NATURAL sources of hydroxyapatite for biomedical applications

Hydroxyapatite (HAp, Ca 10 (PO 4 ) 6 (OH) 2 ) is a calcium phosphate bioceramic that constitutes approximately 70 % of the mineral phase in bone and teeth, making it a critical biomaterial for clinical applications. While synthetic hydroxyapatite has demonstrated clinical success, its limitations, including energy-intensive production processes, suboptimal crystallinity, and reduced biological activity compared to biogenic alternatives, have driven the investigation of naturally derived sources. This review aims to provide a quantitative comparison of natural HAp sources and extraction methods, critically evaluate biomedical applications with performance metrics, assess toxicological and regulatory challenges, and establish specific research priorities for clinical translation. Natural sources, including mammalian bone (bovine, porcine), marine resources (fish scales, fish bone), avian eggshells, and marine corals, yield HAp with inherent trace element substitutions (Mg 2+ , Sr 2+ , Na + , CO 3 2− ) and hierarchical micro-nanostructures that more closely approximate native bone composition, potentially enhancing osteoconductivity, osteointegration, and remodeling kinetics. We systematically analyze extraction protocols (thermal decomposition, alkaline hydrolysis, subcritical water processing), evaluate clinical applications spanning bone regeneration, periodontal therapy, and controlled drug delivery, and critically assess barriers including batch-to-batch variability, pathogen transmission risks, and regulatory complexities. Emerging strategies encompass green extraction technologies, surface functionalization with bioactive molecules, composite fabrication with synthetic polymers, and integration with additive manufacturing for patient-specific implants. This review identifies knowledge gaps in long-term biocompatibility, degradation kinetics, and clinical translation, providing a roadmap for advancing natural hydroxyapatite toward standardized, sustainable biomedical applications.