Abstract
Oxygen is vital for the existence of all multicellular organisms, acting as a signalling molecule regulating cellular activities. Specifically, hypoxia, which occurs when the partial pressure of oxygen falls below 5%, plays a pivotal role during development, regeneration and cancer. Here we report a novel hypoxia-inducible (HI) hydrogel composed of gelatin and ferulic acid that can form hydrogel networks via oxygen consumption in a laccase-mediated reaction. Oxygen levels and gradients within the hydrogels can be accurately controlled and precisely predicted. We demonstrate that HI hydrogels guide vascular morphogenesis in vitro via hypoxia-inducible factors activation of matrix metalloproteinases and promote rapid neovascularization from the host tissue during subcutaneous wound healing. The HI hydrogel is a new class of biomaterials that may prove useful in many applications, ranging from fundamental studies of developmental, regenerative and disease processes through the engineering of healthy and diseased tissue models towards the treatment of hypoxia-regulated disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiopoietin-1 / genetics
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Angiopoietin-1 / metabolism
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Biocompatible Materials
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Cellular Microenvironment*
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Computer Simulation
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Coumaric Acids
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Endothelial Cells / metabolism*
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Gelatin / chemistry
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Gene Expression Profiling
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Humans
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Hydrogels / metabolism*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Laccase
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Matrix Metalloproteinases / genetics
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Matrix Metalloproteinases / metabolism
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Neovascularization, Physiologic / genetics*
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Neovascularization, Physiologic / physiology
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Oxygen / metabolism*
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Oxygen Consumption
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Wound Healing / genetics
Substances
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ANGPT1 protein, human
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Angiopoietin-1
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Basic Helix-Loop-Helix Transcription Factors
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Biocompatible Materials
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Coumaric Acids
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HIF1A protein, human
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Hydrogels
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Hypoxia-Inducible Factor 1, alpha Subunit
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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endothelial PAS domain-containing protein 1
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Gelatin
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ferulic acid
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Laccase
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KDR protein, human
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Vascular Endothelial Growth Factor Receptor-2
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Matrix Metalloproteinases
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Oxygen