{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T01:17:31Z","timestamp":1775092651497,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","award":["BRAV3 (ID: 874827)"],"award-info":[{"award-number":["BRAV3 (ID: 874827)"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/145767\/2019"],"award-info":[{"award-number":["SFRH\/BD\/145767\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["EXCELERATE(DOI10.54499\/2022.10467.PTDC)"],"award-info":[{"award-number":["EXCELERATE(DOI10.54499\/2022.10467.PTDC)"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["Sara Borrel grant (CD22\/00027)"],"award-info":[{"award-number":["Sara Borrel grant (CD22\/00027)"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["CARDIOPRINT (PLEC2021\u2010008127)"],"award-info":[{"award-number":["CARDIOPRINT (PLEC2021\u2010008127)"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["VOLVAD(PID2022\u2010142562OB\u2010I00)"],"award-info":[{"award-number":["VOLVAD(PID2022\u2010142562OB\u2010I00)"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["INVESTTRA(PID2022\u2010142807OA\u2010I00)"],"award-info":[{"award-number":["INVESTTRA(PID2022\u2010142807OA\u2010I00)"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014440","name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","doi-asserted-by":"publisher","award":["MICIU\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["MICIU\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Generation of upscaled quantities of human\u2010induced pluripotent stem cell\u2010derived cardiomyocytes (hiPSC\u2010CM), for therapeutic or testing applications, is both expensive and time\u2010consuming. Herein, a scalable bioprocess for hiPSC\u2010CM expansion in stirred\u2010tank bioreactors (STB) is developed. By combining the continuous activation of the Wnt pathway, through perfusion of CHIR99021, within a mild hypoxia environment, the expansion of hiPSC\u2010CM as aggregates is maximized, reaching 4 billion of pure hiPSC\u2010CM in 2L STB. In particular, the importance of i) controlling the dissolved oxygen at 10% O\n                    <jats:sub>2<\/jats:sub>\n                    to reduce reactive oxygen species production and upregulate genes involved in cell proliferation, resulting in higher expansion rates (tenfold) compared to normoxic conditions, and ii) maintaining constant power input per volume as a scale\u2010up criteria is demonstrated. After expansion, hiPSC\u2010CM further mature in culture, revealing more mature transcriptional signatures, higher sarcomere alignment and improved calcium handling. This new bioprocess opens the door to time\u2010 and cost\u2010effective generation of hiPSC\u2010CM.\n                  <\/jats:p>","DOI":"10.1002\/advs.202410510","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T06:42:32Z","timestamp":1737614552000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Billion\u2010Scale Expansion of Functional hiPSC\u2010Derived Cardiomyocytes in Bioreactors Through Oxygen Control and Continuous Wnt Activation"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2091-4347","authenticated-orcid":false,"given":"Pedro","family":"Vicente","sequence":"first","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2780901 Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade de Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780157 Portugal"}]},{"given":"Lara R.","family":"Inoc\u00eancio","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2780901 Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade de Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780157 Portugal"}]},{"given":"Asier","family":"Ullate\u2010Agote","sequence":"additional","affiliation":[{"name":"Program of Biomedical Engineering Technological Innovation Division CIMA Universidad de Navarra, and Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA)  Pamplona 31008 Spain"}]},{"given":"Ana F.","family":"Louro","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2780901 Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade de Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780157 Portugal"}]},{"given":"Jo\u00e3o","family":"Jacinto","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2780901 Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade de Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780157 Portugal"}]},{"given":"Beatriz","family":"Gamelas","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2780901 Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade de Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780157 Portugal"}]},{"given":"Olalla","family":"Iglesias\u2010Garc\u00eda","sequence":"additional","affiliation":[{"name":"Program of Biomedical Engineering Technological Innovation Division CIMA Universidad de Navarra, and Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA)  Pamplona 31008 Spain"}]},{"given":"Patxi San","family":"Martin\u2010Uriz","sequence":"additional","affiliation":[{"name":"Hemato\u2010oncology Program Cancer Division CIMA Universidad de Navarra, and Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA)  Pamplona 31008 Spain"}]},{"given":"Paula","family":"Aguirre\u2010Ruiz","sequence":"additional","affiliation":[{"name":"Hemato\u2010oncology Program Cancer Division CIMA Universidad de Navarra, and Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA)  Pamplona 31008 Spain"}]},{"given":"Gonzalo R.","family":"R\u00edos\u2010Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Bioengineering Department Universidad Carlos III de Madrid  Madrid 28911 Spain"},{"name":"Department of Cardiology Gregorio Mara\u00f1\u00f3n Health Research Institute (IiSGM) Hospital General Universitario Gregorio Mara\u00f1\u00f3n  Madrid 28007 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV) Instituto Carlos III  Madrid 28029 Spain"}]},{"given":"Mar\u00eda Eugenia","family":"Fern\u00e1ndez\u2010Santos","sequence":"additional","affiliation":[{"name":"Department of Cardiology Gregorio Mara\u00f1\u00f3n Health Research Institute (IiSGM) Hospital General Universitario Gregorio Mara\u00f1\u00f3n  Madrid 28007 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV) Instituto