Microporous Microgel Assemblies Facilitating the Recruitment and Osteogenic Differentiation of Progenitor Cells for Bone Regeneration

ABSTRACT Biomaterials for bone regeneration, additionally to providing structural support and delivering of key biological signals, must promote the recruitment and growth of local progenitor cells. While synthetic biomaterials are tailorable regarding stability and bioactivity, their mesh size often requires proteolytic remodeling for cells to infiltrate and thereby can significantly restrict the progress of regeneration. Here, to improve the recruitment of osteogenic cells, microporous biomaterials with various degrees of stiffness are formed by the confinement of transglutaminase crosslinked polyethylene glycol (TG‐PEG) microgels. Confined microgels are found to be suitable substrates for human bone marrow stromal cells (hBM‐MSCs), that with increasing stiffness reveal improved spreading, Yes‐associated protein (YAP) activation, and heightened recruitment of cells mediated by platelet‐derived growth factor (PDGF)‐BB. Furthermore, upon stimulation with bone morphogenetic protein (BMP)‐2, osteogenic differentiation of hBM‐MSCs is found to be superior when cultured on stiff microgels as compared to encapsulation in bulk hydrogels. Even more compelling, TG‐PEG microgels enable a stiffness‐dependent recruitment of cells from bone defects in vitro. The combination of tunable stiffness and microscale pore structures in microgels provides new perspectives on the design of advanced scaffolds for bone healing, with the potential to improve clinical outcomes in regenerative medicine.