Recent advances in cell-based in vitro models for predicting drug permeability across brain, intestinal, and pulmonary barriers

References

• Amidon GL, Lennernäs H, Shah VP, et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–420. doi: 10.1023/A:1016212804288
   PubMed Web of Science ®Google Scholar
• Horowitz A, Chanez-Paredes SD, Haest X, et al. Paracellular permeability and tight junction regulation in gut health and disease. Nat Rev Gastroenterol Hepatol. 2023;20(7):1–16. doi: 10.1038/s41575-023-00766-3
   PubMed Web of Science ®Google Scholar
• Ingber DE. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat Rev Genet. 2022;23(8):467–491. doi: 10.1038/s41576-022-00466-9
   PubMed Web of Science ®Google Scholar
• Günther C, Rothhammer V, Karow M, et al. The gut-brain axis in inflammatory bowel disease – current and future perspectives. Int J Mol Sci. 2021;22(16):8870. doi: 10.3390/ijms22168870
   PubMed Web of Science ®Google Scholar
• Sicard JF, Le Bihan G, Vogeleer P, et al. Interactions of intestinal bacteria with components of the intestinal mucus. Front Cell Infect Microbiol. 2017;7:387. doi: 10.3389/fcimb.2017.00387
   PubMed Web of Science ®Google Scholar
• France MM, Turner JR. The mucosal barrier at a glance. J Cell Sci. 2017;130(2):307–314. doi: 10.1242/jcs.193482
   PubMed Web of Science ®Google Scholar
• Yu QH, Yang Q. Diversity of tight junctions (TJs) between gastrointestinal epithelial cells and their function in maintaining the mucosal barrier. Cell Biol Int. 2009;33(1):78–82. doi: 10.1016/j.cellbi.2008.09.007
   PubMed Web of Science ®Google Scholar
• Sarmento B, Andrade F, SBd S, et al. Cell-based in vitro models for predicting drug permeability. Expert Opin Drug Metab Toxicol. 2012;8(5):607–621. doi: 10.1517/17425255.2012.673586
   PubMed Web of Science ®Google Scholar
• Sun D, Lennernas H, Welage LS, et al. Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs. Pharm Res. 2002;19(10):1400–1416. doi: 10.1023/A:1020483911355
   PubMed Web of Science ®Google Scholar
• Van Breemen RB, Li Y. Caco-2 cell permeability assays to measure drug absorption. Expert Opin Drug Metab Toxicol. 2005;1(2):175–185. doi: 10.1517/17425255.1.2.175
   PubMedGoogle Scholar
• Hubatsch I, Ragnarsson EG, Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc. 2007;2(9):2111–2119. doi: 10.1038/nprot.2007.303
   PubMed Web of Science ®Google Scholar
• Yamashita S, Furubayashi T, Kataoka M, et al. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur J Pharm Sci. 2000;10(3):195–204. doi: 10.1016/S0928-0987(00)00076-2
   PubMed Web of Science ®Google Scholar
• Fedi A, Vitale C, Ponschin G, et al. In vitro models replicating the human intestinal epithelium for absorption and metabolism studies: a systematic review. J Control Release. 2021;335:247–268. doi: 10.1016/j.jconrel.2021.05.028
   PubMed Web of Science ®Google Scholar
• Lennernäs H, Palm K, Fagerholm U, et al. Comparison between active and passive drug transport in human intestinal epithelial (caco-2) cells in vitro and human jejunum in vivo. Int J Pharm. 1996;127(1):103–107. doi: 10.1016/0378-5173(95)04204-0
   Google Scholar
• Dahlgren D, Lennernäs H. Intestinal permeability and drug absorption: predictive experimental, computational and in vivo approaches. Pharmaceutics. 2019;11(8):411. doi: 10.3390/pharmaceutics11080411
   PubMed Web of Science ®Google Scholar
• Artursson P, Palm K, Luthman K. Caco-2 monolayers in experimental and theoretical predictions of drug transport1PII of original article: S0169-409X(96)00415-2. The article was originally published in advanced drug delivery reviews 22 (1996) 67–84.1. Adv Drug Delivery Rev. 2001;46(1–3):27–43. doi: 10.1016/S0169-409X(00)00128-9
   PubMed Web of Science ®Google Scholar
• Furuse M, Furuse K, Sasaki H, et al. Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells. J Cell Bio. 2001;153(2):263–272. doi: 10.1083/jcb.153.2.263
   PubMed Web of Science ®Google Scholar
• Dukes JD, Whitley P, Chalmers AD. The MDCK variety pack: choosing the right strain. BMC Cell Biol. 2011;12(1):43. doi: 10.1186/1471-2121-12-43
   PubMedGoogle Scholar
• Cho MJ, Thompson DP, Cramer CT, et al. The Madin Darby canine kidney (MDCK) epithelial cell monolayer as a model cellular transport barrier. Pharm Res. 1989;6(1):71–77. doi: 10.1023/A:1015807904558
   PubMed Web of Science ®Google Scholar
• Irvine JD, Takahashi L, Lockhart K, et al. MDCK (Madin–Darby canine kidney) cells: a tool for membrane permeability screening. J Pharm Sci. 1999;88(1):28–33. doi: 10.1021/js9803205
   PubMed Web of Science ®Google Scholar
• Hubatsch I, Ragnarsson EGE, Artursson P. Determination of drug permeability and prediction of drug absorption in caco-2 monolayers. Nat Protoc. 2007;2(9):2111–2119. doi: 10.1038/nprot.2007.303
   PubMed Web of Science ®Google Scholar
• Agarwal S, Jain R, Pal D, et al. Functional characterization of peptide transporters in MDCKII–MDR1 cell line as a model for oral absorption studies. Int J Pharm. 2007;332(1–2):147–152. doi: 10.1016/j.ijpharm.2006.09.056
   PubMedGoogle Scholar
• Tavelin S, Taipalensuu J, Söderberg L, et al. Prediction of the oral absorption of low-permeability drugs using small intestine-like 2/4/A1 cell monolayers. Pharm Res. 2003;20(3):397–405. doi: 10.1023/A:1022699920043
   PubMed Web of Science ®Google Scholar
• Ma TY, Hollander D, Bhalla D, et al. IEC-18, a nontransformed small intestinal cell line for studying epithelial permeability. J Lab Clin Med. 1992;120(2):329–341.
   PubMed Web of Science ®Google Scholar
• Pereira C, Costa J, Sarmento B, et al. 3.3 - Cell-based in vitro models for intestinal permeability studies. Concepts and models for drug permeability studies. United Kingdom:Woodhead publishing; 2016. p. 57–81.
