Overview
The research areas in my lab broadly focus on tissue engineering of 3D microphysiological systems (MPS) and separation technologies to identify rare cells and vesicles in the peripheral blood. We are particularly interested in the transport and trafficking of immune cells (T cells, B cells, and neutrophils), other cells (hematopoietic stem cells, mesenchymal stem cells), and extracellular vesicles through the vascular systems and the extracellular matrix. The vascular supply for these engineered tissues is a major theme as we attempt to model convective transport using microvessels to more realistically simulate the tissue microenvironment. More recently we have manipulated fluid forces in microfluidic designs to capture T cell, B cells, and extracellular vesicles in the peripheral blood for applications in cancer therapeutics and prognostics, as well as immune responses. The projects demand many skills and utilize many techniques/technologies (e.g., microfabrication, microfluidics, transport phenomena, dynamic binding, mathematical modeling) but provides exciting and challenging opportunities to solve important biomedical problems, particularly in the fields of drug discovery and delivery. Below is a more detailed description of the individual projects.
Specific Projects
Extracellular vesicle transport across endothelial and extracellular matrix barriers including the blood-brain barrier
EVs (~30-150 nm diameter) are composite nanoparticles, secreted by cells, and are comprised of a lipid-based membrane surrounding an aqueous core. The membrane and core can each incorporate a wide range of biologically-active molecules (e.g., proteins, nucleic acids). Over the past decade, it has become clear that EVs represent a distinct and fundamental component of how neighboring and distant cells and tissues communicate. EVs represent a potential transformative nanotherapeutic drug delivery platform but the path from the blood to a tissue site is tortuous and laced with opportunities to bind, be modified, or degraded in the endothelium and ECM. As such, the endothelium and the ECM can each be considered as a biological “filter”, thus dictating the distribution and characteristics of EVs in tissue. This project seeks to enhance our understanding of 1) the basic mechanisms of transport that engage native EVs across the endothelial filter; 2) how the ECM filter impacts the character and dose of subpopulation(s) of EVs in tissue; and 3) whether co-localization of binding and bioactive molecules on the EVs contribute to the filtered subpopulations.
(Investigators: Venktesh Shirure, Bhupinder Shergill, and Cassidie Reller)
Force-dependent binding and capture of T and B lymphocytes
In collaboration with Professor Nicole Baumgarth and Xiangdong Zhu, we are using microfluidic technology to control the shear rate to capture rare populations of antigen-specific B and T cells from the peripheral blood. This project has applications to the immune response to viruses and vaccines (B cells) as well as immunotherapy for cancer (T cells).
(Investigators: Venktesh Shirure, Stephen Zhang, Asfa Sher, and Denise Chan)
Hydrodynamic focusing to isolate tumor-derived extracellular vesicles in the peripheral blood
Extracellular vesicles are small (~ 100 nm) lipid vesicles secreted by all cells including tumor cells and subpopulations arrive in the peripheral blood. They can exert numerous biological functions and are thought to play a role in stimulating the “premetastatich niche” and thus facilitating cancer metastasis. The tiny size and near neutral buoyancy requires innovative microfluidic techniques, such as hydrodynamic focusing, to capture them. We are trying to capture tumor-derived extracellular vesicles based on their binding affinity to extracellular matrix proteins.
(Investigators: Venktesh Shirure, Bhupinder Shergill, and Cassidie Reller)