Tissue Engineering and Regenerative Medicine

, Volume 13, Issue 5, pp 447–454 | Cite as

Efficient biomaterials for tissue engineering of female reproductive organs

  • Amin Tamadon
  • Kyu-Hyung Park
  • Yoon Young Kim
  • Byeong-Cheol Kang
  • Seung-Yup KuEmail author
Feature Article Tissue Engineering


Current investigations on the bioengineering of female reproductive tissues have created new hopes for the women suffering from reproductive organ failure including congenital anomaly of the female reproductive tract or serious injuries. There are many surgically restore forms that constitute congenital anomaly, however, to date, there is no treatment except surgical treatment of transplantation for patients who are suffering from anomaly or dysfunction organs like vagina and uterus. Restoring and maintaining the normal function of ovary and uterus require the establishment of biological substitutes that can cover the roles of structural support for cells and passage of secreting molecules. As in the case of constructing other functional organs, reproductive organ manufacturing also needs biological matrices which can provide an appropriate condition for attachment, growth, proliferation and signaling of various kinds of grafted cells. Among the organs, uterus needs special features such as plasticity due to their amazing changes in volume when they are in the state of pregnancy. Although numerous natural and synthetic biomaterials are still at the experimental stage, some biomaterials have already been evaluated their efficacy for the reconstruction of female reproductive tissues. In this review, all the biomaterials cited in recent literature that have ever been used and that have a potential for the tissue engineering of female reproductive organs were reviewed, especially focused on bioengineered ovary and uterus.

