Download PDF
Semin Reprod Med 2023; 41(05): 160-171
DOI: 10.1055/s-0043-1778067
Review Article

Advanced Technologies for Studying Microbiome–Female Reproductive Tract Interactions: Organoids, Organoids-on-a-Chip, and Beyond

Yosun A. Kaya 
,
Marcel R. de Zoete 
2   Department of Medical Microbiology, University Medical Centre, Utrecht, The Netherlands
,
Gaby S. Steba 
1   Division of Female and Baby, Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht, The Netherlands
› Author Affiliations Funding This research was not supported by a specific grant or funding from the public, commercial, or nonprofit sectors. G.S.S. is supported by Merck.
› Further Information
    Permissions and Reprints

Abstract

The female reproductive tract (FRT) is home to diverse microbial communities that play a pivotal role in reproductive health and disorders such as infertility, endometriosis, and cervical cancer. To understand the complex host–microbiota interactions within the FRT, models that authentically replicate the FRT's environment, including the interplay between the microbiota, mucus layer, immune system, and hormonal cycle, are key. Recent strides in organoid and microfluidic technologies are propelling research in this domain, offering insights into FRT–microbiota interactions and potential therapeutic avenues. This review delves into the current state of FRT organoid models and microbe integration techniques, evaluating their merits and challenges for specific research objectives. Emphasis is placed on innovative approaches and applications, including integrating organoids with microfluidics, and using patient-derived biobanks, as this offers potential for deeper mechanistic insights and personalized therapeutic strategies. Modeling various FRT properties in organoids is explored, from encompassing age-related epithelial features, oxygen levels, and hormonal effects to mucus layers, immune responses, and microbial interactions, highlighting their potential to transform reproductive health research and predict possible outcomes.

Keywords

female reproductive tract - organoids - in vitro models - microbiome - host–microbe interactions

Authors' Contribution

G.S.S initiated the study. G.S.S. and Y.A.K. drafted the study design. Y.A.K. performed the literature search and drafted the report. G.S.S. and M.R.d.Z. revised the manuscript critically. Final manuscript was approved by all the authors.




Publication History

Article published online:
23 January 2024

© 2024. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Rizzo AE, Gordon JC, Berard AR, Burgener AD, Avril S. The female reproductive tract microbiome-implications for gynecologic cancers and personalized medicine. J Pers Med 2021; 11 (06) 546
    CrossrefPubMedGoogle Scholar
  • 2 Liptáková A, Čurová K, Záhumenský J, Visnyaiová K, Varga I. Microbiota of female genital tract - functional overview of microbial flora from vagina to uterine tubes and placenta. Physiol Res 2022; 71 (Suppl. 01) S21-S33
    CrossrefPubMedGoogle Scholar
  • 3 Pelzer ES, Willner D, Buttini M, Hafner LM, Theodoropoulos C, Huygens F. The fallopian tube microbiome: implications for reproductive health. Oncotarget 2018; 9 (30) 21541-21551
    CrossrefPubMedGoogle Scholar
