Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Engineered reproductive tissues

Nature Biomedical Engineering volume 4, pages 381–393 (2020)Cite this article

Subjects

An Author Correction to this article was published on 24 April 2020

This article has been updated

Abstract

Engineered male and female biomimetic reproductive tissues are being developed as autonomous in vitro units or as integrated multi-organ in vitro systems to support germ cell and embryo function, and to display characteristic endocrine phenotypic patterns, such as the 28-day human ovulatory cycle. In this Review, we summarize how engineered reproductive tissues facilitate research in reproductive biology, and overview strategies for making engineered reproductive tissues that might eventually allow the restoration of reproductive capacity in patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The female reproductive tract.
Fig. 2: Endocrinology of the hypothalamic–pituitary–gonadal axis.
Fig. 3: The male reproductive tract.
Fig. 4: Strategies for the use of engineered biomaterials in reproductive science and medicine.
Fig. 5: Microfluidic culture models of components of both the male and female reproductive tracts.

Similar content being viewed by others

Change history

References

  1. Morris, R. T. The ovarian graft. New York Med. J. 62, 436 (1895).

    Google Scholar 

  2. Favre-Inhofer, A., Rafii, A., Carbonnel, M., Revaux, A. & Ayoubi, J. M. Uterine transplantation: review in human research. J. Gynecol. Obstet. Hum. Reprod. 47, 213–221 (2018).

    CAS  PubMed  Google Scholar 

  3. Rodriguez, K. M. & Pastuszak, A. W. A history of penile implants. Transl. Androl. Urol. 6, S851–S857 (2017).

    PubMed  PubMed Central  Google Scholar 

  4. Girsdansky, J. & Newman, H. F. Use of a vitallium testicular implant. Am. J. Surg. 53, 514 (1941).

    Google Scholar 

  5. Steptoe, P. C. & Edwards, R. G. Birth after the reimplantation of a human embryo. Lancet 312, 366 (1978).

    Google Scholar 

  6. Silber, S. J. Transplantation of a human testis for anorchia. Fertil. Steril. 30, 181–187 (1978).

    CAS  PubMed  Google Scholar 

  7. Zeilmaker, G. H., Alberda, A. T., van Gent, I., Rijkmans, C. M. P. M. & Drogendijk, A. C. Two pregnancies following transfer of intact frozen-thawed embryos. Fertil. Steril. 42, 293–296 (1984).

    CAS  PubMed  Google Scholar 

  8. Chen, C. Pregnancy after human oocyte cryopreservation. Lancet 1, 884–886 (1986).

    CAS  PubMed  Google Scholar 

  9. Palermo, G., Joris, H., Devroey, P. & Van Steirteghem, A. C. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 340, 17–18 (1992).

    CAS  PubMed  Google Scholar 

  10. Donnez, J. et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 364, 1405–1410 (2004).

    CAS  PubMed  Google Scholar 

  11. Hilders, C. G., Baranski, A. G., Peters, L., Ramkhelawan, A. & Trimbos, J. B. Successful human ovarian autotransplantation to the upper arm. Cancer 101, 2771–2778 (2004).

    PubMed  Google Scholar 

  12. Jadoul, P. et al. Laparoscopic ovariectomy for whole human ovary cryopreservation: technical aspects. Fertil. Steril. 87, 971–975 (2007).

    PubMed  Google Scholar 

  13. Woodruff, T. K. The emergence of a new interdiscipline: oncofertility. Cancer Treat. Res. 138, 3–11 (2007).

    PubMed  Google Scholar 

  14. Xu, M., Kreeger, P. K., Shea, L. D. & Woodruff, T. K. Tissue-engineered follicles produce live, fertile offspring. Tissue Eng. 12, 2739–2746 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Raya-Rivera, A. M. et al. Tissue-engineered autologous vaginal organs in patients: a pilot cohort study. Lancet 384, 329–336 (2014).

    PubMed  Google Scholar 

  16. Xiao, S. et al. In vitro follicle growth supports human oocyte meiotic maturation. Sci. Rep. 5, 17323 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Brännström, M. et al. Livebirth after uterus transplantation. Lancet 385, 607–616 (2015).

    PubMed  Google Scholar 

  18. Xiao, S. et al. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat. Commun. 8, 14584 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Partridge, E. A. et al. An extra-uterine system to physiologically support the extreme premature lamb. Nat. Commun. 8, 15112 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. Laronda, M. M. et al. A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nat. Commun. 8, 15261 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Botman, O. & Wyns, C. Induced pluripotent stem cell potential in medicine, specifically focused on reproductive medicine. Front. Surg. 1, 5 (2014).

    PubMed  PubMed Central  Google Scholar 

  22. Amini Mahabadi, J. et al. Derivation of male germ cells from induced pluripotent stem cells by inducers: a review. Cytotherapy 20, 279–290 (2018).

    CAS  PubMed  Google Scholar 

  23. Poels, J. et al. Transplantation of testicular tissue in alginate hydrogel loaded with VEGF nanoparticles improves spermatogonial recovery. J. Control. Release 234, 79–89 (2016).

    CAS  PubMed  Google Scholar 

  24. Shikanov, A. et al. Fibrin encapsulation and vascular endothelial growth factor delivery promotes ovarian graft survival in mice. Tissue Eng. Part A 17, 3095–3104 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ensign, L. M., Cone, R. & Hanes, J. Nanoparticle-based drug delivery to the vagina: a review. J. Control. Release 190, 500–514 (2014).

