Biohybrid artificial pancreas. Long-term function of discordant islet xenografts in streptozotocin diabetic rats

Long-term function of canine, bovine, and porcine islet xenografts implanted in streptozotocin-induced diabetic rats has been achieved by islet encapsulation within permselective acrylic membrane chambers. Intraperitoneal implants of 1 x 10(4) (n = 11) or 2 x 10(4) (n = 2) encapsulated canine islets reversed the diabetic state of the recipients within 24 hr, with plasma glucose levels dropping from a preimplantation level of 480 +/- 26 (mean +/- SEM) to 97 +/- 4 mg/dl during the first month. Chambers 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 for a mean time of 138 +/- 16 days, whereas the 2 animals that received the higher islet dose maintained function for > 260 days. Membranes containing 2 x 10(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 latter implants were removed at 1 month. All 3 animals promptly reverted to diabetes. The 3-, 6-, 9-, and 12-month graft survival rates for the remaining animals were 100%, 100%, 60%, and 40%, and 100%, 75%, 50%, and 25%, respectively. The transplant recipients showed an approximately 38-54% gain in body weight during the first 100 days after implantation, compared with < 1% (P < 0.001) and 86% (P < 0.001) for the untreated 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 surfaces were generally free of fibrotic overgrowth and exhibited only occasional host cell adherence. Despite a problem of membrane breakage in long-term implants, these results suggest that prolonged survival of discordant transplants of porcine, bovine, and canine islets in diabetic rats can be achieved without immunosuppression.