  • 4 Canha-Gouveia A, Pérez-Prieto I, Rodríguez CM. et al. The female upper reproductive tract harbors endogenous microbial profiles. Front Endocrinol (Lausanne) 2023; 14: 1096050
    CrossrefPubMedGoogle Scholar
  • 5 Yao Y, Cai X, Chen C. et al. The role of microbiomes in pregnant women and offspring: research progress of recent years. Front Pharmacol 2020; 11: 643
    CrossrefPubMedGoogle Scholar
  • 6 Wiesenfeld HC, Hillier SL, Krohn MA. et al. Lower genital tract infection and endometritis: insight into subclinical pelvic inflammatory disease. Obstet Gynecol 2002; 100 (03) 456-463
    PubMedGoogle Scholar
  • 7 Weström L, Joesoef R, Reynolds G, Hagdu A, Thompson SE. Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results. Sex Transm Dis 1992; 19 (04) 185-192
    CrossrefPubMedGoogle Scholar
  • 8 Ravel J, Moreno I, Simón C. Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease. Am J Obstet Gynecol 2021; 224 (03) 251-257
    CrossrefPubMedGoogle Scholar
  • 9 Molina NM, Sola-Leyva A, Haahr T. et al. Analysing endometrial microbiome: methodological considerations and recommendations for good practice. Hum Reprod 2021; 36 (04) 859-879
    CrossrefPubMedGoogle Scholar
  • 10 Dutta D, Clevers H. Organoid culture systems to study host-pathogen interactions. Curr Opin Immunol 2017; 48: 15-22
    CrossrefPubMedGoogle Scholar
  • 11 Kessler M, Hoffmann K, Fritsche K. et al. Chronic Chlamydia infection in human organoids increases stemness and promotes age-dependent CpG methylation. Nat Commun 2019; 10 (01) 1194
    CrossrefPubMedGoogle Scholar
  • 12 Bishop RC, Boretto M, Rutkowski MR, Vankelecom H, Derré I. Murine endometrial organoids to model Chlamydia infection. Front Cell Infect Microbiol 2020; 10: 416
    CrossrefPubMedGoogle Scholar
  • 13 Dolat L, Valdivia RH. An endometrial organoid model of interactions between Chlamydia and epithelial and immune cells. J Cell Sci 2021; 134 (05) jcs252403
    CrossrefPubMedGoogle Scholar
  • 14 Koster S, Gurumurthy RK, Kumar N. et al. Modelling Chlamydia and HPV co-infection in patient-derived ectocervix organoids reveals distinct cellular reprogramming. Nat Commun 2022; 13 (01) 1030
    CrossrefPubMedGoogle Scholar
  • 15 Yu B, McCartney S, Strenk S. et al. Vaginal bacteria elicit acute inflammatory response in fallopian tube organoids. Reprod Sci [Internet]. 2023 Sep 19 [cited 2023 Nov 9]. Accessed December 19, 2023 at: https://link.springer.com/10.1007/s43032-023-01350-5
    PubMedGoogle Scholar
  • 16 Alzamil L, Nikolakopoulou K, Turco MY. Organoid systems to study the human female reproductive tract and pregnancy. Cell Death Differ 2021; 28 (01) 35-51
    CrossrefPubMedGoogle Scholar
  • 17 Clevers H. Modeling development and disease with organoids. Cell 2016; 165 (07) 1586-1597
    CrossrefPubMedGoogle Scholar
  • 18 Izadifar Z, Cotton J, Chen C. et al. Mucus production, host-microbiome interactions, hormone sensitivity, and innate immune responses modeled in human endo- and ecto-cervix chips. [ Internet ]. Bioengineering; 2023 Feb [cited 2023 Aug 19]. Accessed December 19, 2023 at: http://biorxiv.org/lookup/doi/10.1101/2023.02.22.529436
    PubMedGoogle Scholar
  • 19 Petrova MI, Lievens E, Malik S, Imholz N, Lebeer S. Lactobacillus species as biomarkers and agents that can promote various aspects of vaginal health. Front Physiol 2015; 6: 81 . Accessed December 19, 2023 at: http://www.frontiersin.org/Clinical_and_Translational_Physiology/10.3389/fphys.2015.00081/abstract
