Multiscale interface engineering in biohybrid composites for biomedical applications.

Multiscale composites with engineered interfaces have emerged as a cornerstone in the development of next-generation biomedical materials. This review provides a comprehensive and structured overview of interface design strategies spanning nano-to macro-scales, emphasizing their role in modulating mechanical performance, biological signaling, and adaptive functionality. We categorize key approaches into three synergistic domains: hierarchical structuring for mechanical and cellular control, stimuli-responsive interfaces for dynamic biomedical functions, and bioinspired or living systems that mimic and integrate with biological environments. Advanced fabrication techniques-including additive manufacturing, surface nanofunctionalization, and layer-by-layer assembly-are reviewed alongside multiscale characterization tools for structural and interfacial analysis. We further link these interface strategies to a range of biomedical applications, such as osteochondral scaffolds, vascularized implants, antibacterial coatings, smart drug delivery carriers, and neural-integrated electronics. Biological interactions, including protein adsorption, mechanotransduction, and immune modulation, are explored to elucidate how engineered interfaces influence cellular fate and integration. Finally, we outline key challenges-such as manufacturing scalability, long-term biocompatibility, and regulatory approval-and propose forward-looking solutions enabled by AI-driven materials design and organ-on-chip validation. This review serves as a conceptual and technical roadmap for researchers developing multifunctional biomaterials through the lens of multiscale interface engineering.