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Metallic biomaterials play essential roles in modern medical devices, but their long-term performance depends critically on protein adsorption and subsequent cellular responses at material interfaces. This review examines the molecular mechanisms governing these interactions and discusses surface modification strategies for controlling biocompatibility. The physicochemical properties of oxide layers formed on metal surfaces—including Lewis acid-base chemistry, surface charge, surface free energy, and permittivity—collectively determine protein adsorption behavior. Titanium surfaces promote stable protein adsorption through strong coordination bonds with carboxylate groups, while stainless steel surfaces show complex formation with proteins that can lead to metal ion release. Surface modification strategies can be systematically categorized based on two key parameters: effective ligand density (σₑff) and effective mechanical response (Eₑff). Direct control approaches include protein immobilization, self-assembled monolayers, and ionic modifications. The most promising strategies involve coupled control of both parameters through hierarchical surface architectures and three-dimensional modifications. Despite advances in understanding molecular-level interactions, substantial challenges remain in bridging the gap between surface chemistry and tissue-level biological performance. Future developments must address three-dimensional interfacial interactions and develop systems-level approaches integrating multiple scales of biological organization to enable rational design of next-generation metallic biomaterials.
Migita et al. (Thu,) studied this question.