    CrossrefPubMedGoogle Scholar
  • 20 Cazanave C, Manhart LE, Bébéar C. Mycoplasma genitalium, an emerging sexually transmitted pathogen. Med Mal Infect 2012; 42 (09) 381-392
    CrossrefPubMedGoogle Scholar
  • 21 Onderdonk AB, Delaney ML, Fichorova RN. The human microbiome during bacterial vaginosis. Clin Microbiol Rev 2016; 29 (02) 223-238
    CrossrefPubMedGoogle Scholar
  • 22 Gupta S, Kakkar V, Bhushan I. Crosstalk between vaginal microbiome and female health: a review. Microb Pathog 2019; 136: 103696
    CrossrefPubMedGoogle Scholar
  • 23 Lin S, Zhang B, Lin Y, Lin Y, Zuo X. Dysbiosis of cervical and vaginal microbiota associated with cervical intraepithelial neoplasia. Front Cell Infect Microbiol 2022; 12: 767693
    CrossrefPubMedGoogle Scholar
  • 24 Amegashie CP, Gilbert NM, Peipert JF, Allsworth JE, Lewis WG, Lewis AL. Relationship between Nugent score and vaginal epithelial exfoliation. PLoS One 2017; 12 (05) e0177797
    CrossrefPubMedGoogle Scholar
  • 25 Gosmann C, Anahtar MN, Handley SA. et al. Lactobacillus-deficient cervicovaginal bacterial communities are associated with increased HIV acquisition in young South African women. Immunity 2017; 46 (01) 29-37
    CrossrefPubMedGoogle Scholar
  • 26 Moore DE, Soules MR, Klein NA, Fujimoto VY, Agnew KJ, Eschenbach DA. Bacteria in the transfer catheter tip influence the live-birth rate after in vitro fertilization. Fertil Steril 2000; 74 (06) 1118-1124
    CrossrefPubMedGoogle Scholar
  • 27 Mitchell CM, Haick A, Nkwopara E. et al. Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women. Am J Obstet Gynecol 2015; 212 (05) 611.e1-611.e9
    CrossrefPubMedGoogle Scholar
  • 28 Baker JM, Chase DM, Herbst-Kralovetz MM. Uterine microbiota: residents, tourists, or invaders?. Front Immunol 2018; 9: 208
    CrossrefPubMedGoogle Scholar
  • 29 Altmäe S, Rienzi L. Endometrial microbiome: new hope, or hype?. Reprod Biomed Online 2021; 42 (06) 1051-1052
    CrossrefPubMedGoogle Scholar
  • 30 Oberle A, Urban L, Falch-Leis S. et al. 16S rRNA long-read nanopore sequencing is feasible and reliable for endometrial microbiome analysis. Reprod Biomed Online 2021; 42 (06) 1097-1107
    CrossrefPubMedGoogle Scholar
  • 31 Bui BN, van Hoogenhuijze N, Viveen M. et al. The endometrial microbiota of women with or without a live birth within 12 months after a first failed IVF/ICSI cycle. Sci Rep 2023; 13 (01) 3444
    CrossrefPubMedGoogle Scholar
  • 32 Franasiak JM, Werner MD, Juneau CR. et al. Endometrial microbiome at the time of embryo transfer: next-generation sequencing of the 16S ribosomal subunit. J Assist Reprod Genet 2016; 33 (01) 129-136
    CrossrefPubMedGoogle Scholar
  • 33 Winters AD, Romero R, Gervasi MT. et al. Does the endometrial cavity have a molecular microbial signature?. Sci Rep 2019; 9 (01) 9905
    CrossrefPubMedGoogle Scholar
  • 34 Chen K, Cao G, Chen B. et al. Laparoscopic versus open surgery for rectal cancer: a meta-analysis of classic randomized controlled trials and high-quality nonrandomized studies in the last 5 years. Int J Surg 2017; 39: 1-10
    CrossrefPubMedGoogle Scholar
  • 35 Leoni C, Ceci O, Manzari C. et al. Human endometrial microbiota at term of normal pregnancies. Genes (Basel) 2019; 10 (12) 971
