A strategy for integrating essential three-dimensional microphysiological systems of human organs for realistic anticancer drug screening

Abstract

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.

Keywords: Three-dimensional microphysiological systems; anticancer drugs; bone marrow; cardiac tissue; tumor; vasculature.

Figure 1. A prototype drug screening platform

A. The microphysiological systems are developed in a central tissue chamber of individual modules. These microtissues are initially nourished by interstitial flow and later by a perfused capillary network. The medium is pumped around a microfluidic network and is oxygenated through a bubble chamber. A pressure regulator controls “arterial” pressure. Input and output channels on the arterial and venous side, respectively, allow mixing of fresh medium into the system. Individual tissue modules can be connected like jigsaw pieces, and connector valves allow “anastomosis” of microfluidic channels. B. Microfluidic channels are lined by EC and these anastomose with the microvessels in the tissue chamber to form a continuous vascular network linking all of the organs. C. An example how the major organs with a tumor might be placed such that their perfusion is in parallel to each other