Skip to main content

Advertisement

Log in

Bioengineering of Human Corneal Endothelial Cells from Single- to Four-Dimensional Cultures

  • Cornea (T Yamaguchi, Section Editor)
  • Published:
Current Ophthalmology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

To summarize the recent advances of clinical and preclinical studies for corneal endothelial tissue bioengineering.

Recent Findings

The challenges facing the generation of a clinical applicable corneal endothelial graft can be broadly classified into cell source selection, culture medium optimization, scaffold establishment, and the following three- and four-dimensional (4D) corneal construction. Based on the current advances in primary human corneal endothelial cell (HCEC) culture and good manufacturing practice (GMP)–compliant medium development, the first clinical trial of bioengineered HCEC injection therapy has been conducted with encouraging results. Other significant findings include the in vivo experiments of the stem cell–derived HCEC, the development of serum-, xeno-, and additive-free media, and the construction of 4D scaffold.

Summary

It can be anticipated that tissue engineering–based therapy toward corneal endothelial diseases will replace the current keratoplasty method as a promising treatment option in the near future.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Eghrari AO, Riazuddin SA, Gottsch JD. Overview of the cornea: structure, function, and development. Progress in Molecular Biology and Translational Science. 1st ed: Elsevier; 2015. p. 7–23.

  2. Arnalich-Montiel F. Corneal endothelium: applied anatomy. Corneal Regeneration, Therapy and Surgery: Springer; 2019. p. 419–24.

  3. Mathews PM, Lindsley K, Aldave AJ, Akpek EK. Etiology of global corneal blindness and current practices of corneal transplantation: a focused review. Cornea. 2018;37(9):1198–203. https://doi.org/10.1097/ico.0000000000001666.

    Article  PubMed  Google Scholar 

  4. Feizi S. Corneal endothelial cell dysfunction: etiologies and management. TherAdv Ophthalmol. 2018;10:2515841418815802. https://doi.org/10.1177/2515841418815802.

    Article  Google Scholar 

  5. Gain P, Jullienne R, He Z, Aldossary M, Acquart S, Cognasse F, et al. Global survey of corneal transplantation and eye banking. JAMA Ophthalmol. 2016;134(2):167–73.

    PubMed  Google Scholar 

  6. Hori J, Yamaguchi T, Keino H, Hamrah P, Maruyama K. Immune privilege in corneal transplantation. Prog Retin Eye Res. 2019;72:100758.

    PubMed  Google Scholar 

  7. Mehta JS, Kocaba V, Soh YQ. The future of keratoplasty: cell-based therapy, regenerative medicine, bioengineering keratoplasty, gene therapy. Curr Opin Ophthalmol. 2019;30(4):286–91.

    PubMed  Google Scholar 

  8. Dhal A, Brovold M, Atala A, Soker S. Principles of organ bioengineering. Kidney transplantation, bioengineering and regeneration: Elsevier; 2017. p. 873–6.

  9. Bartakova A, Kuzmenko O, Alvarez-Delfin K, Kunzevitzky NJ, Goldberg JL. A cell culture approach to optimized human corneal endothelial cell function. Invest Ophthalmol Vis Sci. 2018;59(3):1617–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Rabionet M, Polonio E, Guerra AJ, Martin J, Puig T, Ciurana J. Design of a scaffold parameter selection system with additive manufacturing for a biomedical cell culture. Materials. 2018;11(8):1427.

    PubMed Central  Google Scholar 

  11. Ranstam J, Cook JA. Considerations for the design, analysis and presentation of in vivo studies. Osteoarthr Cartil. 2017;25(3):364–8.

    CAS  PubMed  Google Scholar 

  12. Hudu SA, Alshrari AS, Syahida A, Sekawi Z. Cell culture, technology: enhancing the culture of diagnosing human diseases. J Clin Diagn Res. 2016;10(3):DE01–DE5. https://doi.org/10.7860/JCDR/2016/15837.7460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pamies D, Hartung T. 21st century cell culture for 21st century toxicology. Chem Res Toxicol. 2017;30(1):43–52. https://doi.org/10.1021/acs.chemrestox.6b00269.

    Article  CAS  PubMed  Google Scholar 

  14. Fan T, Zhao J, Ma X, Xu X, Zhao W, Xu B. Establishment of a continuous untransfected human corneal endothelial cell line and its biocompatibility to denuded amniotic membrane. Mol Vis. 2011;17:469.

