Genetically Encoded Hydrogels with Tunable Viscoelasticity and Biodegradability for Injectable Cell Therapies

Abstract

The widespread prevalence of heart disease, as well as the heart’s inability to regenerate, continues to present a global burden on human health. Therapeutic strategies involving direct injection of stem cell-derived cardiomyocytes into damaged heart muscle significantly outperform acellular strategies in restoring cardiac function post myocardial infarction. Although such cell-based therapies exhibit great promise, long-term survival and engraftment of the injected cardiomyocytes in state-of-the-art formulations remains low (~10%). Towards improving general efficacy of cell therapies, this thesis introduces a self-healing genetically encoded protein-based hydrogel biomaterial that supports minimally invasive cell delivery through catheter injection and enhanced biological function. Exploiting non-covalent self-association of monomeric recombinant proteins to yield stable hydrogels, the simple design is modular and tunable, whereby single point mutations to protein primary sequence produce materials with significantly varied self-healing behavior and biodegradability. Furthermore, the hydrogel can be readily functionalized with bioactive proteins of interest to facilitate specific cell fates and enhanced engraftment. Overall, these materials offer exciting opportunities towards promoting patient recovery after heart attack.