    CrossrefPubMedGoogle Scholar
  • 36 Moreno I, Codoñer FM, Vilella F. et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol 2016; 215 (06) 684-703
    CrossrefPubMedGoogle Scholar
  • 37 Boretto M, Cox B, Noben M. et al. Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Development 2017; 144 (10) 1775-1786
    CrossrefPubMedGoogle Scholar
  • 38 Turco MY, Gardner L, Hughes J. et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat Cell Biol 2017; 19 (05) 568-577
    CrossrefPubMedGoogle Scholar
  • 39 Kessler M, Hoffmann K, Brinkmann V. et al. The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nat Commun 2015; 6 (01) 8989
    CrossrefPubMedGoogle Scholar
  • 40 Heidari-Khoei H, Esfandiari F, Hajari MA, Ghorbaninejad Z, Piryaei A, Baharvand H. Organoid technology in female reproductive biomedicine. Reprod Biol Endocrinol 2020; 18 (01) 64
    CrossrefPubMedGoogle Scholar
  • 41 Michelini M, Rosellini A, Simoncini T, Papini S, Revoltella RP. A three-dimensional organotypic culture of the human uterine exocervix for studying mucosal epithelial differentiation and migrating leukocytes. Differentiation 2004; 72 (04) 138-149
    CrossrefPubMedGoogle Scholar
  • 42 Deng H, Hillpot E, Mondal S, Khurana KK, Woodworth CD. HPV16-immortalized cells from human transformation zone and endocervix are more dysplastic than ectocervical cells in organotypic culture. Sci Rep 2018; 8 (01) 15402
    CrossrefPubMedGoogle Scholar
  • 43 Chumduri C, Gurumurthy RK, Berger H. et al. Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia. Nat Cell Biol 2021; 23 (02) 184-197
    CrossrefPubMedGoogle Scholar
  • 44 Nanki Y, Chiyoda T, Hirasawa A. et al. Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing. Sci Rep 2020; 10 (01) 12581
    CrossrefPubMedGoogle Scholar
  • 45 Kopper O, de Witte CJ, Lõhmussaar K. et al. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nat Med 2019; 25 (05) 838-849
    CrossrefPubMedGoogle Scholar
  • 46 Pierson Smela MD, Kramme CC, Fortuna PRJ. et al. Directed differentiation of human iPSCs to functional ovarian granulosa-like cells via transcription factor overexpression. eLife 2023; 12: e83291
    CrossrefPubMedGoogle Scholar
  • 47 Ali A, Syed SM, Jamaluddin MFB, Colino-Sanguino Y, Gallego-Ortega D, Tanwar PS. Cell lineage tracing identifies hormone-regulated and Wnt-responsive vaginal epithelial stem cells. Cell Rep 2020; 30 (05) 1463-1477.e7
    CrossrefPubMedGoogle Scholar
  • 48 Turco MY, Gardner L, Kay RG. et al. Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature 2018; 564 (7735) 263-267
    CrossrefPubMedGoogle Scholar
  • 49 Han Y, Liu Z, Chen T. Role of vaginal microbiota dysbiosis in gynecological diseases and the potential interventions. Front Microbiol 2021; 12: 643422
    CrossrefPubMedGoogle Scholar
  • 50 Goodfellow L, Verwijs MC, Care A. et al. Vaginal bacterial load in the second trimester is associated with early preterm birth recurrence: a nested case-control study. BJOG 2021; 128 (13) 2061-2072
    CrossrefPubMedGoogle Scholar
  • 51 Han X, Mslati MA, Davies E, Chen Y, Allaire JM, Vallance BA. Creating a more perfect union: modeling intestinal bacteria-epithelial interactions using organoids. Cell Mol Gastroenterol Hepatol 2021; 12 (02) 769-782
