{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T01:06:45Z","timestamp":1774573605590,"version":"3.50.1"},"reference-count":37,"publisher":"Georg Thieme Verlag KG","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Horm Metab Res"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Current insulin therapy fails to fully restore physiological glucose homeostasis\n                    in type 1 diabetes mellitus, with 75% of patients unable to achieve the desired\n                    management targets. While stem cell-derived islets offer promising therapy, they\n                    require an enhanced extracellular matrix support for optimal transplantation\n                    outcomes. To address this challenge, we developed biofunctional endocrine\n                    micro-pancreata using decellularized porcine lung scaffolds seeded with\n                    embryonic stem cell-derived islets. In vivo efficacy was evaluated following\n                    subcutaneous or intraperitoneal transplantation into NOD-SCID mice, followed by\n                    streptozotocin induction of diabetes, with the comprehensive assessment of human\n                    insulin secretion, glucose homeostasis, and graft integration over 3 months. Our\n                    results demonstrated that endocrine micro-pancreata exhibited 1.4-fold-increased\n                    glucose-stimulated insulin secretion in vitro compared to non-responsive free\n                    islets. In vivo, endocrine micro-pancreas recipients maintained significantly\n                    lower glucose levels than controls throughout the experiment. Subcutaneous\n                    endocrine micro-pancreata showed superior performance, with 46% improved glucose\n                    tolerance versus 31% improvement for intraperitoneal delivery. Extensive\n                    CD31-positive neovascularization as well as insulin staining confirmed\n                    successful graft integration and sustained insulin production. Endocrine\n                    micro-pancreata provide a scalable platform for diabetes cell therapy,\n                    demonstrating sustained insulin secretion and improved glycemic control. The\n                    preserved extracellular matrix microenvironment supports islet function and\n                    vascularization, offering significant potential for clinical translation.<\/jats:p>","DOI":"10.1055\/a-2734-1983","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:10:42Z","timestamp":1764202242000},"page":"697-704","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular Matrix-Guided Islet Cell Transplantation Results in\n                    Improved Glycemic Control in a NOD-SCID Mouse Model"],"prefix":"10.1055","volume":"57","author":[{"given":"Ruchama","family":"Korol","sequence":"additional","affiliation":[{"name":"Betalin Therapeutics Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharona","family":"Even-Ram","sequence":"additional","affiliation":[{"name":"Betalin Therapeutics Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kfir","family":"Molakandov","sequence":"additional","affiliation":[{"name":"Kadimastem Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitry","family":"Puchinsky","sequence":"additional","affiliation":[{"name":"Betalin Therapeutics Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maayan","family":"Hemed","sequence":"additional","affiliation":[{"name":"Betalin Therapeutics Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noam","family":"Mizrahi","sequence":"additional","affiliation":[{"name":"Betalin Therapeutics Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itzik","family":"Toledo","sequence":"additional","affiliation":[{"name":"Kadimastem Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Lazar","sequence":"additional","affiliation":[{"name":"Kadimastem Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Chebath","sequence":"additional","affiliation":[{"name":"Kadimastem Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moshe","family":"Tritel","sequence":"additional","affiliation":[{"name":"Life Sciences, Tritel Patents, Ltd, Bet Shemesh, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Racheli","family":"Ofir","sequence":"additional","affiliation":[{"name":"Betalin Therapeutics Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, University Hospital\n                    Carl Gustav Carus, Dresden, Germany"},{"name":"Paul Langerhans Institute Dresden of Helmholtz Centre\n                    Munich, University Hospital Carl Gustav Carus, Dresden, Germany"},{"name":"Center for Regenerative Therapies, Technische Universit\u00e4t\n                    Dresden, Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel","family":"Revel","sequence":"additional","affiliation":[{"name":"Kadimastem Ltd., Jerusalem, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A M James","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Department of Surgery, Clinical Islet Transplant Program,\n                    University of Alberta, Edmonton, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan R.","family":"Bornstein","sequence":"additional","affiliation":[{"name":"University Clinic, Technische Universit\u00e4t Dresden,\n                    Dresden, Germany"},{"name":"Faculty of Life Sciences and Medicine, King\u2019s College\n                    London, London, United Kingdom of Great Britain and Northern\n                    Ireland"},{"name":"Department of Internal Medicine III, University Hospital\n                    Carl Gustav Carus, Dresden, Germany"},{"name":"Paul Langerhans Institute Dresden of Helmholtz Centre\n                    Munich, University Hospital Carl Gustav