Advanced cell-instructive bio-inks: Engineering multiscale niches for functional tissue formation

Three-dimensional bioprinting has transformed tissue fabrication by enabling the precise spatial organization of living cells and biomaterials into biomimetic tissue constructs. However, advances in manufacturing have outpaced the development of bio-inks capable of actively directing tissue formation. Most existing bio-inks remain optimized for printability, rheological behaviour, and structural fidelity, while providing limited control over the biological processes that govern tissue morphogenesis, functional maturation, and regeneration. This review examines the emerging paradigm of cell-instructive bio-inks, which integrate biological regulation directly into material design to recreate the cellular microenvironments that guide tissue development. We present a unifying framework that classifies these bio-inks according to three complementary regulatory dimensions: biochemical niches that regulate cell fate through molecular signalling and regenerative matrices; architectural niches that direct tissue organization through spatial and structural cues; and metabolic niches that modulate oxygen availability, redox homeostasis, and cellular metabolism. We further discuss strategies for integrating these instructive functions within multifunctional bio-inks, together with scalable manufacturing, and artificial intelligence-assisted bio-ink design. By redefining bio-inks as active regulators of cellular behaviour, this review establishes a conceptual framework for engineering next-generation bio-inks capable of orchestrating tissue development, functional maturation, and regenerative outcomes.