Advances in Biomaterials for Tissue Regeneration: From Scaffold Design to CAP-Enabled Interfaces and AI-Driven Optimization.

Biomaterials play a central role in tissue engineering and regeneration by providing scaffolds that support cell adhesion, proliferation and differentiation while modulating the surrounding microenvironment. They represent promising alternatives to traditional surgical approaches that may lead to complications or tissue damage, and their performance is influenced by chemical composition, mechanical behavior, architecture and interfacial properties, all of which can be precisely tuned through advanced fabrication and surface modification strategies. This review synthesizes evidence from a comprehensive literature search across major scientific databases, focusing on highly cited studies and available clinical data, and examines natural and synthetic biomaterials, their biological responses, functional characteristics, and surface modification methods. Emphasis is placed on Cold Atmospheric Plasma (CAP), which selectively modifies the outermost nanolayer of materials, enhancing hydrophilicity, functional group density, protein adsorption and overall cell-material interactions, as well as improving drug loading capacity. The review also considers stem cell interactions with biomaterials and emerging applications of artificial intelligence (AI) for predicting performance and guiding material optimization. Overall, the analysis highlights that natural matrices provide intrinsic bioactivity, synthetic polymers offer tunable mechanics and degradation profiles, and composite systems integrate these advantages. Advances in technologies such as electrospinning and 3D/4D printing enable precise control over architecture, supporting cell colonization and vascularization. Collectively, developments in CAP treatments and AI-driven design strategies are strengthening the regenerative potential of biomaterials and advancing their clinical translation.