Between 2002 and 2010, regenerative engineering was characterized by the rise of scaffold-centered tissue engineering that used three-dimensional porous matrices and bioactive materials to steer cell organization and differentiation across bone, cartilage, and neural systems. Researchers leveraged electrospun fibers, silk, and hydrogel networks to sculpt mechanical cues and microarchitecture, while degradable matrices with integrin-binding sites and matrix metalloproteinase–cleavable linkages enabled invasion, remodeling, and provisional ECM replacement. Vascularization and perfusion strategies, including endothelial–osteoblast interactions and bioreactor-driven maturation, emerged as essential for nutrient delivery and tissue integration. Nerve tissue engineering efforts emphasized aligned nanofibers and protein–polymer composites to direct neurite growth, and translational trajectories highlighted autologous tissue constructs and periosteum‑based delivery approaches that foreshadowed clinical-scale regeneration. Historical Significance: These developments unified scaffold‑driven tissue engineering with early translational regenerative engineering, introducing protease‑responsive, bioactive materials as a central paradigm and laying the groundwork for autologous organ and tissue regeneration concepts that informed subsequent hydrogel and scaffold design, bioreactor paradigms, and cell sheet/scaffold‑free strategies.