Microfabricated Platforms for Mimicking the Biomechanics of the Human Cardiovascular System

The human cardiovascular system is composed of the heart and a complex network of blood vessels, which facilitates the recirculation of blood throughout our body. Its main tasks include the delivery of oxygen and nutrition to different organs, delivery of carbon dioxide and waste materials from different organs, as well as transport of immune cells, proteins, enzymes, and biomarkers across our body. The malfunction of the heart or blood vessels can lead to several chronic or acute cardiovascular diseases, especially in ageing adults. Animal models have been widely used to understand the complex nature of cardiovascular diseases with the goal of discovering drugs to disrupt and delay the development of such diseases. However, large animal models are expensive, time-consuming, low-throughput, and ethically controversial, while small animal models do not accurately recapitulate the physiology and pathology of the human cardiovascular system. In both cases, animal models do not enable the researchers to dissociate the effect of multiple, interlaced parameters on the development of cardiovascular diseases. These limitations have led to the continuous development of various in vitro models to explore the human cardiovascular system. Microfabricated technologies, and in particular microfluidics, enable the creation of more realistic, humanized models of the human cardiovascular system. A key feature of these technologies is their ability to mimic the complex biomechanics of the heart and blood vessels, which is mainly dominated by the shear stress caused by the friction between the blood flow and the vessel walls, and the cyclic stretch of the vessel walls caused by heart pulsation. However, most existing microfabricated models involve complicated, costly, and time-consuming fabrication procedures, which limits their widespread applications. To address this limitation, I dedicated my PhD research to the development of novel microfabricated platforms to recapitulate the complex biomechanics of the human cardiovascular system, which can be created in a timely and costly manner using well-established microfabrication techniques, while are highly modular and controllable. Chapter 1 provides a brief introduction to cyclic stretch systems, introduces the research gaps and the research questions. Chapter 2 describes a 3D printed cyclic stretch system and its application for studying the mechanobiology of endothelial cells. Chapter 3 describes a microfluidic structure with a deformable surface to mimic the cyclic stretch of blood vessel walls. Chapter 4 describes a microfluidic structure incorporated with a large cavity to mimic the cyclic stretch of the heart chambers. Chapter 5 summarises the outcomes of the research and provides suggestions for future work. As my first research contribution, I developed a cam-driven cyclic stretch system to study the mechanobiology of vascular endothelial cells. The system utilized soft, deformable cell culture chambers mounted onto a 3D printed, cam-driven mechanism. The device allowed for exposing endothelial cells to customized cyclic stretch profiles, magnitudes, and frequencies for more than 12 hours. The system accommodated four cell culture chambers, each divided into four segments, enabling 16 experiments to be conducted in parallel. As my second contribution, I developed a highly deformable microfluidic blood vessel model capable of generating customized shear stress and cyclic stretch loads. The model involved a soft, elastomeric membrane mounted on a microfluidic structure, created using well-established 3D printing and soft lithography methods. The model relied on a syringe pump to drive the flow through the system and an automated valve to control the flow. Injection of liquid through the system while closing the valve led to the inflation of the membrane, whereas withdrawal of liquid from the system while closing the valve led to the deflation of the membrane. This simple mechanism was utilized for the cyclic inflation and deflation of the membrane in a highly controlled manner. A comprehensive set of experiments was conducted to characterize the changes in the volume, pressure, and flow rate of the blood vessel model. Experiments demonstrated the utility of this model to induce shear stress and cyclic stretch loads in a simple yet controlled and repeatable manner. As my third research contribution, I pioneered a microfluidic heart chamber model. The model took advantage of a semi-spherical balloon-shaped membrane patterned onto a microfluidic channel. The model was created using 3D printing and soft lithography methods. The same principle used for the cyclic deformation of the blood vessel model was harnessed here for the cyclic inflation and deflation of the heart chamber model. Owing to its large volume and small thickness, the chamber experienced a substantially large deformation. The buckling of the heart chamber model at high flow rates led to its asymmetric deflation. The versatility of the system was demonstrated by examining the cyclic deformation of two serially connected heart chamber models as well as by embedding the model in a soft elastomeric matrix to recapitulate the soft cardiac tissue. Overall, the technologies created during my PhD research facilitate the development of versatile, modular, and highly controllable microfluidic models of the human cardiovascular system in a time- and cost-effective manner. Such technologies will pave the way to better understanding the complex biomechanics of the heart and blood vessels, enabling us to elucidate how biomechanical forces govern the development of cardiovascular diseases in a systematic manner. These technologies also provide a unique platform for examining various drugs as well as strategies to enhance the targeted delivery of drugs to the cardiac and vascular tissues.