The hydrophilic amorphous layer around bone apatite promotes osteogenesis

Biomaterial-based therapies for bone regeneration have long relied on synthetic calcium phosphate particles to improve their overall performance. However, these particles often lack the compositional and structural complexity of their biogenic counterparts and fail to capture the intrinsic heterogeneity of bone mineral across spatial and temporal scales. Here, a series of organic-inorganic composites containing well-defined proxies for biogenic calcium phosphate particles at successive stages of bone biomineralization reveals that osteogenic differentiation of human mesenchymal stem cells increases significantly for partially crystalline hydroxyapatite nanoparticles coated with a hydrophilic amorphous surface layer whose proportion reaches at least 35 %. This coating occurs naturally on bone hydroxyapatite nanoparticles, with a proportion that decreases as the particles age, and may contribute to the unparalleled clinical success of autologous bone grafts. Mechanistically, a hydration shell of tightly bound water molecules on the amorphous layer is proposed to enhance binding of extracellular signaling molecules at the cell-material interface, amplifying osteogenic commitment. These findings provide a mechanistic basis for previous observations that biomimetic hydroxyapatite particles outperform their highly crystalline counterparts, underscore the critical importance of truly bone-mimetic material designs for next-generation bone-regenerative therapies, and offer an unprecedented view of how biophysical surface cues direct stem-cell function. STATEMENT OF SIGNIFICANCE: Amorphous chemical environments naturally occur around the particles of a variety of biominerals, yet they have mainly been associated with physicochemical processes such as ion exchange, crystal growth, and particle assembly. Focusing on bone bioapatite, a calcium phosphate biomineral of major clinical relevance, we show that these amorphous environments also have biological functions. Using a unique series of well-characterized proxies for biogenic calcium phosphate particles at different stages of bone biomineralization, we reveal the critical role of these amorphous chemical environments in regulating osteogenic differentiation of human mesenchymal stem cells. These results emphasize the importance of truly biomimetic designs for developing transformative biomaterials for bone repair and provide mechanistic insight into how nanoscale surface features influence stem cell behavior.