   Google Scholar
• Chen X-M, Elisia I, Kitts DD. Defining conditions for the co-culture of Caco-2 and HT29-MTX cells using Taguchi design. J Pharmacol Toxicol Methods. 2010;61(3):334–342. doi: 10.1016/j.vascn.2010.02.004
   PubMed Web of Science ®Google Scholar
• Hilgendorf C, Spahn‐Langguth H, Regårdh CG, et al. Caco‐2 versus Caco‐2/HT29‐MTX Co‐cultured cell lines: permeabilities via diffusion, inside‐ and outside‐directed carrier‐mediated transport. J Pharm Sci. 2000;89(1):63–75. doi: 10.1002/(SICI)1520-6017(200001)89:1<63:AID-JPS7>3.0.CO;2-6
   PubMed Web of Science ®Google Scholar
• Reale O, Huguet A, Fessard V. Co-culture model of Caco-2/HT29-MTX cells: a promising tool for investigation of phycotoxins toxicity on the intestinal barrier. Chemosphere. 2021;273:128497. doi: 10.1016/j.chemosphere.2020.128497
   Web of Science ®Google Scholar
• Pan F, Han L, Zhang Y, et al. Optimization of Caco-2 and HT29 co-culture in vitro cell models for permeability studies. Int J Food Sci Nutr. 2015;66(6):680–685. doi: 10.3109/09637486.2015.1077792
   PubMed Web of Science ®Google Scholar
• Walter E, Janich S, Roessler BJ, et al. HT29-MTX/Caco-2 cocultures as an in vitro model for the intestinal epithelium: In vitro–in vivo correlation with permeability data from rats and humans. J Pharm Sci. 1996;85(10):1070–1076. doi: 10.1021/js960110x
   PubMed Web of Science ®Google Scholar
• Béduneau A, Tempesta C, Fimbel S, et al. A tunable Caco-2/HT29-MTX co-culture model mimicking variable permeabilities of the human intestine obtained by an original seeding procedure. Eur J Pharm Biopharm. 2014;87(2):290–298. doi: 10.1016/j.ejpb.2014.03.017
   PubMed Web of Science ®Google Scholar
• Mahler GJ, Shuler ML, Glahn RP. Characterization of Caco-2 and HT29-MTX cocultures in an in vitro digestion/cell culture model used to predict iron bioavailability. J Nutr Biochem. 2009;20(7):494–502. doi: 10.1016/j.jnutbio.2008.05.006
   PubMed Web of Science ®Google Scholar
• Araújo F, Sarmento B. Towards the characterization of an in vitro triple co-culture intestine cell model for permeability studies. Int J Pharm. 2013;458(1):128–134. doi: 10.1016/j.ijpharm.2013.10.003
   PubMedGoogle Scholar
• Lozoya-Agullo I, Araújo F, González-Álvarez I, et al. Usefulness of Caco-2/HT29-MTX and Caco-2/HT29-MTX/Raji B coculture models to predict intestinal and colonic permeability compared to Caco-2 monoculture. Mol Pharm. 2017;14(4):1264–1270. doi: 10.1021/acs.molpharmaceut.6b01165
   PubMedGoogle Scholar
• Brück S, Strohmeier J, Busch D, et al. Caco-2 cells – expression, regulation and function of drug transporters compared with human jejunal tissue. Biopharm Drug Dispos. 2017;38(2):115–126. doi: 10.1002/bdd.2025
   PubMed Web of Science ®Google Scholar
• Elzinga J, Grouls M, Hooiveld G, et al. Systematic comparison of transcriptomes of Caco-2 cells cultured under different cellular and physiological conditions. Arch Toxicol. 2023;97(3):737–753. doi: 10.1007/s00204-022-03430-y
   PubMed Web of Science ®Google Scholar
• Kasendra M, Tovaglieri A, Sontheimer-Phelps A, et al. Development of a primary human small intestine-on-a-chip using biopsy-derived organoids. Sci Rep. 2018;8(1):2871. doi: 10.1038/s41598-018-21201-7
   PubMed Web of Science ®Google Scholar
• Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014;345(6194):1247125. doi: 10.1126/science.1247125
   PubMed Web of Science ®Google Scholar
• Clevers H. Modeling development and disease with organoids. Cell. 2016;165(7):1586–1597. doi: 10.1016/j.cell.2016.05.082
   PubMed Web of Science ®Google Scholar
• Zhao Z, Chen X, Dowbaj AM, et al. Organoids. Nat Rev Methods Primers. 2022;2(1):94. doi: 10.1038/s43586-022-00174-y
   PubMedGoogle Scholar
• Piñeiro-Llanes J, Stec DE, Cristofoletti R. Editorial: insights in drug metabolism and transport: 2021. Front Pharmacol. 2023;14:1198598. doi: 10.3389/fphar.2023.1198598
   PubMed Web of Science ®Google Scholar
• Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459(7244):262–265. doi: 10.1038/nature07935
   PubMed Web of Science ®Google Scholar
• Drost J, van Jaarsveld RH, Ponsioen B, et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature. 2015;521(7550):43–47. doi: 10.1038/nature14415
   PubMed Web of Science ®Google Scholar
• Co JY, Margalef-Català M, Monack DM, et al. Controlling the polarity of human gastrointestinal organoids to investigate epithelial biology and infectious diseases. Nat Protoc. 2021;16(11):5171–5192. doi: 10.1038/s41596-021-00607-0
   PubMed Web of Science ®Google Scholar
• Williamson IA, Arnold JW, Samsa LA, et al. A high-throughput organoid microinjection platform to study gastrointestinal microbiota and luminal physiology. Cell Mol Gastroenterol Hepatol. 2018;6(3):301–319. doi: 10.1016/j.jcmgh.2018.05.004
   PubMed Web of Science ®Google Scholar
• Fei K, Zhang J, Yuan J, et al. Present application and perspectives of organoid imaging technology. Bioengineering (Basel). 2022;9(3):121. doi: 10.3390/bioengineering9030121
   PubMedGoogle Scholar
• Villenave R, Wales SQ, Hamkins-Indik T, et al. Human gut-on-a-Chip supports polarized infection of coxsackie B1 virus in vitro. PLoS One. 2017;12(2):e0169412. doi: 10.1371/journal.pone.0169412
   PubMed Web of Science ®Google Scholar
• Karve SS, Pradhan S, Ward DV, et al. Intestinal organoids model human responses to infection by commensal and Shiga toxin producing Escherichia coli. PLoS One. 2017;12(6):e0178966. doi: 10.1371/journal.pone.0178966
   PubMed Web of Science ®Google Scholar
• Bartfeld S, Bayram T, van de Wetering M, et al. In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology. 2015;148(1):126–36.e6. doi: 10.1053/j.gastro.2014.09.042
   PubMed Web of Science ®Google Scholar
• Heo I, Dutta D, Schaefer DA, et al. Modelling cryptosporidium infection in human small intestinal and lung organoids. Nat Microbiol. 2018;3(7):814–823. doi: 10.1038/s41564-018-0177-8
   PubMed Web of Science ®Google Scholar
• Forbester JL, Goulding D, Vallier L, et al. Interaction of Salmonella enterica serovar typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect Immun. 2015;83(7):2926–2934. doi: 10.1128/IAI.00161-15
   PubMed Web of Science ®Google Scholar
• Co JY, Margalef-Català M, Li X, et al. Controlling epithelial polarity: a human enteroid model for host-pathogen interactions. Cell Rep. 2019;26(9):2509–20.e4. doi: 10.1016/j.celrep.2019.01.108
