An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport

Abstract

Diffusion-based bioartificial pancreas (BAP) devices are limited by poor islet viability and functionality due to inadequate mass transfer resulting in islet hypoxia and delayed glucose-insulin kinetics. While intravascular ultrafiltration-based BAP devices possess enhanced glucose-insulin kinetics, the polymer membranes used in these devices provide inadequate ultrafiltrate flow rates and result in excessive thrombosis. Here, we report the silicon nanopore membrane (SNM), which exhibits a greater hydraulic permeability and a superior pore size selectivity compared to polymer membranes for use in BAP applications. Specifically, we demonstrate that the SNM-based intravascular BAP with ~10 and ~40 nm pore sized membranes support high islet viability (>60%) and functionality (<15 minute insulin response to glucose stimulation) at clinically relevant islet densities (5,700 and 11,400 IE/cm2) under convection in vitro. In vivo studies with ~10 nm pore sized SNM in a porcine model showed high islet viability (>85%) at clinically relevant islet density (5,700 IE/cm2), c-peptide concentration of 144 pM in the outflow ultrafiltrate, and hemocompatibility under convection. These promising findings offer insights on the development of next generation of full-scale intravascular devices to treat T1D patients in the future.

Design of Bioartificial Pancreases From the Standpoint of Oxygen Supply

“…When a device is installed at a site where the pressure difference exists, oxygen is supplied by the convective flow of the liquid. Planar‐type BAPs exhibited high islet viability and functionality under convection in vitro and in vivo . Sufficient oxygen supply by this approach might solve the limitation of the form and size of BAP discussed in this study.…”

“…The diffusion coefficients of the materials are determined by the averaged pore size. Planar-type BAPs with nanometer-or micrometersized channels are investigated to determine the optimal channel size for encapsulation (21,(27)(28)(29)(30). Our calculation can provide information on the design of membrane with optimal diffusion coefficient and thickness.…”

Enabling allogeneic therapies: CIRM-funded strategies for immune tolerance and immune evasion

“…Dr Shuvo Roy, also at UCSF, is developing a CIRM‐funded intravascularly implanted macroencapsulation device, a bioartificial pancreas (iBAP) for T1D, that is conceptually different from the Viacyte and Encellin devices. Instead of relying on the proximity of surrounding vasculature to allow exchange of oxygen, glucose, and insulin between the encapsulated cells and the blood system, the iBAP is implanted directly in‐line with a blood vessel to provide enhanced kinetics of glucose sensing and insulin secretion while still isolating the allogeneic human stem cell derived pancreatic beta cells from the immune system using a silicon nanopore membrane 33 …”

Tackling the Concept of Symbiotic Implantable Medical Devices with Nanobiotechnologies

“…The case of having encapsulated cells in a porous smart packaging allowing two‐ways communication will probably be simpler to resolve in terms of regulation as it will follow the rules of the Directives 2002/98/EC, 2004/23/EC, and 2010/53/EU. It consists, for instance as recently described by Song et al, in the concept of having pancreatic islets cells embedded in a silicon nanoporous membrane to facilitate exchanges and maintain the transplant alive for some days. A symbiotic device made of both synthetic and very likely biological materials will probably be considered as an advanced transplant rather than an active medical device.…”