AccScience Publishing / IJB / Online First / DOI: 10.36922/IJB025270262
RESEARCH ARTICLE

3D-bioprinted placenta-on-a-chip platform for modeling the human maternal–fetal barrier

Yazhi Sun1† Henry H. Hwang1† Chandana Tekkatte2,3† Scott A. Lindsay2,3 Anelizze Castro-Martinez2,3 Claire Yu1 Isabella Saldana2,3 Xuanyi Ma1 Omar Farah3,4 Mana M. Parast3,4 Louise C. Laurent2,3* Shaochen Chen1*
Show Less
1 Department of Chemical and Nano Engineering, University of California San Diego, San Diego, CA, United States of America
2 Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California San Diego, San Diego, CA, United States of America
3 Sanford Consortium for Regenerative Medicine, University of California San Diego, San Diego, CA, United States of America
4 Department of Pathology, University of California San Diego, San Diego, CA, United States of America
†These authors contributed equally to this work.
Received: 2 July 2025 | Accepted: 28 July 2025 | Published online: 28 July 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

The placenta plays a vital role in pregnancy by regulating selective exchange between the maternal and fetal circulations and producing essential hormonal signals. In this study, we present an in vitro placenta-on-a-chip platform that leverages 3D bioprinting to replicate the structural and functional features of the human placental barrier. This microengineered system utilizes digital light processing-based 3D bioprinting to fabricate the microfluidic mold and construct 3D encapsulated cell cultures within a biomimetic hydrogel scaffold, enabling co-culture of three human cell types, including two derived from primary placental tissue. The system demonstrated excellent cell viability, high metabolic activity, placental hormone secretion, and native-like selective barrier transport properties. This system offers a versatile platform for experimental perturbations to explore mechanisms of normal placental function and identify contributors to placental dysfunction.