Carus, Dresden, Germany"},{"name":"Center for Regenerative Therapies, Technische Universit\u00e4t\n                    Dresden, Dresden, Germany"},{"name":"Klinik f\u00fcr Endokrinologie, Diabetologie und Klinische Ern\u00e4hrung, Universit\u00e4ts-\n               Spital Z\u00fcrich (USZ) und Universit\u00e4t Z\u00fcrich (UZH), Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1210\/endrev\/bnaa015","article-title":"The evolution of insulin and how it informs therapy and treatment choices","volume":"41","author":"I B Hirsch","year":"2020","journal-title":"Endocr Rev"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"183","DOI":"10.2337\/diaspect.17.3.183","article-title":"Glucose metabolism and regulation: beyond insulin and glucagon","volume":"17","author":"S L Aronoff","year":"2004","journal-title":"Diabetes Spectrum"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"e401","DOI":"10.1097\/TXD.0000000000000841","article-title":"Mortality in people with Type 1 diabetes, severe hypoglycemia, and impaired\n                    awareness of hypoglycemia referred for islet transplantation","volume":"4","author":"M H Lee","year":"2018","journal-title":"Transplant Direct"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"S128","DOI":"10.2337\/dc25-S006","article-title":"6. glycemic goals and hypoglycemia: standards of care in diabetes\u20142025","volume":"48","author":"ADAP P Committee","year":"2025","journal-title":"Diabetes Care"},{"key":"ref6","first-page":"16","article-title":"Long-term complications of diabetes mellitus","volume":"49","author":"A Czech","year":"1993","journal-title":"Farm Pol"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1089\/dia.2023.0320","article-title":"Longitudinal trends in glycemic outcomes and technology use for over 48,000\n                    people with type 1 diabetes (2016\u20132022) from the T1D exchange quality\n                    improvement collaborative","volume":"25","author":"O Ebekozien","year":"2023","journal-title":"Diabetes Technol Ther"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"e3430","DOI":"10.1002\/dmrr.3430","article-title":"The SAGE study: Global observational analysis of glycaemic control,\n                    hypoglycaemia and diabetes management in T1DM","volume":"37","author":"E Renard","year":"2021","journal-title":"Diabetes Metab Res Rev"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"348","DOI":"10.2174\/1871530323666230822095932","article-title":"Investigation of pancreatic-beta cells role in the biological process of\n                    ageing","volume":"24","author":"R Chaudhary","year":"2023","journal-title":"Endocr Metab Immune Disord Drug Targets"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S2213-8587(22)00114-0","article-title":"Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a\n                    single-centre cohort in Canada","volume":"10","author":"B A Marfil-Garza","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1391504","DOI":"10.3389\/fimmu.2024.1391504","article-title":"Pancreatic islet transplantation: current advances and challenges","volume":"15","author":"Q Wang","year":"2024","journal-title":"Front Immunol"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13098-023-01089-8","article-title":"Islet transplantation: overcoming the organ shortage","volume":"15","author":"M Mantovani","year":"2023","journal-title":"Diabetol Metab Syndr"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s13287-025-04293-7","article-title":"A perfect islet: reviewing recent protocol developments and proposing strategies\n                    for stem cell derived functional pancreatic islets","volume":"16","author":"S Sali","year":"2025","journal-title":"Stem Cell Res Ther"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1111\/jdi.14366","article-title":"Toward a cure for diabetes: iPSC and ESC-derived islet cell transplantation\n                    trials","volume":"16","author":"J Fujikura","year":"2025","journal-title":"J Diabetes Investig"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1056\/NEJMoa2506549","article-title":"Stem cell\u2013derived, fully differentiated islets for type 1 diabetes","volume":"393","author":"T W Reichman","year":"2025","journal-title":"N Engl J Med"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1080\/15476278.2018.1517509","article-title":"Rebuilding a better home for transplanted islets","volume":"14","author":"D M Tremmel","year":"2018","journal-title":"Organogenesis"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.stem.2025.02.001","article-title":"Enhanced viability and functional maturity of iPSC-derived islet organoids by\n                    collagen-VI-enriched ECM scaffolds","volume":"32","author":"D Zhu","year":"2025","journal-title":"Cell Stem Cell"},{"issue":"12","key":"ref18","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1002\/jbm.b.34881","article-title":"Collagen-based biomaterials for biomedical applications","volume":"109","author":"E Rezvani Ghomi","year":"2021","journal-title":"J Biomed Mater Res B Appl Biomater"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"rbae008","DOI":"10.1093\/rb\/rbae008","article-title":"Human extracellular matrix (ECM)-like collagen and its bioactivity","volume":"11","author":"H Zhou","year":"2024","journal-title":"Regen Biomater"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"109141","DOI":"10.1016\/j.isci.2024.109141","article-title":"ECM-derived biomaterials for regulating tissue multicellularity and\n                    maturation","volume":"27","author":"A Smandri","year":"2024","journal-title":"iScience"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"10555","DOI":"10.3389\/ti.2022.10555","article-title":"Bioengineering the vascularized