    CAS  PubMed  Google Scholar 

  26. Tanaka, A. et al. Effect of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogels on frozen-thawed human ovarian tissue in a xenograft model. J. Obstet. Gynaecol. Res. 44, 1947–1955 (2018).

    CAS  PubMed  Google Scholar 

  27. Prakapenka, A. V., Bimonte-Nelson, H. A. & Sirianni, R. W. Engineering poly(lactic-co-glycolic acid) (PLGA) micro- and nano-carriers for controlled delivery of 17β-estradiol. Ann. Biomed. Eng. 45, 1697–1709 (2017).

    PubMed  PubMed Central  Google Scholar 

  28. Kashaninejad, N., Shiddiky, M. J. A. & Nguyen, N.-T. Advances in microfluidics-based assisted reproductive technology: from sperm sorter to reproductive system-on-a-chip. Adv. Biosyst. 2, 1700197 (2018).

    Google Scholar 

  29. Weng, L. et al. On-chip oocyte denudation from cumulus-oocyte complexes for assisted reproductive therapy. Lab Chip 18, 3892–3902 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Strauss, J. F. & Barbieri, R. L. Yen and Jaffe’s Reproductive Endocrinology (Elsevier, 2014).

  31. Saunders, P. T. K. et al. Differential expression of oestrogen receptor alpha and beta proteins in the testes and male reproductive system of human and non-human primates. Mol. Hum. Reprod. 7, 227–236 (2001).

    CAS  PubMed  Google Scholar 

  32. Toutain, P.-L., Ferran, A. & Bousquet-Mélou, A. in Comparative and Veterinary Pharmacology (eds Cunningham, F. et al.) 19–48 (Springer, 2010).

  33. Sato, J., Nasu, M. & Tsuchitani, M. Comparative histopathology of the estrous or menstrual cycle in laboratory animals. J. Toxicol. Pathol. 29, 155–162 (2016).

    PubMed  PubMed Central  Google Scholar 

  34. Kanatsu-Shinohara, M. et al. Reconstitution of mouse spermatogonial stem cell niches in culture. Cell Stem Cell 11, 567–578 (2012).

    CAS  PubMed  Google Scholar 

  35. Bylander, A. et al. Rapid effects of progesterone on ciliary beat frequency in the mouse fallopian tube. Reprod. Biol. Endocrinol. 8, 48 (2010).

    PubMed  PubMed Central  Google Scholar 

  36. Cunha, G. R. et al. The endocrinology and developmental biology of the prostate. Endocr. Rev. 8, 338–362 (1987).

    CAS  PubMed  Google Scholar 

  37. Roberts, R. O. et al. Androgen receptor gene polymorphisms and increased risk of urologic measures of benign prostatic hyperplasia. Am. J. Epidemiol. 159, 269–276 (2004).

    PubMed  Google Scholar 

  38. Goldenberg, S. L., Koupparis, A. & Robinson, M. E. Differing levels of testosterone and the prostate: a physiological interplay. Nat. Rev. Urol. 8, 365–377 (2011).

    CAS  PubMed  Google Scholar 

  39. O’Shaughnessy, P. J. Hormonal control of germ cell development and spermatogenesis. Semin. Cell Dev. Biol. 29, 55–65 (2014).

    PubMed  Google Scholar 

  40. Herbst, K. L. & Bhasin, S. Testosterone action on skeletal muscle. Curr. Opin. Clin. Nutr. Metab. Care 7, 271–277 (2004).

    CAS  PubMed  Google Scholar 

  41. Karsenty, G. & Oury, F. Regulation of male fertility by the bone-derived hormone osteocalcin. Mol. Cell. Endocrinol. 382, 521–526 (2014).

    CAS  PubMed  Google Scholar 

  42. Oury, F. et al. Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. J. Clin. Invest. 123, 2421–2433 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim, A. M., Tingen, C. M. & Woodruff, T. K. Sex bias in trials and treatment must end. Nature 465, 688–689 (2010).

    CAS  PubMed  Google Scholar 

  44. Nicodemus, G. D. & Bryant, S. J. Cell encapsulation in biodegradable hydrogels for tissue engineering applications. Tissue Eng. Part B Rev. 14, 149–165 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Khetan, S. & Burdick, J. Cellular encapsulation in 3D hydrogels for tissue engineering. J. Vis. Exp. 32, 1590 (2009).

    Google Scholar 

  46. West, E. R., Shea, L. D. & Woodruff, T. K. Engineering the follicle microenvironment. Semin. Reprod. Med. 25, 287–299 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Joo, S. et al. The effect of collagen hydrogel on 3D culture of ovarian follicles. Biomed. Mater. 11, 065009 (2016).

    PubMed  Google Scholar 

  48. Skory, R. M., Xu, Y., Shea, L. D. & Woodruff, T. K. Engineering the ovarian cycle using in vitro follicle culture. Hum. Reprod. 30, 1386–1395 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Amorim, C. A., Van Langendonckt, A., David, A., Dolmans, M.-M. & Donnez, J. Survival of human pre-antral follicles after cryopreservation of ovarian tissue, follicular isolation and in vitro culture in a calcium alginate matrix. Hum. Reprod. 24, 92–99 (2008).

    PubMed  Google Scholar 

  50. Pangas, S. A., Saudye, H., Shea, L. D. & Woodruff, T. K. Novel approach for the three-dimensional culture of granulosa cell–oocyte complexes. Tissue Eng. 9, 1013–1021 (2003).

