{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:30:00Z","timestamp":1791387000199,"version":"4.3.3"},"reference-count":53,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Quantification of fetal drug exposure remains challenging since sampling from the placenta or fetus during pregnancy is too invasive. Currently existing in vivo (e.g., cord blood sampling) and ex vivo (e.g., placenta perfusion) models have inherent limitations. A placenta-on-a-chip model is a promising alternative. A systematic search was performed in PubMed on 2 February 2023, and Embase on 14 March 2023. Studies were included where placenta-on-a-chip was used to investigate placental physiology, placenta in different obstetric conditions, and\/or fetal exposure to maternally administered drugs. Seventeen articles were included that used comparable approaches but different microfluidic devices and\/or different cultured maternal and fetal cell lines. Of these studies, four quantified glucose transfer, four studies evaluated drug transport, three studies investigated nanoparticles, one study analyzed bacterial infection and five studies investigated preeclampsia. It was demonstrated that placenta-on-a-chip has the capacity to recapitulate the key characteristics of the human placental barrier. We aimed to identify knowledge gaps and provide the first steps towards an overview of current protocols for developing a placenta-on-a-chip, that facilitates comparison of results from different studies. Although models differ, they offer a promising approach for in vitro human placental and fetal drug studies under healthy and pathological conditions.<\/jats:p>","DOI":"10.3390\/jcm12134315","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:45:11Z","timestamp":1687913111000},"page":"4315","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Placenta-on-a-Chip as an In Vitro Approach to Evaluate the Physiological and Structural Characteristics of the Human Placental Barrier upon Drug Exposure: A Systematic Review"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2873-8650","authenticated-orcid":false,"given":"Femke A.","family":"Elzinga","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2986-7094","authenticated-orcid":false,"given":"Behrad","family":"Khalili","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1429-4789","authenticated-orcid":false,"given":"Daan J.","family":"Touw","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"},{"name":"Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deunsinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3984-2163","authenticated-orcid":false,"given":"Jelmer R.","family":"Prins","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4855-8452","authenticated-orcid":false,"given":"Peter","family":"Olinga","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deunsinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henri G. D.","family":"Leuvenink","sequence":"additional","affiliation":[{"name":"Department of Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6670-1577","authenticated-orcid":false,"given":"Harry","family":"van Goor","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, Pathology Section, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne J.","family":"Gordijn","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7541-588X","authenticated-orcid":false,"given":"Anika","family":"Nagelkerke","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deunsinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3551-1201","authenticated-orcid":false,"given":"Paola","family":"Mian","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"ref_1","unstructured":"(2023, February 28). Eurocat\u2014Use of Teratogenic Medication during Pregnancy. Available online: https:\/\/umcgresearch.org\/w\/eurocat-use-of-teratogenic-medication-during-pregnancy."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"20190031","DOI":"10.1098\/rsfs.2019.0031","article-title":"Drug transport across the human placenta: Review of placenta-on-a-chip and previous approaches","volume":"9","author":"Pemathilaka","year":"2019","journal-title":"Interface Focus"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15278","DOI":"10.1038\/s41598-022-19422-y","article-title":"3D microfluidics-assisted modeling of glucose transport in placental malaria","volume":"12","author":"Mosavati","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.thromres.2004.06.038","article-title":"Growth and function of the normal human placenta","volume":"114","author":"Gude","year":"2004","journal-title":"Thromb. Res."},{"key":"ref_6","first-page":"126","article-title":"Drug Interactions at the Human Placenta: What is the Evidence?","volume":"3","author":"Eyal","year":"2012","journal-title":"Front. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1093\/bjaceaccp\/mku013","article-title":"Placental structure, function and drug transfer","volume":"15","author":"Griffiths","year":"2015","journal-title":"Contin. Educ. Anaesth. Crit. Care Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s11022-004-6830-z","article-title":"A reproducible modified method for direct preparation of chorionic villi cytogenetic analysis","volume":"25","author":"Shetty","year":"2003","journal-title":"Methods Cell Sci."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kojima, J., Ono, M., Kuji, N., and Nishi, H. (2022). Human Chorionic Villous Differentiation and Placental Development. