Cuttlebone-derived Hydroxyapatite in Bone Tissue Engineering: A Systematic Review

Introduction: Bone tissue engineering seeks to overcome limitations of conventional grafts in treating craniofacial and orthopaedic defects. Hydroxyapatite (HA) is a widely used substitute, but synthetic forms lack bioactive ions and remodeling capacity. Marine-derived biomaterials, especially Cuttlebone (CB), offer a natural architecture and trace elements that enhance osteogenesis. Aim: To evaluate the regenerative potential of Cuttlebonederived Hydroxyapatite (CB-HA) in preclinical in-vitro and invivo models. Materials and Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a systematic search of PubMed, Scopus, Web of Science, and EBSCO was performed for studies published between 2005 and 2025. Eligible articles investigated CB-HA or its composites in bone regeneration. Data were extracted using the PICO framework, and quality was assessed with the modified SYRCLE tool. Results: The present systematic review included 18 studies. Invitro experiments demonstrated that CB-HA promoted osteoblast proliferation, alkaline phosphatase activity, mineral deposition, and osteogenic gene expression compared with controls. Invivo studies in rat and rabbit models confirmed greater new bone volume, mineralisation, and vascularisation. Composites incorporating polymers or ion substitutions (Si, Sr, Mg, Mn) further improved bioactivity and mechanical performance. No adverse local or systemic effects were reported. Conclusion: CB-HA shows superior osteogenic potential over conventional substitutes, attributed to its biomimetic architecture, porosity, and favourable surface chemistry. With standardised fabrication and long-term animal studies, CBHA holds promise for future clinical translation in orthopaedic, craniofacial, and dental applications.