Functionalization of polycaprolactone scaffolds for tissue engineering: molecular cues, bioactive cell-material interfaces, and translational perspectives

Poly(ε-caprolactone) (PCL) has emerged as a promising scaffold material in regenerative medicine owing to its biodegradability, mechanical strength, and processability. However, its intrinsic hydrophobicity and lack of bioactive motifs restrict cell-material interactions and clinical translation. This review synthesizes advances in PCL surface functionalization, contrasting conventional approaches, such as plasma treatment, hydrolysis/aminolysis, copolymerization, and protein adsorption, with emerging strategies, including layer-by-layer assembly, bioinspired coatings, and nanocomposite engineering. Particular attention is given to how tailored surface chemistries regulate wettability, integrin-mediated adhesion, extracellular matrix deposition, and lineage-specific differentiation. Beyond summarizing methods, this article critically examines translational challenges: balancing modification density with scaffold integrity, spatiotemporal delivery of bioactive cues, immune responses, and long-term in vivo stability. Finally, we highlight future opportunities in bio-orthogonal chemistry, 4D-printed responsive scaffolds, and AI-guided design that are poised to transform PCL from a versatile polymer into a clinically relevant platform for personalized regenerative therapies.