    CAS  PubMed  Google Scholar 

  51. Xu, J. et al. Fibrin promotes development and function of macaque primary follicles during encapsulated three-dimensional culture. Hum. Reprod. 28, 2187–2200 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Desai, N., Abdelhafez, F., Calabro, A. & Falcone, T. Three dimensional culture of fresh and vitrified mouse pre-antral follicles in a hyaluronan-based hydrogel: a preliminary investigation of a novel biomaterial for in vitro follicle maturation. Reprod. Biol. Endocrinol. 10, 29 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Shikanov, A., Smith, R. M., Xu, M., Woodruff, T. K. & Shea, L. D. Hydrogel network design using multifunctional macromers to coordinate tissue maturation in ovarian follicle culture. Biomaterials 32, 2524–2531 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Shikanov, A., Xu, M., Woodruff, T. K. & Shea, L. D. Interpenetrating fibrin–alginate matrices for in vitro ovarian follicle development. Biomaterials 30, 5476–5485 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Choi, J. K., Agarwal, P., Huang, H., Zhao, S. & He, X. The crucial role of mechanical heterogeneity in regulating follicle development and ovulation with engineered ovarian microtissue. Biomaterials 35, 5122–5128 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Lebbe, M. & Woodruff, T. K. Involvement of androgens in ovarian health and disease. Mol. Hum. Reprod. 19, 828–837 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. West-Farrell, E. R. et al. The mouse follicle microenvironment regulates antrum formation and steroid production: alterations in gene expression profiles. Biol. Reprod. 80, 432–439 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Alves-Lopes, J. P., Söder, O. & Stukenborg, J. B. Testicular organoid generation by a novel in vitro three-layer gradient system. Biomaterials 130, 76–89 (2017).

    CAS  PubMed  Google Scholar 

  59. Gholami, K., Pourmand, G., Koruji, M., Ashouri, S. & Abbasi, M. Organ culture of seminiferous tubules using a modified soft agar culture system. Stem Cell Res. Ther. 9, 249 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Vermeulen, M. et al. Generation of organized porcine testicular organoids in solubilized hydrogels from decellularized extracellular matrix. Int. J. Mol. Sci. 20, 5476 (2019).

    CAS  PubMed Central  Google Scholar 

  61. Kessler, M. et al. The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nat. Commun. 6, 8989 (2015).

    CAS  PubMed  Google Scholar 

  62. Zambuto, S. G., Clancy, K. B. H. & Harley, B. A. C. A gelatin hydrogel to study endometrial angiogenesis and trophoblast invasion. Interface Focus 9, 20190016 (2019).

    PubMed  PubMed Central  Google Scholar 

  63. Crapo, P. M., Gilbert, T. W. & Badylak, S. F. An overview of tissue and whole organ decellularization processes. Biomaterials 32, 3233–3243 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Laronda, M. M. et al. Initiation of puberty in mice following decellularized ovary transplant. Biomaterials 50, 20–29 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Eivazkhani, F. et al. Evaluating two ovarian decellularization methods in three species. Mater. Sci. Eng. C 102, 670–682 (2019).

    CAS  Google Scholar 

  66. Hassanpour, A., Talaei-Khozani, T., Kargar-Abarghouei, E., Razban, V. & Vojdani, Z. Decellularized human ovarian scaffold based on a sodium lauryl ester sulfate (SLES)-treated protocol, as a natural three-dimensional scaffold for construction of bioengineered ovaries. Stem Cell Res. Ther. 9, 252 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Alshaikh, A. B. et al. Decellularization of the mouse ovary: comparison of different scaffold generation protocols for future ovarian bioengineering. J. Ovarian Res. 12, 58 (2019).

    PubMed  PubMed Central  Google Scholar 

  68. Mirzaeian, L. et al. Optimizing the cell seeding protocol to human decellularized ovarian scaffold: Application of dynamic system for bio-engineering. Cell J. 22, 227–235 (2019).

    PubMed  PubMed Central  Google Scholar 

  69. Hiraoka, T. et al. STAT3 accelerates uterine epithelial regeneration in a mouse model of decellularized uterine matrix transplantation. JCI Insight 1, e87591 (2016).

    PubMed Central  Google Scholar 

  70. Hellström, M. et al. Bioengineered uterine tissue supports pregnancy in a rat model. Fertil. Steril. 106, 487–496 (2016).

    PubMed  Google Scholar 

  71. Campo, H. et al. De- and recellularization of the pig uterus: a bioengineering pilot study. Biol. Reprod. 96, 34–45 (2017).

    PubMed  Google Scholar 

  72. Olalekan, S. A., Burdette, J. E., Getsios, S., Woodruff, T. K. & Kim, J. J. Development of a novel human recellularized endometrium that responds to a 28-day hormone treatment. Biol. Reprod. 96, 971–981 (2017).

    PubMed  PubMed Central  Google Scholar 

  73. Miyazaki, K. & Maruyama, T. Partial regeneration and reconstruction of the rat uterus through recellularization of a decellularized uterine matrix. Biomaterials 35, 8791–8800 (2014).

    CAS  PubMed  Google Scholar 

  74. Daryabari, S. S. et al. Development of an efficient perfusion-based protocol for whole-organ decellularization of the ovine uterus as a human-sized model and in vivo application of the bioscaffolds. J. Assist. Reprod. Genet. 36, 1211–1223 (2019).

    PubMed  PubMed Central  Google Scholar 

  75. Baert, Y. & Goossens, E. in Methods in Molecular Biology (Ed. Turksen, K.) 121–127 (Humana Press, 2017).

  76. Vermeulen, M., del Vento, F., de Michele, F., Poels, J. & Wyns, C. Development of a cytocompatible scaffold from pig immature testicular tissue allowing human Sertoli cell attachment, proliferation and functionality. Int. J. Mol. Sci. 19, 227 (2018).