Graphical abstract
Keywords
Bioprinting
Microfluidics
Microphysiological system
Organ-on-a-chip
Placenta
Trophoblast stem cells
Funding
This work was supported in part by grants from the National Institutes of Health (NIH) to S.C., L.L., and M.P. (R21HD100132) and the National Science Foundation (NSF) to S.C. (2135720). The UCSD School of Medicine Microscopy Core facility was supported by the NIH grant P30 NS047101.
Conflict of interest
The authors declare no competing interests.
References
  1. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernández-Díaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976–2008. Am J Obstetr Gynecol. 2011;205(1):51.e1-51.e8. doi: 10.1016/j.ajog.2011.02.029
  2. Wesley BD, Sewell CA, Chang CY, Hatfield KP, Nguyen CP. Prescription medications for use in pregnancy–perspective from the US Food and Drug Administration. Am J Obstetr Gynecol. 2021;225(1):21-32. doi: 10.1016/j.ajog.2021.02.032
  3. Zubizarreta ME, Xiao S. Bioengineering models of female reproduction. Bio Des Manuf. 2020;3(3):237. doi: 10.1007/s42242-020-00082-8
  4. Zabel RR, Favaro RR, Groten T, Brownbill P, Jones S. Ex vivo perfusion of the human placenta to investigate pregnancy pathologies. Placenta. 2022;130:1-8. doi: 10.1016/j.placenta.2022.10.006
  5. Glättli SC, Elzinga FA, van der Bijl W, et al. Variability in perfusion conditions and set-up parameters used in ex vivo human placenta models: a literature review. Placenta. 2024;157:37-49. doi: 10.1016/j.placenta.2024.03.007
  6. Carter AM. Animal models of human placentation – a review. Placenta. 2007;28:S41-S47. doi: 10.1016/j.placenta.2006.11.002
  7. Carter AM. Evolution of placental hormones: implications for animal models. Front Endocrinol. 2022;13:891927. doi: 10.3389/fendo.2022.891927
  8. Sood A, Kumar A, Gupta VK, Kim CM, Han SS. Translational nanomedicines across human reproductive organs modeling on microfluidic chips: state-of-the-art and future prospects. ACS Biomater Sci Eng. 2023;9(1):62-84. doi: 10.1021/acsbiomaterials.2c01080
  9. Pu Y, Gingrich J, Veiga-Lopez A. A 3-dimensional microfluidic platform for modeling human extravillous trophoblast invasion and toxicological screening. Lab Chip. 2021;21(3):546-557. doi: 10.1039/D0LC01013H
  10. Heaton SJ, Eady JJ, Parker ML, et al. The use of BeWo cells as an in vitro model for placental iron transport. Am J Physiol Cell Physiol. 2008;295(5):C1445-C1453. doi: 10.1152/ajpcell.00286.2008
  11. Park JY, Mani S, Clair G, et al. A microphysiological model of human trophoblast invasion during implantation. Nat Commun. 2022;13(1):1252. doi: 10.1038/s41467-022-28663-4
  12. Hori T, Okae H, Shibata S, et al. Trophoblast stem cell-based organoid models of the human placental barrier. Nat Commun. 2024;15(1):962. doi: 10.1038/s41467-024-45279-y
  13. Kallol S, Moser-Haessig R, Ontsouka CE, Albrecht C. Comparative expression patterns of selected membrane transporters in differentiated BeWo and human primary trophoblast cells. Placenta. 2018;72-73:48-52. doi: 10.1016/j.placenta.2018.10.008
  14. Cao R, Wang Y, Liu J, Rong L, Qin J. Self-assembled human placental model from trophoblast stem cells in a dynamic organ-on-a-chip system. Cell Prolif. 2023;56(5):e13469. doi: 10.1111/cpr.13469
  15. Cao R, Guo Y, Liu J, et al. Assessment of nanotoxicity in a human placenta-on-a-chip from trophoblast stem cells. Ecotoxicol Environ Saf. 2024;285:117051. doi: 10.1016/j.ecoenv.2024.117051
  16. Lermant A, Rabussier G, Davidson L, Lanz HL, Murdoch CE. Protocol for a placenta-on-a-chip model using trophoblasts differentiated from human induced pluripotent stem cells. STAR Protoc. 2024;5(1):102879. doi: 10.1016/j.xpro.2024.102879
  17. Wang Y, Guo Y, Wang P, et al. An engineered human placental organoid microphysiological system in a vascular niche to model viral infection. Commun Biol. 2025;8(1):669. doi: 10.1038/s42003-025-08057-0
