Emerging Treatments and Technologies B R I E F R E P O R T Safety and Viability of Microencapsulated Human Islets Transplanted Into Diabetic Humans BERNARD E TUCH FRACP PHD1 2 GREGORY W KEOGH FRACS3 LINDY J WILLIAMS BSC2 WEI WU PHD2 JAYNE L FOSTER PHD2 VIJAYGANAPATHY VAITHILINGAM MSC2 ROBERT PHILIPS FRANZCR4 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 Diabetes Care 32 1887 1889 2009 T ransplantation of insulin producing cells placed inside capsules is a strategy that is being trialled to overcome the need for immunosuppressive therapy in insulin dependent diabetic people 1 We have made microcapsules of barium alginate and shown that insulinproducing porcine cells can function as efficiently inside such capsules as when nonencapsulated 2 Moreover human islets placed in these capsules normalize blood glucose levels when engrafted in diabetic mice 3 4 In the current study we transplanted four type 1 diabetic humans with encapsulated human islets RESEARCH DESIGN AND METHODS Cadaver pancreata were obtained with consent and islets were isolated by digestion with collagenase NB1 premium grade and neutral protease NB Serva Germany Islets were placed in barium alginate microcapsules 2 and their median average diameter from eight islet preparations was 340 m range 255 750 Median viability of the encapsulated islets assessed with the fluorescent dyes carboxyfluorescein diacetate and propidium iodide 2 was 73 range 60 80 Purity was 68 range 50 88 and insulin content 2 was 1 1 mU islet equivalents IEQs range 0 1 35 The median stimulation index of the islets exposed to 20 mmol l glucose compared with 2 8 mmol l glucose for 1 h was 1 22 range 1 0 2 4 The median number of IEQs transplanted on each occasion was 178 200 range 98 200 227 900 Conditioned culture medium was free of microbial contamination Of the 14 diabetic people screened for phase 1 of the clinical trial 7 were selected and 4 were transplanted over a period of 19 months The seven with long standing type 1 diabetes had no endogenous insulin production no C peptide in serum during an arginine tolerance test and none in 24 h urine BMI 25 kg m2 and weight 70 kg Those transplanted had antibodies to neither GAD nor islet cell surface antigens ICA512 One person received four islet infusions over 7 months with three in the 1st month a second received two infusions 10 months apart and the other two recipients received one infusion each see Tables A1 and A2 in the online appendix available at http care diabetesjournals org cgi content full dc09 0744 DC1 Infusions were carried out on an outpatient basis in the Department of Medical Imaging Prince of Wales Hospital Sydney Australia No immunosuppression was used but recipients did take both a mild antiinflammatory agent Atorvastatin 20 mg and antioxidants vitamin A 50 000 units vitamin B6 100 mg and vitamin E 750 units after each transplant For the last two islet infusions exenatide 5 g b i d was administered in an attempt to enhance cell survival and function Approval for all the procedures performed was obtained from the Institutional Human Research Ethics Committee From the 1Australian Foundation for Diabetes Research Sydney Australia the 2Diabetes Transplant Unit Prince of Wales Hospital Sydney Australia the 3Department of Surgery Prince of Wales Hospital Sydney Australia and the 4Department of Medical Imaging Prince of Wales Hospital Sydney Australia Corresponding author Bernard Tuch btuch alumni sydney edu au Received 20 April 2009 and accepted 15 June 2009 Published ahead of print at http care diabetesjournals org on 23 June 2009 DOI 10 2337 dc09 0744 Clinical trial reg no ACTRN12609000192280 Australian and New Zealand Clinical Trials Registry 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 The costs of publication of this article were defrayed in part by the payment of page charges This article must therefore be hereby marked advertisement in accordance with 18 U S C Section 1734 solely to indicate this fact care diabetesjournals org RESULTS C peptide was detected in urine on the 1st day after the islet infusion median 0 59 nmol l range 0 11 1 79 0 15 nmol mmol creatinine range 0 06 0 25 with levels declining thereafter and becoming undetectable at 1 4 weeks median 10 days later Both blood glucose levels and insulin requirements were also lower on the 1st day after transplantation by an average means SEM DIABETES CARE VOLUME 32 NUMBER 10 OCTOBER 2009 1887 Seaweed Diabetes Trial of 36 8 and 22 3 respectively but not thereafter An arginine tolerance test was carried out on the 7th day and plasma C peptide was undetectable In the recipient of the four islet infusions urinary C peptide was detected at 6 weeks after the third infusion and continues to remain detectable at 2 5 years C peptide levels are 0 06 0 34 nmol l or 0 02 0 06 nmol mmol creatinine The small amount of insulin being produced did not alter insulin requirements or glycemic control To better understand what was occurring in the transplanted capsules a laparoscopy was performed in the recipient of the four islet infusions at 16 months after the first infusion Large numbers of capsules were found scattered throughout the peritoneal cavity in clusters attached to the parietal peritoneum Fig 1A spleen omentum and kidney A biopsy showed the capsules to be intact and
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