Oxygen-controllable and hypoxia-inducible hydrogels

Abstract

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.

We claim: 
     
         1 . An oxygen-controllable and hypoxia-inducible hydrogel comprising a cross-linked phenolic agent and polymer. 
     
     
         2 . The hydrogel of  claim 1 , wherein the polymer is selected from collagen, gelatin, chitosan, heparin, fibrinogen, hyaluronic acid, chondroitin sulfate, pullulan, xylan, dextran, and polyethylene glycol as well as their derivatives. 
     
     
         3 . The hydrogel of  claim 1 , wherein the phenolic agent is selected from ferulic acid (FA), tyramine (TA), 4-Hydroxyphenylacetic acid, 3-(4-Hydroxyphenyl)propionic acid, Dopamine, Norepinephrine, epinephrine, and their derivatives. 
     
     
         4 . The hydrogel of  claim 2 , wherein the polymer of the composition is gelatin or dextran. 
     
     
         5 . A method of preparing an oxygen-controllable and hypoxia inducible hydrogel comprising:
 selecting a phenolic agent and a polymer;   cross-linking the phenolic agent and the polymer; and   forming a an oxygen-controllable and hypoxia inducible hydrogel,   wherein the cross-linking comprises an enzymatic reaction using an enzyme selected from laccase and tyrosinase.   
     
     
         6 . The method of  claim 5 , wherein the hydrogel induces hypoxia. 
     
     
         7 . The method of  claim 5  wherein the polymer is selected from collagen, gelatin, chitosan, heparin, fibrinogen, hyaluronic acid, chondroitin sulfate, pullulan, xylan, dextran, and polyethylene glycol as well as their derivatives. 
     
     
         8 . The method of  claim 5  wherein the phenolic agent is selected from ferulic acid (FA), tyramine, 4-Hydroxyphenylacetic acid, 3-(4-Hydroxyphenyl)propionic acid, Dopamine, Norepinephrine, epinephrine, and their derivatives. 
     
     
         9 . The method of  claim 5 , wherein the method further comprises adding cells or tissue. 
     
     
         10 . The method of  claim 9 , wherein the cells are pluripotent stem cells, adult stem cells, fibroblasts, endothelial colony-forming cells, human umbilical vein endothelial cells (HUVECs) or tumor cells, and the tissue is tumor tissue. 
     
     
         11 . A three-dimensional microenvironment comprising the hydrogel of  claim 1 . 
     
     
         12 . The hydrogel of one of  claims 1 - 4 , wherein the hydrogel further comprises cells or tissue. 
     
     
         13 . The hydrogel of  claim 12 , wherein the cells or tissue are encapsulated within the hydrogel. 
     
     
         14 . The hydrogel of  claim 12 , wherein the cells are pluripotent stem cells, adult stem cells, fibroblasts, endothelial colony-forming cells, human umbilical vein endothelial cells (HUVECs) or tumor cells, and the tissue is tumor tissue. 
     
     
         15 . The hydrogel of  claim 12 , wherein the cells stimulate vascular tube formation. 
     
     
         16 . The hydrogel of  claim 12 , wherein the hydrogel induces hypoxic conditions in vivo. 
     
     
         17 . The hydrogel of  claim 12 , wherein the hydrogel induces blood vessel recruitment into the hydrogel. 
     
     
         18 . The three-dimensional microenvironment of  claim 11 , wherein the hydrogel further comprises cells or tissue. 
     
     
         19 . The three-dimensional microenvironment of  claim 18 , wherein the cells are pluripotent stem cells, adult stem cells, fibroblasts, endothelial colony-forming cells, human umbilical vein endothelial cells (HUVECs) or tumor cells, and the tissue is tumor tissue. 
     
     
         20 . A method of inducing hypoxic conditions in vivo comprising applying the hydrogel of  claim 12 .