{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:56:32Z","timestamp":1760147792627,"version":"build-2065373602"},"reference-count":70,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:00:00Z","timestamp":1677715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT), Portugal","doi-asserted-by":"publisher","award":["UIDB\/04565\/2020","UIDP\/04565\/2020","LA\/P\/0140\/2020","PTDC\/EMD-TLM\/29728\/2017","REC05-i02 \u2013N\u00ba 01\/C05-i02\/2022"],"award-info":[{"award-number":["UIDB\/04565\/2020","UIDP\/04565\/2020","LA\/P\/0140\/2020","PTDC\/EMD-TLM\/29728\/2017","REC05-i02 \u2013N\u00ba 01\/C05-i02\/2022"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ag\u00eancia Nacional de Inova\u00e7\u00e3o and European Union","award":["UIDB\/04565\/2020","UIDP\/04565\/2020","LA\/P\/0140\/2020","PTDC\/EMD-TLM\/29728\/2017","REC05-i02 \u2013N\u00ba 01\/C05-i02\/2022"],"award-info":[{"award-number":["UIDB\/04565\/2020","UIDP\/04565\/2020","LA\/P\/0140\/2020","PTDC\/EMD-TLM\/29728\/2017","REC05-i02 \u2013N\u00ba 01\/C05-i02\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Today, it is recognized that medicines will eventually be needed during pregnancy to help prevent to, ameliorate or treat an illness, either due to gestation-related medical conditions or pre-existing diseases. Adding to that, the rate of drug prescription to pregnant women has increased over the past few years, in accordance with the increasing trend to postpone childbirth to a later age. However, in spite of these trends, information regarding teratogenic risk in humans is often missing for most of the purchased drugs. So far, animal models have been the gold standard to obtain teratogenic data, but inter-species differences have limited the suitability of those models to predict human-specific outcomes, contributing to misidentified human teratogenicity. Therefore, the development of physiologically relevant in vitro humanized models can be the key to surpassing this limitation. In this context, this review describes the pathway towards the introduction of human pluripotent stem cell-derived models in developmental toxicity studies. Moreover, as an illustration of their relevance, a particular emphasis will be placed on those models that recapitulate two very important early developmental stages, namely gastrulation and cardiac specification.<\/jats:p>","DOI":"10.3390\/ijms24054857","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T02:27:25Z","timestamp":1677810445000},"page":"4857","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Developmental Toxicity Studies: The Path towards Humanized 3D Stem Cell-Based Models"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9795-3323","authenticated-orcid":false,"given":"Mariana A.","family":"Branco","sequence":"first","affiliation":[{"name":"Collaborative Laboratory to Foster Translation and Drug Discovery, Accelbio, 3030-197 Cantanhede, Portugal"},{"name":"IBB\u2014Institute for Bioengineering and Biosciences, Department of Bioengineering Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"given":"Tiago C.","family":"Nunes","sequence":"additional","affiliation":[{"name":"IBB\u2014Institute for Bioengineering and Biosciences, Department of Bioengineering Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2405-5845","authenticated-orcid":false,"given":"Joaquim M. S.","family":"Cabral","sequence":"additional","affiliation":[{"name":"IBB\u2014Institute for Bioengineering and Biosciences, Department of Bioengineering Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6270-4455","authenticated-orcid":false,"given":"Maria Margarida","family":"Diogo","sequence":"additional","affiliation":[{"name":"IBB\u2014Institute for Bioengineering and Biosciences, Department of Bioengineering Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, Instituto Superior T\u00e9cnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,2]]},"reference":[{"key":"ref_1","unstructured":"EMA (2020). ICH S5 (R3) Guideline on Reproductive Toxicology: Detection of Toxicity to Reproduction for Human Pharmaceuticals Step 5, European Medicines Agency, Committee for Medicinal Products for Human Use."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1002\/ajmg.c.30313","article-title":"Evolving knowledge of the teratogenicity of medications in human pregnancy","volume":"157","author":"Adam","year":"2011","journal-title":"Am. J. Med. Genet. Part C Semin. