Skip to main content

Advertisement

SpringerLink
Log in

Animal Models and Alternatives in Vaginal Research: a Comparative Review

  • Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

While developments in gynecologic health research continue advancing, relatively few groups specifically focus on vaginal tissue research for areas like wound healing, device development, and/or drug toxicity. Currently, there is no standardized animal or tissue model that mimics the full complexity of the human vagina. Certain practical factors such as appropriate size and anatomy, costs, and tissue environment vary across species and moreover fail to emulate all aspects of the human vagina. Thus, investigators are tasked with compromising specific properties of the vaginal environment as it relates to human physiology to suit their particular scientific question. Our review aims to facilitate the appropriate selection of a model aptly addressing a particular study by discussing pertinent vaginal characteristics of conventional animal and tissue models. In this review, we first cover common laboratory animals studied in vaginal research—mouse, rat, rabbit, minipig, and sheep—as well as human, with respect to the estrus cycle and related hormones, basic reproductive anatomy, the composition of vaginal layers, developmental epithelial origin, and microflora. In light of these relevant comparative metrics, we discuss potential selection criteria for choosing an appropriate animal vaginal model. Finally, we allude to the exciting prospects of increasing biomimicry for in vitro applications to provide a framework for investigators to model, interpret, and predict human vaginal health.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Cohen CR, Wierzbicki MR, French AL, Morris S, Newmann S, Reno H, et al. Randomized trial of lactin-V to prevent recurrence of bacterial vaginosis. N Engl J Med. 2020;382:1906–15. https://doi.org/10.1056/NEJMoa1915254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bagnall P, Rizzolo D. Bacterial vaginosis: a practical review. J Am Acad Phys Assist. 2017;30:15–21. https://doi.org/10.1097/01.JAA.0000526770.60197.fa.

    Article  Google Scholar 

  3. Blostein F, Levin-Sparenberg E, Wagner J, Foxman B. Recurrent vulvovaginal candidiasis. Ann Epidemiol. 2017;27:575–582.e3.

    Article  Google Scholar 

  4. Ledig S, Wieacker P. Klinische und genetische Aspekte des Mayer-Rokitansky-Küster-Hauser Syndroms. Med Genet. 2018;30:3–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Batista RL, Costa EMF, Rodrigues A d S, et al. Androgen insensitivity syndrome: a review. Arch Endocrinol Metab. 2018;62:227–35.

    Article  Google Scholar 

  6. Fulare S, Deshmukh S, Gupta J. Androgen insensitivity syndrome: a rare genetic disorder. Int J Surg Case Rep. 2020;71:371–3. https://doi.org/10.1016/j.ijscr.2020.01.032.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lev-Sagie A. Vulvar and vaginal atrophy: physiology, clinical presentation, and treatment considerations. Clin Obstet Gynecol. 2015;58:476–91.

    Article  Google Scholar 

  8. Tanmahasamut P, Jirasawas T, Laiwejpithaya S, Areeswate C, Dangrat C, Silprasit K. Effect of estradiol vaginal gel on vaginal atrophy in postmenopausal women: a randomized double-blind controlled trial. J Obstet Gynaecol Res. 2020;46:1425–35. https://doi.org/10.1111/jog.14336.

    Article  CAS  PubMed  Google Scholar 

  9. Iglesia CB, Smithling KR (2017) Pelvic organ prolapse

  10. Kong MK, Bai SW. Surgical treatments for vaginal apical prolapse. Obstet Gynecol Sci. 2016;59:253–60. https://doi.org/10.5468/ogs.2016.59.4.253.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Morris L, Do V, Chard J, Brand AH. Radiation-induced vaginal stenosis: current perspectives. Int J Women's Health. 2017;9:273–9.

    Article  Google Scholar 

  12. Son CH, Law E, Oh JH, Apte AP, Yang TJ, Riedel E, et al. Dosimetric predictors of radiation-induced vaginal stenosis after pelvic radiation therapy for rectal and anal cancer. Int J Radiat Oncol Biol Phys. 2015;92:548–54. https://doi.org/10.1016/j.ijrobp.2015.02.029.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Chanda A, Unnikrishnan V, Richter HE, Lockhart ME. A biofidelic computational model of the female pelvic system to understand effect of bladder fill and progressive vaginal tissue stiffening due to prolapse on anterior vaginal wall. Int J Numer Method Biomed Eng. 2016;32:32. https://doi.org/10.1002/cnm.2767.

    Article  Google Scholar 

  14. Flood JA, Tripp TJ, Davis CC, Hill DR, Schlievert PM. A toroid model for in vitro investigations of toxic shock syndrome toxin-1 production. J Microbiol Methods. 2004;57:283–8. https://doi.org/10.1016/j.mimet.2004.01.005.