  18. Pemathilaka RL, Caplin JD, Aykar SS, et al. Placenta-on-a- Chip: In Vitro Study of Caffeine Transport across Placental Barrier Using Liquid Chromatography Mass Spectrometry. Global Challenges. 2019;3(3):1800112. doi: 10.1002/gch2.201800112
  19. Ma Z, Sagrillo-Fagundes L, Mok S, Vaillancourt C, Moraes C. Mechanobiological regulation of placental trophoblast fusion and function through extracellular matrix rigidity. Sci Rep. 2020;10(1):5837. doi: 10.1038/s41598-020-62659-8
  20. Lee JS, Romero R, Han YM, et al. Placenta-on-a-chip: a novel platform to study the biology of the human placenta. J Matern Fetal Neonatal Med. 2016;29(7):1046-1054. doi: 10.3109/14767058.2015.1038518
  21. Ma X, Yu C, Wang P, et al. Rapid 3D bioprinting of decellularized extracellular matrix with regionally varied mechanical properties and biomimetic microarchitecture. Biomaterials. 2018;185:310-321. doi: 10.1016/j.biomaterials.2018.09.026
  22. Pyo SH, Wang P, Hwang HH, Zhu W, Warner J, Chen S. Continuous optical 3D printing of green aliphatic polyurethanes. ACS Appl Mater Interfaces. 2017;9(1):836-844. doi: 10.1021/acsami.6b12500
  23. Igura K, Zhang X, Takahashi K, Mitsuru A, Yamaguchi S, Takahashi TA. Isolation and characterization of mesenchymal progenitor cells from chorionic villi of human placenta. Cytotherapy. 2004;6(6):543-553. doi: 10.1080/14653240410005366-1
  24. Okae H, Toh H, Sato T, et al. Derivation of human trophoblast stem cells. Cell Stem Cell. 2018;22(1):50-63.e6. doi: 10.1016/j.stem.2017.11.004
  25. Bai T, Peng CY, Aneas I, et al. Establishment of human induced trophoblast stem-like cells from term villous cytotrophoblasts. Stem Cell Res. 2021;56:102507. doi: 10.1016/j.scr.2021.102507
  26. Zhu W, Qu X, Zhu J, et al. Direct 3D bioprinting of prevascularized tissue constructs with complex microarchitecture. Biomaterials. 2017;124:106-115. doi: 10.1016/j.biomaterials.2017.01.042
  27. Teasdale F. Gestational changes in the functional structure of the human placenta in relation to fetal growth: a morphometric study. Am J Obstetr Gynecol. 1980;137(5):560-568. doi: 10.1016/0002-9378(80)90696-1
  28. Blundell C, Yi YS, Ma L, et al. Placental drug transport-on-a-chip: a microengineered in vitro model of transporter-mediated drug efflux in the human placental barrier. Adv Healthc Mater. 2018;7(2):1700786. doi: 10.1002/adhm.201700786
  29. Wice B, Menton D, Geuze H, Schwartz AL. Modulators of cyclic AMP metabolism induce syncytiotrophoblast formation in vitro. Exp Cell Res. 1990;186(2):306-316. doi: 10.1016/0014-4827(90)90310-7
  30. Das S, Jegadeesan JT, Basu B. Gelatin methacryloyl (GelMA)-based biomaterial inks: process science for 3D/4D printing and current status. Biomacromolecules. 2024;25(4):2156-2221. doi: 10.1021/acs.biomac.3c01271.
  31. Tang C, Jin M, Ma B, et al. RGS2 promotes estradiol biosynthesis by trophoblasts during human pregnancy. Exp Mol Med. 2023;55(1):240-252. doi: 10.1038/s12276-023-00927-z
  32. Shutt DA, Smith ID, Shearman RP. Oestrone, oestradiol- 17beta and oestriol levels in human foetal plasma during gestation and at term. J Endocrinol. 1974;60(2):333-341. doi: 10.1677/joe.0.0600333
  33. Johnson MS, Jackson DL, Schust DJ. Endocrinology of pregnancy. In: Skinner MK, ed. Encyclopedia of Reproduction (Second Edition). Academic Press, Cambridge, MA, USA.; 2018:469-476. doi: 10.1016/B978-0-12-801238-3.64672-X
  34. Malek A, Sager R, Schneider H. Transport of proteins across the human placenta. Am J Reprod Immunol. 1998;40(5):347-351. doi: 10.1111/j.1600-0897.1998.tb00064.x
  35. Tal R, Taylor HS. Endocrinology of pregnancy. In: Feingold KR, Ahmed SF, Anawalt B, Blackman MR, Boyce A, Chrousos G, et al., eds. Endotext. MDText.com, Inc., South Dartmouth, MA, USA.; 2000. http://www.ncbi.nlm.nih.gov/books/NBK278962/. Accessed May 15, 2025.
