Pressure-Driven Insulin Release Overcomes Limitations of Diffusion for Encapsulated Islet Cell Therapy

Abstract

AbstractCadaveric islet and stem cell-derived transplantation show great promise as therapeutic approaches for type 1 diabetes. To address the immunocompatibility challenge, numerous cellular macroencapsulation techniques, which rely upon diffusion to transport insulin across the immunoprotective barrier, have been proposed. Although several of these devices were advanced to human clinical trials, they uniformly failed to achieve physiologic glucose control or insulin independence. Indeed, based upon mathematical modeling and empiric evidence, diffusion-based encapsulation devices are fundamentally incompatible with homeostatic on-demand insulin delivery and physiologic glucose regulation. To realize the potential of achieving insulin independence through macroencapsulated cell-based therapy, we propose the necessity of a second driving force. Herein, we provide both theoretical proof and experimental demonstration that modest (11-kPa) micropump-applied pressure considerably enhances insulin flux across immunoisolation membranes by nearly three orders of magnitude, enabling precise delivery of both bolus and basal insulin. Furthermore, pressure-driven insulin efflux from encapsulated mouse and human islets is fast and repeatable. As such, we urge caution against further advancement of diffusion-based immune-isolating macroencapsulation devices that do not incorporate a secondary driving force for precise temporal regulation of peptide delivery.One Sentence SummaryDiffusion-based insulin delivery from macroencapsulated islet cells is incompatible with physiologic glucose control, a constraint addressed through pressure-based insulin delivery.