Carlos III  Madrid 28029 Spain"}]},{"given":"Alain","family":"van Mil","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Center Utrecht Laboratory of Experimental Cardiology, Circulatory Health Research Center, University Utrecht University Medical Center Utrecht University Utrecht  Utrecht 3508 GA The Netherlands"}]},{"given":"Joost P. G.","family":"Sluijter","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Center Utrecht Laboratory of Experimental Cardiology, Circulatory Health Research Center, University Utrecht University Medical Center Utrecht University Utrecht  Utrecht 3508 GA The Netherlands"}]},{"given":"Felipe","family":"Pr\u00f3sper","sequence":"additional","affiliation":[{"name":"Hematology and Cell Therapy Cl\u00ednica Universidad de Navarra  Pamplona 31008 Spain"},{"name":"Hemato\u2010oncology Program Cancer Division CIMA Universidad de Navarra, and Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA)  Pamplona 31008 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red C\u00e1ncer (CIBERONC)  Madrid 28029 Spain"}]},{"given":"Manuel M Mazo","family":"Vega","sequence":"additional","affiliation":[{"name":"Program of Biomedical Engineering Technological Innovation Division CIMA Universidad de Navarra, and Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA)  Pamplona 31008 Spain"},{"name":"Hematology and Cell Therapy Cl\u00ednica Universidad de Navarra  Pamplona 31008 Spain"}]},{"given":"Paula M.","family":"Alves","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2780901 Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade de Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780157 Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5013-6625","authenticated-orcid":false,"given":"Margarida","family":"Serra","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2780901 Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade de Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780157 Portugal"}]}],"member":"311","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"e_1_2_9_1_1","volume":"12","author":"Khan M. A. B.","year":"2020","journal-title":"Cureus"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2020.00955"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibtech.2012.03.003"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.09.013"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.150"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101560"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22063005"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiotec.2017.01.004"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2019.09.001"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2999"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.06.001"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.03.009"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-24954-3"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.032"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2020.02.008"},{"key":"e_1_2_9_16_1","first-page":"323","volume-title":"New Bioprocessing Strategies: Development and Manufacturing of Recombinant Antibodies and Proteins","author":"Abraham E.","year":"2018"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-chembioeng-092120-033922"},{"key":"e_1_2_9_18_1","first-page":"5929","volume":"15","author":"Prondzynski M.","year":"2024","journal-title":"bioRxiv"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.089"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100334"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.047904"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cophys.2020.02.001"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2017.033"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2015.08.002"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.32058"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2021.674260"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-020-01618-6"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2017.08.025"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2018.07.020"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2005"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0023657"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.011490"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.304472"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsbiomaterials.3c01302"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.teb.2011.0040"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/sctm.20-0453"},{"key":"e_1_2_9_37_1","first-page":"36","volume":"21","author":"Muralidharan N.","year":"2023","journal-title":"BioProcess Int."},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4162"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2018.01.039"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2016.09.024"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2018.08.003"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.09.025"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.04.005"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2019.10.001"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.05.004"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107925"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-08713-4"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.5966\/sctm.2015-0428"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/7651_2016_333"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.1041348"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232416211"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202410510","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T19:47:41Z","timestamp":1765828061000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202410510"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,23]]},"references-count":52,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/advs.202410510"],"URL":"https:\/\/doi.org\/10.1002\/advs.202410510","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,23]]},"assertion":[{"value":"2024-08-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2410510"}}