3D Bioprinting of Multicellular Stem Cell‐Derived Constructs to Model Pancreatic Cell Differentiation

Abstract In vitro models of the pancreas can aid in developing therapies for pancreatic diseases. Nonetheless, most pancreatic tissue engineering is limited to insulin‐secreting β‐cells or pancreatic adenocarcinoma models. Combining all essential tissue components, including exocrine, endocrine, and blood vasculature, is crucial to recapitulate native tissue organization. In this study, extrusion‐based 3D bioprinting to create pancreatic tissue constructs containing both endocrine and exocrine compartments is exploited. Mouse pluripotent stem cell‐derived pancreatic progenitors, pancreatic endothelial cells, and mesenchymal stem cells are bioprinted. During postprinting cultivation, the cells differentiated into exocrine and endocrine lineages, resulting in vascularized pancreatic tissue‐like constructs with multiple cell types. However, the bioprinted constructs contracted significantly postprinting, hindering control of cell positioning and shape preservation. Therefore, 2 strategies to reduce the contraction and deformation of the bioprinted constructs are developed. These bioprinting techniques and biomaterial combinations allow us to investigate the influence of construct design and cellular composition on pancreatic cell fate. The results reveal that increased construct stiffness and endothelial component presence significantly promoted endocrine while suppressing exocrine differentiation. Overall, a novel strategy for pancreatic tissue engineering that advances and holds promise for pancreas disease and development modeling, as well as pharmaceutical testing is demonstrated.