The research areas in my lab broadly focus on tissue engineering of 3D microphysiological systems (MPS) including: 1) the microcirculation; 2) the tumor microenvironment (brain, prostate, and breast cancer), 3) bone marrow, and 4) the immune system. 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. Our general approach is biology-directed in that we supply a minimal architecture (matrix, nutrients), and allow the microsystem to develop and remodel to meet metabolic and functional needs. 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.
Extracellular vesicle transport across endothelial and extracellular matrix barriers
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 Bryan Nguyen)
Tumor progression and metastasis (Intravasation and Extravasation)
Survival rates in cancer drop precipitously when the primary tumor develops the “skills” needed to metastasize to distant sites. Metastasis is complex and involves both intravasation into the circulation and extravasastion from the circulation to a distant tissue. Both of these key steps involve the microcirculation. We are developing tissue engineered models of the vascularized tumor microenvironment which can provide new levels of spatial and temporal resolution of these phenomena, and thus answer new questions to improve our understanding of tumor progression. Specific efforts include: 1) characterizing diffusion, convection, and binding of tumor-derived small extracellular vesicles (EVs) and how this phenomenon can potentially guide monocyte trafficking in the tumor microenvironment; and 2) CAR-T cell trafficking and immunosuppression in the tumor microenvironment
(Investigators: Venktesh Shirure, Raj Bains)
In vitro 3D model of human bone marrow.
Adult human bone marrow produces nearly 200 billion neutrophils every single day. This rapid cell production is susceptible to drugs and disease making neutropenia one of the first signs of bone marrow failure. We have designed a 3D model of human bone marrow that includes a perfusable network of microvessels that replicates granulopoiesis (the production of neutrophils) and can thus be used to investigate a host of mechanistic problems related to the daily production and egress (into the circulation) of neutrophils.
(Investigators: Evelyn Zarate-Sanchez and Bhupinder Shergill)
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 and Ahmed Alhassan)
Extramedullary granulopoiesis in the skin
In collaboration with Professor Scott Simon, we have developed a simple 3D model of the skin and are exploring novel mechanisms of immune defense against pathogens such as methicillin-resistent staphylococcus aureus (MRSA). This mechanisms involves the release of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow into the circulation where these cells can traffic to the skin and undergo local (or extramedullary) granulopoiesis.
(Investigators: Evan Cirves)