Twenty years of islet-on-a-chip: microfluidic tools for dissecting islet metabolism and function.

Pancreatic islets are metabolically active micron-sized tissues responsible for controlling blood glucose through the secretion of insulin and glucagon. A loss of functional islet mass results in type 1 and 2 diabetes. Islet-on-a-chip devices are powerful microfluidic tools used to trap and study living ex vivo human and murine pancreatic islets and potentially stem cell-derived islet organoids. Devices developed over the past twenty years offer the ability to treat islets with controlled and dynamic microenvironments to mimic in vivo conditions and facilitate diabetes research. In this review, we explore the various islet-on-a-chip devices used to immobilize islets, regulate the microenvironment, and dynamically detect islet metabolism and insulin secretion. We first describe and assess the various methods used to immobilize islets including chambers, dam-walls, and hydrodynamic traps. We subsequently describe the surrounding methods used to create glucose gradients, enhance the reaggregation of dispersed islets, and control the microenvironment of stem cell-derived islet organoids. We focus on the various methods used to measure insulin secretion including capillary electrophoresis, droplet microfluidics, off-chip ELISAs, and on-chip fluorescence anisotropy immunoassays. Additionally, we delve into the various multiparametric readouts (NAD(P)H, Ca 2+ -activity, and O 2 -consumption rate) achieved primarily by adopting a microscopy-compatible optical window into the devices. By critical assessment of these advancements, we aim to inspire the development of new devices by the microfluidics community and accelerate the adoption of islet-on-a-chip devices by the wider diabetes research and clinical communities.