   PubMed Web of Science ®Google Scholar
• Kakni P, López-Iglesias C, Truckenmüller R, et al. Reversing epithelial polarity in pluripotent stem cell-derived intestinal organoids. Front Bioeng Biotechnol. 2022;10:879024. doi: 10.3389/fbioe.2022.879024
   PubMed Web of Science ®Google Scholar
• Kakni P, López-Iglesias C, Truckenmüller R, et al. PSC-derived intestinal organoids with apical-out orientation as a tool to study nutrient uptake, drug absorption and metabolism. Front Mol Biosci. 2023;10:1102209. doi: 10.3389/fmolb.2023.1102209
   PubMed Web of Science ®Google Scholar
• Nikolaev M, Mitrofanova O, Broguiere N, et al. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis. Nature. 2020;585(7826):574–578. doi: 10.1038/s41586-020-2724-8
   PubMed Web of Science ®Google Scholar
• Valiei A, Aminian-Dehkordi J, Mofrad MRK. Gut-on-a-chip models for dissecting the gut microbiology and physiology. APL Bioeng. 2023;7(1):011502. doi: 10.1063/5.0126541
   PubMed Web of Science ®Google Scholar
• Kim HJ, Huh D, Hamilton G, et al. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip. 2012;12(12):2165–2174. doi: 10.1039/c2lc40074j
   PubMed Web of Science ®Google Scholar
• Hagiwara Y, Kumagai H, Ouwerkerk N, et al. A novel in vitro membrane permeability methodology using three-dimensional Caco-2 tubules in a microphysiological system which better mimics in vivo physiological conditions. J Pharm Sci. 2022;111(1):214–224. doi: 10.1016/j.xphs.2021.11.016
   PubMed Web of Science ®Google Scholar
• Yeon JH, Park JK. Drug permeability assay using microhole-trapped cells in a microfluidic device. Anal Chem. 2009;81(5):1944–1951. doi: 10.1021/ac802351w
   PubMed Web of Science ®Google Scholar
• Kasendra M, Luc R, Yin J, et al. Duodenum intestine-chip for preclinical drug assessment in a human relevant model. Elife. 2020;9. doi: 10.7554/eLife.50135
   PubMed Web of Science ®Google Scholar
• Marzorati M, Vanhoecke B, De Ryck T, et al. The HMI™ module: a new tool to study the host-microbiota interaction in the human gastrointestinal tract in vitro. BMC Microbiol. 2014;14(1):133–. doi: 10.1186/1471-2180-14-133
   PubMedGoogle Scholar
• Zietek T, Giesbertz P, Ewers M, et al. Organoids to study intestinal nutrient transport, drug uptake and metabolism – update to the human model and expansion of applications. Front Bioeng Biotechnol. 2020;8:577656. doi: 10.3389/fbioe.2020.577656
   PubMed Web of Science ®Google Scholar
• Hofer M, Lutolf MP. Engineering organoids. Nat Rev Mater. 2021;6(5):402–420. doi: 10.1038/s41578-021-00279-y
   PubMed Web of Science ®Google Scholar
• Hayeshi R, Hilgendorf C, Artursson P, et al. Comparison of drug transporter gene expression and functionality in caco-2 cells from 10 different laboratories. Eur J Pharm Sci. 2008;35(5):383–396. doi: 10.1016/j.ejps.2008.08.004
   PubMed Web of Science ®Google Scholar
• Davidov T, Efraim Y, Hayam R, et al. Extracellular matrix hydrogels originated from different organs mediate tissue-specific properties and function. Int J Mol Sci. 2021;22(21):11624. doi: 10.3390/ijms222111624
   PubMed Web of Science ®Google Scholar
• Zhao Y, Gan L, Ren L, et al. Factors influencing the blood-brain barrier permeability. Brain Res. 2022;1788:147937. doi: 10.1016/j.brainres.2022.147937
   PubMed Web of Science ®Google Scholar
• Serlin Y, Shelef I, Knyazer B, et al. Anatomy and physiology of the blood–brain barrier. Semin Cell Dev Biol. 2015;38:2–6. doi: 10.1016/j.semcdb.2015.01.002
   PubMed Web of Science ®Google Scholar
• Knox EG, Aburto MR, Clarke G, et al. The blood-brain barrier in aging and neurodegeneration. Mol Psychiatry. 2022;27(6):2659–2673. doi: 10.1038/s41380-022-01511-z
   PubMed Web of Science ®Google Scholar
• Aragón-González A, Shaw PJ, Ferraiuolo L. Blood–brain barrier disruption and its involvement in neurodevelopmental and neurodegenerative disorders. Int J Mol Sci. 2022;23(23):15271. doi: 10.3390/ijms232315271
   PubMed Web of Science ®Google Scholar
• Huang X, Hussain B, Chang J. Peripheral inflammation and blood–brain barrier disruption: effects and mechanisms. CNS Neurosci Ther. 2021;27(1):36–47. doi: 10.1111/cns.13569
   PubMed Web of Science ®Google Scholar
• Stavropoulos F, Georgiou E, Sargiannidou I, et al. Dysregulation of blood-brain barrier and exacerbated inflammatory response in cx47-deficient mice after induction of eae. Pharmaceuticals. 2021;14(7):621. doi: 10.3390/ph14070621
   Web of Science ®Google Scholar
• Lundquist S, Renftel M, Brillault J, et al. Prediction of drug transport through the blood-brain barrier in vivo: a comparison between two in vitro cell models. Pharm Res. 2002;19(7):976–981. doi: 10.1023/A:1016462205267
   PubMed Web of Science ®Google Scholar
• Lohmann C, Hüwel S, Galla HJ. Predicting blood-brain barrier permeability of drugs: evaluation of different in vitro assays. J Drug Target. 2002;10(4):263–276. doi: 10.1080/10611860290031903
   PubMed Web of Science ®Google Scholar
• Ye L, Yang X, Yang Z, et al. The role of efflux transporters on the transport of highly toxic aconitine, mesaconitine, hypaconitine, and their hydrolysates, as determined in cultured Caco-2 and transfected MDCKII cells. Toxicol Lett. 2013;216(2–3):86–99. doi: 10.1016/j.toxlet.2012.11.011
   PubMed Web of Science ®Google Scholar
• Hellinger É, Veszelka S, Tóth AE, et al. Comparison of brain capillary endothelial cell-based and epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) cell-based surrogate blood–brain barrier penetration models. Eur J Pharm Biopharm. 2012;82(2):340–351. doi: 10.1016/j.ejpb.2012.07.020
   PubMed Web of Science ®Google Scholar
• Liu H, Huang L, Li Y, et al. Correlation between membrane protein expression levels and transcellular transport activity for breast cancer resistance protein. Drug Metab Dispos. 2017;45(5):449–456. doi: 10.1124/dmd.116.074245
   PubMed Web of Science ®Google Scholar
• Feng B, West M, Patel NC, et al. Validation of human MDR1-MDCK and BCRP-MDCK cell lines to improve the prediction of brain penetration. J Pharm Sci. 2019;108(7):2476–2483. doi: 10.1016/j.xphs.2019.02.005
   PubMed Web of Science ®Google Scholar
