Bone matrix-inspired whitlockite porous ceramic with effects of autophagy activation contributes to bone regeneration

Whitlockite (WH), a natural magnesium-containing calcium phosphate second in abundance only to hydroxyapatite (HAp) in the inorganic phase of bone tissue, has attracted great attention in bone repair recently. Previous studies have shown that porous structures play a pivotal role in bone defect repair using biomaterials. However, the traditional fabrication process of porous ceramic through high-temperature sintering frequently results in the dehydration and breakdown of WH. To overcome this challenge, we develop an innovative fabrication of porous whitlockite ceramic <i>via in-situ</i> phase transformation from calcium phosphate ceramic. Furthermore, we perform molecular dynamics (MD) and determine intermediates to delve into a comprehensive exploration of the underpinning mechanism of the transformation. <i>In-vitro</i> cellular responses reveal the superior cell proliferation, adhesion, spreading, migration, and osteogenic and angiogenic differentiation of porous WH ceramic. Mechanistically, our results reveal that the Mg²⁺-mediated regulation of ATP levels activates the AMPK-FoxO signaling axis, which enhances osteogenesis through autophagy. Intramuscular implantation evaluation confirms the satisfactory osteoinduction, and further rat mandibular defect implantation reveals significant bone regeneration in comparison to calcium phosphate ceramic. Together, the porous WH ceramic encompasses enhanced potential for the regenerative amelioration of bone defects.