BIOHYBRID ARTIFICIAL PANCREAS - LONG-TERM FUNCTION OF DISCORDANT ISLET XENOGRAFTS IN STREPTOZOTOCIN-DIABETIC RATS

Long-term function of canine, bovine, and porcine islet xenografts imp lanted in streptozotocin-induced diabetic rats has been achieved by is let encapsulation within permselective acrylic membrane chambers. Intr aperitoneal implants of 1x10(4) (n=11) or 2x10(4) (n=2) encapsulated c anine islets reversed the diabetic state of the recipients within 24 h r, with plasma glucose levels dropping from a preimplantation level of 480+/-26 (mean +/- SEM) to 97+/-4 mg/dl during the first month. Chamb ers from 2 of the animals were removed, bisected, and reimplanted at 1 week and 2 months; both animals reverted to hyperglycemia (glucose, > 200 mg/dl) in < 2 weeks. The remaining implants maintained function f or a mean time of 138+/-16 days, whereas the 2 animals that received t he higher islet dose maintained function for > 260 days. Membranes con taining 2x10(4) bovine (n=6) or porcine (n=10) islets also normalized glucose concentrations, with plasma glucose levels dropping from 468+/ - 61 to 91+/-10 (bovine) and 97+/-11 (porcine) mg/dl during the first month (vs. 94+/-3 mg/dl for nondiabetic control rats). Three of the la tter implants were removed at 1 month. All 3 animals promptly reverted to diabetes. The 3-, 6-, 9-, and la-month graft survival rates for th e remaining animals were 100%, 100%, 60%, and 40%, and 100%, 75%, 50%, and 25%, respectively. The transplant recipients showed an approximat ely 38-54% gain in body weight during the first 100 days after implant ation, compared with < 1% (P<0.001) and 86% (P<0.001) for the untreate d diabetic (n=5) and normal control (n=6) groups. Immunohistochemical staining of long-term grafts (1-20 months) revealed varying degrees of alpha-, beta-, and delta-cell granulation; the external membrane surf aces were generally free of fibrotic overgrowth and exhibited only occ asional host cell adherence. Despite a problem of membrane breakage in longterm implants, these results suggest that prolonged survival of d iscordant transplants of porcine, bovine, and canine islets in diabeti c rats can be achieved without immunosuppression.