• Poller B, Wagenaar E, Tang SC, et al. Double-transduced MDCKII cells to study human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) interplay in drug transport across the blood−brain barrier. Mol Pharm. 2011;8(2):571–582. doi: 10.1021/mp1003898
   PubMedGoogle Scholar
• Colclough N, Alluri RV, Tucker JW, et al. Utilising a dual human transporter MDCKII-MDR1-BCRP cell line to assess efflux at the blood brain barrier (BBB). Drug Metab Dispos. 2023;52(2):95–105. doi: 10.1124/dmd.123.001476
   Google Scholar
• Veszelka S, Tóth A, Walter FR, et al. Comparison of a rat primary cell-based blood-brain barrier model with epithelial and brain endothelial cell lines: gene expression and drug transport. Front Mol Neurosci. 2018;11:166. doi: 10.3389/fnmol.2018.00166
   PubMed Web of Science ®Google Scholar
• Weksler BB, Subileau EA, Perrière N, et al. Blood-brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J. 2005;19(13):1872–1874. doi: 10.1096/fj.04-3458fje
   PubMed Web of Science ®Google Scholar
• Sánchez-Dengra B, González-Álvarez I, Sousa F, et al. In vitro model for predicting the access and distribution of drugs in the brain using hCMEC/D3 cells. Eur J Pharm Biopharm. 2021;163:120–126. doi: 10.1016/j.ejpb.2021.04.002
   PubMed Web of Science ®Google Scholar
• Sun J, Ou W, Han D, et al. Comparative studies between the murine immortalized brain endothelial cell line (bEnd.3) and induced pluripotent stem cell-derived human brain endothelial cells for paracellular transport. PLoS One. 2022;17(5):e0268860. doi: 10.1371/journal.pone.0268860
   PubMed Web of Science ®Google Scholar
• Veszelka S, Tóth A, Walter FR, et al. Comparison of a rat primary cell-based blood-brain barrier model with epithelial and brain endothelial cell lines: gene expression and drug transport [original research]. Front Mol Neurosci. 2018;11:11. doi: 10.3389/fnmol.2018.00166
   PubMed Web of Science ®Google Scholar
• Yang S, Mei S, Jin H, et al. Identification of two immortalized cell lines, ECV304 and bEnd3, for in vitro permeability studies of blood-brain barrier. PLoS One. 2017;12(10):e0187017. doi: 10.1371/journal.pone.0187017
   PubMed Web of Science ®Google Scholar
• Eigenmann DE, Xue G, Kim KS, et al. Comparative study of four immortalized human brain capillary endothelial cell lines, hCMEC/D3, hBMEC, TY10, and BB19, and optimization of culture conditions, for an in vitro blood–brain barrier model for drug permeability studies. Fluids Barriers CNS. 2013;10(1):33. doi: 10.1186/2045-8118-10-33
   PubMedGoogle Scholar
• Bagchi S, Chhibber T, Lahooti B, et al. In-vitro blood-brain barrier models for drug screening and permeation studies: an overview. Drug Des Devel Ther. 2019;13:3591–3605. doi: 10.2147/DDDT.S218708
   PubMed Web of Science ®Google Scholar
• Jackson S, Meeks C, Vézina A, et al. Model systems for studying the blood-brain barrier: applications and challenges. Biomaterials. 2019;214:119217. doi: 10.1016/j.biomaterials.2019.05.028
   PubMed Web of Science ®Google Scholar
• Ogunshola OO. In vitro modeling of the blood-brain barrier: simplicity versus complexity. Curr Pharm Des. 2011;17(26):2755–2761. doi: 10.2174/138161211797440159
   PubMed Web of Science ®Google Scholar
• Sánchez-Dengra B, González-Álvarez I, González-Álvarez M, et al. New in vitro methodology for kinetics distribution prediction in the brain. An additional step towards an animal-free approach. Animals (Basel). 2021;11(12):11. doi: 10.3390/ani11123521
   Google Scholar
• Abbott NJ, Rönnbäck L, Hansson E. Astrocyte–endothelial interactions at the blood–brain barrier. Nat Rev Neurosci. 2006;7(1):41–53. doi: 10.1038/nrn1824
   PubMed Web of Science ®Google Scholar
• Janzer RC, Raff MC. Astrocytes induce blood–brain barrier properties in endothelial cells. Nature. 1987;325(6101):253–257. doi: 10.1038/325253a0
   PubMed Web of Science ®Google Scholar
• Wolburg H, Neuhaus J, Kniesel U, et al. Modulation of tight junction structure in blood-brain barrier endothelial cells effects of tissue culture, second messengers and cocultured astrocytes. J Cell Sci. 1994;107(5):1347–1357. doi: 10.1242/jcs.107.5.1347
   PubMedGoogle Scholar
• Bell RD, Winkler EA, Sagare AP, et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010;68(3):409–427. doi: 10.1016/j.neuron.2010.09.043
   PubMed Web of Science ®Google Scholar
• Hatherell K, Couraud P-O, Romero IA, et al. Development of a three-dimensional, all-human in vitro model of the blood–brain barrier using mono-, co-, and tri-cultivation transwell models. J Neurosci Methods. 2011;199(2):223–229. doi: 10.1016/j.jneumeth.2011.05.012
   PubMed Web of Science ®Google Scholar
• Brown LS, Foster CG, Courtney JM, et al. Pericytes and neurovascular function in the healthy and diseased brain. Front Cell Neurosci. 2019;13:282. doi: 10.3389/fncel.2019.00282
   PubMed Web of Science ®Google Scholar
• Gaillard PJ, van der Sandt ICJ, Voorwinden LH, et al. Astrocytes increase the functional expression of P-glycoprotein in an in vitro model of the blood-brain barrier. Pharm Res. 2000;17(10):1198–1205. doi: 10.1023/A:1026406528530
   PubMed Web of Science ®Google Scholar
• Sá-Pereira I, Brites D, Brito MA. Neurovascular unit: a focus on pericytes. Mol Neurobiol. 2012;45(2):327–347. doi: 10.1007/s12035-012-8244-2
   PubMed Web of Science ®Google Scholar
• Jamieson JJ, Linville RM, Ding YY, et al. Role of iPSC-derived pericytes on barrier function of iPSC-derived brain microvascular endothelial cells in 2D and 3D. Fluids Barriers CNS. 2019;16(1):15. doi: 10.1186/s12987-019-0136-7
   PubMedGoogle Scholar
• Berezowski V, Landry C, Dehouck M-P, et al. Contribution of glial cells and pericytes to the mRNA profiles of P-glycoprotein and multidrug resistance-associated proteins in an in vitro model of the blood–brain barrier. Brain Res. 2004;1018(1):1–9. doi: 10.1016/j.brainres.2004.05.092
   PubMed Web of Science ®Google Scholar
• Zozulya A, Weidenfeller C, Galla H-J. Pericyte–endothelial cell interaction increases MMP-9 secretion at the blood–brain barrier in vitro. Brain Res. 2008;1189:1–11. doi: 10.1016/j.brainres.2007.10.099
   PubMed Web of Science ®Google Scholar
• Seo S, Nah S-Y, Lee K, et al. Triculture model of in vitro BBB and its application to study BBB-Associated chemosensitivity and drug delivery in glioblastoma. Adv Funct Mater. 2022;32(10):2106860. doi: 10.1002/adfm.202106860
   Web of Science ®Google Scholar
