Long-term viability and function of transplanted islets macroencapsulated at high density are achieved by enhanced oxygen supply

Abstract

Transplantation of encapsulated islets can cure diabetes without immunosuppression, but oxygen supply limitations can cause failure. We investigated a retrievable macroencapsulation device wherein islets are encapsulated in a planar alginate slab and supplied with exogenous oxygen from a replenishable gas chamber. Translation to clinically-useful devices entails reduction of device size by increasing islet surface density, which requires increased gas chamber pO2. Here we show that islet surface density can be substantially increased safely by increasing gas chamber pO2 to a supraphysiological level that maintains all islets viable and functional. These levels were determined from measurements of pO2 profiles in islet-alginate slabs. Encapsulated islets implanted with surface density as high as 4,800 islet equivalents/cm3 in diabetic rats maintained normoglycemia for more than 7 months and provided near-normal intravenous glucose tolerance tests. Nearly 90% of the original viable tissue was recovered after device explantation. Damaged islets failed after progressively shorter times. The required values of gas chamber pO2 were predictable from a mathematical model of oxygen consumption and diffusion in the device. These results demonstrate feasibility of developing retrievable macroencapsulated devices small enough for clinical use and provide a firm basis for design of devices for testing in large animals and humans.

Oxygen generating biomaterial improves the function and efficacy of beta cells within a macroencapsulation device

“…In situ oxygen supplementation has been clearly shown to significantly improve the survival of beta cell transplants in rodent, nonhuman primate, and pilot human trials [6,20,21,46]. The incorporation of an oxygen tank into the implant, however, relies on daily tank purging and oxygen refilling using an exogenous port system to maintain cell survival; noncompliance of this task can abruptly result in graft destabilization [47].…”

“…While facilitating host revascularization around the implants can improve peripheral oxygen levels, the diffusional length scales imposed by a macroencapsulation device results in extensive hypoxic-induced cell death and dysfunction [13][14][15] Strategies employed for local oxygen delivery to the implant can be largely divided into: 1) extra-corporeal oxygen delivery systems, which transport oxygen gas to the implant site; and 2) oxygen releasing biomaterials, which discharge absorbed or entrapped oxygen and/or generate oxygen via chemical reaction [16][17][18][19]. While the incorporation of a gas tank within an implant has demonstrated the potential of oxygen supplementation to improve islet survival and function within macrodevices [6,20,21], these implants require daily purging and oxygen replenishment via an external port system. To avoid the need for daily patient compliance and to minimize the additional volume added by the oxygen tank, we sought to engineer an in situ delivery approach using self-sustaining oxygen-generating biomaterial.…”

In vivo Environment Swiftly Restricts Human Pancreatic Progenitors Toward Mono-Hormonal Identity via a HNF1A/HNF4A Mechanism

“…Although this assumption is required for executing the analysis, the possibility that encapsulation effects vary between in vitro and in vivo environments should be kept in mind. Several previous studies reported increased starvation/hypoxia-based oxidative stress in encapsulated native human islets, as well as aggregated cells (Jacobs-Tulleneers-Thevissen et al, 2013;Weir, 2013;Barra and Tse, 2018;Evron et al, 2018), likely due to capsule's size and density of the encapsulated structure. Yet, our analysis indicated that the observed changes in the redox balance are consistent with a more islet-like fingerprint, suggesting that single cells in suspension benefit of improved nutrient and oxygen exposure.…”

Chemical Strategies for Improving Islet Transplant Outcomes

“…In addition to immuno-isolation and prevention of fibrosis, another challenge of islet encapsulation is maintaining adequate oxygen supply for cell functionality [186]. This challenge is especially relevant in the design of macroencapsulation devices, which contain many islets within a robust structure.…”