Key Words

Tissue engineering Biomaterial Ovary Uterus 


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  1. 1.
    SGO Clinical Practice Endometrial Cancer Working Group, Burke WM, Orr J, Leitao M, Salom E, Gehrig P, et al. Endometrial cancer:a review and current management strategies:part II. Gynecol Oncol 2014;134:393–402.CrossRefGoogle Scholar
  2. 2.
    Vassilakopoulou M, Boostandoost E, Papaxoinis G, de La Motte Rouge T, Khayat D, Psyrri A. Anticancer treatment and fertility:effect of therapeutic modalities on reproductive system and functions. Crit Rev Oncol Hematol 2016;97:328–334.CrossRefPubMedGoogle Scholar
  3. 3.
    Doherty L, Mutlu L, Sinclair D, Taylor H. Uterine fibroids:clinical manifestations and contemporary management. Reprod Sci 2014;21:1067–1092.CrossRefPubMedGoogle Scholar
  4. 4.
    Berman JR, Bassuk J. Physiology and pathophysiology of female sexual function and dysfunction. World J Urol 2002;20:111–118.CrossRefPubMedGoogle Scholar
  5. 5.
    Salama M, Mallmann P. Emergency fertility preservation for female patients with cancer:clinical perspectives. Anticancer Res 2015;35:3117–3127.PubMedGoogle Scholar
  6. 6.
    Carlson MJ, Thiel KW, Leslie KK. Past, present, and future of hormonal therapy in recurrent endometrial cancer. Int J Womens Health 2014;6:429–435.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Iavazzo C, Gkegkes ID. Possible role of DaVinci Robot in uterine transplantation. J Turk Ger Gynecol Assoc 2015;16:179–180.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cervelló I, Santamaría X, Miyazaki K, Maruyama T, Simón C. Cell Therapy and tissue engineering from and toward the uterus. Semin Reprod Med 2015;33:366–372.CrossRefPubMedGoogle Scholar
  9. 9.
    Hellström M, El-Akouri RR, Sihlbom C, Olsson BM, Lengqvist J, Bäckdahl H, et al. Towards the development of a bioengineered uterus:comparison of different protocols for rat uterus decellularization. Acta Biomater 2014;10:5034–5042.CrossRefPubMedGoogle Scholar
  10. 10.
    Li WX, Liang GT, Yan W, Zhang Q, Wang W, Zhou XM, et al. Artificial uterus on a microfluidic chip. Chin J Anal Chem 2013;41:467–472.CrossRefGoogle Scholar
  11. 11.
    Labrie F. All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause. J Steroid Biochem Mol Biol 2015;145:133–138.CrossRefPubMedGoogle Scholar
  12. 12.
    Jeong JH, Park JR, JIn ES, Min JK, Jeon SR, Kim DK, et al. Adipose tissue-derived stem cells in the ovariectomy-induced postmenopausal osteoporosis rat model. Tissue Eng Regen Med 2015;12:28–36.CrossRefGoogle Scholar
  13. 13.
    Wese ER, Shea LD, Woodruff TK. Engineering the follicle microenvironment. Semin Reprod Med 2007;25:287–299.CrossRefGoogle Scholar
  14. 14.
    Vanacker J, Luyckx V, Dolmans MM, Des Rieux A, Jaeger J, Van Langendonckt A, 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 2012;33:6079–6085.CrossRefPubMedGoogle Scholar
  15. 15.
    Berkholtz CB, Lai BE, Woodruff TK, Shea LD. Distribution of extracellular matrix proteins type I collagen, type IV collagen, fibronectin, and laminin in mouse folliculogenesis. Histochem Cell Biol 2006;126:583–592.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Shea LD, Woodruff TK, Shikanov A. Bioengineering the ovarian follicle microenvironment. Annu Rev Biomed Eng 2014;16:29–52.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Smith RM, Woodruff TK, Shea LD. Designing follicle-environment interactions with biomaterials. Cancer Treat Res 2010;156:11–24.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nat Biotechnol 2014;32:773–785.CrossRefPubMedGoogle Scholar
  19. 19.
    Andrade LR, Salgado LT, Farina M, Pereira MS, Mourão PA, Amado Filho GM. Ultrastructure of acidic polysaccharides from the cell walls of brown algae. J Struct Biol 2004;145:216–225.CrossRefPubMedGoogle Scholar
  20. 20.
    Kedem A, Hourvitz A, Fisch B, Shachar M, Cohen S, Ben-Haroush A, et al. Alginate scaffold for organ culture of cryopreserved-thawed human ovarian cortical follicles. J Assist Reprod Genet 2011;28:761–769.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lee SH, Chung HY, Shin HI, Park DJ, Choi JH. Osteogenic activity of chitosan-based hybrid scaffold prepared by polyelectrolyte complex formation with alginate. Tissue Eng Regen Med 2014;11:106–112.CrossRefGoogle Scholar
  22. 22.
    Camboni A, Van Langendonckt A, Donnez J, Vanacker J, Dolmans MM, Amorim CA. Alginate beads as a tool to handle, cryopreserve and culture isolated human primordial/primary follicles. Cryobiology 2013;67:64–69.CrossRefPubMedGoogle Scholar
  23. 23.
