Islet-on-chip: promotion of islet health and function <i>via</i> encapsulation within a polymerizable fibrillar collagen scaffold.

Abstract

The protection and interrogation of pancreatic β-cell health and function <i>ex vivo</i> is a fundamental aspect of diabetes research, including mechanistic studies, evaluation of β-cell health modulators, and development and quality control of replacement β-cell populations. However, present-day islet culture formats, including traditional suspension culture as well as many recently developed microfluidic devices, suspend islets in a liquid microenvironment, disrupting mechanochemical signaling normally found <i>in vivo</i> and limiting β-cell viability and function <i>in vitro</i>. Herein, we present a novel three-dimensional (3D) microphysiological system (MPS) to extend islet health and function <i>ex vivo</i> by incorporating a polymerizable collagen scaffold to restore biophysical support and islet-collagen mechanobiological cues. Informed by computational models of gas and molecular transport relevant to β-cell physiology, a MPS configuration was down-selected based on simulated oxygen and nutrient delivery to collagen-encapsulated islets, and 3D-printing was applied as a readily accessible, low-cost rapid prototyping method. Recreating critical aspects of the <i>in vivo</i> microenvironment within the MPS <i>via</i> perfusion and islet-collagen interactions mitigated post-isolation ischemia and apoptosis in mouse islets over a 5-day period. In contrast, islets maintained in traditional suspension formats exhibited progressive hypoxic and apoptotic cores. Finally, dynamic glucose-stimulated insulin secretion measurements were performed on collagen-encapsulated mouse islets in the absence and presence of well-known chemical stressor thapsigargin using the MPS platform and compared to conventional protocols involving commercial perifusion machines. Overall, the MPS described here provides a user-friendly islet culture platform that not only supports long-term β-cell health and function but also enables multiparametric evaluations.