    CrossrefPubMedGoogle Scholar
  • 52 Chen Y, Cao K, Liu H. et al. Heat killed Salmonella typhimurium protects intestine against radiation injury through Wnt signaling pathway. J Oncol 2021; 2021: 5550956
    PubMedGoogle Scholar
  • 53 Fischer S, Ückert AK, Landenberger M. et al. Human peptide α-defensin-1 interferes with Clostridioides difficile toxins TcdA, TcdB, and CDT. FASEB J 2020; 34 (05) 6244-6261
    CrossrefPubMedGoogle Scholar
  • 54 Naito T, Mulet C, De Castro C. et al. Lipopolysaccharide from crypt-specific core microbiota modulates the colonic epithelial proliferation-to-differentiation balance. MBio 2017; 8 (05) e01680-e17
    CrossrefPubMedGoogle Scholar
  • 55 Poletti M, Arnauts K, Ferrante M, Korcsmaros T. Organoid-based models to study the role of host-microbiota interactions in IBD. J Crohn's Colitis 2021; 15 (07) 1222-1235
    CrossrefPubMedGoogle Scholar
  • 56 Yokoi Y, Nakamura K, Yoneda T. et al. Paneth cell granule dynamics on secretory responses to bacterial stimuli in enteroids. Sci Rep 2019; 9 (01) 2710
    CrossrefPubMedGoogle Scholar
  • 57 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 (03) 301-319
    CrossrefPubMedGoogle Scholar
  • 58 Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A. et al; Genomics England Research Consortium. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli. Nature 2020; 580 (7802) 269-273
    CrossrefPubMedGoogle Scholar
  • 59 Ginga NJ, Slyman R, Kim GA. et al. Perfusion system for modification of luminal contents of human intestinal organoids and real time imaging analysis of microbial populations. Micromachines (Basel) 2022; 13 (01) 131
    CrossrefPubMedGoogle Scholar
  • 60 Puschhof J, Pleguezuelos-Manzano C, Martinez-Silgado A. et al. Intestinal organoid cocultures with microbes. Nat Protoc 2021; 16 (10) 4633-4649
    CrossrefPubMedGoogle Scholar
  • 61 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 (01) 126-136.e6
    CrossrefPubMedGoogle Scholar
  • 62 McCracken KW, Catá EM, Crawford CM. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 2014; 516 (7531) 400-404
    CrossrefPubMedGoogle Scholar
  • 63 Leslie JL, Huang S, Opp JS. et al. Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect Immun 2015; 83 (01) 138-145
    CrossrefPubMedGoogle Scholar
  • 64 Dolat L, Carpenter VK, Chen YS. et al. Chlamydia repurposes the actin-binding protein EPS8 to disassemble epithelial tight junctions and promote infection. Cell Host Microbe 2022; 30 (12) 1685-1700.e10
    CrossrefPubMedGoogle Scholar
  • 65 Co JY, Margalef-Català M, Monack DM, Amieva MR. Controlling the polarity of human gastrointestinal organoids to investigate epithelial biology and infectious diseases. Nat Protoc 2021; 16 (11) 5171-5192
    CrossrefPubMedGoogle Scholar
  • 66 Co JY, Margalef-Català M, Li X. et al. Controlling epithelial polarity: a human enteroid model for host-pathogen interactions. Cell Rep 2019; 26 (09) 2509-2520.e4
    CrossrefPubMedGoogle Scholar
  • 67 Rajan A, Robertson MJ, Carter HE. et al. Enteroaggregative E. coli adherence to human heparan sulfate proteoglycans drives segment and host specific responses to infection. PLoS Pathog 2020; 16 (09) e1008851
    CrossrefPubMedGoogle Scholar
