Human pluripotent stem cell (hPSC)-derived islet cells provide promising resources for diabetes studies, cell replacement treatment and drug screening. Recently, hPSC-derived organoids have represented a new class of in vitro organ models for disease modeling and regenerative medicine. However, rebuilding biomimetic human islet organoids from hPSCs remains challenging. Here, we present a new strategy to engineer human islet organoids derived from human induced pluripotent stem cells (hiPSCs) using an organ-on-a-chip platform combined with stem cell developmental principles. The microsystem contains a multi-layer microfluidic device that allows controllable aggregation of embryoid bodies (EBs), in situ pancreatic differentiation and generation of heterogeneous islet organoids in parallel under perfused 3D culture in a single device. The generated islet organoids contain heterogeneous islet-specific α and β-like cells that exhibit favorable growth and cell viability. They also show enhanced expression of pancreatic β-cell specific genes and proteins (PDX1 and NKX6.1) and increased β-cell hormone specific INS gene and C-peptide protein expressions under perfused 3D culture conditions compared to static cultures. In addition, the islet organoids exhibit more sensitive glucose-stimulated insulin secretion (GSIS) and higher Ca²⁺ flux, indicating the role of biomimetic mechanical flow in promoting endocrine cell differentiation and maturation of islet organoids. This islet-on-a-chip system is robust and amenable to real-time imaging and in situ tracking of islet organoid growth, which may provide a promising platform for organoid engineering, disease modeling, drug testing and regenerative medicine.

Diabetic nephropathy is a major chronic renal complication of diabetes mellitus, and is the leading cause of end-stage kidney diseases. Establishing a disease model of diabetic nephropathy in vitro can accelerate the understanding of its mechanisms and pharmaceutical development. We provide the proof-of-principle for using a glomerulus-on-a-chip microdevice that reconstitutes organ-level kidney functions to create a human disease model of early stage diabetic nephropathy on chip. The microfluidic device, which recapitulates the glomerular microenvironment, consists of parallel channels lined by isolated primary glomerular microtissues that experience fluid flow to mimic the glomerular filtration barrier (GFB), including glomerular endothelial cells, 3D basement membrane and podocytes. This device was used to reproduce high glucose-induced critical pathological responses in diabetic nephropathy as observed in humans. The results reveal that hyperglycemia plays a crucial role in the development of increased barrier permeability to albumin and glomerular dysfunction that lead to proteinuria. This organ-on-a-chip microdevice mimics the critical pathological responses of glomerulus that are characteristic of diabetic nephropathy that has not been possible by cell-based and animal models, providing a useful platform for studying the mechanism of diabetic nephropathy and developing an effective therapy in glomerular diseases.