Whitlockite as a next-generation biomaterial for bone regeneration: A systematic review of evidence for bone regeneration.

Background: Whitlockite (WH), a magnesium-enriched calcium phosphate mineral, is emerging as a promising biomaterial in bone tissue engineering due to its chemical similarity to natural bone and dual role in promoting osteogenesis and regulating bone resorption. Compared to conventional materials like hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), WH offers higher solubility, superior ion release (notably Mg), and enhanced bioactivity.

Objective: This systematic review evaluates the in vivo efficacy of WH-based biomaterials in bone regeneration. Key outcomes include bone volume fraction (BV/TV), bone mineral density (BMD), osteogenic marker expression, and histological bone quality.

Methods: A comprehensive search of PubMed, Web of Science, Google Scholar, and Cochrane Central was conducted up to March 2025. Eligible studies assessed WH-based materials in animal bone defect models with quantifiable regenerative outcomes. Two reviewers independently performed data extraction and quality assessment using the SYRCLE Risk of Bias tool. Meta-analysis was not feasible due to significant heterogeneity across models, scaffold types, and endpoints.

Results: Seventeen animal studies (rats, mice, rabbits) met inclusion criteria. WH was used in forms such as nanoparticles, granules, and scaffolds with polymers like chitosan and gelatin. WH consistently outperformed HA and β-TCP with up to a 2-6 % increase in BV/TV, BMD, and histological bone formation. Upregulation of ALP, OCN, RUNX2, and COL1 was observed. Doped WH variants and composites enhanced osteoinductive and angiogenic responses. No adverse effects were reported.

Conclusion: WH demonstrates superior osteogenic and biocompatible properties over traditional calcium phosphates. Future standardized, long-term studies are needed to support clinical translation for orthopedic and dental bone regeneration.