BACKGROUND: Transplantation of pancreatic islets into subcutaneous cavities in diabetic rats may be as or even more effective than transplantation into the portal vein. Identifying the optimal timing of the individual steps in this procedure is critical. METHODS: Macroporous scaffolds were placed in the subcutaneous tissue of diabetic male Lewis rats for 7 or 28 d and the healing of the tissue inside the scaffolds was monitored. A marginal syngeneic graft comprising 4 islets/g of recipient body weight was transplanted at the best timing focusing mainly on vascularization. Recipients were monitored for blood glucose levels and tolerance tests. Histological examination was performed in all implanted scaffolds. The presence of individual endocrine cells was analyzed in detail. RESULTS: Blood glucose levels remained within the physiological range in all recipients until the end of experiment as well as body weight increase. Coefficients of glucose assimilation were normal or slightly reduced with no statistically significant differences between the groups 40 and 80 d after transplantation. Histological analysis revealed round viable islets in the liver similar to those in pancreas, but alpha cells practically disappeared, whereas islets in the scaffolds formed clusters of cells surrounded by rich vascular network and the alpha cells remained partially preserved. CONCLUSIONS: Subcutaneous transplantation of pancreatic islets is considerably less invasive but comparably efficient as commonly used islet transplantation into the portal vein. In consideration of alpha and beta cell ratio, the artificial subcutaneous cavities represent a promising site for future islet transplantation therapy.

1st Faculty of Medicine Charles University Prague Czech Republic

3rd Faculty of Medicine Charles University Prague Czech Republic

Center of Experimental Medicine Prague Czech Republic

Department of Transplant Pathology Institute for Clinical and Experimental Medicine Prague Czech Republic

Diabetes Center Institute for Clinical and Experimental Medicine Prague Czech Republic

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Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343:230–238.

Voglová B, Zahradnická M, Girman P, et al. Benefits of islet transplantation as an alternative to pancreas transplantation: retrospective study of more than 10 ten years of experience in a single center. Rev Diabet Stud. 2017;14:10–21.

Registry CIT. Collaboratve Islet Transplant Registry. Published 2018.

Andres A, Kin T, O’Gorman D, et al. Impact of adverse pancreatic injury at surgical procurement upon islet isolation outcome. Transpl Int. 2014;27:1135–1142.

Berkova Z, Saudek F, Girman P, et al. Combining donor characteristics with immunohistological data improves the prediction of islet isolation success. J Diabetes Res. 2016;2016:4214328.

Eich T, Eriksson O, Lundgren T; Nordic Network for Clinical Islet Transplantation. Visualization of early engraftment in clinical islet transplantation by positron-emission tomography. N Engl J Med. 2007;356:2754–2755.

Jirak D, Kriz J, Strzelecki M, et al. Monitoring the survival of islet transplants by MRI using a novel technique for their automated detection and quantification. MAGMA. 2009;22:257–265.

Saudek F, Jirák D, Girman P, et al. Magnetic resonance imaging of pancreatic islets transplanted into the liver in humans. Transplantation. 2010;90:1602–1606.

Carlsson PO, Mattsson G. Oxygen tension and blood flow in relation to revascularization in transplanted adult and fetal rat pancreatic islets. Cell Transplant. 2002;11:813–820.

Carlsson PO, Palm F, Andersson A, et al. Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site. Diabetes. 2001;50:489–495.

Bellin MD, Parazzoli S, Oseid E, et al. Defective glucagon secretion during hypoglycemia after intrahepatic but not nonhepatic islet autotransplantation. Am J Transplant. 2014;14:1880–1886.

Lau J, Jansson L, Carlsson PO. Islets transplanted intraportally into the liver are stimulated to insulin and glucagon release exclusively through the hepatic artery. Am J Transplant. 2006;6:967–975.

Halberstadt CR, Williams D, Emerich D, et al. Subcutaneous transplantation of islets into streptozocin-induced diabetic rats. Cell Transplant. 2005;14:595–605.

Jiang K, Weaver JD, Li Y, et al. Local release of dexamethasone from macroporous scaffolds accelerates islet transplant engraftment by promotion of anti-inflammatory M2 macrophages. Biomaterials. 2017;114:71–81.

