Measuring and Programming Piconewton Receptor Forces for Synthetic Mechanobiology

Project Summary: Mechanical forces are critical in diverse biological processes, including coagulation, cancer metastasis, embryonic development, and immune function. Individual receptors exert forces at the piconewton scale, one trillionth the force required to lift an apple. Our lab seeks to develop novel “mechanoimaging” technologies that convert receptor level forces into visible light via fluorescence. We also seek to use programmed cellular forces to control biology, with a special focus on regulating the function of immune cells. Here, we propose to quantify and control receptor-level forces in viscoelastic materials. Despite their importance to biology, receptor-level forces have not been measured in viscoelastic materials. This is a fundamental limitation in the field of mechanobiology because biological tissues are viscoelastic, meaning they exhibit time-dependent deformation under applied force. With our mechanoimaigng technology, we will determine the magnitude and distribution of forces that cells use to interact with and physically remodel viscoelastic biomaterials. By measuring fibroblast and cancer cell forces transmitted to viscoelastic biomaterials, we will learn how cells physically remodel and migrate within the viscoelastic extracellular matrix. Additionally, we will seek to answer key questions in T cell immunology. Reductionist in vitro experiments reveal that T cells transmit forces via their T cell receptor and that these forces are critical for T cell activation. Whether T cells transmit forces that facilitate activation in viscoelastic materials is unknown. We seek to test the hypothesis that viscoelasticity produces defects in T cell mediated cytotoxicity in diseases such as cancer. To address this hypothesis, we will measure T cell forces in viscoelastic materials, quantifying both cell- material and cell-cell forces. Finally, we cannot always engineer the mechanical properties of a tissue or a cell. Accordingly, this proposal aims to engineer cells to exert strong forces even in viscoelastic materials via creating Artificial Mechanoreceptors that circumvent normal mechanoregulation, a capability with implications for optimizing cancer immunotherapy.