Mimicking the nanostructure of bone and understanding the interactions between the nanoscale inorganic and organic components of the extracellular bone matrix are crucial for the design of biomaterials with structural properties and a functionality similar to the natural bone tissue. Generally, these interactions involve anionic and/or cationic functional groups as present in the organic matrix, which exhibit a strong affinity for either calcium or phosphate ions from the mineral phase of bone. This study reviews the interactions between the mineral and organic extracellular matrix components in bone tissue as a source of inspiration for the design of novel nanocomposites. After providing a brief description of the various structural levels of bone and its main constituents, a concise overview is presented on the process of bone mineralization as well as the interactions between calcium phosphate (CaP) nanocrystals and the organic matrix of bone tissue. Bioinspired synthetic approaches for obtaining nanocomposites are subsequently addressed, with specific focus on chemical groups that have affinity for CaPs or are involved in stimulating and controlling mineral formation, that is, anionic functional groups, including carboxyl, phosphate, sulfate, hydroxyl, and catechol groups.

Injectable composite colloidal gels are developed for regeneration of osteoporotic bone defects through a bottom-up assembly from bisphosphonatefunctionalized gelatin and bioactive glass particles. Upon bisphosphonate functionalization, gelatin nanoparticles show superior adhesion toward bioactive glass particles, resulting in elastic composite gels. By tuning their composition, these composite colloidal gels combine mechanical robustness with self-healing ability. The composite colloidal gels support cell proliferation and differentiation in vitro without requiring any osteogenic supplement. In vivo evaluation of the composite colloidal gels reveals their capacity to support the regeneration of osteoporotic bone defects. Furthermore, the bisphosphonate modification of gelatin induces a therapeutic effect on the peri-implantation region by enhancing the bone density of the osteoporotic bone tissue. Consequently, these composite colloidal gels offer new therapeutic opportunities for treatment of osteoporotic bone defects.

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Gelatin nanoparticles can be tuned with respect to their drug loading efficiency, degradation rate, and release kinetics, which renders these drug carriers highly suitable for a wide variety of biomedical applications. The ease of functionalization has rendered gelatin an interesting candidate material to introduce specific motifs for selective targeting to specific organs, but gelatin nanoparticles have not yet been modified to increase their affinity to mineralized tissue. By means of conjugating bone-targeting alendronate to biocompatible gelatin nanoparticles, a simple method is developed for the preparation of gelatin nanoparticles which exhibit strong affinity to mineralized surfaces. It has been shown that the degree of alendronate functionalization can be tuned by controlling the glutaraldehyde crosslinking density, the molar ratio between alendronate and glutaraldehyde, as well as the pH of the conjugation reaction. Moreover, it has been shown that the affinity of gelatin nanoparticles to calcium phosphate increases considerably upon functionalization with alendronate. In summary, gelatin nanoparticles have been developed, which exhibit great potential for use in bone-specific drug delivery and regenerative medicine.