Tissue engineering (TE) has revolutionized regenerative medicine by integrating scaffolds, cells, and bioactive molecules to repair or replace damaged tissues; the core triad of TE are scaffolds, cells, and biochemical signals. Although advances in biomaterials development and scaffold fabrication techniques have led to significant progress in TE, the effective delivery of bioactive agents, such as growth factors (GFs), antibiotics, anti-inflammatories, and small molecules, remains a challenge due to their short half-lives and uncontrolled release kinetics. This study explores the synergistic potential of drug delivery systems (DDS) embedded within tissue-engineered scaffolds, emphasizing their role in enhancing regenerative outcomes through controlled spatiotemporal release of therapeutic agents. This review highlights drug-activated scaffolds as a transformative solution, combining structural support with localized, sustained drug release to modulate cellular behaviours (proliferation, differentiation, ECM production) and mitigate systemic side effects. We classify bioactive agents by function and analyse their incorporation methods, pre-, during-, or post-scaffold fabrication, to achieve precise release profiles tailored to specific tissues. Key mechanisms of drug loading and release are critically evaluated. Despite progress, challenges persist in scalability, regulatory approval, and mimicking natural healing cues. We discuss emerging trends, including innovative scaffolds with on-demand drug release and combinatorial approaches leveraging biomaterials and stem cells. By bridging gaps between DDS and TE, this paradigm promises to overcome limitations of conventional transplants and synthetic implants. Future directions include optimizing bioink formulations for 3D bioprinting, improving bioactive agent stability, and addressing translational barriers for clinical adoption. This comprehensive review underscores the potential of bioactivated scaffolds to redefine regenerative strategies, offering insights into design principles, therapeutic applications, and hurdles for next-generation TE solutions.
