Microtechnologies For Controlling And Probing Multicellular Interaction Heterogeneity In Human Diseases

Abstract

Under physiological conditions, cells function within a tissue context where they interact with other cells through soluble signaling and cell-cell adhesions. Aberrations in these interactions are known to contribute to various human diseases, most notable being cancer and developmental disorders. Current technologies for studying cell-cell interaction heterogeneity are still limited by the consistency and throughput in which they can control cellular interactions across different length scales, as well as the ability to account for inter-patient variability. I will present micropatterning and microfluidic technologies designed to understand how changes in inter-cellular interactions are manifested in stem cell differentiation fates and drug responses. I will illustrate the use of micropatterned human pluripotent stem cells (hPSCs) to generate cell adhesion-mediated mechanical gradients, which in turn can spatially direct neural differentiation for form organized 3D neuroepithelium (NE) structures. These 3D micropatterned NE structures can be related to early neural tube development and are sensitive to drugs that cause a class of human birth defects known as neural tube defects (NTD), demonstrating their utility as a developmental disease model.  In the context of cancer, we have developed Patient-Derived Micro-Avatar Chips (PD-MAC), which integrate the biological diverse characteristics of patient-derived tumor cells and the high configurability of microfluidic systems, to study tumor-environment interactions at the cellular and systemic level. A 3D microenvironment can be engineered using micro-structures to support the formation and remodeling of patient-derived parental and metastatic oral squamous cell carcinoma (OSCC) into 3D micro-tumors (PD-mTs). We have developed a modular approach to achieve system integration with various microfluidic components, such as micro-pumps, valves, and a second tissue chip to facilitate the scaling of the PD-MAC to study systemic effects of chemotherapeutic drugs. Finally, we demonstrate the manipulation of parental and metastatic OSCC tumor and immune (NK) cells using hydrodynamic trapping arrays to investigate differential immune-mediated cytotoxicity

Bio

Yi-Chin Toh obtained her B.Eng in Chemical Engineering and PhD in Bioengineering from the National University of Singapore in 2001 and 2008 respectively. She did her post-doctoral training at the Massachusetts Institute of Technology in 2008 before joining the Institute of Bioengineering and Nanotechnology, A*STAR as a research scientist in 2010. Currently, she is an Assistant Professor with the Department of Biomedical Engineering in the National University of Singapore.  Her research interest is in designing and engineering micro-systems to control and understand the spatio-temporal relationships between cellular microenvironments and stem cell fate specification during normal and pathogenic tissue patterning. These micro-engineered stem cell models will in turn be translated into scalable platforms for disease modeling and drug testing applications. Dr Toh is a recipient of the National University of Singapore Research Scholarship, A*STAR Graduate Scholarship and A*STAR International Fellowship.