Posttransplant oxygen inhalation improves the outcome of subcutaneous islet transplantation: A promising clinical alternative to the conventional intrahepatic site

Abstract

Subcutaneous tissue is a promising site for islet transplantation, due to its large area and accessibility, which allows minimally invasive procedures for transplantation, graft monitoring, and removal of malignancies as needed. However, relative to the conventional intrahepatic transplantation site, the subcutaneous site requires a large number of islets to achieve engraftment success and diabetes reversal, due to hypoxia and low vascularity. We report that the efficiency of subcutaneous islet transplantation in a Lewis rat model is significantly improved by treating recipients with inhaled 50% oxygen, in conjunction with prevascularization of the graft bed by agarose-basic fibroblast growth factor. Administration of 50% oxygen increased oxygen tension in the subcutaneous site to 140 mm Hg, compared to 45 mm Hg under ambient air. In vitro, islets cultured under 140 mm Hg oxygen showed reduced central necrosis and increased insulin release, compared to those maintained in 45 mm Hg oxygen. Six hundred syngeneic islets subcutaneously transplanted into the prevascularized graft bed reversed diabetes when combined with postoperative 50% oxygen inhalation for 3 days, a number comparable to that required for intrahepatic transplantation; in the absence of oxygen treatment, diabetes was not reversed. Thus, we show oxygen inhalation to be a simple and promising approach to successfully establishing subcutaneous islet transplantation.

Impact of Oxygen on Pancreatic Islet Survival

“…We studied the effect of systemic oxygenation on the SC islet transplantation using syngeneic islet transplantation in rats. 95 Inhalation of 50% O 2 increased SC pO 2 to 140 mmHg from 45 mmHg measured in control rats inhaled 21% O 2 . A continuous 50% O 2 treatment for 3 days reversed diabetes with 600 islets/rat (3500 IEQ/kg), whereas controls without O 2 treatment remained diabetic.…”

“… 94 Subcutaneously placed islets also suffer from hypoxia around 45 mmHg. 95 If islets do survive, the islet capillary networks recover and establish a connection to the recipient vascular system. However, this requires 10 to 30 days, depending on the animal species and transplantation site.…”

A Collagen Based Cryogel Bioscaffold that Generates Oxygen for Islet Transplantation

“…As boundary conditions, fixed concentrations were used for the top and bottom (as those are in contact with surrounding tissues) and symmetry conditions were used for the left and right borders (as the model represents only a small part of a whole bioscaffold). Cryogel‐CPO bioscaffolds were assumed to be in an aqueous media at physiological temperature (37 °C) with an oxygen concentration of c oxy = 0.050 mol m −3 corresponding to typical tissue oxygenation,29–32 and a glucose concentration of 8 × 10 −3 m corresponding to normal glucose levels in mice 33. The oxygen generation rate was assumed to be constant and was incorporated into the model as a continuous release (reaction rate per unit volume) across the entire bioscaffold; the rate used was 0.01 m m −3 s −1 , which corresponds to a rate of 0.1 × 10 −3 m d −1 per bioscaffold for the bioscaffold (based on its volume).…”

Tissue‐engineering approaches in pancreatic islet transplantation

“…Some strategies have been used to overcome these limitations, including encapsulation, scaffolds, accessory cells, and/or trophic factors such as fibroblast growth factor (aFGF and bFGF) or vascular endothelial growth factor (VEGF) plus hepatocyte growth factor (HGF; Golocheikine et al, 2010;Kawakami et al, 2000;Kawakami et al, 2001;Sakata et al, 2014;Smink et al, 2017). In the last year, a few studies of subcutaneous islet transplantation have been published, highlighting the great interest of the scientific community in using this anatomical site (Bertuzzi & De Carlis, 2018;Farina et al, 2017;Hsu, Fu, & Wang, 2017;Komatsu et al, 2017;Pathak et al, 2017;Pepper et al, 2017;Perez-Basterrechea et al, 2017;Uematsu et al, 2018;Vlahos, Cober, & Sefton, 2017). However, there have been few attempts to apply this approach in humans.…”