• Sánchez-Dengra B, García-Montoya E, González-Álvarez I, et al. Establishment and validation of a new co-culture for the evaluation of the permeability through the blood–brain barrier in patients with glioblastoma. Pharmaceutics. 2023;15(5):15. doi: 10.3390/pharmaceutics15051431
   Web of Science ®Google Scholar
• Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat Neurosci. 2016;19(6):771–783. doi: 10.1038/nn.4288
   PubMed Web of Science ®Google Scholar
• Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):7–35. doi: 10.1007/s00401-009-0619-8
   PubMed Web of Science ®Google Scholar
• Linville RM, Searson PC. Next-generation in vitro blood–brain barrier models: benchmarking and improving model accuracy. Fluids Barriers CNS. 2021;18(1):56–. doi: 10.1186/s12987-021-00291-y
   PubMed Web of Science ®Google Scholar
• Easton AS, Sarker MH, Fraser PA. Two components of blood-brain barrier disruption in the rat. J Physiol. 1997;503(3):613–623. doi: 10.1111/j.1469-7793.1997.613bg.x
   PubMed Web of Science ®Google Scholar
• Shi L, Zeng M, Sun Y, et al. Quantification of blood-brain barrier solute permeability and brain transport by multiphoton microscopy. J Biomech Eng. 2014;136(3):136. doi: 10.1115/1.4025892
   Web of Science ®Google Scholar
• Sabbagh MF, Nathans J. A genome-wide view of the de-differentiation of central nervous system endothelial cells in culture. Elife. 2020;9:e51276–e. doi: 10.7554/eLife.51276
   PubMed Web of Science ®Google Scholar
• Bernas MJ, Cardoso FL, Daley SK, et al. Establishment of primary cultures of human brain microvascular endothelial cells to provide an in vitro cellular model of the blood-brain barrier. Nat Protoc. 2010;5(7):1265–1272. doi: 10.1038/nprot.2010.76
   PubMed Web of Science ®Google Scholar
• Dalla C, Pavlidi P, Sakelliadou DG, et al. Sex differences in blood-brain barrier transport of psychotropic drugs. Front Behav Neurosci. 2022;16:844916. doi: 10.3389/fnbeh.2022.844916
   PubMed Web of Science ®Google Scholar
• Allen JB, Ludtka C, James BD. Sex as a biological variable in tissue engineering and regenerative medicine. Annu Rev Biomed Eng. 2023;25(1):311–331. doi: 10.1146/annurev-bioeng-092222-030857
   PubMedGoogle Scholar
• Loewa A, Feng JJ, Hedtrich S. Human disease models in drug development. Nat Rev Bioeng. 2023;1(8):545–559. doi: 10.1038/s44222-023-00063-3
   Google Scholar
• Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626–638. doi: 10.1038/nri.2016.90
   PubMed Web of Science ®Google Scholar
• Lock R, Al Asafen H, Fleischer S, et al. A framework for developing sex-specific engineered heart models. Nat Rev Mater. 2022;7(4):295–313. doi: 10.1038/s41578-021-00381-1
   PubMed Web of Science ®Google Scholar
• Zeng Z, Surewaard BGJ, Wong CHY, et al. Sex-hormone-driven innate antibodies protect females and infants against EPEC infection. Nat Immunol. 2018;19(10):1100–1111. doi: 10.1038/s41590-018-0211-2
   PubMed Web of Science ®Google Scholar
• Moon Y, Lim C, Kim Y, et al. Sex-related differences in regional blood–brain barrier integrity in non-demented elderly subjects. Int J Mol Sci. 2021;22(6):2860. doi: 10.3390/ijms22062860
   PubMed Web of Science ®Google Scholar
• Weber CM, Clyne AM. Sex differences in the blood–brain barrier and neurodegenerative diseases. APL Bioeng. 2021;5(1):011509. doi: 10.1063/5.0035610
   PubMed Web of Science ®Google Scholar
• Gao S, Bell EC, Zhang Y, et al. Racial disparity in drug disposition in the digestive tract. Int J Mol Sci. 2021;22(3):1038. doi: 10.3390/ijms22031038
   PubMed Web of Science ®Google Scholar
• Sheth AN, Lahiri CD, Ofotokun I. Sex and gender differences in infection and treatments for infectious diseases. Cham: Springer International Publishing; 2015. Sex Differences in Metabolism and Pharmacokinetics. p. 75–102.
   Google Scholar
• Mai Y, Murdan S, Awadi M, et al. Establishing an in vitro permeation model to predict the in vivo sex-related influence of PEG 400 on oral drug absorption. Int J Pharm. 2018;542(1–2):280–287. doi: 10.1016/j.ijpharm.2018.03.002
   PubMedGoogle Scholar
• Tsamandouras N, Kostrzewski T, Stokes CL, et al. Quantitative assessment of population variability in hepatic drug metabolism using a perfused three-dimensional human liver microphysiological system. J Pharmacol Exp Ther. 2017;360(1):95–105. doi: 10.1124/jpet.116.237495
   PubMed Web of Science ®Google Scholar
• Bauer H-C, Krizbai IA, Bauer H, et al. “You Shall Not Pass” – tight junctions of the blood brain barrier. Front Neurosci. 2014;8. doi: 10.3389/fnins.2014.00392
   Web of Science ®Google Scholar
• Zihni C, Mills C, Matter K, et al. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016;17(9):564–580. doi: 10.1038/nrm.2016.80
   PubMed Web of Science ®Google Scholar
• Beese M, Wyss K, Haubitz M, et al. Effect of cAMP derivates on assembly and maintenance of tight junctions in human umbilical vein endothelial cells. BMC Cell Biol. 2010;11(1):68–. doi: 10.1186/1471-2121-11-68
   PubMedGoogle Scholar
• Furihata T, Kawamatsu S, Ito R, et al. Hydrocortisone enhances the barrier properties of HBMEC/ciβ, a brain microvascular endothelial cell line, through mesenchymal-to-endothelial transition-like effects. Fluids Barriers CNS. 2015;12(1):7–. doi: 10.1186/s12987-015-0003-0
   PubMedGoogle Scholar
• Ishizaki T, Chiba H, Kojima T, et al. Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood–brain-barrier endothelial cells via protein kinase A-dependent and -independent pathways. Exp Cell Res. 2003;290(2):275–288. doi: 10.1016/S0014-4827(03)00354-9
   PubMed Web of Science ®Google Scholar
• Qiao J, Huang F, Lum H. PKA inhibits RhoA activation: a protection mechanism against endothelial barrier dysfunction. Am J Physiol Lung Cell Mol Physiol. 2003;284(6):L972–L80. doi: 10.1152/ajplung.00429.2002
   PubMed Web of Science ®Google Scholar
• Poller B, Gutmann H, Krähenbühl S, et al. The human brain endothelial cell line hCMEC/D3 as a human blood-brain barrier model for drug transport studies. J Neurochem. 2008;107(5):1358–1368. doi: 10.1111/j.1471-4159.2008.05730.x
   PubMed Web of Science ®Google Scholar
• Weksler B, Romero IA, Couraud PO. The hCMEC/D3 cell line as a model of the human blood brain barrier. Fluids Barriers CNS. 2013;10(1):16. doi: 10.1186/2045-8118-10-16
   PubMedGoogle Scholar