endocrine pancreas: a fine-tuned interplay\n                    between vascularization, extracellular-matrix-based scaffold architecture, and\n                    insulin-producing cells","volume":"35","author":"C Pignatelli","year":"2022","journal-title":"Transplant Int"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1900\/RDS.2017.14.334","article-title":"Polymeric Scaffolds for Pancreatic Tissue Engineering: A Review","volume":"14","author":"N Kumar","year":"2018","journal-title":"Rev Diabet Stud"},{"issue":"21\/22","key":"ref23","first-page":"2691","article-title":"Beta cells secrete significant and regulated levels of insulin for long periods\n                    when seeded onto acellular micro-scaffolds","volume":"21","author":"R V Sionov","year":"2015"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1152\/advan.00167.2012","article-title":"Interactions between the central nervous system and pancreatic islet secretions:\n                    a historical perspective","volume":"37","author":"D P Begg","year":"2013","journal-title":"Adv Physiol Educ"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1002\/jbm.a.37158","article-title":"Decellularization of porcine whole lung to obtain a clinical-scale bioengineered\n                    scaffold","volume":"109","author":"Y Li","year":"2021","journal-title":"J Biomed Mater Res, Part A"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.athoracsur.2013.04.022","article-title":"Decellularization of human and porcine lung tissues for pulmonary tissue\n                    engineering","volume":"96","author":"J D O\u2019Neill","year":"2013","journal-title":"Ann Thorac Surg"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1055\/a-1041-3305","article-title":"Lung based engineered micro-pancreas sustains human beta cell survival and\n                    functionality","volume":"51","author":"O Goldman","year":"2019","journal-title":"Horm Metab Res"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"635405","DOI":"10.3389\/fendo.2021.635405","article-title":"Selection for CD26\u2212 and CD49A+ cells from pluripotent stem cells-derived\n                    islet-like clusters improves therapeutic activity in diabetic mice","volume":"12","author":"K Molakandov","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1210\/en.2013-1805","article-title":"Assessment of the metabolic pathways associated with glucose-stimulated biphasic\n                    insulin secretion","volume":"155","author":"M Huang","year":"2014","journal-title":"Endocrinology."},{"issue":"07","key":"ref30","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1210\/endo.143.7.8901","article-title":"Human \u03b2 cells are exceedingly resistant to streptozotocin in vivo","volume":"143","author":"H Yang","year":"2002","journal-title":"Endocrinology"},{"issue":"12","key":"ref31","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1007\/s00125-003-1241-2","article-title":"Mechanism underlying resistance of human pancreatic beta cells against toxicity\n                    of streptozotocin and alloxan [5]","volume":"46","author":"M Elsner","year":"2003","journal-title":"Diabetologia"},{"issue":"05","key":"ref32","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1172\/JCI118308","article-title":"Human and rat beta cells differ in glucose transporter but not in glucokinase\n                    gene expression","volume":"96","author":"A De Vos","year":"1995","journal-title":"J Clin Invest"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3390\/bioengineering12020136","article-title":"Towards safety and regulation criteria for clinical applications of\n                    decellularized organ-derived matrices","volume":"12","author":"EV A van Hengel","year":"2025","journal-title":"Bioengineering"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.1016\/j.biomaterials.2011.01.057","article-title":"An overview of tissue and whole organ decellularization processes","volume":"32","author":"P M Crapo","year":"2011","journal-title":"Biomaterials"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"e12643","DOI":"10.1111\/xen.12643","article-title":"Solid-phase silica-based extraction leads to underestimation of residual DNA in\n                    decellularized tissues","volume":"28","author":"T C Schmitz","year":"2021","journal-title":"Xenotransplantation"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1093\/ndt\/gfae023","article-title":"Porcine endogenous retroviruses in xenotransplantation","volume":"39","author":"J Denner","year":"2024","journal-title":"Nephrol, Dial, Transplant"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/s11892-018-1072-7","article-title":"Can We Re-engineer the endocrine pancreas?","volume":"18","author":"A Citro","year":"2018","journal-title":"Curr Diab Rep"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"1558137","DOI":"10.3389\/fcell.2025.1558137","article-title":"The role of endothelial cells in pancreatic islet development, transplantation\n                    and culture","volume":"13","author":"A Geng","year":"2025","journal-title":"Front Cell Dev Biol"}],"container-title":["Hormone and Metabolic Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2734-1983.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:38:44Z","timestamp":1774571924000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2734-1983"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,11]]},"published-print":{"date-parts":[[2025,12]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2734-1983","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0018-5043","1439-4286"],"issn-type":[{"value":"0018-5043","type":"print"},{"value":"1439-4286","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}