Overview
There are six areas of research in my lab, all of which broadly focus on tissue engineering of 3D microphysiological systems (MPS): 1) the microcirculation; 2) cardiac tissue; 3) the tumor microenvironment (breast and colon cancer), 4) bone marrow, pancreatic islets, and 6) the immune system. The vascular supply for these engineered tissues is a major theme as we attempt to model convective transport using real human 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, stem cell biology, transport phenomena, mathematical modeling) but provides exciting and challenging opportunities to solve important biomedical problems, particularly in the fields of drug discovery and developmental biology. Below is a more detailed description of the individual projects.
Specific Projects
In vitro 3D Disease Model of Atrial Conduction
Nearly 1 in 10 adults over the age of 65 in the U.S. suffer from atrial fibrillation (AF) leading to approximately $6 billion annually in healthcare costs. Because advanced age is a primary risk factor for developing AF, the overall incidence is expected to rise steadily over the coming decades as our population ages. Current therapeutic interventions have remarkably poor efficacy and/or untoward side effects due in large part to our inability to target the root cause of the disease and provide specificity for the atria and the patient. The central objective of this project is to create and validate a robust 3D microphysiological model of abnormal human atrial conduction using induced pluripotent stem cells from the patient.
(Investigators: Sergey Yechikov)
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 tumor microenvironment with a perfused human vasculature, including primary breast, colon, and pancreatic cancer, 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 (sEVs) 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, Matt Curtis, Pete Sariano)
In vitro 3D model of Human Bone Marrow.
For women in the U.S., breast cancer ranks second in the frequency of cancer diagnoses (first is skin cancer), and second as the cause of death due to cancer (first is lung cancer). Overall five-year survival rates now approach 90%, and have increased steadily since the mid 1970s (~ 70%). However, approximately 20% of women with breast cancer will suffer a recurrence, a third of the time occurring >10 years after initial treatment. The most common site of breast cancer metastasis is the bone, and, importantly, at the time of the initial diagnosis approximately 40% of women with breast cancer already have microscopic disseminated tumor cells (DTC) in the bone marrow. Importantly, bone marrow DTCs have a low proliferation rate, many markers of cancer stem cells, and are resistant to current therapies. The presence of DTCs is associated with worsened survival and a higher incidence of relapse. This project proposes to combine microfluidic and tissue engineering technology to create a 3D in vitro model of human bone marrow that includes perfused human capillaries.
(Investigators: Venktesh Shirure 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 virsuses and vaccines (B cells) as well as immunotherapy for cancer (T cells).
(Investigators: Venktesh Shirure and Zach Rollins)
3-D Microphysiological model of the Pancreatic Islet
This multidisciplinary project is a joint effort between UCSD, UCI, and UCD and is developing a novel in vitro platform to create a human islet micro-organ perfused with human microvessels in a microfluidic device with all components derived from a single human induced pluripotent stem cell (hiPSC) source. Our role is to create a model microfluidic system that controls and measure the oxygen tension and glucose delivery to the pancreatic islet.
(Investigators: Venktesh Shirure and Bhupinder Shergill)