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"690.e1","DOI":"10.1016\/j.ajog.2014.06.013","article-title":"Trends in pregnancy labeling and data quality for US-approved pharmaceuticals","volume":"211","author":"Gray","year":"2014","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1097\/AOG.0b013e3182a9ca67","article-title":"Exclusion of Pregnant Women From Industry-Sponsored Clinical Trials","volume":"122","author":"Shields","year":"2013","journal-title":"Obstet. Gynecol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fped.2014.00009","article-title":"Obstetric pharmacokinetic dosing studies are urgently needed","volume":"2","author":"McCormack","year":"2014","journal-title":"Front. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1053\/j.semperi.2015.08.002","article-title":"Epidemiology of Medications Use in Pregnancy Martina","volume":"39","author":"Ayad","year":"2018","journal-title":"Semin. Perinatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.2105\/AJPH.2013.301416","article-title":"Shifts in Intended and Unintended Pregnancies in the United States, 2001\u20132008","volume":"104","author":"Finer","year":"2014","journal-title":"Am. J. Public Health"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"104184","DOI":"10.1016\/j.msard.2022.104184","article-title":"Fingolimod, teriflunomide and cladribine for the treatment of multiple sclerosis in women of childbearing age: Description of drug utilization and exposed pregnancies in Germany","volume":"67","author":"Platzbecker","year":"2022","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.reprotox.2021.01.006","article-title":"Macrolide and lincosamide antibiotic exposure in the first trimester of pregnancy and risk of congenital anomaly: A European case-control study","volume":"100","author":"Leke","year":"2021","journal-title":"Reprod. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/acer.14511","article-title":"Glutathione Protects the Developing Heart from Defects and Global DNA Hypomethylation Induced by Prenatal Alcohol Exposure","volume":"45","author":"Jawaid","year":"2021","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1002\/phar.1649","article-title":"A Review of Antibiotic Use in Pregnancy","volume":"35","author":"Bookstaver","year":"2015","journal-title":"Pharmacother. J. Hum. Pharmacol. Drug Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1001\/jamapsychiatry.2020.2453","article-title":"Maternal Use of Specific Antidepressant Medications During Early Pregnancy and the Risk of Selected Birth Defects","volume":"77","author":"Anderson","year":"2020","journal-title":"JAMA Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1111\/bcp.12849","article-title":"The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: A systematic review and meta-analysis","volume":"81","author":"Iessa","year":"2016","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9914931","DOI":"10.1155\/2022\/9914931","article-title":"Fetal Congenital Cardiac and Vascular Disorders Associated with Sertraline Treatment during Pregnancy: Analysis of FAERS Data","volume":"2022","author":"Hong","year":"2022","journal-title":"BioMed Res. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1111\/1471-0528.16772","article-title":"Antidepressant use in pregnancy and severe cardiac malformations: Danish register-based study","volume":"128","author":"Kolding","year":"2021","journal-title":"BJOG Int. J. Obstet. Gynaecol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Koutras, A., Ntounis, T., Fasoulakis, Z., Papalios, T., Pittokopitou, S., Prokopakis, I., Syllaios, A., Valsamaki, A., Chionis, A., and Symeonidis, P. (2022). Cancer Treatment and Immunotherapy during Pregnancy. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14102080"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11912-020-0862-7","article-title":"Pregnancy and Cancer: The INCIP Project","volume":"22","author":"Maggen","year":"2020","journal-title":"Curr. Oncol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.ncl.2009.06.006","article-title":"Teratogenic Effects of Antiepileptic Medications","volume":"27","author":"Tomson","year":"2009","journal-title":"Neurol. Clin."