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23148003"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.1021\/acs.molpharmaceut.2c00216","article-title":"Placental Nanoparticle Uptake-On-a-Chip: The Impact of Trophoblast Syncytialization and Shear Stress","volume":"19","author":"Abostait","year":"2022","journal-title":"Mol. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.placenta.2004.10.002","article-title":"Human placental explants in culture: Approaches and assessments","volume":"26","author":"Miller","year":"2005","journal-title":"Placenta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/clpt.2011.66","article-title":"The human placental perfusion model: A systematic review and development of a model to predict in vivo transfer of therapeutic drugs","volume":"90","author":"Hutson","year":"2011","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/0250-474X.51941","article-title":"Drug use in pregnancy; a point to ponder","volume":"71","author":"Sachdeva","year":"2009","journal-title":"Indian J. Pharm. Sci."},{"key":"ref_14","first-page":"225","article-title":"In vitro models for studying trophoblast transcellular transport","volume":"122","author":"Bode","year":"2006","journal-title":"Methods Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1210\/en.2007-1282","article-title":"Human chorionic gonadotropin stimulates trophoblast invasion through extracellularly regulated kinase and AKT signalling","volume":"149","author":"Prast","year":"2008","journal-title":"Endocrinology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1111601","DOI":"10.3389\/fphar.2023.1111601","article-title":"Drug exposure during pregnancy: Current understanding and approaches to measure maternal-fetal drug exposure","volume":"14","author":"Hudson","year":"2023","journal-title":"Front. Pharmacol."},{"key":"ref_17","unstructured":"(2023, March 19). PRISMA. Available online: https:\/\/prisma-statement.org\/."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1039\/C6LC00259E","article-title":"A microphysiological model of the human placental barrier","volume":"16","author":"Blundell","year":"2016","journal-title":"Lab Chip"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mosavati, B., Oleinikov, A.V., and Du, E. (2020). Development of an Organ-on-a-Chip-Device for Study of Placental Pathologies. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228755"},{"key":"ref_20","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. Fetal Neonatal Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1021\/acsabm.2c00121","article-title":"Transport of Maternally Administered Pharmaceutical Agents Across the Placental Barrier In Vitro","volume":"5","author":"Pemathilaka","year":"2022","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_22","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":"2","author":"Pemathilaka","year":"2019","journal-title":"Glob. Chall."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4574","DOI":"10.1039\/D2LC00691J","article-title":"Testing of drugs using human feto-maternal interface organ-on-chips provide insights into pharmacokinetics and efficacy","volume":"22","author":"Richardson","year":"2022","journal-title":"Lab Chip"},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"e2100609","DOI":"10.1002\/adbi.202100609","article-title":"Microfluidic Co-Culture Platform to Recapitulate the Maternal-Placental-Embryonic Axis","volume":"5","author":"Boos","year":"2021","journal-title":"Adv. Biol."},{"key":"ref_26","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_27","doi-asserted-by":"crossref","unstructured":"Ko, G., Jeon, T.J., and Kim, S.M. (2022). Trophoblast Migration with Different Oxygen Levels in a Gel-Patterned Microfluidic System. Micromachines, 13.","DOI":"10.3390\/mi13122216"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s13206-021-00035-y","article-title":"A PDMS-Based Interdigitated Platform for Trophoblast Invasion Study Under Oxygen Stress Conditions","volume":"15","author":"Cho","year":"2021","journal-title":"Biochip J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.actbio.2023.04.033","article-title":"Healthy and diseased placenta barrier on-a-chip models suitable for high-throughput studies","volume":"164","author":"Rabussier","year":"2022","journal-title":"Acta Biomater."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s00018-022-04648-w","article-title":"A placenta-on-a-chip model to determine the regulation of FKBPL and galectin-3 in preeclampsia","volume":"80","author":"Ghorbanpour","year":"2023","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1039\/D0LC01013H","article-title":"A 3-dimensional microfluidic platform for modeling human extravillous trophoblast invasion and toxicological screening","volume":"21","author":"Pu","year":"2021","journal-title":"Lab Chip"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"432","DOI":"10.15283\/ijsc20074","article-title":"Human Placenta-Derived ECM Supports Tri-Lineage Differentiation of Human Induced Pluripotent Stem Cells","volume":"13","author":"Murchison","year":"2020","journal-title":"Int. J. Stem Cells"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2217\/rme-2018-0112","article-title":"Use of extracellular matrix hydrogen from human placenta to restore hair-inductive potential of dermal papilla cells","volume":"14","author":"Zhang","year":"2019","journal-title":"Regen. Med."