  36. Kozler P, Pokorný J. Altered blood-brain barrier permeability and its effect on the distribution of Evans blue and sodium fluorescein in the rat brain applied by intracarotid injection. Physiol Res. 2003;52(5):607-14. doi: 10.33549/physiolres.930289
  37. Wevers NR, Nair AL, Fowke TM, et al. Modeling ischemic stroke in a triculture neurovascular unit on-a-chip. Fluids Barriers CNS. 2021;18(1):59. doi: 10.1186/s12987-021-00294-9
  38. Schaffenrath J, Huang SF, Wyss T, Delorenzi M, Keller A. Characterization of the blood–brain barrier in genetically diverse laboratory mouse strains. Fluids Barriers CNS. 2021;18(1):34. doi: 10.1186/s12987-021-00269-w
  39. Zambuto SG, Clancy KBH, Harley BAC. A gelatin hydrogel to study endometrial angiogenesis and trophoblast invasion. Interface Focus. 2019;9(5):20190016. doi: 10.1098/rsfs.2019.0016
  40. Kılıç F, Kayadibi Y, Yüksel MA, et al. Shear wave elastography of placenta: in vivo quantitation of placental elasticity in preeclampsia. Diagn Interv Radiol. 2015; 21(3):202-207. doi: 10.5152/dir.2014.14338
  41. Tarbell JM. Shear stress and the endothelial transport barrier. Cardiovasc Res. 2010;87(2):320-330. doi: 10.1093/cvr/cvq146
  42. Blundell C, Tess ER, Schanzer ASR, et al. A microphysiological model of the human placental barrier. Lab Chip. 2016;16(16):3065-3073. doi: 10.1039/C6LC00259E
  43. Boos JA, Misun PM, Brunoldi G, et al. Microfluidic co-culture platform to recapitulate the maternal–placental– embryonic axis. Adv Biol. 2021;5(8):2100609. doi: 10.1002/adbi.202100609
  44. Bhide A, Aboo A, Sawant M, Majumder A, Paul D, Modi D. Placenta on chip: a modern approach to probe feto-maternal interface. In: Mohanan PV, ed. Microfluidics and Multi Organs on Chip. Springer Nature, Singapore.; 2022:359-380. doi: 10.1007/978-981-19-1379-2_16
  45. Cole LA. Biological functions of hCG and hCG-related molecules. Reprod Biol Endocrinol. 2010;8(1):102. doi: 10.1186/1477-7827-8-102
  46. Brandes JM, Tavoloni N, Potter BJ, Sarkozi L, Shepard MD, Berk PD. A new recycling technique for human placental cotyledon perfusion: Application to studies of the fetomaternal transfer of glucose, inulin, and antipyrine. Am J Obstetr Gynecol. 1983;146(7):800-806. doi: 10.1016/0002-9378(83)91081-5
  47. Hahn T, Barth S, Weiss U, Mosgoeller W, Desoye G. Sustained hyperglycemia in vitro down-regulates the GLUT1 glucose transport system of cultured human term placental trophoblast: a mechanism to protect fetal development? FASEB J. 1998;12(12):1221-1231. doi: 10.1096/fasebj.12.12.1221
  48. Brownbill P, Sebire N, McGillick EV, Ellery S, Murthi P. Ex vivo dual perfusion of the human placenta: disease simulation, therapeutic pharmacokinetics and analysis of off-target effects. In: Murthi P, Vaillancourt C, eds. Preeclampsia: Methods and Protocols. Springer, New York, NY, USA.; 2018:173-189. doi: 10.1007/978-1-4939-7498-6_14
  49. Kouthouridis S, Saha P, Ludlow M, N. Truong BY, Zhang B. Late-stage placental barrier model for transport studies of prescription drugs during pregnancy. Lab Chip. 2025;25(13):3168-3184. doi: 10.1039/D5LC00075K
  50. Rabussier G, Bünter I, Bouwhuis J, et al. Healthy and diseased placental barrier on-a-chip models suitable for standardized studies. Acta Biomater. 2023;164:363-376. doi: 10.1016/j.actbio.2023.04.033
  51. Palmeira P, Quinello C, Silveira-Lessa AL, Zago CA, Carneiro-Sampaio M. IgG placental transfer in healthy and pathological pregnancies. J Immunol Res. 2012;2012(1):985646. doi: 10.1155/2012/985646
  52. Karakis V, Britt JW, Jabeen M, San Miguel A, Rao BM. Derivation of human trophoblast stem cells from placentas at birth. J Biol Chem. 2025;301(6):108505. doi: 10.1016/j.jbc.2025.108505

 

 



Share
Back to top
International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing