Background. Understanding the effects of capsule composition and transplantation site on graft outcomes of encapsulated islets will aid in the development of more effective strategies for islet transplantation without immunosuppression. Methods. Here, we evaluated the effects of transplanting alginate (ALG)-based microcapsules (Micro) in the confined and wellvascularized epididymal fat pad (EFP) site, a model of the human omentum, as opposed to free-floating in the intraperitoneal cavity (IP) inmice.We also examined the effects of reinforcing ALGwith polyethylene glycol (PEG). To allow transplantation in the EFP site, weminimized capsule size to 500 ± 17 ?m. Unlike ALG, PEGresists osmotic stress, hence we generated hybridmicrocapsules by mixing PEG and ALG (MicroMix) or by coating ALG capsules with a 15 ± 2 ?m PEG layer (Double). Results.We found improved engraftment of fully allogeneic BALB/c islets in Micro capsules transplanted in the EFP (median reversal time [MRT], 1 day) versus the IP site (MRT, 5 days; P < 0.01) in diabetic C57BL/6mice and ofMicro encapsulated (MRT, 8 days) versus naked (MRT, 36 days; P < 0.01) baboon islets transplanted in the EFP site. Although in vitro viability and functionality of islets within MicroMix and Double capsules were comparable to Micro, addition of PEG to ALG inMicroMix capsules improved engraftment of allogeneic islets in the IP site, but resulted deleterious in the EFP site, probably due to lower biocompatibility. Conclusions. Our results suggest that capsule composition and transplant site affect graft outcomes through their effects on nutrient availability, capsule stability, and biocompatibility.
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