The importance of the rheological properties of biological media, including the cytoplasm, the extracellular matrix and biological gels such as mucus is being appreciated in understanding intracellular transport, pathogen clearance, drug delivery, to name a few. Correspondingly, forces in biological contexts, as driven by molecular motors and filament polymerization, is understood as essential for the understanding of cell division and motility, intracellular trafficking of vesicles, and the beating of cilia that are responsible for bacterial locomotion and mucus hydrodynamics. We propose to develop magnetic bead manipulation into a new microscopic technology for studying forces and rheology in biological systems. There are three trends that make now the opportune time to make rapid progress. First, there has been a growing development of magnetic separation technology that has led to the availability of a wide range of magnetic particles, in size and functionality, and the incorporation of micro-fabricated magnetic pole systems onto silicon wafers. Second, while bead rheology is a decades old technology, there have been recent developments in the application of submicron-sized beads for measuring the complex viscoelastic moduli of biological gels, including the analysis of Brownian motion and two-particle correlation functions. The third development has been in the area of user interfaces. The application of advanced 3D visualization in real time, combined with haptic (touch-sensitive) control and display of force probes has been demonstrated in atomic force microscopy. We propose to bring these three developments into a system that a) applies forces to magnetic beads suspended inside biological media using micro-fabricated pole geometries that will allow b) the simultaneous use of h numerical aperture optics for nanometer scale particle tracking and 3D confocal microscopy, and c) advanced user interfaces for the immediate understanding of complex data sets and control of the instrument. The last feature of the system, the user interface and instrument control, will be supported almost entirely from an existing NCRR grant.
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