|Joshua Hall, 2nd Year
Program: Mechanical Engineering
Advisor: Juan Jimenez PhD.
Education: Worcester Polytechnic Institute, BS, Biochemistry, 2016
With my undergraduate background in biochemistry, and graduate focus in bioengineering and fluid mechanics, my goal is to bridge medicine and biology with engineering to study complex fluid-flow dependent diseases, with an interdisciplinary approach. My main PhD project is to elucidate the role that fluid flow plays in cancer ‘in-transit’ metastasis. ‘In-transit’ metastases arise from the lymphatic vessels located between a primary tumor and the regional lymph nodes. Lymphangions, the functional units of lymphatic vessels, contain valves to prevent backflow, which induce a heterogeneous flow field. The fluid surrounding lymphatic valves forms recirculation zones with low flow velocity, causing local endothelial cells (EC) to experience significantly reduced wall shear stress (WSS). In the cardiovascular and lymphatic systems, WSS from fluid flow affects EC gene expression which can result in disease progression when flow conditions induce a disease-prone phenotype. Our laboratory’s previous work, in the context of stents, atherosclerosis, and lymphatic vessels, demonstrated that altering the WSS experienced by EC can shift the EC phenotype in vivo and in vitro to a disease prone phenotype, with direct correlation to areas of clinical importance in patients.
We hypothesize that the fluid flow in lymphangion recirculation zones leads to a pro-metastatic EC phenotype, leading to changes in the expression of cell adhesion molecules and tumor cells, attracting chemokines that increase the incidence of circulating tumor cell extravasation into the adjacent tissue. I will be using a flow chamber to simulate physiological fluid flow past a monolayer of lymphatic ECs. I will compare the gene expression of ECs exposed to recirculation zone flow to ECs exposed to standard lymphatic vessel flow to elucidate the role of fluid flow on metastatic-relevant genes in ECs. To test this in a functional assay, I have designed a PDMS based microfluidic device with the same geometry and size scale of a lymphatic vessel via soft lithography. After lining the device with collagen and seeding lymphatic ECs, I will circulate media with cancer cells (specifically melanoma, a cancer type with ‘in-transit’ metastases in vivo) using a peristaltic pump, capable of reproducing physiological pulsatile flow. Using video microscopy I will observe circulating tumor cell adhesion in real time. I expect that tumor cells will adhere to ECs in recirculation zones at a higher rate than at other regions in the device.
Elucidating the role of fluid flow in ‘in transit’ metastasis is critical in understanding pathways to stop this process of metastasis in vivo, and create new therapeutic approaches. By combining fluid dynamics and engineering principles with molecular biology tools, our interdisciplinary studies will shed light on this important, however often overlooked, process in cancer metastasis.
A smaller project involves a collaboration with Dr. Pablo Visconti in the Department of Veterinary and Animal Science at UMass-Amherst utilizing a combination of microfluidics and chemistry to study the effects of chemotaxis on sperm motility. We hypothesize that gradients of chemoattractants such as progesterone play a key role in directing sperm cells toward the ovum during fertilization. Along with several undergraduate students that I supervise, we designed and created a microfluidic device that can yield varying chemotactic gradients to test our hypothesis. A different chemical concentration is applied to each of six channels, and the sperm are visually monitored to quantify the number, direction, and travel velocity of sperm near each channel to determine which concentration gradient is favored by sperm cells. These studies will provide insights into sperm chemoattraction, with broad implications for both fertility and contraception.