    Article  CAS  PubMed  Google Scholar 

  15. Costin GE, Raabe HA, Priston R, Evans E, Curren RD. Vaginal irritation models: the current status of available alternative and in vitro tests. ATLA Altern to Lab Anim. 2011;39:317–37.

    Article  CAS  Google Scholar 

  16. Steele C, Fidel PL. Cytokine and chemokine production by human oral and vaginal epithelial cells in response to Candida albicans. Infect Immun. 2002;70:577–83. https://doi.org/10.1128/IAI.70.2.577-583.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Inada K, Hayashi S, Iguchi T, Sato T. Establishment of a primary culture model of mouse uterine and vaginal stroma for studying in vitro estrogen effects. Exp Biol Med. 2006;231:303–10. https://doi.org/10.1177/153537020623100310.

    Article  CAS  Google Scholar 

  18. Kufaishi H, Alarab M, Drutz H, Lye S, Shynlova O. Comparative characterization of vaginal cells derived from premenopausal women with and without severe pelvic organ prolapse. Reprod Sci. 2016;23:931–43. https://doi.org/10.1177/1933719115625840.

    Article  CAS  PubMed  Google Scholar 

  19. Hympanova L, Rynkevic R, Urbankova I, Blacher S, de Landsheere L, Mackova K, et al. Morphological and functional changes in the vagina following critical lifespan events in the ewe. Gynecol Obstet Investig. 2019;84:360–8. https://doi.org/10.1159/000495348.

    Article  CAS  Google Scholar 

  20. Abramowitch SD, Feola A, Jallah Z, Moalli PA. Tissue mechanics, animal models, and pelvic organ prolapse: a review. Eur J Obstet Gynecol Reprod Biol. 2009;144:S146–58.

    Article  Google Scholar 

  21. Cunha GR, Sinclair A, Ricke WA, Robboy SJ, Cao M, Baskin LS. Reproductive tract biology: of mice and men. Differentiation. 2019;110:49–63.

    Article  CAS  Google Scholar 

  22. Rendi MH, Muehlenbachs A, Garcia RL, Boyd KL. Female reproductive system. In: Comparative anatomy and histology. Elsevier Inc.; 2012. p. 253–84.

    Google Scholar 

  23. Grasso P, Rozhavskaya M, Reichert LE. In vivo effects of human follicle-stimulating hormone-related synthetic peptide hFSH-β-(81-95) and its subdomain hFSH-β-(90-95) on the mouse estrous cycle. Biol Reprod. 1998;58:821–5. https://doi.org/10.1095/biolreprod58.3.821.

    Article  CAS  PubMed  Google Scholar 

  24. Carretero, A., Ruberte, J. & Navarro M Anastrozole-an overview | ScienceDirect Topics. In: Morphol Mouse Phenotyping. https://www.sciencedirect.com/topics/neuroscience/anastrozole. Accessed 18 Sep 2020

  25. Grant-Tschudy KS, Wira CR. Effect of estradiol on mouse uterine epithelial cell transepithelial resistance (TER). Am J Reprod Immunol. 2004;52:252–62. https://doi.org/10.1111/j.1600-0897.2004.00218.x.

    Article  PubMed  Google Scholar 

  26. Imagawa W, Pedchenko VK, Helber J, Zhang H. Hormone/growth factor interactions mediating epithelial/stromal communication in mammary gland development and carcinogenesis. J Steroid Biochem Mol Biol. 2002;80:213–30. https://doi.org/10.1016/S0960-0760(01)00188-1.

    Article  CAS  PubMed  Google Scholar 

  27. Miyagawa S, Iguchi T. Epithelial estrogen receptor 1 intrinsically mediates squamous differentiation in the mouse vagina. Proc Natl Acad Sci U S A. 2015;112:12986–91. https://doi.org/10.1073/pnas.1513550112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li S, Herrera GG, Tam KK, Lizarraga JS, Beedle MT, Winuthayanon W. Estrogen action in the epithelial cells of the mouse vagina regulates neutrophil infiltration and vaginal tissue integrity. Sci Rep. 2018;8:11247. https://doi.org/10.1038/s41598-018-29423-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Davis BJ, Travlos G, McShane T. Reproductive endocrinology and toxicological pathology over the life span of the female rodent. Toxicol Pathol. 2001;29:77–83. https://doi.org/10.1080/019262301301418874.

