Stimuli-responsive 4D-bioprinted constructs for musculoskeletal tissue regeneration: Shape-morphing mechanisms, cell-laden bioink engineering, and preclinical outcomes

Introduction: Musculoskeletal disorders impose a substantial global disability burden. Conventional 3D bioprinting cannot replicate the dynamic, anisotropic architecture of bone, cartilage, skeletal muscle, and cardiac muscle. Four-dimensional (4D) bioprinting addresses this by integrating stimuli-responsive materials into constructs, enabling programmed shape transformation and adaptive behavior following implantation. Methods: This narrative review examines primary experimental research on stimuli-responsive 4D-bioprinted musculoskeletal constructs, drawing on in vitro, in vivo, and combined outcomes from leading peer-reviewed journals. Results: Evidence spans four stimuli modalities - magnetic actuation, near-infrared (NIR) photothermal response, thermoresponsive swelling-shrinking transitions, and shape memory polymer (SMP) recovery - applied across bone, cartilage, skeletal muscle, and cardiac constructs. Bioink formulations from silk fibroin-gelatin composites and alginate-polydopamine inks to GelMA-based hydrogels and polyester SMPs present trade-offs between printability, shape fidelity, and cellular compatibility. Cross-study synthesis identifies stiffness trajectory, architectural anisotropy, and dynamic deformation as primary mechano-biological axes directing cell fate decisions. Preclinical studies document encouraging ossification and chondrogenesis outcomes, though constructs fall short of native tissue mechanical benchmarks. Conclusion: Translational barriers range from fundamental physical constraints - including the mechanical performance gap and stimulus penetration depth limitations - to incremental engineering challenges amenable to near-term resolution. Passive hydration-driven deployment represents the most clinically tractable strategy, while multifunctional bioinks integrating stimuli-responsiveness, bioactive factor presentation, and cell-instructive surface chemistry define the primary material development direction.