    PubMed Central  Google Scholar 

  77. Kargar-Abarghouei, E., Vojdani, Z., Hassanpour, A., Alaee, S. & Talaei-Khozani, T. Characterization, recellularization, and transplantation of rat decellularized testis scaffold with bone marrow-derived mesenchymal stem cells. Stem Cell Res. Ther. 9, 324 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Akbarzadeh, A. et al. Decellularised whole ovine testis as a potential bio-scaffold for tissue engineering. Reprod. Fertil. Dev. 31, 1665–1673 (2019).

    CAS  PubMed  Google Scholar 

  79. Barreto, R. S. N., Romagnolli, P., Fratini, P., Mess, A. M. & Miglino, M. A. Mouse placental scaffolds: a three-dimensional environment model for recellularization. J. Tissue Eng. 10, 1–11 (2019).

    CAS  Google Scholar 

  80. Favaron, P. O. et al. Establishment of 3-dimensional scaffolds from hemochorial placentas. Placenta 81, 32–41 (2019).

    CAS  PubMed  Google Scholar 

  81. Motamed, M. et al. Tissue engineered human amniotic membrane application in mouse ovarian follicular culture. Ann. Biomed. Eng. 45, 1664–1675 (2017).

    CAS  PubMed  Google Scholar 

  82. Oktay, K., Bedoschi, G., Pacheco, F., Turan, V. & Emirdar, V. First pregnancies, live birth, and in vitro fertilization outcomes after transplantation of frozen-banked ovarian tissue with a human extracellular matrix scaffold using robot-assisted minimally invasive surgery. Am. J. Obstet. Gynecol. 214, 94.e1–94.e9 (2016).

    Google Scholar 

  83. Baert, Y. et al. Derivation and characterization of a cytocompatible scaffold from human testis. Hum. Reprod. 30, 256–267 (2015).

    CAS  PubMed  Google Scholar 

  84. Baert, Y. et al. Primary human testicular cells self-organize into organoids with testicular properties. Stem Cell Rep. 8, 30–38 (2017).

    CAS  Google Scholar 

  85. Baert, Y., Rombaut, C. & Goossens, E. in Methods in Molecular Biology (Ed. Turksen, K.) 283–290 (Humana, 2017).

  86. Park, M. H. et al. Effects of extracellular matrix protein-derived signaling on the maintenance of the undifferentiated state of spermatogonial stem cells from porcine neonatal testis. Asian-Australasian J. Anim. Sci. 29, 1398–1406 (2016).

    CAS  Google Scholar 

  87. Scarrit, M. E., Pashos, N. C. & Bunnell, B. A. A review of cellularization strategies for tissue engineering of whole organs. Front. Bioeng. Biotechnol. 3, 43 (2015).

    Google Scholar 

  88. Jakus, A. E. et al. “Tissue papers” from organ-specific decellularized extracellular matrices. Adv. Funct. Mater. 27, 1700992 (2017).

    PubMed  PubMed Central  Google Scholar 

  89. Rezaei Topraggaleh, T., Rezazadeh Valojerdi, M., Montazeri, L. & Baharvand, H. A testis-derived macroporous 3D scaffold as a platform for the generation of mouse testicular organoids. Biomater. Sci. 7, 1422–1436 (2019).

    CAS  PubMed  Google Scholar 

  90. Henning, N. F., LeDuc, R. D., Even, K. A. & Laronda, M. M. Proteomic analyses of decellularized porcine ovaries identified new matrisome proteins and spatial differences across and within ovarian compartments. Sci. Rep. 9, 20001 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Ouni, E., Vertommen, D., Chiti, M. C., Dolmans, M. M. & Amorim, C. A. A draft map of the human ovarian proteome for tissue engineering and clinical applications. Mol. Cell. Proteomics 18, S159–S173 (2019).

    CAS  PubMed  Google Scholar 

  92. Murphy, S. V. & Atala, A. 3D bioprinting of tissues and organs. Nat. Biotechnol. 32, 773–785 (2014).

    CAS  PubMed  Google Scholar 

  93. Billiet, T., Vandenhaute, M., Schelfhout, J., Van Vlierberghe, S. & Dubruel, P. A review of trends and limitations in hydrogel-rapid prototyping for tissue engineering. Biomaterials 33, 6020–6041 (2012).

    CAS  PubMed  Google Scholar 

  94. Raffel, N. et al. Novel approach for the assessment of ovarian follicles infiltration in polymeric electrospun patterned scaffolds. PLoS ONE 14, e0215985 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Baert, Y., Dvorakova-Hortova, K., Margaryan, H. & Goossens, E. Mouse in vitro spermatogenesis on alginate-based 3D bioprinted scaffolds. Biofabrication 11, 035011 (2019).

    CAS  PubMed  Google Scholar 

  96. Kuo, C.-Y. et al. Development of a 3D printed, bioengineered placenta model to evaluate the role of trophoblast migration in preeclampsia. ACS Biomater. Sci. Eng. 2, 1817–1826 (2016).

    CAS  PubMed  Google Scholar 

  97. Kuo, C. Y. et al. Trophoblast–endothelium signaling involves angiogenesis and apoptosis in a dynamic bioprinted placenta model. Biotechnol. Bioeng. 116, 181–192 (2019).

    CAS  PubMed  Google Scholar 

  98. Paul, K. et al. 3D bioprinted endometrial stem cells on melt electrospun poly ε-caprolactone mesh for pelvic floor application promote anti-inflammatory responses in mice. Acta Biomater. 97, 162–176 (2019).

