New Alginate Microcapsule System for Angiogenic Protein Delivery and Immunoisolation of Islets for Transplantation in the Rat Omentum Pouch

Abstract

Severe hypoxia caused by a lack of vascular supply and an inability to retrieve encapsulated islets transplanted in the peritoneal cavity for biopsy and subsequent evaluation are obstacles to clinical application of encapsulation strategies for islet transplantation. We recently proposed an omentum pouch model as an alternative site of encapsulated islet transplantation and have also described a multi-layer microcapsule system suitable for coencapsulation of islets with angiogenic protein in which the latter could be encapsulated in an external layer to induce vascularization of the encapsulated islet graft. The purpose of the present study was to determine the angiogenic efficacy of fibroblast growth factor (FGF-1) released from the external layer of the new capsule system in the omentum pouch graft. We prepared 2 groups of alginate microspheres, each measuring ~600 μm in diameter with a semipermeable poly-L-ornithine (PLO) membrane separating 2 alginate layers. While one group of microcapsules contained no protein (control), FGF-1 (1.794 μg/100 microcapsules) was encapsulated in the external layer of the other (test) group. From each of the 2 groups, 100 microcapsules were transplanted separately in an omentum pouch created in each normal Lewis rat and were retrieved after 14 days for analysis of vessel density using the technique of serial sample sections stained for CD31 with quantitative three-dimensional imaging. We found that FGF-1 released from the external layer of the test microcapsules induced a mean ± SD vessel density (mm2) of 198.8 ± 59.2 compared with a density of 128.9 ± 10.9 in pouches measured in control capsule implants (P = .03; n = 5 animals/group). We concluded that the external layer of our new alginate microcapsule system is an effective drug delivery device for enhancement of graft neovascularization in a retrievable omentum pouch.

Stimulation of vascularization of a subcutaneous scaffold applicable for pancreatic islet‐transplantation enhances immediate post‐transplant islet graft function but not long‐term normoglycemia

“…This suggestion is corroborated by the observations of McQuilling et al25 and Khanna et al26 who found enhanced vascularization for aFGF‐containing capsules implanted into the omental pouch. However, transplantation of islets in these aFGF microcapsules in the omental pouch did not result in better transplantation outcomes, c‐peptide levels, and glycemic control was less beneficial than in controls not containing aFGF 36.…”

“…Often multiple injections of high concentrations are required which result in abnormal vascularization and are associated with undesired side effects such as leaky vessels, growth of tumor‐like vessels, or hemangiomas 20. Therefore, several groups including ours focused on the development of a controlled release system for angiogenic growth factors 24, 25, 26, 27…”

Applications of particulate oxygen-generating substances (POGS) in the bioartificial pancreas

“…The hypoxic conditions are especially harmful to the islets due to the fact that the islet βcells have high metabolic requirements; they require approximately 10 to 12 % of blood flow to the pancreas, while only accounting for 1 to 2 % of the gland’s weight 11, 12 . Several strategies have been proposed to reduce hypoxic burden on islets including the use of angiogenic growth factors such as FGF-1 to improve angiogenesis and reduce time to engraftment 13 and implanting encapsulated islets within highly vascularized transplant sites, such as the omentum 14, 15 . While these approaches have improved graft function, the hypoxic burden still remains a challenge.…”

Encapsulated islets transplantation: Past, present and future

“…Fresh islet transplantation is recommended for a good outcome [1] and, if immediate transplantation cannot be done, cold pres-ervation (4 ℃ in UW solution) before transplantation is recommended over 37 ℃ culture for preventing islet loss and preserving the size, shape and function of islets [16] . While there are many transplantation sites (kidney [17][18][19] , muscle [20] , omentum [21] , testis [22] , bone marrow [23] and some other organs) for islet transplantation in animal experiments, liver is the only the transplantation site used in a clinical setting. The islets are injected into the recipient liver via the portal vein.…”