Injectable phase-separated tetra-armed poly(ethylene glycol) hydrogel scaffold allows sustained release of growth factors to enhance the repair of critical bone defects

With the rising prevalence of bone-related injuries, it is crucial to improve treatments for fractures and defects. Tissue engineering offers a promising solution in the form of injectable hydrogel scaffolds that can sustain the release of growth factors like bone morphogenetic protein-2 (BMP-2) for bone repair. Recently, we discovered that tetra-PEG hydrogels (Tetra gels) undergo gel-gel phase separation (GGPS) at low polymer content, resulting in hydrophobicity and tissue affinity. In this work, we examined the potential of a newer class of gel, the oligo-tetra-PEG gel (Oligo gel), as a growth factor-releasing scaffold. We investigated the extent of GGPS occurring in the two gels and assessed their ability to sustain BMP-2 release and osteogenic potential in a mouse calvarial defect model. The Oligo gel underwent a greater degree of GGPS than the Tetra gel, exhibiting higher turbidity, hydrophobicity, and pore formation. The Oligo gel demonstrated sustained protein or growth factor release over a 21-day period from protein release kinetics and osteogenic cell differentiation studies. Finally, BMP-2-loaded Oligo gels achieved complete regeneration of critical-sized calvarial defects within 28 days, significantly outperforming Tetra gels. The easy formulation, injectability, and capacity for sustained release makes the Oligo gel a promising candidate therapeutic biomaterial. •Oligo gels undergo stronger gel-gel phase separation than conventional Tetra gels at low polymer content.•Strong gel-gel phase separation provides enhanced hydrophobicity and pore formation.•Oligo gels sustain protein or growth factor release based on release kinetics and cell differentiation assays in vitro.•Oligo gels sustain bone morphogenetic protein-2, BMP-2, release to enhance critical bone defect repair in mice in vivo.