  • 68 Ahmad V, Yeddula SGR, Telugu BP, Spencer TE, Kelleher AM. Development of polarity-reversed endometrial epithelial organoids. [ Internet ]. Cell Biology; 2023 . Accessed December 19, 2023 at: http://biorxiv.org/lookup/doi/10.1101/2023.08.18.553918
    PubMedGoogle Scholar
  • 69 Foulke-Abel J, In J, Kovbasnjuk O. et al. Human enteroids as an ex-vivo model of host-pathogen interactions in the gastrointestinal tract. Exp Biol Med (Maywood) 2014; 239 (09) 1124-1134
    CrossrefPubMedGoogle Scholar
  • 70 Ettayebi K, Crawford SE, Murakami K. et al. Replication of human noroviruses in stem cell-derived human enteroids. Science 2016; 353 (6306) 1387-1393
    CrossrefPubMedGoogle Scholar
  • 71 VanDussen KL, Marinshaw JM, Shaikh N. et al. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 2015; 64 (06) 911-920
    CrossrefPubMedGoogle Scholar
  • 72 In J, Foulke-Abel J, Zachos NC. et al. Enterohemorrhagic Escherichia coli reduce mucus and intermicrovillar bridges in human stem cell-derived colonoids. Cell Mol Gastroenterol Hepatol 2016; 2 (01) 48-62.e3
    CrossrefPubMedGoogle Scholar
  • 73 Roodsant T, Navis M, Aknouch I. et al. A human 2D primary organoid-derived epithelial monolayer model to study host-pathogen interaction in the small intestine. Front Cell Infect Microbiol 2020; 10: 272
    CrossrefPubMedGoogle Scholar
  • 74 Kozuka K, He Y, Koo-McCoy S. et al. Development and characterization of a human and mouse intestinal epithelial cell monolayer platform. Stem Cell Reports 2017; 9 (06) 1976-1990
    CrossrefPubMedGoogle Scholar
  • 75 Wang Y, Chiang IL, Ohara TE. et al. Long-term culture captures injury-repair cycles of colonic stem cells. Cell 2019; 179 (05) 1144-1159.e15
    CrossrefPubMedGoogle Scholar
  • 76 DiMarco RL, Su J, Yan KS, Dewi R, Kuo CJ, Heilshorn SC. Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids. Integr Biol 2014; 6 (02) 127-142
    CrossrefPubMedGoogle Scholar
  • 77 Zhu Y, Yang Y, Guo J. et al. Ex vivo 2D and 3D HSV-2 infection model using human normal vaginal epithelial cells. Oncotarget 2017; 8 (09) 15267-15282
    CrossrefPubMedGoogle Scholar
  • 78 Wang Y, Qin J. Advances in human organoids-on-chips in biomedical research. Life Med 2023; 2 (01) lnad007
    CrossrefPubMedGoogle Scholar
  • 79 Nie J, Gao Q, Wang Y. et al. Vessel-on-a-chip with hydrogel-based microfluidics. Small 2018; 14 (45) e1802368
    CrossrefPubMedGoogle Scholar
  • 80 Bhatia SN, Ingber DE. Microfluidic organs-on-chips. Nat Biotechnol 2014; 32 (08) 760-772
    CrossrefPubMedGoogle Scholar
  • 81 Huh D, Torisawa YS, Hamilton GA, Kim HJ, Ingber DE. Microengineered physiological biomimicry: organs-on-chips. Lab Chip 2012; 12 (12) 2156-2164
    CrossrefPubMedGoogle Scholar
  • 82 Rifes P, Isaksson M, Rathore GS. et al. Modeling neural tube development by differentiation of human embryonic stem cells in a microfluidic WNT gradient. Nat Biotechnol 2020; 38 (11) 1265-1273
    CrossrefPubMedGoogle Scholar
  • 83 Karzbrun E, Kshirsagar A, Cohen SR, Hanna JH, Reiner O. Human brain organoids on a chip reveal the physics of folding. Nat Phys 2018; 14 (05) 515-522
    CrossrefPubMedGoogle Scholar
  • 84 Homan KA, Gupta N, Kroll KT. et al. Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nat Methods 2019; 16 (03) 255-262
    CrossrefPubMedGoogle Scholar
  • 85 Zhang YS, Aleman J, Shin SR. et al. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc Natl Acad Sci U S A 2017; 114 (12) E2293-E2302
