a model system that has the potential to distinguish the efficacy of new chemotherapeutic agents. A critical barrier to developing new anti-cancer drugs is the creation of a realistic in vitro model of the tumor microenvironment that has the potential to simulate key features such as the leaky and tortuous microcirculation These features of the tumor microcirculation probably play an important role in early metastatic events such as intravasation. The steps in the development of the perfused solid tumor will be creating an environment in which rapid and reproducible anastomosis between the vessel network and the microfluidic channels occurs, and validating the response of the system to a panel of wellcharacterized anti-tumor drugs
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