Biomaterials-modulated multicellular crosstalk in 3D bioprinted constructs

3D bioprinted scaffolds, dynamically regulated by bioactive biomaterials, have emerged as a promising strategy for tissue engineering. A major challenge of 3D bioprinted constructs lies in accurately replicating the intricate architecture and physiological complexity of native tissues. However, the conventional mono-cellular constructs exhibited limited biological function (such as immunomodulation, angiogenesis and neurogenesis etc.), due to the simplicity of cell types. Therefore, it is of great significance to elucidate the biomaterials-modulated cellular communication mechanism within multicellular scaffolds, as well as to reveal coordinated regeneration mechanisms of multiple tissues in vivo . In this review, the advancements in bioink compositions and spatial architectures of the bioprinted multicellular scaffolds were first summarized, with a focus on biomimetic multicellular structure, such as upper-lower layer, inner-outer layer and patterned structure. The regulatory mechanisms underlying how biomaterials modulate multicellular crosstalk in bioprinted scaffolds were systematically highlighted and summarized, including the exchange of secretory proteins, the stimulation of paracrine secretion, the regulation of cell differentiation and so on. Furthermore, the stimulatory effect and critical role of multicellular scaffolds in the application of complex tissue engineering were elucidated. This review elaborates on the multicellular construction strategies and multicellular crosstalk mechanisms in 3D bioprinted constructs, which are of great importance for the future development of 3D bioprinted biomaterials with advanced tissue regeneration strategies.