    CrossrefPubMedGoogle Scholar
  • 86 Schuster B, Junkin M, Kashaf SS. et al. Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids. Nat Commun 2020; 11 (01) 5271
    CrossrefPubMedGoogle Scholar
  • 87 Kim HJ, Li H, Collins JJ, Ingber DE. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc Natl Acad Sci U S A 2016; 113 (01) E7-E15
    PubMedGoogle Scholar
  • 88 Trujillo-de Santiago G, Lobo-Zegers MJ, Montes-Fonseca SL, Zhang YS, Alvarez MM. Gut-microbiota-on-a-chip: an enabling field for physiological research. Microphysiol Syst 2018; 2: 7
    PubMedGoogle Scholar
  • 89 Mahajan G, Doherty E, To T. et al. Vaginal microbiome-host interactions modeled in a human vagina-on-a-chip. Microbiome 2022; 10 (01) 201
    CrossrefPubMedGoogle Scholar
  • 90 Ng KYB, Mingels R, Morgan H, Macklon N, Cheong Y. In vivo oxygen, temperature and pH dynamics in the female reproductive tract and their importance in human conception: a systematic review. Hum Reprod Update 2018; 24 (01) 15-34
    CrossrefPubMedGoogle Scholar
  • 91 de Oliveira NS, de Lima ABF, de Brito JCR, Sarmento ACA, Gonçalves AKS, Eleutério Jr J. Postmenopausal vaginal microbiome and microbiota. Front Reprod Health 2022; 3: 780931
    CrossrefPubMedGoogle Scholar
  • 92 Zhang Y, Chen R, Zhang D, Qi S, Liu Y. Metabolite interactions between host and microbiota during health and disease: Which feeds the other?. Biomed Pharmacother 2023; 160: 114295
    CrossrefPubMedGoogle Scholar
  • 93 Sozzi E, Kajtez J, Bruzelius A. et al. Silk scaffolding drives self-assembly of functional and mature human brain organoids. Front Cell Dev Biol 2022; 10: 1023279
    CrossrefPubMedGoogle Scholar
  • 94 Shah P, Fritz JV, Glaab E. et al. A microfluidics-based in vitro model of the gastrointestinal human-microbe interface. Nat Commun 2016; 7 (01) 11535
    CrossrefPubMedGoogle Scholar
  • 95 Punzón-Jiménez P, Labarta E. The impact of the female genital tract microbiome in women health and reproduction: a review. J Assist Reprod Genet 2021; 38 (10) 2519-2541
    CrossrefPubMedGoogle Scholar
  • 96 Hibaoui Y, Feki A. Organoid models of human endometrial development and disease. Front Cell Dev Biol 2020; 8: 84
    CrossrefPubMedGoogle Scholar
  • 97 Xiao S, Coppeta JR, Rogers HB. et al. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat Commun 2017; 8 (01) 14584
    CrossrefPubMedGoogle Scholar
  • 98 Izadifar Z, Sontheimer-Phelps A, Lubamba BA. et al. Modeling mucus physiology and pathophysiology in human organs-on-chips. Adv Drug Deliv Rev 2022; 191: 114542
    CrossrefPubMedGoogle Scholar
  • 99 Elstein M. Cervical mucus: its physiological role and clinical significance. In: Chantler EN, Elder JB, Elstein M. eds. Mucus in Health and Disease—II [Internet]. Boston, MA: Springer; 1982 [cited 2023 Sep 19]. pp. 301–318. (Advances in Experimental Medicine and Biology; vol. 144). Accessed December 19, 2023 at: http://link.springer.com/10.1007/978-1-4615-9254-9_50
    PubMedGoogle Scholar
  • 100 Lacroix G, Gouyer V, Gottrand F, Desseyn JL. The cervicovaginal mucus barrier. Int J Mol Sci 2020; 21 (21) 8266
    CrossrefPubMedGoogle Scholar
  • 101 Mohanty T, Doke PP, Khuroo SR. Effect of bacterial vaginosis on preterm birth: a meta-analysis. Arch Gynecol Obstet 2023; 308 (04) 1247-1255