    Article  CAS  PubMed  Google Scholar 

  30. Lee Silver’s Mouse Genetics. http://www.informatics.jax.org/silver/. Accessed 18 Sep 2020

  31. Robboy SJ, Kurita T, Baskin L, Cunha GR. New insights into human female reproductive tract development. Differentiation. 2017;97:9–22. https://doi.org/10.1016/j.diff.2017.08.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kurita T, Nakamura H (2008) Embryology of the uterus. In: The endometrium: molecular, cellular and clinical perspectives, second edition. CRC Press, pp 1–18

  33. Koff AK. Development of the vagina in the human fetus. Contrib Embryol. 1933;24:59–91.

    CAS  PubMed  Google Scholar 

  34. Forsberg J (1963) Derivation and differentiation of the vaginal epithelium. Lund

    Google Scholar 

  35. Cunha GR. Stromal induction and specification of morphogenesis and cytodifferentiation of the epithelia of the mullerian ducts and urogenital sinus during development of the uterus and vagina in mice. J Exp Zool. 1976;196:361–9. https://doi.org/10.1002/jez.1401960310.

    Article  CAS  PubMed  Google Scholar 

  36. Kurita T. Developmental origin of vaginal epithelium. Differentiation. 2010;80:99–105. https://doi.org/10.1016/j.diff.2010.06.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vrbanac A, Riestra AM, Coady A, Knight R, Nizet V, Patras KA. The murine vaginal microbiota and its perturbation by the human pathogen group B Streptococcus. BMC Microbiol. 2018;18:197. https://doi.org/10.1186/s12866-018-1341-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Moalli PA, Howden NS, Lowder JL, Navarro J, Debes KM, Abramowitch SD, et al. A rat model to study the structural properties of the vagina and its supportive tissues. Am J Obstet Gynecol. 2005;192:80–8. https://doi.org/10.1016/j.ajog.2004.07.008.

    Article  PubMed  Google Scholar 

  39. Liang R, Knight K, Nolfi A, Abramowitch S, Moalli PA. Differential effects of selective estrogen receptor modulators on the vagina and its supportive tissues. Menopause. 2016;23:129–37. https://doi.org/10.1097/GME.0000000000000502.

    Article  PubMed  Google Scholar 

  40. Bartos L (1977) Vaginal impedance measurement used for mating in the rat

  41. Krinke GJ. The laboratory rat: Elsevier; 2000.

  42. Goldman JM, Murr AS, Cooper RL. The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies. Birth Defects Res Part B - Dev Reprod Toxicol. 2007;80:84–97.

    Article  CAS  Google Scholar 

  43. Yuan Y-D, Carlson RG. Structure, cyclic change, and function, vagina and vulva, rat. Berlin, Heidelberg: Springer; 1987. p. 161–8.

    Google Scholar 

  44. Brown C. Urethral catheterization of the female rat. Lab Anim (NY). 2011;40:111–2. https://doi.org/10.1038/laban0411-111.

    Article  Google Scholar 

  45. Suckow M, Weisbroth S, Franklin C. The laboratory rat: Elsevier Inc.; 2006.

  46. Reis LO, Sopena JMG, Fávaro WJ, Martin MC, Simão AFL, Reis RB, et al. características anatômicas da cateterização da uretra e bexiga de camundongos e ratos fêmeas. instrumento essencial na pesquisa pré clínica. Acta Cir Bras. 2011;26:106–10. https://doi.org/10.1590/S0102-86502011000800019.

    Article  PubMed  Google Scholar 

  47. Long J, Evans HM The oestrous cycle in the rat and its associated phenomena

  48. Quesenberry K, Carpenter J. Ferrets, rabbits, and rodents: clinical medicine and surgery: Elsevier Inc.; 2012.

  49. Alperin M, Feola A, Duerr R, Moalli P, Abramowitch S. Pregnancy-and delivery-induced biomechanical changes in rat vagina persist postpartum. Int Urogynecol J. 2010;21:1169–74. https://doi.org/10.1007/s00192-010-1149-6.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Alperin M, Tuttle LJ, Conner BR, Dixon DM, Mathewson MA, Ward SR, et al. Comparison of pelvic muscle architecture between humans and commonly used laboratory species. Int Urogynecol J. 2014;25:1507–15. https://doi.org/10.1007/s00192-014-2423-9.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Maldonado PA, Montoya TI, Acevedo JF, Keller PW, Word RA. Effects of vaginal conjugated equine estrogens and ospemifene on the rat vaginal wall and lower urinary tract. Biol Reprod. 2017;96:81–92. https://doi.org/10.1095/biolreprod.116.144428.

