Intermittent Low-Magnitude Pressure Applied Across Macroencapsulation Devices Enables Physiological Insulin Delivery Dynamics.

Abstract

Cadaveric islet and stem cell-derived transplantation hold promise as treatments for type 1 diabetes. To tackle the issue of immunocompatibility, numerous cellular macroencapsulation techniques that use diffusion to transport insulin across an immunoisolating barrier have been developed. However, despite several devices progressing to human clinical trials, none have successfully attained physiological glucose control or insulin independence. Based on empirical evidence, macroencapsulation methods with multilayered, high islet surface density are incompatible with on-demand insulin delivery and physiological glucose regulation when solely reliant on diffusion. An additional driving force is essential to overcome the distance limit of diffusion. In this study, we present both theoretical evidence and experimental validation that applying pressure, at levels comparable to physiological diastolic blood pressure, significantly enhances insulin flux across immunoisolation membranes, increasing it by nearly three orders of magnitude. This significant enhancement in transport rate allows for precise, subminute regulation of both bolus and basal insulin delivery. By incorporating this technique with a pump-based extravascular system, we demonstrate the ability to rapidly reduce glucose levels in diabetic rodent models, replicating the timescale and therapeutic effect of subcutaneous insulin injection or infusion. This advance provides a potential path toward achieving insulin independence with islet macroencapsulation. Numerous islet macroencapsulation techniques use diffusion to transport insulin across an immunoisolating barrier. Despite some devices reaching clinical trials, none have achieved physiological glucose control or insulin independence. Empirical evidence shows that high-density islet macroencapsulation methods cannot achieve on-demand insulin delivery and glucose regulation with diffusion alone. An additional driving force is needed. Appling a subminute pressure at physiological levels can achieve on-demand insulin delivery from macroencapsulated islets and glucose regulation. Incorporating pressure-based enhancements in macroencapsulation systems could lead to successful clinical outcomes.