    CrossrefPubMedGoogle Scholar
  • 102 Cohen CR, Lingappa JR, Baeten JM. et al. Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples. PLoS Med 2012; 9 (06) e1001251
    CrossrefPubMedGoogle Scholar
  • 103 Arslan SY, Yu Y, Burdette JE. et al. Novel three dimensional human endocervix cultures respond to 28-day hormone treatment. Endocrinology 2015; 156 (04) 1602-1609
    CrossrefPubMedGoogle Scholar
  • 104 Zhang F, Dai J, Chen T. Role of Lactobacillus in female infertility via modulating sperm agglutination and immobilization. Front Cell Infect Microbiol 2021; 10: 620529
    CrossrefPubMedGoogle Scholar
  • 105 Venneri MA, Franceschini E, Sciarra F, Rosato E, D'Ettorre G, Lenzi A. Human genital tracts microbiota: dysbiosis crucial for infertility. J Endocrinol Invest 2022; 45 (06) 1151-1160
    CrossrefPubMedGoogle Scholar
  • 106 Puca JF, Hoyne G. Microbial dysbiosis and disease pathogenesis of endometriosis, could there be a link? Medical-Research [Internet]. 2017 [cited 2023 Sep 19];01(01). Accessed December 19, 2023 at: http://www.alliedacademies.org/articles/microbial-dysbiosis-and-disease-pathogenesis-of-endometriosis-could-therebe-a-link-6652.html
    PubMedGoogle Scholar
  • 107 Jia Z, Guo Z, Yang CT, Prestidge C, Thierry B. “Mucus-on-chip”: a new tool to study the dynamic penetration of nanoparticulate drug carriers into mucus. Int J Pharm 2021; 598: 120391
    CrossrefPubMedGoogle Scholar
  • 108 Martyn F, McAuliffe FM, Wingfield M. The role of the cervix in fertility: is it time for a reappraisal?. Hum Reprod 2014; 29 (10) 2092-2098
    CrossrefPubMedGoogle Scholar
  • 109 Kutteh WH, Moldoveanu Z, Mestecky J. Mucosal immunity in the female reproductive tract: correlation of immunoglobulins, cytokines, and reproductive hormones in human cervical mucus around the time of ovulation. AIDS Res Hum Retroviruses 1998; 14 (Suppl. 01) S51-S55
    PubMedGoogle Scholar
  • 110 Kutteh WH, Prince SJ, Hammond KR, Kutteh CC, Mestecky J. Variations in immunoglobulins and IgA subclasses of human uterine cervical secretions around the time of ovulation. Clin Exp Immunol 1996; 104 (03) 538-542
    CrossrefPubMedGoogle Scholar
  • 111 Monin L, Whettlock EM, Male V. Immune responses in the human female reproductive tract. Immunology 2020; 160 (02) 106-115
    CrossrefPubMedGoogle Scholar
  • 112 Li H, Zang Y, Wang C. et al. The interaction between microorganisms, metabolites, and immune system in the female genital tract microenvironment. Front Cell Infect Microbiol 2020; 10: 609488
    CrossrefPubMedGoogle Scholar
  • 113 Kushnir VA, Smith GD, Adashi EY. The future of IVF: the new normal in human reproduction. Reprod Sci 2022; 29 (03) 849-856
    CrossrefPubMedGoogle Scholar
  • 114 Li WX, Liang GT, Yan W. et al. Artificial uterus on a microfluidic chip. Chin J Anal Chem 2013; 41 (04) 467-472
    CrossrefPubMedGoogle Scholar
  • 115 Gnecco JS, Pensabene V, Li DJ. et al. Compartmentalized culture of perivascular stroma and endothelial cells in a microfluidic model of the human endometrium. Ann Biomed Eng 2017; 45 (07) 1758-1769
    CrossrefPubMedGoogle Scholar
  • 116 Jang KJ, Otieno MA, Ronxhi J. et al. Reproducing human and cross-species drug toxicities using a Liver-Chip. Sci Transl Med 2019; 11 (517) eaax5516
    CrossrefPubMedGoogle Scholar