Cells push and pull on their surroundings, generating and sensing mechanical forces. We experience these forces each time our heart beats, our ears hear, or a wound heals. Mechanical forces affect other processes like stem-cell proliferation and differentiation, ion-channel gating, synaptic plasticity, and the development and maintenance of cell organization, multicellular tissues, organs, and animals. Despite its widespread importance in biology, the influence of mechanical stress on cell and tissue function remains poorly understood. The few tools that exist for measuring forces today are either direct, but unsuitable for use in living cells and tissues or indirect, relying on biochemical or molecular changes or simplified mechanical models to infer mechanical stresses. The proposed research unites materials science, photophysics, and fundamental biology to develop biocompatible optical reporters of mechanical force designed to monitor and quantify forces within and between cells and those generated by organs. The technology we seek to develop is based on state-of-the-art inorganic upconverting nanoparticles (NP) that are tiny (<10nm), biocompatible, and emit light in a manner that depends on mechanical compression or extension. We will synthesize and optimize NP reporters of compressive, tensile and shear forces, determining the influence of surface chemistry on mechanosensitivity and biocompatibility, and demonstrate a first-in-animals pilot study using first-generation NP mechanoreporters to determine forces generated by food consumption in C. elegans nematodes, an invertebrate model used to investigate many fundamental biological principles.
The ability of cells to detect and respond to mechanical force is crucial for the proper development, renewal, and function of tissues and organs and its dysfunction is linked to cancer, arthritis, heart disease, and certain cognitive deficits. We propose a new technology to visualize and quantify forces in living tissues that is based on biocompatible nanoparticles that emit light in proportion to applied force. This technology will accelerate fundamental discoveries about intercellular forces, unravel their relation to biochemical and electrical signals, and potentially enable new disease diagnostics.
