Marine biological waste as a source of hydroxyapatite for bone tissue engineering applications

The demand for bone graft substitutes for orthopedics and dentistry is constantly growing due to the increase of ageing-related diseases. Synthetic hydroxyapatite (HA) is largely used as a bone graft material thanks to its biocompatibility, osteointegration, osteoconductive and osteoinductive properties and similarity to biological apatite, the main mineral component of bones and teeth. Biogenic apatite has gained attention due to its peculiar intrinsic characteristics: multi-doped ion composition and micro- and nano-scale architecture make naturalderived HA particularly promising for biomedical applications. At the same time, the growing interest in green materials is pushing towards the use of more sustainable biomaterials precursors, including re-use materials: marine waste, such as mollusk-shells, shellfish carapaces, cuttlefish bone, and fishbone have become widely studied sources of biogenic HA. Indeed, they are rich in calcium carbonate (CaCO3), which can be converted into HA by environmentally sustainable processes. This allows the transformation of waste into valuable materials, while paying attention to the issues of sustainability and circular economy. In this review, we listed and discussed the methods to produce HA starting from shell-derived CaCO3, describing all the steps and synthesis routes proposed for the conversion procedure, with a special focus on the different species of marine shells used. We discussed the use of HA alone or in combination with other materials (natural and synthetic polymers), used to enhance the mechanical and biological properties. We summarized the types of devices obtained by marine-derived HA, including nanorods, particulates and scaffolds and we described their in vitro and in vivo behavior. The up-to-date literature was summarized in tables with a special focus on the in vitro and in vivo biological evaluation of such materials. In conclusion, composite biomaterials based on marine-derived biogenic HA are reported as potential candidates for synthetic bone substitutes highlighting their potential, limitations and future perspectives.