    Xu M, West E, Shea LD, Woodruff TK. Identification of a stage-specific permissive in vitro culture environment for follicle growth and oocyte development. Biol Reprod 2006;75:916–923.CrossRefPubMedGoogle Scholar
  24. 24.
    Xu M, Kreeger PK, Shea LD, Woodruff TK. Tissue-engineered follicles produce live, fertile offspring. Tissue Eng 2006;12:2739–2746.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Tagler D, Makanji Y, Tu T, Bernabé BP, Lee R, Zhu J, et al. Promoting extracellular matrix remodeling via ascorbic acid enhances the survival of primary ovarian follicles encapsulated in alginate hydrogels. Biotechnol Bioeng 2014;111:1417–1429.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tagler D, Tu T, Smith RM, Anderson NR, Tingen CM, Woodruff TK, et al. Embryonic fibroblasts enable the culture of primary ovarian follicles within alginate hydrogels. Tissue Eng Part A 2012;18:1229–1238.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Park KE, Kim YY, Ku SY, Baek SM, Huh Y, Kim YJ, et al. Effects of alginate hydrogels on in vitro maturation outcome of mouse preantral follicles. Tissue Eng Regen Med 2012;9:170–174.CrossRefGoogle Scholar
  28. 28.
    Chiu CL, Hecht V, Duong H, Wu B, Tawil B. Permeability of three-dimensional fibrin constructs corresponds to fibrinogen and thrombin concentrations. Biores Open Access 2012;1:34–40.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sese N, Cole M, Tawil B. Proliferation of human keratinocytes and cocultured human keratinocytes and fibroblasts in three-dimensional fibrin constructs. Tissue Eng Part A 2011;17:429–437.CrossRefPubMedGoogle Scholar
  30. 30.
    Luyckx V, Dolmans MM, Vanacker J, Scalercio SR, Donnez J, Amorim CA. First step in developing a 3D biodegradable fibrin scaffold for an artificial ovary. J Ovarian Res 2013;6:83.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Luyckx V, Dolmans MM, Vanacker J, Legat C, Fortuño Moya C, Donnez J, et al. A new step toward the artificial ovary:survival and proliferation of isolated murine follicles after autologous transplantation in a fibrin scaffold. Fertil Steril 2014;101:1149–1156.CrossRefPubMedGoogle Scholar
  32. 32.
    Soares M, Sahrari K, Chiti MC, Amorim CA, Ambroise J, Donnez J, et al. The best source of isolated stromal cells for the artificial ovary:medulla or cortex, cryopreserved or fresh? Hum Reprod 2015;30:1589–1598.CrossRefPubMedGoogle Scholar
  33. 33.
    Duong H, Wu B, Tawil B. Modulation of 3D fibrin matrix stiffness by intrinsic fibrinogen-thrombin compositions and by extrinsic cellular activity. Tissue Eng Part A 2009;15:1865–1876.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Xu M, West-Farrell ER, Stouffer RL, Shea LD, Woodruff TK, Zelinski MB. Encapsulated three-dimensional culture supports development of nonhuman primate secondary follicles. Biol Reprod 2009;81:587–594.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Shikanov A, Xu M, Woodruff TK, Shea LD. A method for ovarian follicle encapsulation and culture in a proteolytically degradable 3 dimensional system. J Vis Exp 2011;(49). pii:2695.PubMedGoogle Scholar
  36. 36.
    Shea LD, Woodruff TK, Shikanov A. US20120142069 A1. Interpenetrating biomaterial matrices and uses thereof. Evanston:Northwestern University;2012.Google Scholar
  37. 37.
    Dikovsky D, Bianco-Peled H, Seliktar D. Proteolytically degradable photo-polymerized hydrogels made from PEG-fibrinogen adducts. Adv Eng Mater 2010;12:B200–B209.CrossRefGoogle Scholar
  38. 38.
    Peled E, Boss J, Bejar J, Zinman C, Seliktar D. A novel poly(ethylene glycol)-fibrinogen hydrogel for tibial segmental defect repair in a rat model. J Biomed Mater Res A 2007;80:874–884.CrossRefPubMedGoogle Scholar
  39. 39.
    Lerer-Serfaty G, Samara N, Fisch B, Shachar M, Kossover O, Seliktar D, et al. Attempted application of bioengineered/biosynthetic supporting matrices with phosphatidylinositol-trisphosphate-enhancing substances to organ culture of human primordial follicles. J Assist Reprod Genet 2013;30:1279–1288.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kossowska-Tomaszczuk K, Pelczar P, Güven S, Kowalski J, Volpi E, De Geyter C, et al. A novel three-dimensional culture system allows prolonged culture of functional human granulosa cells and mimics the ovarian environment. Tissue Eng Part A 2010;16:2063–2073.CrossRefPubMedGoogle Scholar
  41. 41.
    Riva F, Omes C, Fassina L, Vaghi P, Reguzzoni M, Casasco M, et al. 3D culture of multipotent cells derived from waste human ovarian follicular liquid and seeded onto gelatin cryogel. Ital J Anat Embryol 2013;118:162.Google Scholar
  42. 42.