    Article  PubMed  Google Scholar 

  52. Hamner J, Florian-Rodriguez M, Acevedo J, Shi H, Word RA. Protease inhibition improves healing of the vaginal wall after obstetrical injury: results from a preclinical animal model. Sci Rep. 2020;10:1–11. https://doi.org/10.1038/s41598-020-63031-6.

    Article  CAS  Google Scholar 

  53. Montoya TI, Maldonado PA, Acevedo JF, Word RA. Effect of vaginal or systemic estrogen on dynamics of collagen assembly in the rat vaginal wall. Biol Reprod. 2015;92:43. https://doi.org/10.1095/biolreprod.114.118638.

    Article  CAS  PubMed  Google Scholar 

  54. Mao M, Li Y, Zhang Y, Kang J, Zhu L. Tissue composition and biomechanical property changes in the vaginal wall of ovariectomized young rats. Biomed Res Int. 2019;2019:2019–0. https://doi.org/10.1155/2019/8921284.

    Article  CAS  Google Scholar 

  55. Ben Menachem-Zidon O, Parkes I, Chill HH, Reubinoff B, Sandberg K, Ji H, et al. Age-associated differences in macrophage response in a vaginal wound healing rat model. Int Urogynecol J. 2020;31:1803–9. https://doi.org/10.1007/s00192-020-04266-9.

    Article  PubMed  Google Scholar 

  56. Del Vecchio FR. Zur Entwicklung der kaudalen Abschnitte der Müllerschen Gänge bei der Ratte (Rattus norvegicus). Cells Tissues Organs. 1982;113:235–45. https://doi.org/10.1159/000145560.

    Article  Google Scholar 

  57. Sánchez-Ferrer ML, Acién MI, Sánchez del Campo F, et al. Experimental contributions to the study of the embryology of the vagina. Hum Reprod. 2006;21:1623–8. https://doi.org/10.1093/humrep/del031.

    Article  PubMed  Google Scholar 

  58. Noguchi K, Tsukumi K, Urano T Qualitative and quantitative differences in normal vaginal flora of conventionally reared mice, rats, hamsters, rabbits, and dogs

  59. Levy M, Bassis CM, Kennedy E, Yoest KE, Becker JB, Bell J, et al. The rodent vaginal microbiome across the estrous cycle and the effect of genital nerve electrical stimulation. PLoS One. 2020;15:e0230170. https://doi.org/10.1371/journal.pone.0230170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Green KA, Zarek SM, Catherino WH. Gynecologic health and disease in relation to the microbiome of the female reproductive tract. Fertil Steril. 2015;104:1351–7.

    Article  Google Scholar 

  61. Acartürk F, Robinson JR. Vaginal permeability and enzymatic activity studies in normal and ovariectomized rabbits. Pharm Res. 1996;13:779–83. https://doi.org/10.1023/A:1016016120392.

    Article  PubMed  Google Scholar 

  62. Rodríguez-Antolín J, Xelhuantzi N, García-Lorenzana M, Cuevas E, Hudson R, Martínez-Gómez M. General tissue characteristics of the lower urethral and vaginal walls in the domestic rabbit. Int Urogynecol J. 2009;20:53–60. https://doi.org/10.1007/s00192-008-0727-3.

    Article  Google Scholar 

  63. Laber-Laird K, Swindle MM, Flecknell P (eds. . (Dr. KL-LD of CMMUCSC (USA)) (1996) Handbook of rodent and rabbit medicine. Pergamon/Elsevier Science Ltd.

  64. Manning P. The biology of the laboratory rabbit. 2nd ed. San Diego: Academic Press; 1994.

    Google Scholar 

  65. Kahrmann B. V. Popesko, V. Rajtová and J. Horák: A colour atlas of the anatomy of small laboratory animals. Vol. II. Rat, Mouse, Hamster. 253 Seiten, 209 Abb. Wolfe Publishing Ltd., London 1992. Preis 335.— DM. Food Nahrung. 1994;38:447–7. https://doi.org/10.1002/food.19940380421.

  66. Eckstein P, Jackson MC, Millman N, Sobrero AJ. Comparison of vaginal tolerance tests of spermicidal preparations in rabbits and monkeys. J Reprod Fertil. 1969;20:85–93. https://doi.org/10.1530/jrf.0.0200085.

    Article  CAS  PubMed  Google Scholar 

  67. Oh SJ, Hong SK, Kim SW, Paick JS. Histological and functional aspects of different regions of the rabbit vagina. Int J Impot Res. 2003;15:142–50. https://doi.org/10.1038/sj.ijir.3900986.