• Ohtsuki S, Ikeda C, Uchida Y, et al. Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood–brain barrier Model. Mol Pharm. 2013;10(1):289–296. doi: 10.1021/mp3004308
   PubMed Web of Science ®Google Scholar
• Partyka PP, Godsey GA, Galie JR, et al. Mechanical stress regulates transport in a compliant 3D model of the blood-brain barrier. Biomaterials. 2017;115:30–39. doi: 10.1016/j.biomaterials.2016.11.012
   PubMed Web of Science ®Google Scholar
• Linville RM, Sklar MB, Grifno GN, et al. Three-dimensional microenvironment regulates gene expression, function, and tight junction dynamics of iPSC-derived blood–brain barrier microvessels. Fluids Barriers CNS. 2022;19(1):87. doi: 10.1186/s12987-022-00377-1
   PubMed Web of Science ®Google Scholar
• Choi K-D, Yu J, Smuga-Otto K, et al. Hematopoietic and endothelial differentiation of human induced pluripotent stem cells. Stem Cells. 2009;27(3):559–567. doi: 10.1634/stemcells.2008-0922
   PubMed Web of Science ®Google Scholar
• He Y, Yao Y, Tsirka SE, et al. Cell-culture models of the blood–brain barrier. Stroke. 2014;45(8):2514–2526. doi: 10.1161/STROKEAHA.114.005427
   PubMed Web of Science ®Google Scholar
• Lippmann ES, Azarin SM, Kay JE, et al. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol. 2012;30(8):783–791. doi: 10.1038/nbt.2247
   PubMed Web of Science ®Google Scholar
• Ronaldson PT, Davis TP. Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke. Curr Pharm Des. 2012;18(25):3624–3644. doi: 10.2174/138161212802002625
   PubMed Web of Science ®Google Scholar
• Bergmann S, Lawler SE, Qu Y, et al. Blood–brain-barrier organoids for investigating the permeability of CNS therapeutics. Nat Protoc. 2018;13(12):2827–2843. doi: 10.1038/s41596-018-0066-x
   PubMed Web of Science ®Google Scholar
• Fernandes DC, Reis RL, Oliveira JM. Advances in 3D neural, vascular and neurovascular models for drug testing and regenerative medicine. Drug Discov Today. 2021;26(3):754–768. doi: 10.1016/j.drudis.2020.11.009
   PubMed Web of Science ®Google Scholar
• Simonneau C, Duschmalé M, Gavrilov A, et al. Investigating receptor-mediated antibody transcytosis using blood–brain barrier organoid arrays. Fluids Barriers CNS. 2021;18(1):43. doi: 10.1186/s12987-021-00276-x
   PubMed Web of Science ®Google Scholar
• Pașca SP, Arlotta P, Bateup HS, et al. A nomenclature consensus for nervous system organoids and assembloids. Nature. 2022;609(7929):907–910. doi: 10.1038/s41586-022-05219-6
   PubMed Web of Science ®Google Scholar
• Fedele G, Cazzaniga A, Castiglioni S, et al. The presence of BBB hastens neuronal differentiation of cerebral organoids – The potential role of endothelial derived BDNF. Biochem Biophys Commun. 2022;626:30–37. doi: 10.1016/j.bbrc.2022.07.112
   PubMed Web of Science ®Google Scholar
• Yan L, Dwiggins CW, Moriarty RA, et al. Matrix stiffness regulates the tight junction phenotypes and local barrier properties in tricellular regions in an iPSC-derived BBB model. Acta Biomater. 2023;167:109–120. doi: 10.1016/j.actbio.2023.06.003
   PubMed Web of Science ®Google Scholar
• Tilling T, Korte D, Hoheisel D, et al. Basement membrane proteins influence brain capillary endothelial barrier function in vitro. J Neurochem. 1998;71(3):1151–1157. doi: 10.1046/j.1471-4159.1998.71031151.x
   PubMed Web of Science ®Google Scholar
• Pranda MA, Gray KM, DeCastro AJL, et al. Tumor cell mechanosensing during incorporation into the brain microvascular endothelium. Cell Mol Bioeng. 2019;12(5):455–480. doi: 10.1007/s12195-019-00591-2
   PubMed Web of Science ®Google Scholar
• Cucullo L, Hossain M, Puvenna V, et al. The role of shear stress in blood-brain barrier endothelial physiology. BMC Neurosci. 2011;12(1):40. doi: 10.1186/1471-2202-12-40
   PubMedGoogle Scholar
• Griep LM, Wolbers F, de Wagenaar B, et al. BBB on CHIP: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function. Biomed Microdevices. 2013;15(1):145–150. doi: 10.1007/s10544-012-9699-7
   PubMed Web of Science ®Google Scholar
• Booth R, Kim H. Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). Lab Chip. 2012;12(10):1784–1792. doi: 10.1039/c2lc40094d
   PubMed Web of Science ®Google Scholar
• Wang YI, Abaci HE, Shuler ML. Microfluidic blood–brain barrier model provides in vivo-like barrier properties for drug permeability screening. Biotechnol Bioeng. 2017;114(1):184–194. doi: 10.1002/bit.26045
   PubMed Web of Science ®Google Scholar
• Nijmeh J, Levy BD. Lipid-derived mediators are pivotal to leukocyte and lung cell responses in sepsis and ARDS. Cell Biochem Biophys. 2021;79(3):449–459. doi: 10.1007/s12013-021-01012-w
   PubMed Web of Science ®Google Scholar
• Knight DA, Holgate ST. The airway epithelium: structural and functional properties in health and disease. Respirology. 2003;8(4):432–446. doi: 10.1046/j.1440-1843.2003.00493.x
   PubMed Web of Science ®Google Scholar
• Peteranderl C, Sznajder JI, Herold S, et al. Inflammatory responses regulating alveolar ion transport during pulmonary infections. Front Immunol. 2017;8:446. doi: 10.3389/fimmu.2017.00446
   PubMed Web of Science ®Google Scholar
• Eriksson J, Sjögren E, Thörn H, et al. Pulmonary absorption – estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis. Eur J Pharm Biopharm. 2018;124:1–12. doi: 10.1016/j.ejpb.2017.11.013
   PubMed Web of Science ®Google Scholar
• Furubayashi T, Inoue D, Nishiyama N, et al. Comparison of various cell lines and three-dimensional mucociliary tissue model systems to estimate drug permeability using an in vitro transport study to predict nasal drug absorption in rats. Pharmaceutics. 2020;12(1):79. doi: 10.3390/pharmaceutics12010079
   PubMed Web of Science ®Google Scholar
• Tronde A, Nordén B, Marchner H, et al. Pulmonary absorption rate and bioavailability of drugs in vivo in rats: structure – absorption relationships and physicochemical profiling of inhaled drugs. J Pharm Sci. 2003;92:1216–1233. doi: 10.1002/jps.10386
   PubMed Web of Science ®Google Scholar
• Miller AJ, Spence JR. In vitro models to study human lung development, disease and homeostasis. Physiology. 2017;32(3):246–260. doi: 10.1152/physiol.00041.2016
   PubMed Web of Science ®Google Scholar
• Wise J, Lechner JF. Culture of epithelial cells. Hoboken (NJ): Wiley Online Library; 2002. Chapter 8, Normal human bronchial epithelial cell culture; p. 257–276.