    Laronda MM, Rutz AL, Xiao S, Whelan KA, Woodruff TK, Shah RN. 3D printed scaffold architecture influences ovarian follicle function. Tissue Eng Part A 2015;21:S30.Google Scholar
  43. 43.
    Laronda MM, Rutz AL, Jakus AE, Xiao S, Whelan KA, Wertheim JA, et al. Ovarian follicles develop and ovulate within a bioengineered artificial ovary. Tissue Eng Part A 2014;20:S44.Google Scholar
  44. 44.
    Jaganathan H, Godin B. Biocompatibility assessment of Si-based nanoand micro-particles. Adv Drug Deliv Rev 2012;64:1800–1819.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Catalano PN, Bourguignon NS, Alvarez GS, Libertun C, Diaz LU, Desimone MF, et al. Sol-gel immobilized ovarian follicles:collaboration between two different cell types in hormone production and secretion. J Mater Chem 2012;22:11681–11687.CrossRefGoogle Scholar
  46. 46.
    Wijesinghe W, Jeon YJ. Biological activities and potential industrial applications of fucose rich sulfated polysaccharides and fucoidans isolated from brown seaweeds:a review. Carbohydr Polym 2012;88:13–20.CrossRefGoogle Scholar
  47. 47.
    Krotz SP, Robins JC, Ferruccio TM, Moore R, Steinhoff MM, Morgan JR, et al. In vitro maturation of oocytes via the pre-fabricated self-assembled artificial human ovary. J Assist Reprod Genet 2010;27:743–750.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Laronda MM, Jakus AE, Whelan KA, Wertheim JA, Shah RN, Woodruff TK. Initiation of puberty in mice following decellularized ovary transplant. Biomaterials 2015;50:20–29.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kakehi K, Kinoshita M, Yasueda S. Hyaluronic acid:separation and biological implications. J Chromatogr B Analyt Technol Biomed Life Sci 2003;797:347–355.CrossRefPubMedGoogle Scholar
  50. 50.
    Kim JT, Lee DY, Kim EJ, Jang JW, Cho NI. Tissue response to implants of hyaluronic acid hydrogel prepared by microbeads. Tissue Eng Regen Med 2014;11:32–38.CrossRefGoogle Scholar
  51. 51.
    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 2012;10:29.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Yalcinkaya TM, Sittadjody S, Opara EC. Scientific principles of regenerative medicine and their application in the female reproductive system. Maturitas 2014;77:12–19.CrossRefPubMedGoogle Scholar
  53. 53.
    Huh Y, Kim YY, Ku SY. Perspective of bioartificial uterus as gynecological regenerative medicine. Tissue Eng Regen Med 2012;9:233–239.CrossRefGoogle Scholar
  54. 54.
    Johannesson L, Enskog A, Dahm-Kähler P, Hanafy A, Chai DC, Mwenda JM, et al. Uterus transplantation in a non-human primate:long-term follow-up after autologous transplantation. Hum Reprod 2012;27:1640–1648.CrossRefPubMedGoogle Scholar
  55. 55.
    Deonandan R, Green S, van Beinum A. Ethical concerns for maternal surrogacy and reproductive tourism. J Med Ethics 2012;38:742–745.CrossRefPubMedGoogle Scholar
  56. 56.
    Atala A, Yoo JJ. Construction of an artificial uterus;provide biocompatible matrix, prefuse with cell population, culture cells, recover artificial uterine tissue. Boston:Google Patents;2008.Google Scholar
  57. 57.
    Li X, Sun H, Lin N, Hou X, Wang J, Zhou B, et al. Regeneration of uterine horns in rats by collagen scaffolds loaded with collagen-binding human basic fibroblast growth factor. Biomaterials 2011;32:8172–8181.CrossRefPubMedGoogle Scholar
  58. 58.
    Campbell GR, Turnbull G, Xiang L, Haines M, Armstrong S, Rolfe BE, et al. The peritoneal cavity as a bioreactor for tissue engineering visceral organs:bladder, uterus and vas deferens. J Tissue Eng Regen Med 2008;2:50–60.CrossRefPubMedGoogle Scholar
  59. 59.
    Miyazaki K, Maruyama T. Partial regeneration and reconstruction of the rat uterus through recellularization of a decellularized uterine matrix. Biomaterials 2014;35:8791–8800.CrossRefPubMedGoogle Scholar
  60. 60.
    Santoso EG, Yoshida K, Hirota Y, Aizawa M, Yoshino O, Kishida A, et al. Application of detergents or high hydrostatic pressure as decellularization processes in uterine tissues and their subsequent effects on in vivo uterine regeneration in murine models. PLoS One 2014;9:e103201.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Roberts CP, Rock JA. Surgical methods in the treatment of congenital anomalies of the uterine cervix. Curr Opin Obstet Gynecol 2011;23:251–257.CrossRefPubMedGoogle Scholar
  62. 62.
    Ding JX, Chen XJ, Zhang XY, Zhang Y, Hua KQ. Acellular porcine small intestinal submucosa graft for cervicovaginal reconstruction in eight patients with malformation of the uterine cervix. Hum Reprod 2014;29:677–682.CrossRefPubMedGoogle Scholar
  63. 63.
