Peritoneal dissolved oxygen and function of encapsulated adult porcine islets transplanted in streptozotocin diabetic mice

Abstract

Background Alginate‐encapsulated islet xenografts have restored normoglycemia in diabetic animals for various periods of time. Plausible mechanisms of graft failure in vivo include immune rejection and hypoxia. We sought to understand the effects of encapsulated adult porcine islet (API) dosage on the peritoneal dissolved oxygen (DO) level in correlation to the achieved glycemic regulation in diabetic mice. Methods Adult porcine islets encapsulated in barium alginate were transplanted intraperitoneally in streptozotocin diabetic BALB/c mice at 6000 and 4000 islet equivalents (IEQ) and in normal mice at 500 IEQ; APIs encapsulated in calcium alginate were transplanted at 6000 IEQ in diabetic mice. In all cases, cell‐free barium alginate capsules containing a perfluorocarbon emulsion were co‐implanted for DO measurements using 19F NMR spectroscopy. Blood glucose levels and peritoneal DO were measured over 60 days or until graft failure. Explanted capsules were evaluated microscopically and histologically. Results Both barium and calcium alginate‐encapsulated APIs at 6000 IEQ reversed diabetes until day 60; barium alginate‐encapsulated APIs at 4000 IEQ also reversed diabetes but with a higher failure rate. Transplanted APIs significantly reduced the peritoneal DO, approximately in a dose‐dependent manner. The number of viable islets and the insulin content per capsule decreased over time. Capsules retrieved from normoglycemic mice exhibited minimal host cell adherence. Conclusions Transplantation of encapsulated APIs can reduce peritoneal DO to severely hypoxic levels. Although normoglycemia could be maintained within the study period, the DO levels suggest that hypoxia is a factor contributing to loss of islet viability and insulin secretion with time in mice.

Optimization of An O2-Balanced Bioartificial Pancreas for Type 1 Diabetes Using Statistical Design of Experiment.

“…This maturation process may further be impacted by low O 2 tensions in the graft 44,45 carry the 600,000 IEQ needed to achieve normoglycemia in adult human patient 5,19 . Moreover, the total number of islets required to reach therapeutic e ciency in humans might be decreased in this O 2balanced BAP 4,28,48,49 . In the past, the amount of islets necessary has been de ned based on naked pancreatic human islets transplanted into the liver 19 .…”

Optimization of an O2-balanced bioartificial pancreas for type 1 diabetes using statistical design of experiment

“…Use of such an O 2 balanced BAP would lead to an acceptable device size of approximately 180 cm 2 that would carry the 600,000 IEQ needed to achieve normoglycemia in adult human patient 5 , 19 . Moreover, the total number of islets required to reach therapeutic efficiency in humans might be decreased in this O 2 -balanced BAP 4 , 28 , 48 , 49 . In the past, the amount of islets necessary has been defined based on naked pancreatic human islets transplanted into the liver 19 .…”

A porcine islet-encapsulation device that enables long-term discordant xenotransplantation in immunocompetent diabetic mice

“…Although the insulin content of individual encapsulated islets retrieved from mice has been reported, it is difficult to fully retrieve intraperitoneal microcapsules and total insulin secretion in all capsules cannot be quantified. 35 This is another outstanding aspect of our device.…”