    CAS  PubMed  Google Scholar 

  99. Ovsianikov, A., Khademhosseini, A. & Mironov, V. The synergy of scaffold-based and scaffold-free tissue engineering strategies. Trends Biotechnol. 36, 348–357 (2018).

    CAS  PubMed  Google Scholar 

  100. Huch, M. & Koo, B.-K. Modeling mouse and human development using organoid cultures. Development 142, 3113–3125 (2015).

    CAS  PubMed  Google Scholar 

  101. Cui, X., Hartanto, Y. & Zhang, H. Advances in multicellular spheroids formation. J. Roy. Soc. Interface 14, 20160877 (2017).

    Google Scholar 

  102. De Gregorio, V. et al. An engineered cell-instructive stroma for the fabrication of a novel full thickness human cervix equivalent in vitro. Adv. Healthc. Mater. 6, 1601199 (2017).

    Google Scholar 

  103. Karolina Zuk, A., Wen, X., Dilworth, S., Li, D. & Ghali, L. Modeling and validating three dimensional human normal cervix and cervical cancer tissues in vitro. J. Biomed. Res. 31, 240–247 (2017).

    PubMed  Google Scholar 

  104. von Kopylow, K. et al. Dynamics, ultrastructure and gene expression of human in vitro organized testis cells from testicular sperm extraction biopsies. Mol. Hum. Reprod. 24, 123–134 (2018).

    Google Scholar 

  105. Higaki, S. et al. In vitro differentiation of fertile sperm from cryopreserved spermatogonia of the endangered endemic cyprinid honmoroko (Gnathopogon caerulescens). Sci. Rep. 7, 42852 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Azizi, H., Skutella, T. & Shahverdi, A. Generation of mouse spermatogonial stem-cell-colonies in a non-adherent culture. Cell J. 19, 238–249 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. Lin, Z. Y. C. et al. Sphere-formation culture of testicular germ cells in the common marmoset, a small New World monkey. Primates 57, 129–135 (2016).

    PubMed  Google Scholar 

  108. Pendergraft, S. S., Sadri-Ardekani, H., Atala, A. & Bishop, C. E. Three-dimensional testicular organoid: a novel tool for the study of human spermatogenesis and gonadotoxicity in vitro. Biol. Reprod. 96, 720–732 (2017).

    PubMed  Google Scholar 

  109. Strange, D. P. et al. Human testicular organoid system as a novel tool to study Zika virus pathogenesis. Emerg. Microbes Infect. 7, 82 (2018).

    PubMed  PubMed Central  Google Scholar 

  110. Murphy, A. R., Wiwatpanit, T., Lu, Z., Davaadelger, B. & Kim, J. J. Generation of multicellular human primary endometrial organoids. J. Vis. Exp. 152, e60384 (2019).

    Google Scholar 

  111. Sakib, S., Yu, Y., Voigt, A., Ungrin, M. & Dobrinski, I. Generation of porcine testicular organoids with testis specific architecture using microwell culture. J. Vis. Exp. 152, e60387 (2019).

    Google Scholar 

  112. Sakib, S. et al. Formation of organotypic testicular organoids in microwell culture†. Biol. Reprod. 100, 1648–1660 (2019).

    PubMed  PubMed Central  Google Scholar 

  113. Zhang, B., Korolj, A., Lai, B. F. L. & Radisic, M. Advances in organ-on-a-chip engineering. Nat. Rev. Mater. 3, 257–278 (2018).

    Google Scholar 

  114. Bhatia, S. N. & Ingber, D. E. Microfluidic organs-on-chips. Nat. Biotechnol. 32, 760–772 (2014).

    CAS  PubMed  Google Scholar 

  115. Kim, M. S., Bae, C. Y., Wee, G., Han, Y. M. & Park, J. K. A microfluidic in vitro cultivation system for mechanical stimulation of bovine embryos. Electrophoresis 30, 3276–3282 (2009).

    CAS  PubMed  Google Scholar 

  116. Zhu, J. et al. Human fallopian tube epithelium co-culture with murine ovarian follicles reveals crosstalk in the reproductive cycle. Mol. Hum. Reprod. 22, 756–767 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. García, E. V. et al. Bovine embryo-oviduct interaction in vitro reveals an early cross talk mediated by BMP signaling. Reproduction 153, 631–643 (2017).

    PubMed  Google Scholar 

  118. Ferraz, M. A. M. M. et al. Improved bovine embryo production in an oviduct-on-a-chip system: prevention of poly-spermic fertilization and parthenogenic activation. Lab Chip 17, 905–916 (2017).

    CAS  PubMed  Google Scholar 

  119. Komeya, M. et al. Long-term ex vivo maintenance of testis tissues producing fertile sperm in a microfluidic device. Sci. Rep. 6, 21472 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. De Michele, F. et al. Preserved seminiferous tubule integrity with spermatogonial survival and induction of Sertoli and Leydig cell maturation after long-term organotypic culture of prepubertal human testicular tissue. Hum. Reprod. 32, 32–45 (2017).

    PubMed  Google Scholar 

  121. Yamanaka, H. et al. A monolayer microfluidic device supporting mouse spermatogenesis with improved visibility. Biochem. Biophys. Res. Commun. 500, 885–891 (2018).

    CAS  PubMed  Google Scholar 

  122. Gnecco, J. S. et al. Compartmentalized culture of perivascular stroma and endothelial cells in a microfluidic model of the human endometrium. Ann. Biomed. Eng. 45, 1758–1769 (2017).

