Avidity-Controlled Hydrogels for Delivery of Induced Pluripotent Stem Cell-Derived Endothelial Cells and Growth Factors

We have developed protein-polyethylene glycol (PEG) hybrid hydrogels that form physical gels upon mixing to control the co-delivery of cells and growth factors. This hydrogel is a mixture of a linear, engineered protein that undergoes a sol-gel phase transition upon noncovalent complexation with an 8-arm PEG that has been decorated with either one or two repeats of a proline-rich peptide (P1 or P2, respectively) . Because of the dynamic nature of the molecular recognition between the two components, the hydrogels are reversibly shear-thinning and self-healing. The P2 variants exhibited higher storage moduli and slower release of encapsulated vascular endothelial growth factor (VEGF) compared to the P1 variants, demonstrating the ability to tune the hydrogel bulk properties through a biomimetic peptide-avidity strategy. Human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) adopted a well-spread morphology within the three-dimensional hydrogels, which also provided significant protection from cell damage during ejection through a fine-gauge syringe needle. In a mouse hindlimb ischemia model of peripheral arterial disease, co-delivery of hiPSC-ECs and VEGF within the hydrogel was found to reduce inflammation and promote muscle tissue regeneration compared to a saline control.