    Article  PubMed  Google Scholar 

  68. CARR EB (1953) The development of the rabbit vagina. J Anat 87:423–431

  69. Barberini F, Correr S, Santis FDE, Motta PM. The epithelium of the rabbit vagina: a microtopographical study by light, transmission and scanning electron microscopy. Arch Histol Cytol. 1991;54:365–78. https://doi.org/10.1679/aohc.54.365.

    Article  CAS  PubMed  Google Scholar 

  70. Bollen P, Ellegaard L. The Göttingen minipig in pharmacology and toxicology. Pharmacol Toxicol. 1997;80:3–4. https://doi.org/10.1111/j.1600-0773.1997.tb01980.x.

    Article  CAS  PubMed  Google Scholar 

  71. Helke KL, Nelson KN, Sargeant AM, Jacob B, McKeag S, Haruna J, et al. Pigs in toxicology: breed differences in metabolism and background findings. Toxicol Pathol. 2016;44:575–90. https://doi.org/10.1177/0192623316639389.

    Article  CAS  PubMed  Google Scholar 

  72. Christoffersen B, Ribel U, Raun K, Golozoubova V, Pacini G. Evaluation of different methods for assessment of insulin sensitivity in Göttingen minipigs: introduction of a new, simpler method. Am J Phys Regul Integr Comp Phys. 2009;297:R1195–201. https://doi.org/10.1152/ajpregu.90851.2008.

    Article  CAS  Google Scholar 

  73. Gutierrez K, Dicks N, Glanzner WG, Agellon LB, Bordignon V. Efficacy of the porcine species in biomedical research. Front Genet. 2015;6. https://doi.org/10.3389/fgene.2015.00293.

  74. Helke KL, Nelson KN, Sargeant AM, Jacob B, McKeag S, Haruna J, et al. Background pathological changes in minipigs. Toxicol Pathol. 2016;44:325–37.

    Article  CAS  Google Scholar 

  75. Howroyd PC, Peter B, De Rijk E. Review of sexual maturity in the minipig. Toxicol Pathol. 2016;44:607–11.

    Article  Google Scholar 

  76. de Rijk E, Van Den Brink H, Lensen J, et al. Estrous cycle-dependent morphology in the reproductive organs of the female Göttingen minipig. Toxicol Pathol. 2014;42:1197–211. https://doi.org/10.1177/0192623314526136.

    Article  PubMed  Google Scholar 

  77. Peter B, De Rijk EPCT, Zeltner A, Emmen HH. Sexual maturation in the female Göttingen minipig. Toxicol Pathol. 2016;44:482–5. https://doi.org/10.1177/0192623315621413.

    Article  CAS  PubMed  Google Scholar 

  78. Lorenzen E, Follmann F, Jungersen G, Agerholm JS. A review of the human vs. porcine female genital tract and associated immune system in the perspective of using minipigs as a model of human genital Chlamydia infection. Vet Res. 2015:46.

  79. Lorenzen E, Agerholm JS, Grossi AB, Bojesen AM, Skytte C, Erneholm K, et al. Characterization of cytological changes, IgA, IgG and IL-8 levels and pH value in the vagina of prepubertal and sexually mature Ellegaard Göttingen minipigs during an estrous cycle. Dev Comp Immunol. 2016;59:57–62. https://doi.org/10.1016/j.dci.2016.01.006.

    Article  CAS  PubMed  Google Scholar 

  80. Noguchi M, Miura N, Ando T, et al. Profiles of reproductive hormone in the microminipig during the normal estrous cycle. In Vivo (Brooklyn). 2015;29:17–22.

    CAS  Google Scholar 

  81. Ettrup KS, Glud AN, Orlowski D, Fitting LM, Meier K, Soerensen JC, et al. Basic surgical techniques in the göttingen minipig: intubation, bladder catheterization, femoral vessel catheterization, and transcardial perfusion. J Vis Exp. 2011;2652. https://doi.org/10.3791/2652.

  82. Squier CA, Mantz MJ, Schlievert PM, Davis CC. Porcine vagina ex vivo as a model for studying permeability and pathogenesis in mucosa. J Pharm Sci. 2008;97:9–21. https://doi.org/10.1002/jps.21077.

    Article  CAS  PubMed  Google Scholar 

  83. Tortereau A, Howroyd P, Lorentsen H. Onset of puberty and normal histological appearances of the reproductive organs in peripubertal female Göttingen minipigs. Toxicol Pathol. 2013;41:1116–25. https://doi.org/10.1177/0192623313482777.

    Article  PubMed  Google Scholar 

  84. Baxter JS. Some observations on the development of the vagina in the pig. J Anat. 1934;68:239–250.1.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Kobayashi A, Behringer RR. Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet. 2003;4:969–80.