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"197","DOI":"10.2165\/00002018-200427030-00004","article-title":"Malformation Rates in Children of Women with Untreated Epilepsy","volume":"27","author":"Fried","year":"2004","journal-title":"Drug Saf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1053\/j.semperi.2009.02.010","article-title":"The Global Impact of Pre-eclampsia and Eclampsia","volume":"33","author":"Duley","year":"2009","journal-title":"Semin. Perinatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e2021052151","DOI":"10.1542\/peds.2021-052151","article-title":"Environmental Exposures and Congenital Heart Disease","volume":"149","author":"Boyd","year":"2022","journal-title":"Pediatrics"},{"key":"ref_22","unstructured":"Pruss-Ustun, A.C.C. (2023, January 30). Preventing Disease through Healthy Environments: Towards an Estimate of the Environmental Burden of Diseasee. Available online: https:\/\/apps.who.int\/iris\/handle\/10665\/43457."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/bdrc.20219","article-title":"Cardiac developmental toxicity","volume":"93","author":"Mahler","year":"2011","journal-title":"Birth Defects Res. Part C Embryo Today Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/pr.2014.128","article-title":"A detailed comparison of mouse and human cardiac development","volume":"76","author":"Krishnan","year":"2014","journal-title":"Pediatr. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ddmod.2018.04.001","article-title":"Animal models for heart valve research and development","volume":"24","author":"Kheradvar","year":"2017","journal-title":"Drug Discov. Today Dis. Model."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"595488","DOI":"10.3389\/fcell.2020.595488","article-title":"Heart Development and Regeneration in Non-mammalian Model Organisms","volume":"8","author":"Xia","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1642684","DOI":"10.1155\/2018\/1642684","article-title":"Using Zebrafish for Investigating the Molecular Mechanisms of Drug-Induced Cardiotoxicity","volume":"2018","author":"Zakaria","year":"2018","journal-title":"Biomed Res. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.yrtph.2008.04.008","article-title":"The challenge of reproductive and developmental toxicology under REACH","volume":"51","author":"Scialli","year":"2008","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1002\/bdrc.20175","article-title":"In vitro developmental toxicology assays: A review of the state of the science of rodent and zebrafish whole embryo culture and embryonic stem cell assays","volume":"90","author":"Zhang","year":"2010","journal-title":"Birth Defects Res. Part C Embryo Today Rev."},{"key":"ref_30","unstructured":"Mohammed, O.J., and Pratten, M.K. (2019). Developmental Toxicology: Methods and Protocols, Humana."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1007\/s00204-020-02856-6","article-title":"A novel human pluripotent stem cell-based assay to predict developmental toxicity","volume":"94","author":"Lauschke","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/B978-0-08-046884-6.01503-7","article-title":"Fundamental concepts, current regulatory design and interpretation","volume":"12","author":"Daston","year":"2010","journal-title":"Compr. Toxicol. Elsevier"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s41231-019-0050-7","article-title":"Lost in translation: The valley of death across preclinical and clinical divide\u2013identification of problems and overcoming obstacles","volume":"4","author":"Seyhan","year":"2019","journal-title":"Transl. Med. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Flamier, A., Singh, S., and Rasmussen, T.P. (2017). A standardized human embryoid body platform for the detection and analysis of teratogens. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171101"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1186\/s13287-016-0449-2","article-title":"Comparison of a teratogenic transcriptome-based predictive test based on human embryonic versus inducible pluripotent stem cells","volume":"7","author":"Shinde","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"115792","DOI":"10.1016\/j.taap.2021.115792","article-title":"Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies","volume":"433","author":"Konala","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Meganathan, K., Jagtap, S., Wagh, V., Winkler, J., Gaspar, J.A., Hildebrand, D., Trusch, M., Lehmann, K., Hescheler, J., and Schl\u00fcter, H. (2012). Identification of Thalidomide-Specific Transcriptomics and Proteomics Signatures during Differentiation of Human Embryonic Stem Cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044228"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.reprotox.2020.10.011","article-title":"Focus on germ-layer markers: A human stem cell-based model for in vitro teratogenicity testing","volume":"98","author":"Jaklin","year":"2020","journal-title":"Reprod. