Engineering next-generation organoids: A review on bioprinting strategies, bioink innovations, and frontier...

While organoids hold immense promise as in vitro three-dimensional (3D) models, their translational utility is fundamentally constrained by passive diffusion limits (>800 μm), which inevitably trigger necrotic core formation and stochastic structural heterogeneity. This review elucidates how bioprinting shatters these physical bottlenecks by executing a paradigm shift toward spatiotemporal determinism. We systematically decode the mechanobiological evolution of bioinks-charting the transition from exogenous static matrices, which now function as temporal controllers via tunable stress relaxation to direct YAP/TAZ mechanotransduction, to the emerging paradigm of "engineerable living bioinks" driven by endogenous, cadherin-mediated fluid-to-solid jamming transitions. Furthermore, we critically evaluate frontier spatial strategies, highlighting how sacrificial networks and deterministic multi-material assembly establish active convective infrastructures and precise biophysical boundary conditions. By enforcing this rigorous baseline, these technologies definitively rectify pharmacokinetic/pharmacodynamic (PK/PD) distortions-eradicating false-positive noise in high-throughput screening and bridging the post-implantation mass transport vacuum-elevating organoids from stochastic clusters to highly predictive pathophysiological macro-models. Ultimately, we posit that transitioning from isolated morphological fabrication to resolving the inherent systemic metabolic paradoxes of multi-lineage integration is the absolute prerequisite for clinical translation.