    Article  CAS  Google Scholar 

  86. Lorenzen E, Kudirkiene E, Gutman N, Grossi AB, Agerholm JS, Erneholm K, et al. The vaginal microbiome is stable in prepubertal and sexually mature Ellegaard Göttingen Minipigs throughout an estrous cycle. Vet Res. 2015;46:125. https://doi.org/10.1186/s13567-015-0274-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ellegaard L, Cunningham A, Edwards S, Grand N, Nevalainen T, Prescott M, et al. Welfare of the minipig with special reference to use in regulatory toxicology studies. J Pharmacol Toxicol Methods. 2010;62:167–83. https://doi.org/10.1016/j.vascn.2010.05.006.

    Article  CAS  PubMed  Google Scholar 

  88. (2004) Science, medicine, and animals. National Academies Press

  89. Monticello TM, Haschek WM. Swine in translational research and drug development. Toxicol Pathol. 2016;44:297–8.

    Article  CAS  Google Scholar 

  90. Entrican G, Wheelhouse NM. Immunity in the female sheep reproductive tract. Vet Res. 2006;37:295–309.

    Article  CAS  Google Scholar 

  91. Schoenian SG, Burfening PJ. Ovulation rate, lambing rate, litter size and embryo survival of Rambouillet sheep selected for high and low reproductive rate. J Anim Sci. 1990;68:2263–70. https://doi.org/10.2527/1990.6882263x.

    Article  CAS  PubMed  Google Scholar 

  92. (2003) SID sheep production handbook. American Sheep Industry Association, Centennial Colo.

  93. Vincent KL, Bourne N, Bell BA, Vargas G, Tan A, Cowan D, et al. High resolution imaging of epithelial injury in the sheep cervicovaginal tract: a promising model for testing safety of candidate microbicides. Sex Transm Dis. 2009;36:312–8. https://doi.org/10.1097/OLQ.0b013e31819496e4.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Moss JA, Malone AM, Smith TJ, Kennedy S, Nguyen C, Vincent KL, et al. Pharmacokinetics of a multipurpose pod-intravaginal ring simultaneously delivering five drugs in an ovine model. Antimicrob Agents Chemother. 2013;57:3994–7. https://doi.org/10.1128/AAC.00547-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Holt JDS, Cameron D, Dias N, Holding J, Muntendam A, Oostebring F, et al. The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides. Antimicrob Agents Chemother. 2015;59:3761–70. https://doi.org/10.1128/AAC.04954-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rubod C, Boukerrou M, Brieu M, Dubois P, Cosson M. Biomechanical properties of vaginal tissue. Part 1: New Experimental Protocol. J Urol. 2007;178:320–5. https://doi.org/10.1016/j.juro.2007.03.040.

    Article  PubMed  Google Scholar 

  97. Bulmer D. The epithelia of the developing female genital tract in the sheep. Acta Anat (Basel). 1964;57:349–66. https://doi.org/10.1159/000142563.

    Article  CAS  Google Scholar 

  98. Swartz JD, Lachman M, Westveer K, O’Neill T, Geary T, Kott RW, et al. Characterization of the vaginal microbiota of ewes and cows reveals a unique microbiota with low levels of lactobacilli and near-neutral pH. Front Vet Sci. 2014;1. https://doi.org/10.3389/fvets.2014.00019.

  99. McKinley M and VDO (2012) Human anatomy, 3rd ed. McGraw-Hill, New York, NY

  100. Widmaier EP, Raff H, KTS. Vander’s human physiology : the mechanisms of body function. 12th ed. New York: McGraw-Hill; 2011.

    Google Scholar 

  101. Coss D. Regulation of reproduction via tight control of gonadotropin hormone levels. Mol Cell Endocrinol. 2018;463:116–30. https://doi.org/10.1016/j.mce.2017.03.022.

    Article  CAS  PubMed  Google Scholar 

  102. Buffet NC, Djakoure C, Maitre SC, Bouchard P. Regulation of the human menstrual cycle. Front Neuroendocrinol. 1998;19:151–86. https://doi.org/10.1006/frne.1998.0167.

    Article  CAS  Google Scholar 

  103. Pendergrass PB, Reeves CA, Belovicz MW, Molter DJ, White JH. The shape and dimensions of the human vagina as seen in three-dimensional vinyl polysiloxane casts. Gynecol Obstet Investig. 1996;42:178–82. https://doi.org/10.1159/000291946.

