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Hydrogels, highly hydrated cross-linked polymer networks, have emerged as powerful synthetic analogs of extracellular matrices for basic cell studies as well as promising biomaterials for regenerative medicine applications. A critical advantage of these synthetic matrices over natural networks is that bioactive functionalities, such as cell adhesive sequences and growth factors, can be incorporated in precise densities while the substrate mechanical properties are independently controlled. We have engineered poly(ethylene glycol) [PEG]-maleimide hydrogels to study epithelial morphogenesis and identified independent contributions of biophysical and biochemical properties of these materials to this developmental process. In another application, we have developed synthetic hydrogels that support improved pancreatic islet engraftment, vascularization and function in diabetic models. These studies establish these biofunctional hydrogels as promising platforms for basic science studies and biomaterial carriers for cell delivery, engraftment and enhanced tissue repair.