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Strategies that mimic the spatial complexity of natural tissues can provide cellular scaffolds to probe fundamental questions in cell biology and offer new materials for regenerative medicine. Here, the authors demonstrate a light‐guided patterning platform that uses natural engineered extracellular matrix (ECM) proteins as a substrate to program cellular behaviors. A photocaged diene which undergoes Diels–Alder‐based click chemistry upon uncaging with 365 nm light is utilized. By interfacing with commercially available maleimide dienophiles, patterning of common ECM proteins (collagen, fibronectin Matrigel, laminin) with readily purchased functional small molecules and growth factors is achieved. Finally, the use of this platform to spatially control ERK activity and migration in mammalian cells is highlighted, demonstrating programmable cell behavior through patterned chemical modification of natural ECM.
A radical‐free, Diels–Alder‐based photopatterning platform is presented which enables the spatially defined modification of protein‐based hydrogels with dienophile‐bearing biomolecules. By utilizing commercially available maleimide‐functionalized streptavidin and biotinylated species of interest, a robust mix‐and‐match platform is demonstrated. Through the immobilization of biotinylated growth factors, the use of these engineered substrates to program cell behaviors is highlighted.