    PubMed  PubMed Central  Google Scholar 

  123. Lee, J. S. et al. Placenta-on-a-chip: a novel platform to study the biology of the human placenta. J. Matern. Neonatal Med. 29, 1046–1054 (2016).

    CAS  Google Scholar 

  124. Blundell, C. et al. A microphysiological model of the human placental barrier. Lab Chip 16, 3065–3073 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Nishiguchi, A. et al. In vitro placenta barrier model using primary human trophoblasts, underlying connective tissue and vascular endothelium. Biomaterials 192, 140–148 (2019).

    CAS  PubMed  Google Scholar 

  126. Pemathilaka, R. L., Caplin, J. D., Aykar, S. S., Montazami, R. & Hashemi, N. N. Placenta-on-a-chip: in vitro study of caffeine transport across placental barrier using liquid chromatography mass spectrometry. Glob. Challenges 3, 1800112 (2019).

    Google Scholar 

  127. Arumugasaamy, N., Hurley-Novatny, A., Lembong, J., Kim, P. C. W. & Fisher, J. P. Assessing SSRIs’ effects on fetal cardiomyocytes utilizing placenta-fetus model. Acta Biomater. 99, 258–268 (2019).

    PubMed  PubMed Central  Google Scholar 

  128. Arumugasaamy, N., Gudelsky, A., Hurley-Novatny, A., Kim, P. C. W. & Fisher, J. P. Model placental barrier phenotypic response to fluoxetine and sertraline: a comparative study. Adv. Healthc. Mater. 8, e1900476 (2019).

    PubMed  PubMed Central  Google Scholar 

  129. Yin, F. et al. A 3D human placenta-on-a-chip model to probe nanoparticle exposure at the placental barrier. Toxicol. Vitr. 54, 105–113 (2019).

    CAS  Google Scholar 

  130. Arumugasaamy, N. et al. Biomimetic placenta-fetus model demonstrating maternal–fetal transmission and fetal neural toxicity of Zika virus. Ann. Biomed. Eng. 46, 1963–1974 (2018).

    PubMed  Google Scholar 

  131. Abbas, Y. et al. A microfluidics assay to study invasion of human placental trophoblast cells. J. R. Soc. Interface 14, 20170131 (2017).

    PubMed  PubMed Central  Google Scholar 

  132. Li, S.-S. et al. Modeling ovarian cancer multicellular spheroid behavior in a dynamic 3D peritoneal microdevice. J. Vis. Exp. 120, e55337 (2017).

    Google Scholar 

  133. Zhou, H. et al. Hydrogel based 3-dimensional (3D) system for toxicity and high-throughput (HTP) analysis for cultured murine ovarian follicles. PLoS ONE 10, e0140205 (2015).

    PubMed  PubMed Central  Google Scholar 

  134. Xiao, S. et al. Doxorubicin has dose-dependent toxicity on mouse ovarian follicle development, hormone secretion, and oocyte maturation. Toxicol. Sci. 157, 320–329 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Meng, C.-X., Andersson, K. L., Bentin-Ley, U., Gemzell-Danielsson, K. & Lalitkumar, P. G. L. Effect of levonorgestrel and mifepristone on endometrial receptivity markers in a three-dimensional human endometrial cell culture model. Fertil. Steril. 91, 256–264 (2009).

    CAS  PubMed  Google Scholar 

  136. Laronda, M. M., Burdette, J. E., Kim, J. & Woodruff, T. K. Recreating the female reproductive tract in vitro using iPSC technology in a linked microfluidics environment. Stem Cell Res. Ther. 4, S13 (2013).

    PubMed  PubMed Central  Google Scholar 

  137. Cooper, A. R. et al. The time is now for a new approach to primary ovarian insufficiency. Fertil. Steril. 95, 1890–1897 (2011).

    PubMed  Google Scholar 

  138. De Vos, M., Smitz, J. & Woodruff, T. K. Fertility preservation in women with cancer. Lancet 384, 1302–1310 (2014).

    PubMed  PubMed Central  Google Scholar 

  139. Jeruss, J. S. & Woodruff, T. K. Preservation of fertility in patients with cancer. N. Engl. J. Med. 360, 902–911 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Donnez, J. & Dolmans, M.-M. Fertility preservation in women. N. Engl. J. Med. 377, 1657–1665 (2017).

    PubMed  Google Scholar 

  141. Donnez, J., Dolmans, M.-M., Diaz, C. & Pellicer, A. Ovarian cortex transplantation: time to move on from experimental studies to open clinical application. Fertil. Steril. 104, 1097–1098 (2015).

    PubMed  Google Scholar 

  142. Amorim, C. A. & Shikanov, A. The artificial ovary: current status and future perspectives. Future Oncol. 12, 2323–2332 (2016).

    CAS  PubMed  Google Scholar 

  143. Kniazeva, E. et al. Primordial follicle transplantation within designer biomaterial grafts produce live births in a mouse infertility model. Sci. Rep. 5, 17709 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Rios, P. D. et al. Retrievable hydrogels for ovarian follicle transplantation and oocyte collection. Biotechnol. Bioeng. 115, 2075–2086 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Vanacker, J. et al. Transplantation of an alginate-matrigel matrix containing isolated ovarian cells: first step in developing a biodegradable scaffold to transplant isolated preantral follicles and ovarian cells. Biomaterials 33, 6079–6085 (2012).

    CAS  PubMed  Google Scholar 

  146. Day, J. R. et al. Immunoisolating poly(ethylene glycol) based capsules support ovarian tissue survival to restore endocrine function. J. Biomed. Mater. Res. Part A 106, 1381–1389 (2018).

