Soft Hydrogels for Balancing Cell Proliferation and Differentiation

Hydrogels have been widely explored for the delivery of cells in a variety of regenerative medicine applications due to their ability to mimic both the biochemical and physical cues of cell microniches. For bone regeneration, in particular, stiff hydrogels mimicking osteoid stiffness have been utilized due to the fact that stiff substrates favor stem cell osteogenic differentiation. Unlike cell adhesion in two dimensions, three-dimensional hydrogels offer mechanical stimulation but limit the cell spreading and growth due to the dense matrix network. Therefore, we designed degradable, soft hydrogels (∼0.5 kPa) mimicking the soft bone marrow stiffness, with incorporated matrix metalloproteinase (MMP)-cleavable sites and RGD-based adhesive sites, to enhance the spreading and proliferation of the encapsulated cells, which are commonly inhibited in nondegradable and/or stiff implants. When the hydrogels were cultured on rigid surfaces to mirror the microenvironment of bone defects in vivo, the cells were shown to migrate toward the interface and differentiate down the osteogenic lineage, enhanced by the codelivery of bone morphogenetic protein-2 (BMP-2). Furthermore, this soft hydrogel might find applications in therapeutic interventions since it is easily injectable and cost-efficient. Taken together, we have designed a new system to balance cell growth and differentiation for improving hydrogel-based bone regenerative medicine strategies.