The goal of our research program is to understand and engineer the fundamental structure and functions in living tissue and organ systems of our human body from nanometer, micrometer to centimeter scale. The fundamentals and technology requirements of our program includes a mixture of biomechanics, transport phenomena, microfluidic technologies, and biology and medicine. The success of our research achievement may lead towards clinical applications for regenerative tissue and organs, and therapeutic applications and health industry with deconstructive in vivo-mimicking models.
Embryonic development requires vascular growth, as do many physiological and pathological processes in adults, including tissue regeneration, cardiovascular diseases, and tumor progression. Blood vessels grow through three distinct processes: vasculogenesis, angiogenesis, and arteriogenesis. These terms describe, respectively, de novo growth of new blood vessels, growth of new vessels from preexisting ones, and increases in the size of preexisting vessels. Much attention has been devoted to sprouting angiogenesis and genetic mechanisms underlying cardiovascular development. Nevertheless, little is known about the factors that govern vascular remodeling — the dynamic modification of existing vascular structure — particularly as a function of circulating blood flow and vascular wall components. Our interest is to build in vitro vascular models to control vascular structure. Our research carried in this theme aims 1) to examine the effects on vessel density and branching induced by changes in hydrodynamic flow and pressure in in vitro vessels containing only of endothelial cells or both endothelial and smooth muscle cells; 2) to determine the differences in vascular remodeling responses in linear vs. branching systems; and 3) to extend the previous aim by developing a mature vascularized bed in vitro with a capillary plexus connecting an arterial network (at high pressure) and venous network (at low pressure).
Blood is the source of our life and safeguards our health. The main function of a blood vessel is to carry blood. The interaction between blood and the vessel wall controls the homeostasis in normal physiology, and when disturbed, it may initiate many diseases and progression. For example, in patients with sepsis syndrome, extensive microvessel leak and intravascular thrombosis may lead to sudden death; in patients with systemic inflammation such as thrombotic thrombocytopenia and sickle cell disease, extensive thrombosis develops in small vessels; in patients with moyamoya syndrome, there are often vessel blockages associated with extensive growth of small collateral vessels in the brain. These diseases produce high morbidity and mortality, and treatments remain inefficient. We collaborate with Dr. José López in Puget Sound Blood Center, and built artificial vessels with appropriate geometries and human-only components to understand the initiation and progression of thrombosis. We also collaborate with Drs. Joe Smith and Alexis Kaushansky in Center for Infectious Disease Research to understand the vascular dysfunction in cerebral malaria.
Organ on a chip
Almost all the organ systems comprise complex physiological environment, including cellular (many types of cells and cell-cell interactions), biochemical (cytokines secreted from cells and extracellular matrix signals), and biophysical components (mechanical stress and oxygen tension). Animal model is too complex to study contribution of individual components and current in vitro model is not able to mimic the complex in vivo condition. The goal of our lab is to develop in vivo mimicking microenvironment to build and understand the organ functional units.
>> bone marrow niche
The bone marrow produces nearly 500 billion blood cells per day in an adult human. Each type of blood cell is required for life: red blood cells deliver oxygen, white blood cells provide immunity, and platelets prevent bleeding, among other functions of these cells. Dysregulation of blood cell production leads to severe anemia, leukopenia, and thrombocytopenia, and produces substantial morbidity and mortality. We are developing an in vitro microfluidic bone marrow niche (μBMN) that recapitulates the bone marrow in its cellular and matrix components, but which can also be manipulated to determine the roles of each component in the functioning of a normal bone marrow, and allow us to elucidate and control hematopoiesis.
>> heart regeneration
Myocardial infarction and heart failure represent the main cause of death in many countries. Regenerating functional heart tissue has become an important therapeutic objective to replace the infarcted myocardium. Our goal is to develop a perfusable cardiac tissue patch and study possible cardiac tissue maturation induced by hemodynamic flow through the vasculature. Our long-term goal is to pre-program the microenvironment of regenerative cardiac patches to optimize vascular functional efficiency, and consequently structural and functional features of cardiac tissue. As our research evolves, we will extend our pre-vascularized cardiac tissue in animal models and further toward the clinic.
>> kidney filtration on a chip
We are in a team led by Kidney Research Institute to design, implement and test a tissue engineered human kidney peritubular microphysiological system. The system is expected to fully evaluate uptake, metabolism and elimination of xenobiotics in a human kidney tissue derived, in vitro 3-dimensional system that accurately reflects human physiology. It is also expected to further assess the response to kidney injury inflicted by endogenous and exogenous toxicants, as well as from pathogens. Our lab focus on recreating kidney microvasculature from human components, and study their baseline of barrier function, vascular integrity and non-thrombotic properties.
We are also in active collaboration with Dr. Stuart Shankland to start rebuilding kidney glomeruli filtration barrier in 3D. We aim to study the regeneration of podocytes from progenitor cells and their interactions with the glomeruli microvasculature in this system.