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      Safety and Viability of Microencapsulated Human Islets Transplanted Into Diabetic Humans

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          Abstract

          OBJECTIVE

          Transplantation of insulin-producing cells placed inside microcapsules is being trialled to overcome the need for immunosuppressive therapy.

          RESEARCH DESIGN AND METHODS

          Four type 1 diabetic patients with no detectable C-peptide received an intraperitoneal infusion of islets inside microcapsules of barium alginate (mean 178,200 islet equivalents on each of eight occasions).

          RESULTS

          C-peptide was detected on day 1 post-transplantation, and blood glucose levels and insulin requirements decreased. C-peptide was undetectable by 1–4 weeks. In a multi-islet recipient, C-peptide was detected at 6 weeks after the third infusion and remains detectable at 2.5 years. Neither insulin requirements nor glycemic control was affected. Capsules recovered at 16 months were surrounded by fibrous tissue and contained necrotic islets. No major side effects or infection occurred.

          CONCLUSIONS

          While allografting of encapsulated human islets is safe, efficacy of the cells needs to improve for the therapy to make an impact on the clinical scene.

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          Most cited references7

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          Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation.

          The long-term viability and function of transplanted encapsulated neonatal porcine islets was examined in a diabetic patient. A 41-yr-old Caucasian male with type 1 diabetes for 18 yr was given an intraperitoneal transplant of alginate-encapsulated porcine islets at the dose of 15,000 islet equivalents (IEQs)/kg bodyweight (total dose 1,305,000 IEQs) via laparoscopy. By 12 weeks following the transplant, his insulin dose was significantly reduced by 30% (P = 0.0001 by multiple regression tests) from 53 units daily prior to transplant. The insulin dose returned to the pre-transplant level at week 49. Improvement in glycaemic control continued as reflected by total glycated haemoglobin of 7.8% at 14 months from a pre-transplant level of 9.3%. Urinary porcine C-peptide peaked at 4 months (9.5 ng/ml) and remained detectable for 11 months (0.6 ng/ml). The patient was followed as part of a long-term microbiologic monitoring programme which subsequently showed no evidence of porcine viral or retroviral infection. At laparoscopy 9.5 yr after transplantation, abundant nodules were seen throughout the peritoneum. Biopsies of the nodules showed opacified capsules containing cell clusters that stained as live cells under fluorescence microscopy. Immunohistology noted sparse insulin and moderate glucagon staining cells. The retrieved capsules produced a small amount of insulin when placed in high glucose concentrations in vitro. An oral glucose tolerance test induced a small rise in serum of immuno-reactive insulin, identified as porcine by reversed phase high pressure liquid chromatography. This form of xenotransplantation treatment has the potential for sustained benefit in human type 1 diabetics.
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            Molecular basis of biomaterial-mediated foreign body reactions.

            Despite being inert and nontoxic, implanted biomaterials often trigger adverse foreign body reactions such as inflammation, fibrosis, infection, and thrombosis. With regard to the inflammatory responses to biomaterial implants, it was previously found that a crucial precedent event was the spontaneous adsorption and denaturation of fibrinogen on implant surfaces. It was further found that interactions between the phagocyte integrin Mac-1 (CD11b/CD18) and one short sequence within the fibrinogen D domain (gamma 190-202; P1) at least partially explained phagocyte accumulation on implant surfaces. However, the reason that adsorbed fibrinogen is proinflammatory--while soluble fibrinogen clearly is not--remained obscure. In this study, therefore, the question of how fibrinogen is converted to a proinflammatory state when adsorbed to biomaterial surfaces is investigated. In soluble fibrinogen, the 13 amino acid P1 sequence was found to be hidden. However, the adsorption and denaturation of fibrinogen on the surfaces of commonly used biomaterials lead to the exposure of P1 and a second neo-epitope, gamma 377-395 (P2), which also interacts with Mac-1 and is similarly occult in the soluble protein. The extent of biomaterial-mediated P1 and P2 exposure appears directly related to the severity of inflammatory responses to a test panel of biomaterials. Finally, thrombin-mediated conversion of fibrinogen to fibrin also exposes both P1 and P2 epitopes. These observations may help explain both the inflammation caused by many types of implanted biomaterials and that which occurs naturally following thrombotic events. (Blood. 2001;98:1231-1238)
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              Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases.

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                Author and article information

                Journal
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                October 2009
                23 June 2009
                : 32
                : 10
                : 1887-1889
                Affiliations
                [1] 1Australian Foundation for Diabetes Research, Sydney, Australia;
                [2] 2Diabetes Transplant Unit, Prince of Wales Hospital, Sydney, Australia;
                [3] 3Department of Surgery, Prince of Wales Hospital, Sydney Australia;
                [4] 4Department of Medical Imaging, Prince of Wales Hospital, Sydney, Australia.
                Author notes
                Corresponding author: Bernard Tuch, btuch@ 123456alumni.sydney.edu.au .
                Article
                0744
                10.2337/dc09-0744
                2752920
                19549731
                12347aff-3e3c-47b9-811e-8bceda23b0e4
                © 2009 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 20 April 2009
                : 15 June 2009
                Categories
                Original Research
                Emerging Treatments and Technologies

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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