    Article  CAS  Google Scholar 

  104. Luo J, Betschart C, Ashton-Miller JA, DeLancey JOL. Quantitative analyses of variability in normal vaginal shape and dimension on MR images. Int Urogynecol J. 2016;27:1087–95. https://doi.org/10.1007/s00192-016-2949-0.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Appelbaum AH, Zuber JK, Levi-D’Ancona R, Cohen HL. Vaginal anatomy on MRI: new information obtained using distention. South Med J. 2018;111:691–7. https://doi.org/10.14423/SMJ.0000000000000889.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Barnhart KT, Izquierdo A, Pretorius ES, Shera DM, Shabbout M, Shaunik A. Baseline dimensions of the human vagina. Hum Reprod. 2006;21:1618–22. https://doi.org/10.1093/humrep/del022.

    Article  PubMed  Google Scholar 

  107. Anderson DJ, Marathe J, Pudney J. The structure of the human vaginal stratum corneum and its role in immune defense. Am J Reprod Immunol. 2014;71:618–23. https://doi.org/10.1111/aji.12230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Patton DL, Thwin SS, Meier A, et al (2000) Epithelial cell layer thickness and immune cell populations in the normal human vagina at different stages of the menstrual cycle. In: American Journal of Obstetrics and Gynecology. Mosby Inc., pp 967–973

  109. Farage M, Maibach H. Lifetime changes in the vulva and vagina. Arch Gynecol Obstet. 2006;273:195–202.

    Article  Google Scholar 

  110. Zhou JZ, Way SS, Chen K. Immunology of the uterine and vaginal mucosae. Trends Immunol. 2018;39:302–14.

    Article  CAS  Google Scholar 

  111. Ulrich D, Edwards SL, Letouzey V, Su K, White JF, Rosamilia A, et al. Regional variation in tissue composition and biomechanical properties of postmenopausal ovine and human vagina. PLoS One. 2014;9:e104972. https://doi.org/10.1371/journal.pone.0104972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci U S A. 2011;108:4680–7. https://doi.org/10.1073/pnas.1002611107.

    Article  PubMed  Google Scholar 

  113. Nunn KL, Forney LJ. Unraveling the dynamics of the human vaginal microbiome. Yale J Biol Med. 2016;89:331–7.

    PubMed  PubMed Central  Google Scholar 

  114. Gajer P, Brotman RM, Bai G, et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med. 2012;4:132ra52. https://doi.org/10.1126/scitranslmed.3003605.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Pybus V, Onderdonk AB. Microbial interactions in the vaginal ecosystem, with emphasis on the pathogenesis of bacterial vaginosis. Microbes Infect. 1999;1:285–92.

    Article  CAS  Google Scholar 

  116. Martin HL, Richardson BA, Nyange PM, Lavreys L, Hillier SL, Chohan B, et al. Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1 and sexually transmitted disease acquisition. J Infect Dis. 1999;180:1863–8. https://doi.org/10.1086/315127.

    Article  CAS  PubMed  Google Scholar 

  117. Chen B, Wen Y, Yu X, Polan ML. Elastin metabolism in pelvic tissues: is it modulated by reproductive hormones? Am J Obstet Gynecol. 2005;192:1605–13. https://doi.org/10.1016/j.ajog.2004.11.027.

    Article  CAS  PubMed  Google Scholar 

  118. Krebs FC, Miller SR, Catalone BJ, Fichorova R, Anderson D, Malamud D, et al. Comparative in vitro sensitivities of human immune cell lines, vaginal and cervical epithelial cell lines, and primary cells to candidate microbicides nonoxynol 9, C31G, and sodium dodecyl sulfate. Antimicrob Agents Chemother. 2002;46:2292–8. https://doi.org/10.1128/AAC.46.7.2292-2298.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zalenskaya IA, Joseph T, Bavarva J, Yousefieh N, Jackson SS, Fashemi T, et al. Gene expression profiling of human vaginal cells in vitro discriminates compounds with pro-inflammatory and mucosa-altering properties: novel biomarkers for preclinical testing of HIV microbicide candidates. PLoS One. 2015;10:e0128557. https://doi.org/10.1371/journal.pone.0128557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Rajan N, Pruden DL, Kaznari H, et al. Characterization of an immortalized human vaginal epithelial cell line. J Urol. 2000;163:616–22. https://doi.org/10.1016/S0022-5347(05)67946-3.

    Article  CAS  PubMed  Google Scholar 

  121. Medel S, Alarab M, Kufaishi H, Drutz H, Shynlova O. Attachment of primary vaginal fibroblasts to absorbable and nonabsorbable implant materials coated with platelet-rich plasma: Potential application in pelvic organ prolapse surgery. Female Pelvic Med Reconstr Surg. 2015;21:190–7. https://doi.org/10.1097/SPV.0000000000000178.