   Google Scholar
• Haghi M, Ong HX, Traini D, et al. Across the pulmonary epithelial barrier: integration of physicochemical properties and human cell models to study pulmonary drug formulations. Pharmacol Ther. 2014;144(3):235–252. doi: 10.1016/j.pharmthera.2014.05.003
   PubMed Web of Science ®Google Scholar
• Sibinovska N, Žakelj S, Kristan K. Suitability of RPMI 2650 cell models for nasal drug permeability prediction. Euro J Pharm Biopharm. 2019;145:85–95. doi: 10.1016/j.ejpb.2019.10.008
   PubMed Web of Science ®Google Scholar
• Foster KA, Avery ML, Yazdanian M, et al. Characterization of the Calu-3 cell line as a tool to screen pulmonary drug delivery. Int J Pharm. 2000;208(1–2):1–11. doi: 10.1016/S0378-5173(00)00452-X
   PubMedGoogle Scholar
• Mathias NR, Timoszyk J, Stetsko PI, et al. Permeability characteristics of calu-3 human bronchial epithelial cells: in vitro-in vivo correlation to predict lung absorption in rats. J Drug Target. 2002;10(1):31–40. doi: 10.1080/10611860290007504
   PubMed Web of Science ®Google Scholar
• Grainger CI, Greenwell LL, Lockley DJ, et al. Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier. Pharm Res. 2006;23(7):1482–1490. doi: 10.1007/s11095-006-0255-0
   PubMed Web of Science ®Google Scholar
• Wan H, Winton H, Soeller C, et al. Tight junction properties of the immortalized human bronchial epithelial cell lines Calu-3 and 16HBE14o. Eur Respir J. 2000;15(6):1058–1068. doi: 10.1034/j.1399-3003.2000.01514.x
   PubMed Web of Science ®Google Scholar
• Forbes B, Shah A, Martin GP, et al. The human bronchial epithelial cell line 16HBE14o – as a model system of the airways for studying drug transport. Int J Pharm. 2003;257(1–2):161–167. doi: 10.1016/S0378-5173(03)00129-7
   PubMed Web of Science ®Google Scholar
• Salomon JJ, Muchitsch VE, Gausterer JC, et al. The cell line NCl-H441 is a useful in vitro model for transport studies of human distal lung epithelial barrier. Mol Pharm. 2014;11(3):995–1006. doi: 10.1021/mp4006535
   PubMed Web of Science ®Google Scholar
• Hoffmann W, Gradinaru J, Farcal L, et al. Establishment of a human 3D tissue-based assay for upper respiratory tract absorption. Appl In Vitro Toxicol. 2018;4(2):139–148. doi: 10.1089/aivt.2017.0035
   Google Scholar
• Kreft ME, Jerman UD, Lasič E, et al. The characterization of the human cell line Calu-3 under different culture conditions and its use as an optimized in vitro model to investigate bronchial epithelial function. Eur J Pharm Sci. 2015;69:1–9. doi: 10.1016/j.ejps.2014.12.017
   PubMed Web of Science ®Google Scholar
• Stentebjerg-Andersen A, Notlevsen IV, Brodin B, et al. Calu-3 cells grown under AIC and LCC conditions: implications for dipeptide uptake and transepithelial transport of substances. Eur J Pharm Biopharm. 2011;78(1):19–26. doi: 10.1016/j.ejpb.2010.12.030
   PubMed Web of Science ®Google Scholar
• Barilli A, Visigalli R, Ferrari F, et al. Organic cation transporters (OCTs) in EpiAirway™, a cellular model of normal human bronchial epithelium. Biomedicines. 2020;8(5):127. doi: 10.3390/biomedicines8050127
   PubMed Web of Science ®Google Scholar
• Hamilton KO, Backstrom G, Yazdanian MA, et al. P-glycoprotein efflux pump expression and activity in Calu-3 cells. J Pharm Sci. 2001;90(5):647–658. doi: 10.1002/1520-6017(200105)90:5<647:AID-JPS1021>3.0.CO;2-G
   PubMed Web of Science ®Google Scholar
• Mukherjee M, Pritchard DI, Bosquillon C. Evaluation of air-interfaced Calu-3 cell layers for investigation of inhaled drug interactions with organic cation transporters in vitro. Int J Pharm. 2012;426(1–2):7–14. doi: 10.1016/j.ijpharm.2011.12.036
   PubMed Web of Science ®Google Scholar
• Sibinovska N, Žakelj S, Roškar R, et al. Suitability and functional characterization of two Calu-3 cell models for prediction of drug permeability across the airway epithelial barrier. Int J Pharm. 2020;585:119484. doi: 10.1016/j.ijpharm.2020.119484
   PubMedGoogle Scholar
• Mathia NR, Timoszyk J, Stetsko PI, et al. Permeability characteristics of calu-3 human bronchial epithelial cells: in vitro-in vivo correlation to predict lung absorption in rats. J Drug Target. 2002;10(1):31–40. doi: 10.1080/10611860290007504
   PubMed Web of Science ®Google Scholar
• Paturi DK, Kwatra D, Ananthula HK, et al. Identification and functional characterization of breast cancer resistance protein in human bronchial epithelial cells (Calu-3). Int J Pharm. 2010;384(1–2):32–38. doi: 10.1016/j.ijpharm.2009.09.037
   PubMed Web of Science ®Google Scholar
• Sakamoto A, Matsumaru T, Yamamura N, et al. Drug transporter protein quantification of immortalized human lung cell lines derived from tracheobronchial epithelial cells (Calu-3 and BEAS2-B), Bronchiolar-alveolar cells (NCI-H292 and NCI-H441), and alveolar type II-like cells (A549) by liquid chromatography-tandem Mass spectrometry. J Pharm Sci. 2015;104(9):3029–3038. doi: 10.1002/jps.24381
   PubMed Web of Science ®Google Scholar
• Rotoli BM, Barilli A, Visigalli R, et al. Characterization of ABC transporters in EpiAirway™, a cellular model of normal human bronchial epithelium. Int J Mol Sci. 2020;21(9):3190. doi: 10.3390/ijms21093190
   PubMed Web of Science ®Google Scholar
• Neuhaus W, Samwer F, Kunzmann S, et al. Lung endothelial cells strengthen, but brain endothelial cells weaken barrier properties of a human alveolar epithelium cell culture model. Differentiation. 2012;84(4):294–304. doi: 10.1016/j.diff.2012.08.006
   PubMed Web of Science ®Google Scholar
• Ren H, Birch NP, Suresh V, et al. An optimised human cell culture model for alveolar epithelial transport. PLoS One. 2016;11(10):e0165225. doi: 10.1371/journal.pone.0165225
   PubMed Web of Science ®Google Scholar
• Nickel S, Selo MA, Fallack J, et al. Expression and activity of breast cancer resistance protein (BCRP/ABCG2) in human distal lung epithelial cells in vitro. Pharm Res. 2017;34(12):2477–2487. doi: 10.1007/s11095-017-2172-9
   PubMed Web of Science ®Google Scholar
• Salomon JJ, Gausterer JC, Selo MA, et al. OCTN2-mediated acetyl-l-carnitine transport in human pulmonary epithelial cells in vitro. Pharmaceutics. 2019;11(8):396. doi: 10.3390/pharmaceutics11080396
   PubMed Web of Science ®Google Scholar
• Dekali S, Gamez C, Kortulewski T, et al. Assessment of an in vitro model of pulmonary barrier to study the translocation of nanoparticles. Toxicol Rep. 2014;1:157–171. doi: 10.1016/j.toxrep.2014.03.003
   PubMedGoogle Scholar
• Costa A, de Souza Carvalho-Wodarz C, Seabra V, et al. Triple co-culture of human alveolar epithelium, endothelium and macrophages for studying the interaction of nanocarriers with the air-blood barrier. Acta Biomater. 2019;91:235–247. doi: 10.1016/j.actbio.2019.04.037
   PubMed Web of Science ®Google Scholar
• Xu J, Jackson SK. Current considerations for the effective safety evaluation of drugs in vitro. Mini Rev Med Chem. 2009;9(7):861–868. doi: 10.2174/138955709788452577
   PubMed Web of Science ®Google Scholar