    CAS  Google Scholar 

  147. Felder, S. et al. Reconstruction of the ovary microenvironment utilizing macroporous scaffold with affinity-bound growth factors. Biomaterials 205, 11–22 (2019).

    CAS  PubMed  Google Scholar 

  148. Sittadjody, S. et al. Encapsulation of mesenchymal stem cells in 3D ovarian cell constructs promotes stable and long-term hormone secretion with improved physiological outcomes in a syngeneic rat model. Ann. Biomed. Eng. 48, 1058–1070 (2020).

    PubMed  Google Scholar 

  149. David, A., Day, J. & Shikanov, A. Immunoisolation to prevent tissue graft rejection: current knowledge and future use. Exp. Biol. Med. 241, 955–961 (2016).

    CAS  Google Scholar 

  150. David, A. et al. Restoring ovarian endocrine function with encapsulated ovarian allograft in immune competent mice. Ann. Biomed. Eng. 45, 1685–1696 (2017).

    PubMed  Google Scholar 

  151. Sittadjody, S. et al. In vivo transplantation of 3D encapsulated ovarian constructs in rats corrects abnormalities of ovarian failure. Nat. Commun. 8, 1858 (2017).

    PubMed  PubMed Central  Google Scholar 

  152. Yakhnenko, I., Wong, W. K., Katkov, I. I. & Itkin-Ansari, P. Cryopreservation of human insulin expressing cells macro-encapsulated in a durable therapeutic immunoisolating device theracyte. Cryo-Lett. 33, 518–531 (2012).

    Google Scholar 

  153. Veiseh, O. et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat. Mater. 14, 643–651 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Calafiore, R. et al. Microencapsulated pancreatic islet allografts into nonimmunosuppressed patients with type 1 diabetes: first two cases. Diabetes Care 29, 137–138 (2006).

    PubMed  Google Scholar 

  155. Edmonds, M. E., Orwig, K. E. & Brannigan, R. E. in Textbook of Oncofertility Research and Practice: A Multidisciplinary Approach (eds Woodruff, T. K. et al.) 385–394 (Springer, 2019).

  156. Kaneko, H. et al. Generation of live piglets for the first time using sperm retrieved from immature testicular tissue cryopreserved and grafted into nude mice. PLoS ONE 8, e70989 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Hermann, B. P. et al. Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm. Cell Stem Cell 11, 715–726 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Fayomi, A. P. et al. Autologous grafting of cryopreserved prepubertal rhesus testis produces sperm and offspring. Science 363, 1314–1319 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Liu, Z. et al. Generation of macaques with sperm derived from juvenile monkey testicular xenografts. Cell Res. 26, 139–142 (2016).

    PubMed  Google Scholar 

  160. Ohta, H. & Wakayama, T. Generation of normal progeny by intracytoplasmic sperm injection following grafting of testicular tissue from cloned mice that died postnatally. Biol. Reprod. 73, 390–395 (2005).

    CAS  PubMed  Google Scholar 

  161. Poels, J., Van Langendonckt, A., Many, M.-C., Wese, F.-X. & Wyns, C. Vitrification preserves proliferation capacity in human spermatogonia. Hum. Reprod. 28, 578–589 (2013).

    CAS  PubMed  Google Scholar 

  162. Medrano, J. V. et al. Germ cell transplantation into mouse testes procedure. Fertil. Steril. 102, e11–e12 (2014).

    CAS  PubMed  Google Scholar 

  163. Poels, J. et al. In search of better spermatogonial preservation by supplementation of cryopreserved human immature testicular tissue xenografts with N-acetylcysteine and testosterone. Front. Surg. 1, 47 (2014).

    PubMed  PubMed Central  Google Scholar 

  164. de Michele, F. et al. Haploid germ cells generated in organotypic culture of testicular tissue from prepubertal boys. Front. Physiol. 9, 1413 (2018).

    PubMed  PubMed Central  Google Scholar 

  165. Lee, K. H. et al. Vitrified canine testicular cells allow the formation of spermatogonial stem cells and seminiferous tubules following their xenotransplantation into nude mice. Sci. Rep. 6, 21919 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Honaramooz, A., Megee, S. O., Rathi, R. & Dobrinski, I. Building a testis: formation of functional testis tissue after transplantation of isolated porcine (Sus scrofa) Testis Cells. Biol. Reprod. 76, 43–47 (2007).

    CAS  PubMed  Google Scholar 

  167. Brinster, R. L. Germline stem cell transplantation and transgenesis. Science 296, 2174–2176 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Xin, L. et al. A collagen scaffold loaded with human umbilical cord-derived mesenchymal stem cells facilitates endometrial regeneration and restores fertility. Acta Biomater. 92, 160–171 (2019).

    CAS  PubMed  Google Scholar 

  169. 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. 10, 1652–1658 (2013).

    PubMed  Google Scholar 

  170. Ding, J.-X., Chen, X.-J., Zhang, X.-y, Zhang, Y. & Hua, K.-Q. Acellular porcine small intestinal submucosa graft for cervicovaginal reconstruction in eight patients with malformation of the uterine cervix. Hum. Reprod. 29, 677–682 (2014).

    PubMed  Google Scholar 

  171. Ding, J.-X., Zhang, X., Chen, L. & Hua, K.-Q. Vaginoplasty using acellular porcine small intestinal submucosa graft in two patients with Meyer-von-Rokitansky-Küster-Hauser syndrome: a prospective new technique for vaginal reconstruction. Gynecol. Obstet. Invest. 75, 93–96 (2013).