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.stemcr.2019.01.022","article-title":"Single-Cell RNA Sequencing of Human Embryonic Stem Cell Differentiation Delineates Adverse Effects of Nicotine on Embryonic Development","volume":"12","author":"Guo","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"117002","DOI":"10.1289\/EHP11208","article-title":"Cardiac Development in the Presence of Cadmium: An in Vitro Study Using Human Embryonic Stem Cells and Cardiac Organoids","volume":"130","author":"Wu","year":"2022","journal-title":"Environ. Health Perspect."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.reprotox.2021.08.003","article-title":"In vitro teratogenicity testing using a 3D, embryo-like gastruloid system","volume":"105","author":"Mantziou","year":"2021","journal-title":"Reprod. Toxicol."},{"key":"ref_42","first-page":"224","article-title":"Developmental toxicity of remdesivir, an anti-COVID-19 drug, is implicated by in vitro assays using morphogenetic embryoid bodies of mouse and human pluripotent stem cells","volume":"115","author":"Marikawa","year":"2022","journal-title":"Birth Defects Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1093\/toxsci\/kft239","article-title":"A High-Throughput Screen for Teratogens Using Human Pluripotent Stem Cells","volume":"137","author":"Kameoka","year":"2014","journal-title":"Toxicol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10038","DOI":"10.1038\/srep10038","article-title":"A method for human teratogen detection by geometrically confined cell differentiation and migration","volume":"5","author":"Xing","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8491","DOI":"10.1038\/s41598-017-09178-1","article-title":"In Vitro Micropatterned Human Pluripotent Stem Cell Test (\u03bcP-hPST) for Morphometric-Based Teratogen Screening","volume":"7","author":"Xing","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"12960","DOI":"10.1038\/s41598-018-31192-0","article-title":"Disruption of mesoderm formation during cardiac differentiation due to developmental exposure to 13-cis-retinoic acid","volume":"8","author":"Liu","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.toxlet.2019.03.008","article-title":"Arsenic trioxide blocked proliferation and cardiomyocyte differentiation of human induced pluripotent stem cells: Implication in cardiac developmental toxicity","volume":"309","author":"Bao","year":"2019","journal-title":"Toxicol. Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.scitotenv.2018.09.247","article-title":"HHS Public Access","volume":"651","author":"Fu","year":"2020","journal-title":"Sci. Total Environ."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"152422","DOI":"10.1016\/j.tox.2020.152422","article-title":"Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity","volume":"435","author":"Ye","year":"2020","journal-title":"Toxicology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1002\/bdr2.2001","article-title":"A novel human stem cell-based biomarker assay for in vitro assessment of developmental toxicity","volume":"114","author":"Jamalpoor","year":"2022","journal-title":"Birth Defects Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Galanjuk, S., Z\u00fchr, E., D\u00f6nmez, A., Bartsch, D., Kurian, L., Tigges, J., and Fritsche, E. (2022). The Human Induced Pluripotent Stem Cell Test as an Alternative Method for Embryotoxicity Testing. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063295"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1007\/s00204-021-03018-y","article-title":"Creating a human-induced pluripotent stem cell-based NKX2.5 reporter gene assay for developmental toxicity testing","volume":"95","author":"Lauschke","year":"2021","journal-title":"Arch. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Schmidt, C., Deyett, A., Ilmer, T., Caballero, A.T., Haendeler, S., Pimpale, L., Netzer, M.A., Ginistrelli, L.C., Cirigliano, M., and Mancheno, E.J. (2022). Multi-chamber cardioids unravel human heart development and cardiac defects. bioRxiv.","DOI":"10.1101\/2022.07.14.499699"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1016\/j.stemcr.2021.03.013","article-title":"Engineering spatial-organized cardiac organoids for developmental toxicity testing","volume":"16","author":"Hoang","year":"2021","journal-title":"Stem Cell Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3356","DOI":"10.1021\/acsbiomaterials.8b00653","article-title":"Placental Barrier-on-a-Chip: Modeling Placental Inflammatory Responses to Bacterial Infection","volume":"4","author":"Zhu","year":"2018","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.3109\/14767058.2015.1038518","article-title":"Placenta-on-A-chip: A novel platform to study the biology of the human placenta","volume":"29","author":"Lee","year":"2016","journal-title":"J. Matern. Neonatal Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1700786","DOI":"10.1002\/adhm.201700786","article-title":"Placental Drug Transport-on-a-Chip: A Microengineered In Vitro Model of Transporter-Mediated Drug Efflux in the Human Placental Barrier","volume":"7","author":"Blundell","year":"2018","journal-title":"Adv. Healthc. Mater."