Collagen-Based Bioactive Materials for Tissue Engineering: From Fundamental Properties to Clinical Translation and Future Horizons

Abstract

Collagen, the predominant structural protein in the extracellular matrix (ECM), has gained significant attention as a natural bioactive material for tissue engineering. Its intrinsic biocompatibility, biodegradability, and low immunogenicity, together with cell-recognition motifs such as Arg-Gly -Asp (RGD), enable specific interactions with integrins and growth factors that regulate cell adhesion, migration, and differentiation. Recent progress in collagen-based scaffold design including hydrogels, sponges, nanofibers, and composite matrices, has expanded its use across multiple tissue systems such as bone, cartilage, skin, vascular, corneal, and neural regeneration. Incorporation of synthetic polymers (e.g., polycaprolactone, polylactic acid, polyethylene glycol) and inorganic bioactives (e.g., hydroxyapatite, bioactive glass, silica nanoparticles) has enhanced the mechanical performance and degradation control of collagen-based constructs, addressing the limitations of native collagen. Nevertheless, batch variability, rapid enzymatic degradation, and limited long-term stability continue to constrain clinical applications. Emerging directions, including recombinant and marine-derived collagens, nanocomposite reinforcement, gene-activated matrices, and 3D/4D bioprinting technologies, are opening new pathways toward personalized, scalable, and immunocompatible tissue-engineered products. This review synthesizes two decades of progress, arguing that the convergence of recombinant sourcing, smart composite design, and advanced biofabrication is poised to overcome historical limitations and unlock the full potential of collagen for patient-specific regenerative therapies.