(4oq) Mechanical Engineering of Immune Cell Movement in Tissues and Across Vasculature

My research goal is to establish the biophysical mechanisms, involving principles from fluid and solid mechanics, underlying T cell movement in tissues and across vasculature.

During my PhD training, my research focused on developing two microfluidic platforms for multiphase sample delivery to detectors based on ionizing radiation. Firstly, I developed microfluidic nozzles to create liquid sheet jets for unique X-ray spectroscopy and identified scaling theories that predict sheet jet geometry strictly from nozzle geometry, flow rate, and thermophysical fluid properties (Ha et al., Phys Rev Fluids 2018). The nozzle design has become a standard SLAC user toolkit and has found increasing applications for electron and high-power laser sources, serving broader communities across many countries. Secondly, I pioneered a water-in-oil droplet microfluidic platform for single-cell radiopharmaceutical studies. Named flow radiocytometry, this platform enables high-throughput single-cell analysis of radiotracer uptake, addressing spatial resolution limitations in conventional methods. By quantifying [18F]-FDG radiotracer uptake in single human breast cancer cells, I assessed cellular heterogeneity in cancer metabolism. This single-cell platform can employ other radiotracers to investigate radiolabeled drug incorporation and biological substrate transport, offering potential applications in small-molecule drug development and bioanalytical assays (Ha et al., Biosens. Bioelec. 2021).

My postdoctoral research, partially funded by NSF Postdoc Fellowship in Biology, unveiled biophysical mechanisms mediating immune cell migration through confining microenvironments. I designed composite hydrogel scaffolds with collagen ligands to mimic soft tissue microenvironments. These hydrogels, nanoporous and tunable in their mechanical properties, revealed that T cells can reshape the matrix to create pathways for migration. Notably, matrix shear strength emerged as the most significant predictor of efficient cell movement, indicating material failure during cell-induced matrix remodeling. Furthermore, analysis of human pancreas tumors revealed significantly higher shear strengths compared to normal tissues, suggesting a potential mechanism for impeding T cell infiltration in cancer due to enhanced tissue strength. Currently, I am unraveling the molecular mechanisms underlying these phenomena, and the work is in preparation for publication. The study will provide insights into how altered microenvironments impact immune cell migration, offering potential guidance for therapeutic interventions aimed at boosting immune cell infiltration into tumors or fibrotic areas and designing biomaterials for therapeutic T cell delivery.

Additionally, I have discovered a potential mechanism that suggests an autonomous T cell movement within the bloodstream in lymph nodes. In the bloodstream, fluid dynamics primarily dictate the spatial distribution of cells across the vessel's cross-section. Deformable microparticles, such as white blood cells (WBCs), are naturally directed towards the center of blood vessels by microfluidic lift forces, while rigid particles are pushed towards the edges. This central positioning protects WBCs from damaging wall shear stress but presents a significant challenge for naïve T cells, which must reach the vessel walls—a process called WBC margination—to extravasate into lymph nodes. Past research has regarded blood cells as passive particles and has not established a consistent fluid dynamic mechanism for their distribution. However, considering that T cells are living entities, they may actively participate to ensure effective margination. My pilot study outcomes suggest naïve T cells self-stiffen to autonomously marginate and endure shear stress in lymph node bloodstream.

Looking ahead, I aim to establish an independent research lab to investigate the interplay of fluid and solid mechanics and cell movement using tunable hydrogels and microfluidics. Firstly, I will continue to elucidate the fluid dynamic and biophysical mechanisms underlying the autonomous immune cell movement across the bloodstream. Secondly, I will identify the strategies employed by immune cells to endure deadly wall shear stress during margination and extravasation. This work will not only enrich our understanding of circulating cell movement across the vasculature but also spotlight potential vulnerabilities in abnormal immune responses and the pathogenesis of immune disorders.

Teaching Interests

Throughout my academic journey, I have gained valuable experience in teaching and mentoring students, nurturing their growth and passion for learning. As a Course Assistant for “Linear Algebra with Application to Engineering Computations” course at Stanford University, I delivered two 1.5-hour workshops to a class of 143 students and held weekly office hours. The student evaluations reflected my effectiveness as an instructor, as I received a score of 4 out of 5. In addition, I have been dedicated to mentoring both undergraduate and graduate students in research. These experiences, coupled with my deep understanding of fluid mechanics, have fostered a strong interest in teaching courses that bridge the gap between theory and application in the field of biomedical engineering.

As a faculty member in the future, I am interested in teaching mathematics and mechanics courses for both undergraduate and graduate students, including partial differential equations for engineering, fluid mechanics, microhydrodynamics, thermodynamics, and solid mechanics.