Kasoju N, Pátíková A, Wawrzynska E, et al. Bioengineering a pre-vascularized pouch for subsequent islet transplantation using VEGF-loaded polylactide capsules. Biomater Sci. 2020;8:631–647.

Kriz J, Vilk G, Mazzuca DM, et al. A novel technique for the transplantation of pancreatic islets within a vascularized device into the greater omentum to achieve insulin independence. Am J Surg. 2012;203:793–797.

Pepper AR, Gala-Lopez B, Pawlick R, et al. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat Biotechnol. 2015;33:518–523.

Pepper AR, Gala-Lopez B, Ziff O, et al. Revascularization of transplanted pancreatic islets and role of the transplantation site. Clin Dev Immunol. 2013;2013:352315.

Pileggi A, Molano RD, Ricordi C, et al. Reversal of diabetes by pancreatic islet transplantation into a subcutaneous, neovascularized device. Transplantation. 2006;81:1318–1324.

Yasunami Y, Nakafusa Y, Nitta N, et al. A novel subcutaneous site of islet transplantation superior to the liver. Transplantation. 2018;102:945–952.

Juang JH, Bonner-Weir S, Ogawa Y, et al. Outcome of subcutaneous islet transplantation improved by polymer device. Transplantation. 1996;61:1557–1561.

Smink AM, Hertsig DT, Schwab L, et al. A retrievable, efficacious polymeric scaffold for subcutaneous transplantation of rat pancreatic islets. Ann Surg. 2017;266:149–157.

Uematsu SS, Inagaki A, Nakamura Y, et al. The optimization of the prevascularization procedures for improving subcutaneous islet engraftment. Transplantation. 2018;102:387–395.

Vlahos AE, Cober N, Sefton MV. Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets. Proc Natl Acad Sci U S A. 2017;114:9337–9342.

Weaver JD, Headen DM, Hunckler MD, et al. Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation. Biomaterials. 2018;172:54–65.

Weidling J, Sameni S, Lakey JR, et al. Method measuring oxygen tension and transport within subcutaneous devices. J Biomed Opt. 2014;19:087006.

Diegelmann RF, Evans MC. Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci. 2004;9:283–289.

Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res. 2010;89:219–229.

Gálisová A, Fábryová E, Jirák D, et al. Multimodal imaging reveals improvement of blood supply to an artificial cell transplant site induced by bioluminescent mesenchymal stem cells. Mol Imaging Biol. 2017;19:15–23.

Chen X, Zhang X, Larson CS, et al. In vivo bioluminescence imaging of transplanted islets and early detection of graft rejection. Transplantation. 2006;81:1421–1427.

Pepper AR, Pawlick R, Gala-Lopez B, et al. Diabetes is reversed in a murine model by marginal mass syngeneic islet transplantation using a subcutaneous cell pouch device. Transplantation. 2015;99:2294–2300.

Fabryova E, Jirak D, Girman P, et al. Effect of mesenchymal stem cells on the vascularization of the artificial site for islet transplantation in rats. Transplant Proc. 2014;46:1963–1966.

Kriz J, Jirak D, Koblas T, et al. Dynamic contrast-enhanced magnetic resonance imaging as a tool to monitor the blood supply to an artificial cavity used as a site for islet transplantation in rats. Transplant Proc. 2011;43:3226–3230.

Komatsu H, Rawson J, Barriga A, et al. Posttransplant oxygen inhalation improves the outcome of subcutaneous islet transplantation: a promising clinical alternative to the conventional intrahepatic site. Am J Transplant. 2018;18:832–842.

Hirabaru M, Kuroki T, Adachi T, et al. A method for performing islet transplantation using tissue-engineered sheets of islets and mesenchymal stem cells. Tissue Eng Part C Methods. 2015;21:1205–1215.

Ludwig B, Rotem A, Schmid J, et al. Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist. Proc Natl Acad Sci U S A. 2012;109:5022–5027.

Gálisová A, Fábryová E, Sticová E, et al. The optimal timing for pancreatic islet transplantation into subcutaneous scaffolds assessed by multimodal imaging. Contrast Media Mol Imaging. 2017;2017:5418495.

Decellularized Pancreatic Tail as Matrix for Pancreatic Islet Transplantation into the Greater Omentum in Rats