Bioprinting functional human islet tissue models with vascular elements by aggregate-based co-culture and self-assembly

Diabetes is a severe metabolic disease worldwide. Current treatments, including islet/pancreas transplantation and insulin therapy, are limited by donor shortages and incomplete glycaemic control. Islet organoids, three-dimensional (3D) cell aggregates that mimic pancreatic islets, offer a powerful tool for diabetes research, drug screening, and transplantation therapies. However, challenges remain in engineering methods for the scalable preparation of human islet organoids (hIOs) with homogeneous consistency and controllable incorporation of vascular elements. Here, we develop a novel bioengineering approach for the stable production of human islet tissue models with vascular elements using 3D bioprinting-based organoid co-culture and cell self-assembly principles. Human adipose-derived mesenchymal stem cells are differentiated into massive and uniform human islet β-like cell aggregates (hICAs) by an off-the-shelf polydimethylsiloxane user-defined micropatterning platform system. A tri-module thermal-controlled bioprinting process employing a gelatin/alginate/matrigel bioink is used for the 3D bioprinting of hICAs and human umbilical vein endothelial cells (HUVECs). Compared with bioprinting of solely hICAs, co-bioprinting and co-culture of hICAs and HUVECs demonstrate morphogenesis recapitulating human islet development, significantly upregulated gene expression of pancreatic islet-related and endothelial cell-related markers, and islet function, i.e., glucose-stimulated insulin secretion. Thus, the self-assembly of hICAs and HUVECs for forming hIOs with vascular elements mimics natural human pancreatic islets and may promote functional maturity. Our method provides a scalable platform for generating vascularized aggregation-based tissue models, supporting studies of pancreatic development and diabetes therapy.