Vascular organ-on-a-chip platforms for disease modeling

Abstract

Organs-on-chips have emerged as viable platforms for expediting the drug development process. These systems potentially enable the prediction of human responses towards pharmaceutical compounds, and the development and testing of nanomedicines, chemicals, and even biopharmaceuticals. In the past decade, advances in microfluidics technologies have facilitated the development of organs-on-chips as simple, reproducible, and scalable platforms that recapitulate organ-level functions, by incorporation of biological materials such as cells and biophysical cues. The use of a small number of cells and culture media volume makes this approach cost effective and scalable. Different microfabrication techniques have enabled the creation of dynamic microenvironments to apply shear stress, strain, and/or interfaces on different biological materials. In this context, the cardiovascular system is one of the most important organ systems where biophysical forces play a crucial role. Millions of people are diagnosed every year with different cardiovascular diseases, and aging represents the number one risk factor. In this context, organ-on-a-chip devices hold promise to revolutionize drug discovery by unveiling responses unobserved using conventional cell culture systems that lack the dynamics of living systems, potentially expediting the drug discovery process. Additionally, with the advent of organs-on-a-chip, a new set of tools and sensors is required to monitor cell responses in real-time and harness the potential of the technology. Here, we first provide a broad landscape analysis on the state-of-the-art organ-on-a-chip technologies. We identify challenges and opportunities in the cardiovascular arena, and lay out areas of potential benefit in the drug development pipeline. We have developed a new progeria-on-a-chip device to examine the effects of biomechanical strain in the context of vascular aging and disease. The vasculature-on-a-chip recapitulates markers of hypertension under pathological strain, which are observed under angiotensin II treatment. Smooth muscle cells derived from human induced pluripotent stem cells of Hutchinson Gilford Progeria Syndrome donors, but not from healthy donors, showed an exacerbated inflammatory response to strain. In particular, we observed increased levels of inflammatory markers, as well as DNA damage. Pharmacological intervention with a statin or a farnesyltransferase inhibitor reversed the strain-induced damage by shifting gene expression profile away from inflammation. In addition, we have developed a set of tools to operate and monitor organ-on-a-chip systems. We have first created a mini-microscope capable of real-time monitoring of cell morphology and behavior, either under bright light or fluorescence. Such monitoring approach allows the cheap and scalable integration of imaging analysis to organ-on-a-chip systems. Finally, we have developed an Augmented Reality solution to monitor and control organ-on-a-chip devices via Google Glass. The set of software and hardware created allow performing research remotely, when experimental conditions present a danger to the experimenter. The tool also aims to lay ground on the future applications of augmented reality in laboratory settings. The devices and tools created in this thesis aim at providing a platform to be implemented in drug discovery platforms, allowing high-throughput control and analysis of multiple test conditions in a model of vascular disease and aging