},{"key":"ref_34","first-page":"634","article-title":"Vascular Endothelial Growth Factor expression in peripheral blood of patients with pregnancy induced hypertension syndrome and its clinical significance","volume":"30","author":"Ren","year":"2014","journal-title":"Pak. J. Med. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.ajog.2011.02.029","article-title":"Medication use during pregnancy, with particular focus on prescription drugs: 1976\u20132008","volume":"205","author":"Mitchell","year":"2011","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1038\/s41596-020-0381-x","article-title":"Establishment and differentiation of long-term trophoblast organoid cultures from the human placenta","volume":"15","author":"Sheridan","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41586-018-0753-3","article-title":"Trophoblast organoids as a model for maternal-fetal interactions during human placentation","volume":"563","author":"Turco","year":"2018","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.stem.2022.04.004","article-title":"Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens","volume":"29","author":"Karvas","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.stemcr.2018.07.004","article-title":"Self-Renewing Trophoblast Organoids Recapitulate the Developmental Program of the Early Human Placenta","volume":"11","author":"Haider","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Deng, J., Wei, W., Chen, Z., Lin, B., Zhao, W., Luo, Y., and Zhang, X. (2019). Engineered Liver-on-a-Chip Platform to Mimic Liver Functions and Its Biomedical Applications: A Review. Micromachines, 10.","DOI":"10.3390\/mi10100676"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"031505","DOI":"10.1063\/5.0048986","article-title":"Liver-Heart on chip models for drug safety","volume":"5","author":"Ferrari","year":"2021","journal-title":"APL Bioeng."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"061502","DOI":"10.1063\/5.0106855","article-title":"Liver-on-a-chip: Considerations, advances, and beyond","volume":"16","author":"Yang","year":"2022","journal-title":"Biomicrofluidics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1093460","DOI":"10.3389\/fimmu.2023.1093460","article-title":"Recapitulating essential pathophysiological characteristics in lung-on-a-chip for disease studies","volume":"14","author":"Zhang","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1039\/C7LC01224A","article-title":"Nanofiber membrane supported lung-on-a-chip microdevice for anti-cancer drug testing","volume":"18","author":"Yang","year":"2018","journal-title":"Lab Chip"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"100182","DOI":"10.1016\/j.mtbio.2021.100182","article-title":"Investigation of the role of the autophagic protein LC3B in the regulation of human airway epithelium cell differentiation in COPD using a biomimetic model","volume":"13","author":"Chen","year":"2021","journal-title":"Mater. Today"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"014101","DOI":"10.1088\/1758-5090\/ac93b6","article-title":"Modular assembly of bioprinted perfusable blood vessel and tracheal epithelium for studying inflammatory respiratory diseases","volume":"15","author":"Nam","year":"2022","journal-title":"Biofabrication"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1021\/acsbiomaterials.8b01262","article-title":"Bioengineered in Vitro Tissue Model of Fibroblast Activation for Modeling Pulmonary Fibrosis","volume":"5","author":"Sundarakrishnan","year":"2019","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1039\/c2lc40074j","article-title":"Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow","volume":"12","author":"Kim","year":"2012","journal-title":"Lab Chip"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1038\/s41598-018-21201-7","article-title":"Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids","volume":"8","author":"Kasendra","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"83","DOI":"10.5115\/acb.20.234","article-title":"JEG-3 placental cells in toxicology studies: A promising tool to reveal pregnancy disorders","volume":"54","author":"Olivier","year":"2021","journal-title":"Anat. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.bbrc.2016.11.062","article-title":"Small molecule absorption by PDMS in the context of drug response bioassays","volume":"482","author":"Firth","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s10404-010-0605-4","article-title":"Cyclic olefin polymers: Emerging materials for lab-on-a-chip applications","volume":"9","author":"Nunes","year":"2010","journal-title":"Microfluid. Nanofluidics"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1093\/molehr\/gaz018","article-title":"Emerging concepts of shear stress in placental development and function","volume":"25","author":"Morley","year":"2019","journal-title":"Mol. Hum. Reprod."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/13\/4315\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:01:56Z","timestamp":1760126516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/13\/4315"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,27]]},"references-count":53,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["jcm12134315"],"URL":"https:\/\/doi.org\/10.3390\/jcm12134315","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,27]]}}}