    Li M, Zhang Z. Laparoscopically assisted biomaterial graft for reconstruction in congenital atresia of vagina and cervix. Fertil Steril 2013;100:1784–1787.CrossRefPubMedGoogle Scholar
  64. 64.
    House M, Sanchez CC, Rice WL, Socrate S, Kaplan DL. Cervical tissue engineering using silk scaffolds and human cervical cells. Tissue Eng Part A 2010;16:2101–2112.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Hoemann CD, Sun J, Légaré A, McKee MD, Buschmann MD. Tissue engineering of cartilage using an injectable and adhesive chitosan-based cell-delivery vehicle. Osteoarthritis Cartilage 2005;13:318–329.CrossRefPubMedGoogle Scholar
  66. 66.
    Berillo D, Elowsson L, Kirsebom H. Oxidized dextran as crosslinker for chitosan cryogel scaffolds and formation of polyelectrolyte complexes between chitosan and gelatin. Macromol Biosci 2012;12:1090–1099.CrossRefPubMedGoogle Scholar
  67. 67.
    Helenius G, Bäckdahl H, Bodin A, Nannmark U, Gatenholm P, Risberg B. In vivo biocompatibility of bacterial cellulose. J Biomed Mater Res A 2006;76:431–438.CrossRefPubMedGoogle Scholar
  68. 68.
    Reza AT, Nicoll SB. Characterization of novel photocrosslinked carboxymethylcellulose hydrogels for encapsulation of nucleus pulposus cells. Acta Biomater 2010;6:179–186.CrossRefPubMedGoogle Scholar
  69. 69.
    Yu C, Bianco J, Brown C, Fuetterer L, Watkins JF, Samani A, et al. Porous decellularized adipose tissue foams for soft tissue regeneration. Biomaterials 2013;34:3290–3302.CrossRefPubMedGoogle Scholar
  70. 70.
    Grover CN, Cameron RE, Best SM. Investigating the morphological, mechanical and degradation properties of scaffolds comprising collagen, gelatin and elastin for use in soft tissue engineering. J Mech Behav Biomed Mater 2012;10:62–74.CrossRefPubMedGoogle Scholar
  71. 71.
    Aboushwareb T, Eberli D, Ward C, Broda C, Holcomb J, Atala A, et al. A keratin biomaterial gel hemostat derived from human hair:evaluation in a rabbit model of lethal liver injury. J Biomed Mater Res B Appl Biomater 2009;90:45–54.PubMedGoogle Scholar
  72. 72.
    Fini M, Motta A, Torricelli P, Giavaresi G, Nicoli Aldini N, Tschon M, et al. The healing of confined critical size cancellous defects in the presence of silk fibroin hydrogel. Biomaterials 2005;26:3527–3536.CrossRefPubMedGoogle Scholar
  73. 73.
    Peach MS, Kumbar SG, James R, Toti US, Balasubramaniam D, Deng M, et al. Design and optimization of polyphosphazene functionalized fiber matrices for soft tissue regeneration. J Biomed Nanotechnol 2012;8:107–124.CrossRefPubMedGoogle Scholar
  74. 74.
    Gualandi C, Soccio M, Govoni M, Valente S, Lotti N, Munari A, et al. Poly(butylene/diethylene glycol succinate) multiblock copolyester as a candidate biomaterial for soft tissue engineering:solid-state properties, degradability, and biocompatibility. J Bioact Compat Polym 2012;27:244–264.CrossRefGoogle Scholar
  75. 75.
    Guo X, Park H, Young S, Kretlow JD, van den Beucken JJ, Baggett LS, et al. Repair of osteochondral defects with biodegradable hydrogel composites encapsulating marrow mesenchymal stem cells in a rabbit model. Acta Biomater 2010;6:39–47.CrossRefPubMedGoogle Scholar
  76. 76.
    Efe T, Getgood A, Schofer MD, Fuchs-Winkelmann S, Mann D, Paletta JR, et al. The safety and short-term efficacy of a novel polyurethane meniscal scaffold for the treatment of segmental medial meniscus deficiency. Knee Surg Sports Traumatol Arthrosc 2012;20:1822–1830.CrossRefPubMedGoogle Scholar
  77. 77.
    Flynn L, Dalton PD, Shoichet MS. Fiber templating of poly(2-hydroxyethyl methacrylate) for neural tissue engineering. Biomaterials 2003;24:4265–4272.CrossRefPubMedGoogle Scholar
  78. 78.
    Lai JY, Chen KH, Hsiue GH. Tissue-engineered human corneal endothelial cell sheet transplantation in a rabbit model using functional biomaterials. Transplantation 2007;84:1222–1232.CrossRefPubMedGoogle Scholar

Copyright information

© The Korean Tissue Engineering and Regenerative Medicine Society and Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Amin Tamadon
    • 1
  • Kyu-Hyung Park
    • 1
  • Yoon Young Kim
    • 2
  • Byeong-Cheol Kang
    • 3
    • 4
  • Seung-Yup Ku
    • 1
    Email author
  1. 1.Department of Obstetrics and GynecologySeoul National University College of MedicineSeoulKorea
  2. 2.Biomedical Research InstituteSeoul National University HospitalSeoulKorea
  3. 3.Department of Experimental Animal Research, Biomedical Research InstituteSeoul National University HospitalSeoulKorea
  4. 4.Graduate School of Translational MedicineSeoul National University College of MedicineSeoulKorea

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