    Article  PubMed  Google Scholar 

  122. Cruz Y, Hudson R, Pacheco P, Lucio RA, Martı́nez-Gómez M. Anatomical and physiological characteristics of perineal muscles in the female rabbit. Physiol Behav. 2002;75:33–40. https://doi.org/10.1016/S0031-9384(01)00638-2.

    Article  CAS  PubMed  Google Scholar 

  123. Patnaik SS, Borazjani A, Brazile B, et al (2016) Pelvic floor biomechanics from animal models. In: Biomechanics of the female pelvic floor. Elsevier Inc., pp 131–148

  124. Ishii A, Ogawa B, Koyama T, Nakanishi Y, Sasaki M. Influence of the estrus cycle on the evaluation of a vaginal irritation study in intact and ovariectomized rats. J Toxicol Pathol. 2017;30:161–8. https://doi.org/10.1293/tox.2016-0059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ashton-Miller JA, DeLancey JOL. On the biomechanics of vaginal birth and common sequelae. Annu Rev Biomed Eng. 2009;11:163–76.

    Article  CAS  Google Scholar 

  126. Scudellari M. A decade of : iPS Cells. Nature. 2016;534:310–2. https://doi.org/10.1038/534310a.

    Article  PubMed  Google Scholar 

  127. Knight E, Przyborski S. Advances in 3D cell culture technologies enabling tissue-like structures to be created in vitro. J Anat. 2015;227:746–56.

    Article  Google Scholar 

  128. Jakubowska W, Chabaud S, Saba I, Galbraith T, Berthod F, Bolduc S. Prevascularized tissue-engineered human vaginal mucosa: in vitro optimization and in vivo validation. Tissue Eng - Part A. 2020;26:811–22. https://doi.org/10.1089/ten.tea.2020.0036.

    Article  CAS  PubMed  Google Scholar 

  129. Zhang JK, Du RX, Zhang L, et al. A new material for tissue engineered vagina reconstruction: acellular porcine vagina matrix. J Biomed Mater Res - Part A. 2017;105:1949–59. https://doi.org/10.1002/jbm.a.36066.

    Article  CAS  Google Scholar 

  130. Zhu L, Zhou H, Sun Z, Lou W, Lang J. Anatomic and sexual outcomes after vaginoplasty using tissue-engineered biomaterial graft in patients with Mayer-Rokitansky-Küster-Hauser syndrome: a new minimally invasive and effective surgery. J Sex Med. 2013;10:1652–8. https://doi.org/10.1111/jsm.12143.

    Article  PubMed  Google Scholar 

  131. Sarmento B, Andrade F, Da Silva SB, et al. Cell-based in vitro models for predicting drug permeability. Expert Opin Drug Metab Toxicol. 2012;8:607–21.

    Article  CAS  Google Scholar 

  132. Guaderrama NM, Nager CW, Liu J, Pretorius DH, Mittal RK. The vaginal pressure profile. Neurourol Urodyn. 2005;24:243–7. https://doi.org/10.1002/nau.20112.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the Texas Children’s Hospital’s Office of Surgical research, especially Drs. Sundeep Keswani, Swathi Balaji, and Hector Martinez-Valdez for their helpful discussions and editorial support. The breadth of this review covering 3D models was supported in part by Lazarus3D.

Funding

This work was funded in part by a granted K08 award (GM135638-01) and seed funding by the Department of Obstetrics and Gynecology at Baylor College of Medicine.

Author information

Author notes

  1. Jennifer M. McCracken and Gisele A. Calderon contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, 77030, USA

    Jennifer M. McCracken, Gisele A. Calderon, Courtney N. Sullivan & Julie C. E. Hakim

  2. Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, USA

    Andrew J. Robinson & Elizabeth Cosgriff-Hernandez

  3. Department of Pediatric Surgery, Texas Children’s Hospital, Houston, TX, 77030, USA

    Julie C. E. Hakim

Authors
  1. Jennifer M. McCracken
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gisele A. Calderon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew J. Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Courtney N. Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elizabeth Cosgriff-Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julie C. E. Hakim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julie C. E. Hakim.

Ethics declarations

Ethics Approval

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McCracken, J.M., Calderon, G.A., Robinson, A.J. et al. Animal Models and Alternatives in Vaginal Research: a Comparative Review. Reprod. Sci. 28, 1759–1773 (2021). https://doi.org/10.1007/s43032-021-00529-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-021-00529-y

Keywords

Search

Navigation