Novel hydrogels that can serve as 3D hypoxic microenvironments are disclosed. Oxygen controllable, hypoxia-inducible hydrogels (HI hydrogels) are composed of a phenolic agent and polymer backbone, which can form hydrogel networks via oxygen consumption in an enzyme-mediated crosslinking reaction. The HI hydrogels are degradable, cytocompatible, and have tunable mechanical properties. Oxygen levels and gradients within the HI hydrogels are controlled and precisely predicted. As a result, the HI hydrogels induce prolonged hypoxic conditions. The HI hydrogels guide vascular morphogenesis in vitro by activating hypoxia-inducible factors and promote neovascularization from tissue, as well as stimulate tissue in dynamic in vivo environments. The HI hydrogels are a new class of biomaterials that are useful in many applications, ranging from the engineering of de novo tissues and disease models to the treatment of vascular disorders.