• Khalil AS, Jaenisch R, Mooney DJ. Engineered tissues and strategies to overcome challenges in drug development. Adv Drug Delivery Rev. 2020;158:116–139. doi: 10.1016/j.addr.2020.09.012
   PubMed Web of Science ®Google Scholar
• Visigalli R, Rotoli BM, Ferrari F, et al. Expression and function of ABC transporters in human alveolar epithelial cells. Biomolecules. 2022;12(9):1260. doi: 10.3390/biom12091260
   PubMed Web of Science ®Google Scholar
• Mercier C, Jacqueroux E, He Z, et al. Pharmacological characterization of the 3D MucilAir™ nasal model. Eur J Pharm Biopharm. 2019;139:186–196. doi: 10.1016/j.ejpb.2019.04.002
   PubMed Web of Science ®Google Scholar
• Tratnjek L, Kreft M, Kristan K, et al. Ciliary beat frequency of in vitro human nasal epithelium measured with the simple high-speed microscopy is applicable for safety studies of nasal drug formulations. Toxicol Vitro. 2020;66:104865. doi: 10.1016/j.tiv.2020.104865
   PubMed Web of Science ®Google Scholar
• Sakagami M. In vitro, ex vivo and in vivo methods of lung absorption for inhaled drugs. Adv Drug Delivery Rev. 2020;161-162:63–74. doi: 10.1016/j.addr.2020.07.025
   PubMed Web of Science ®Google Scholar
• Reus AA, Maas WJM, Jansen HT, et al. Feasibility of a 3D human airway epithelial model to study respiratory absorption. Toxicol Vitro. 2014;28(2):258–264. doi: 10.1016/j.tiv.2013.10.025
   PubMed Web of Science ®Google Scholar
• McCauley KB, Hawkins F, Serra M, et al. Efficient derivation of functional human airway epithelium from pluripotent stem cells via temporal regulation of wnt signaling. Cell Stem Cell. 2017;20(6):844–57. e6. doi: 10.1016/j.stem.2017.03.001
   PubMed Web of Science ®Google Scholar
• Jacob A, Morley M, Hawkins F, et al. Differentiation of human pluripotent stem cells into functional lung alveolar epithelial cells. Cell Stem Cell. 2017;21(4):472–88. e10. doi: 10.1016/j.stem.2017.08.014
   PubMed Web of Science ®Google Scholar
• Miller AJ, Dye BR, Ferrer-Torres D, et al. Generation of lung organoids from human pluripotent stem cells in vitro. Nat Protoc. 2019;14(2):518–540. doi: 10.1038/s41596-018-0104-8
   PubMed Web of Science ®Google Scholar
• Chiu MC, Zhang S, Li C, et al. Apical-out human airway organoids modeling SARS-CoV-2 infection. Viruses. 2023;15(5):15. doi: 10.3390/v15051166
   Web of Science ®Google Scholar
• Han Y, Duan X, Yang L, et al. Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature. 2021;589(7841):270–275. doi: 10.1038/s41586-020-2901-9
   PubMed Web of Science ®Google Scholar
• Cochin M, Touret F, Driouich J-S, et al. Hydroxychloroquine and azithromycin used alone or combined are not effective against SARS-CoV-2 ex vivo and in a hamster model. Antiviral Res. 2022;197:105212. doi: 10.1016/j.antiviral.2021.105212
   PubMed Web of Science ®Google Scholar
• Huh D, Matthews BD, Mammoto A, et al. Reconstituting organ-level lung functions on a chip. Science. 2010;328(5986):1662–1668. doi: 10.1126/science.1188302
   PubMed Web of Science ®Google Scholar
• Hikmet F, Méar L, Edvinsson Å, et al. The protein expression profile of ACE2 in human tissues. Mol Syst Biol. 2020;16(7):e9610. doi: 10.15252/msb.20209610
   PubMed Web of Science ®Google Scholar
• Si L, Bai H, Rodas M, et al. A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics. Nat Biomed Eng. 2021;5(8):815–829. doi: 10.1038/s41551-021-00718-9
   PubMed Web of Science ®Google Scholar
• Stucki AO, Stucki JD, Hall SR, et al. A lung-on-a-chip array with an integrated bio-inspired respiration mechanism. Lab Chip. 2015;15(5):1302–1310. doi: 10.1039/C4LC01252F
   PubMed Web of Science ®Google Scholar
• Richardson E, Sze H, Hughes D, et al. Assessment of inhaled medications using an in vitro human alveolar microphysiological system. Eur Respir J. 2022;60:3714.
   Web of Science ®Google Scholar
• Benam KH, Königshoff M, Eickelberg O. Breaking the in vitro barrier in respiratory medicine. Engineered microphysiological systems for chronic obstructive pulmonary disease and beyond. Am J Respir Crit Care Med. 2018;197(7):869–875. doi: 10.1164/rccm.201709-1795PP
   PubMed Web of Science ®Google Scholar
• Chen R, Lan Z, Ye J, et al. Cytokine Storm: the primary determinant for the pathophysiological evolution of COVID-19 deterioration [review]. Front Immunol. 2021;12:12. doi: 10.3389/fimmu.2021.589095
   Web of Science ®Google Scholar
• Meyer F, Wendling D, Demougeot C, et al. Cytokines and intestinal epithelial permeability: a systematic review. Autoimmun Rev. 2023;22(6):103331. doi: 10.1016/j.autrev.2023.103331
   PubMed Web of Science ®Google Scholar
• Cirit M, Stokes CL. Maximizing the impact of microphysiological systems with in vitro – in vivo translation. Lab Chip. 2018;18(13):1831–1837. doi: 10.1039/C8LC00039E
   PubMed Web of Science ®Google Scholar
• Wang K, Man K, Liu J, et al. Microphysiological systems: design, fabrication, and applications. ACS Biomater Sci Eng. 2020;6(6):3231–3257. doi: 10.1021/acsbiomaterials.9b01667
   PubMed Web of Science ®Google Scholar
• Rumsey JW, Lorance C, Jackson M, et al. Classical complement pathway inhibition in a “human-on-a-Chip” model of autoimmune demyelinating neuropathies. Adv Ther. 2022;5(6):2200030. doi: 10.1002/adtp.202200030
   Google Scholar
• Ajalik RE, Alenchery RG, Cognetti JS, et al. Human organ-on-a-chip microphysiological systems to model musculoskeletal pathologies and accelerate therapeutic discovery. Front Bioeng Biotechnol. 2022;10:846230. doi: 10.3389/fbioe.2022.846230
   PubMed Web of Science ®Google Scholar
• Azizgolshani H, Coppeta JR, Vedula EM, et al. High-throughput organ-on-chip platform with integrated programmable fluid flow and real-time sensing for complex tissue models in drug development workflows. Lab Chip. 2021;21(8):1454–1474. doi: 10.1039/D1LC00067E
   PubMed Web of Science ®Google Scholar
• Cao UMN, Zhang Y, Chen J, et al. Microfluidic organ-on-a-chip: a Guide to biomaterial choice and fabrication. Int J Mol Sci. 2023;24(4):3232. doi: 10.3390/ijms24043232
   PubMed Web of Science ®Google Scholar
• Pediaditakis I, Kodella KR, Manatakis DV, et al. A microengineered brain-chip to model neuroinflammation in humans. iScience. 2022;25(8):104813. doi: 10.1016/j.isci.2022.104813
   PubMed Web of Science ®Google Scholar
• Geiger R, Rahman S, Tariq I, et al. Assessment of drug permeability using a lung microphysiological system. Poster presented at: FDA Science Forum: Advancing Regulatory Science Through Innovation; 2023 Jun 13–14. https://www.fda.gov/science-research/about-science-research-fda/fda-science-forum
   Google Scholar
• Duodenum Intestine Chip [Internet]. Emulate, Inc; [cited 2024 Apr 29]. Available from: https://emulatebio.com/duodenum-intestine-chip/
   Google Scholar
• Comparison of the OrganoPlate® and the Transwell® platform for in vitro intestinal permeability assays [Internet]. MIMETAS; [cited 2024 Apr 29]. Available from: https://go.mimetas.com/in-vitro-intestinal-permeability-assay?_ga=2.202520085.587184889.1714069237-173907669.1714069237
   Google Scholar