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.tiv.2018.08.014","article-title":"A 3D human placenta-on-a-chip model to probe nanoparticle exposure at the placental barrier","volume":"54","author":"Yin","year":"2019","journal-title":"Toxicol. Vitr."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1800112","DOI":"10.1002\/gch2.201800112","article-title":"Placenta-on-a-Chip: In Vitro Study of Caffeine Transport across Placental Barrier Using Liquid Chromatography Mass Spectrometry","volume":"3","author":"Pemathilaka","year":"2019","journal-title":"Glob. Chall."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.stemcr.2020.06.003","article-title":"Naive Human Embryonic Stem Cells Can Give Rise to Cells with a Trophoblast-like Transcriptome and Methylome","volume":"15","author":"Cinkornpumin","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e52504","DOI":"10.7554\/eLife.52504","article-title":"Derivation of trophoblast stem cells from na\u00efve human pluripotent stem cells","volume":"9","author":"Dong","year":"2020","journal-title":"Elife"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.toxlet.2015.09.011","article-title":"Human placental cell and tissue uptake of doxorubicin and its liposomal formulations","volume":"239","author":"Soininen","year":"2015","journal-title":"Toxicol. Lett."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Tenreiro, M.F., Branco, M.A., Cotovio, J.P., Cabral, J.M.S., Fernandes, T.G., and Diogo, M.M. (2023). Advancing organoid design through co-emergence, assembly, and bioengineering. Trends Biotechnol., 1\u201316.","DOI":"10.1016\/j.tibtech.2022.12.021"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.stem.2020.05.004","article-title":"Human-iPSC-Derived Cardiac Stromal Cells Enhance Maturation in 3D Cardiac Microtissues and Reveal Non-cardiomyocyte Contributions to Heart Disease","volume":"26","author":"Giacomelli","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_65","first-page":"1008","article-title":"Three-dimensional cardiac microtissues composed of cardiomyocytes and endothelial cells co-differentiated from human pluripotent stem cells","volume":"144","author":"Giacomelli","year":"2017","journal-title":"Development"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"9229","DOI":"10.1038\/s41598-019-45047-9","article-title":"Transcriptomic analysis of 3D Cardiac Differentiation of Human Induced Pluripotent Stem Cells Reveals Faster Cardiomyocyte Maturation Compared to 2D Culture","volume":"9","author":"Branco","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1038\/s41596-018-0076-8","article-title":"Use of human induced pluripotent stem cell\u2013derived cardiomyocytes to assess drug cardiotoxicity","volume":"13","author":"Sharma","year":"2018","journal-title":"Nat. Protoc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6981","DOI":"10.1038\/s41467-022-34730-7","article-title":"Human multilineage pro-epicardium\/foregut organoids support the development of an epicardium\/myocardium organoid","volume":"13","author":"Branco","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/s41587-021-00815-9","article-title":"Human heart-forming organoids recapitulate early heart and foregut development","volume":"39","author":"Drakhlis","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"104486","DOI":"10.1016\/j.isci.2022.104486","article-title":"A Combined Human Gastruloid Model of Cardiogenesis and Neurogenesis","volume":"25","author":"Olmsted","year":"2022","journal-title":"iScience"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4857\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:46:14Z","timestamp":1760121974000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/5\/4857"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,2]]},"references-count":70,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24054857"],"URL":"https:\/\/doi.org\/10.3390\/ijms24054857","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,3,2]]}}}