    PubMed  Google Scholar 

  172. Li, Y. et al. Bone marrow mesenchymal stem cells could acquire the phenotypes of epithelial cells and accelerate vaginal reconstruction combined with small intestinal submucosa. Cell Biol. Int. 39, 1225–1233 (2015).

    CAS  PubMed  Google Scholar 

  173. Pinto Medeiros Dias, M. T. et al. Tilapia fish skin as a new biologic graft for neovaginoplasty in Mayer-Rokitansky-Kuster-Hauser syndrome: a video case report. Fertil. Steril. 112, 174–176 (2019).

    PubMed  Google Scholar 

  174. Dabaghi, M. et al. An artificial placenta type microfluidic blood oxygenator with double-sided gas transfer microchannels and its integration as a neonatal lung assist device. Biomicrofluidics 12, 044101 (2018).

    PubMed  PubMed Central  Google Scholar 

  175. Hunt, P. A. et al. Bisphenol a exposure causes meiotic aneuploidy in the female mouse. Curr. Biol. 13, 546–553 (2003).

    CAS  PubMed  Google Scholar 

  176. ART Success Rates. Centers for Disease Control and Prevention https://www.cdc.gov/art/artdata/index.html (2019).

  177. Campo-Engelstein, L., Chen, D., Baratz, A. B., Johnson, E. K. & Finlayson, C. The ethics of fertility preservation for pediatric patients with differences (disorders) of sex development. J. Endocr. Soc. 1, 638–645 (2017).

    PubMed  PubMed Central  Google Scholar 

  178. Woodruff, T. K., Zoloth, L., Campo-Engelstein, L. & Rodriguez, S. Oncofertility: ethical, legal, social, and medical perspectives. Preface. Cancer Treat. Res. 156, 5–7 (2010).

    Google Scholar 

  179. Segers, S., Mertes, H., de Wert, G., Dondorp, W. & Pennings, G. Balancing ethical pros and cons of stem cell derived gametes. Ann. Biomed. Eng. 45, 1620–1632 (2017).

    PubMed  Google Scholar 

  180. Basco, D., Campo-Engelstein, L. & Rodriguez, S. Insuring against infertility: expanding state infertility mandates to include fertility preservation technology for cancer patients. J. Law Med. Ethics 38, 832–839 (2010).

    PubMed  PubMed Central  Google Scholar 

  181. Fleetwood, A. & Campo-Engelstein, L. The impact of infertility: why ART should be a higher priority for women in the global South. Canc. Treat. 156, 237–248 (2010).

    Google Scholar 

  182. Campo-Engelstein, L. Consistency in insurance coverage for iatrogenic conditions resulting from cancer treatment including fertility preservation. J. Clin. Oncol. 28, 1284–1286 (2010).

    PubMed  PubMed Central  Google Scholar 

  183. Chatzinikolaou, N. The ethics of assisted reproduction. J. Reprod. Immunol. 85, 3–8 (2010).

    PubMed  Google Scholar 

  184. Brezina, P. R. & Zhao, Y. The ethical, legal, and social issues impacted by modern assisted reproductive technologies. Obstet. Gynecol. Int. 2012, 686253 (2012).

    PubMed  PubMed Central  Google Scholar 

  185. Campo-Engelstein, L. Offering testicular tissue cryopreservation to boys: the increasing importance of biological fatherhood. Am. J. Bioeth. 13, 39–40 (2013).

    PubMed  Google Scholar 

  186. Alves-Lopes, J. P., Söder, O. & Stukenborg, J. B. Use of a three-layer gradient system of cells for rat testicular organoid generation. Nat. Protoc. 13, 248–259 (2018).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Stacey C. Tobin for editorial assistance on the manuscript. The work in the Woodruff laboratory has been supported by the National Institutes of Health (NIH) through a variety of Institutes and Offices, including the National Center for Advancing Translational Sciences (NCATS), the National Institute of Environmental Health Sciences (NIEHS), the Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), the Office of Women's Health Research (ORWH) and the NIH Common Fund. We are currently funded by the National Institute for Environmental Health Sciences/National Center for Advancing Translational Sciences (grant nos. UH3TR001207 and 4UH3ES029073-03), the Bill & Melinda Gates Foundation (grant no. OPP1161206), the Thomas J. Watkin’s Memorial Professorship, the National Institute of Aging (grant no. F30AG058387, awarded to E.S.G.) and the National Institute for Child Health and Development (grant no. F31HD089693, awarded to M.E.E.). All other grants mentioned are awarded to T.K.W.

Author information

Author notes

  1. These authors contributed equally: E. S. Gargus, H. B. Rogers, K. E. McKinnon, M. E. Edmonds.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Emma S. Gargus, Hunter B. Rogers, Kelly E. McKinnon, Maxwell E. Edmonds & Teresa K. Woodruff

Authors
  1. Emma S. Gargus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hunter B. Rogers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kelly E. McKinnon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maxwell E. Edmonds
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Teresa K. Woodruff
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.K.W. conceived the project, supervised the work and edited the manuscript. E.S.G., H.B.R., M.E.E. and K.E.M. performed the literature review and wrote and revised the manuscript. E.S.G., H.B.R. and K.E.M. prepared the figures and tables.

Corresponding author

Correspondence to Teresa K. Woodruff.

Ethics declarations

Competing interests

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

Gargus, E.S., Rogers, H.B., McKinnon, K.E. et al. Engineered reproductive tissues. Nat Biomed Eng 4, 381–393 (2020). https://doi.org/10.1038/s41551-020-0525-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-020-0525-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing