Protein adsorption at material interface: mechanistic design framework for engineering ceramic scaffolds for bone repair applications

Ceramic materials are widely used in bone tissue engineering applications due to their chemical similarity to human bone, along with their inherent biocompatibility. Bone scaffolds fabricated with ceramics thus serve as a framework for supporting new bone formation through cell attachment, proliferation, and differentiation, and subsequently integrate with the host tissue. However, the cells are unable to attach directly to the implanted ceramic surfaces. Instead, they interact with the dynamic layer of proteins adsorbed on the material surface, which mediates cell adhesion and proliferation via specific integrin-ligand signalling. Therefore, rather than a passive process, protein adsorption can be utilized as a design criterion to develop advanced ceramic scaffolds. Despite extensive efforts in surface modification, the mechanistic relationship between ceramic surface properties, protein adsorption behaviour, and subsequent osteogenic signalling remains fragmented across the literature. This review emphasizes the central and often underexplored role of protein adsorption in mediating the initial cell-ceramic interactions critical for bone tissue regeneration. In contrast to previous pieces of literature, this paper critically examines the studies in the past decade, with special focus on the last five years, on how the protein-ceramic interaction can be manipulated to improve its biocompatibility, which adds to the novelty of this review. By critically evaluating the in vitro and in vivo studies, we propose that the protein adsorption on ceramic scaffolds can be treated as a controllable bio-instructive design parameter for next-generation osteoinductive ceramics. This review highlights the multifaceted nature of protein adsorption and its pivotal role in developing more biocompatible ceramic materials for bone tissue engineering.