    PubMed  PubMed Central  Google Scholar 

  15. Schmedt T, Chen Y, Nguyen TT, Li S, Bonanno JA, Jurkunas UV. Telomerase immortalization of human corneal endothelial cells yields functional hexagonal monolayers. PLoS One. 2012;7(12):e51427.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang W, Ogando DG, Kim ET, Choi M-J, Li H, Tenessen JM, et al. Conditionally immortal Slc4a11−/− mouse corneal endothelial cell line recapitulates disrupted glutaminolysis seen in Slc4a11−/− mouse model. Invest Ophthalmol Vis Sci. 2017;58(9):3723–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kageyama T, Hayashi R, Hara S, Yoshikawa K, Ishikawa Y, Yamato M, et al. Spontaneous acquisition of infinite proliferative capacity by a rabbit corneal endothelial cell line with maintenance of phenotypic and physiological characteristics. J Tissue Eng Regen Med. 2017;11(4):1057–64.

    CAS  PubMed  Google Scholar 

  18. Hesse M, Kuerten D, Walter P, Plange N, Johnen S, Fuest M. The effect of air, SF 6 and C3F8 on immortalized human corneal endothelial cells. Acta Ophthalmol. 2017;95(4):e284–e90.

    CAS  PubMed  Google Scholar 

  19. •• Thieme D, Reuland L, Lindl T, Kruse F, Fuchsluger T. Optimized human platelet lysate as novel basis for a serum-, xeno-, and additive-free corneal endothelial cell and tissue culture. J Tissue Eng Regen Med. 2018;12(2):557–64 The development of high-quality serum-, xeno-, and additive-free media for HCEC cultivation.

    CAS  PubMed  Google Scholar 

  20. Wei X, Luo D, Yan Y, Yu H, Sun L, Wang C, et al. Kojic acid inhibits senescence of human corneal endothelial cells via NF-κB and p21 signaling pathways. Exp Eye Res. 2019;180:174–83.

    CAS  PubMed  Google Scholar 

  21. Zhang K, Pang K, Wu X. Isolation and transplantation of corneal endothelial cell–like cells derived from in-vitro-differentiated human embryonic stem cells. Stem Cells Dev. 2014;23(12):1340–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. McCabe KL, Kunzevitzky NJ, Chiswell BP, Xia X, Goldberg JL, Lanza R. Efficient generation of human embryonic stem cell-derived corneal endothelial cells by directed differentiation. PLoS One. 2015;10(12):e0145266. https://doi.org/10.1371/journal.pone.0145266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chen P, Chen JZ, Shao CY, Li CY, Zhang YD, Lu WJ, et al. Treatment with retinoic acid and lens epithelial cell-conditioned medium in vitro directed the differentiation of pluripotent stem cells towards corneal endothelial cell-like cells. Exp Ther Med. 2015;9(2):351–60.

    PubMed  Google Scholar 

  24. Song Q, Yuan S, An Q, Chen Y, Mao FF, Liu Y, et al. Directed differentiation of human embryonic stem cells to corneal endothelial cell-like cells: a transcriptomic analysis. Exp Eye Res. 2016;151:107–14.

    CAS  PubMed  Google Scholar 

  25. Hanson C, Arnarsson A, Hardarson T, Lindgård A, Daneshvarnaeini M, Ellerström C, et al. Transplanting embryonic stem cells onto damaged human corneal endothelium. World J Stem Cells. 2017;9(8):127–32.

    PubMed  PubMed Central  Google Scholar 

  26. • Zhang C, Du L, Sun P, Shen L, Zhu J, Pang K, et al. Construction of tissue-engineered full-thickness cornea substitute using limbal epithelial cell-like and corneal endothelial cell-like cells derived from human embryonic stem cells. Biomaterials. 2017;124:180–94 The first animal experiment using the full-thickness artificial cornea substitute derived from embryonic stem cell.

    CAS  PubMed  Google Scholar 

  27. Chen X, Wu L, Li Z, Dong Y, Pei X, Huang Y, et al. Directed differentiation of human corneal endothelial cells from human embryonic stem cells by using cell-conditioned culture media. Invest Ophthalmol Vis Sci. 2018;59(7):3028–36.

    CAS  PubMed  Google Scholar 

  28. Zhao JJ, Afshari NA. Generation of human corneal endothelial cells via in vitro ocular lineage restriction of pluripotent stem cells. Invest Ophthalmol Vis Sci. 2016;57(15):6878–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. • Foster JW, Wahlin K, Adams SM, Birk DE, Zack DJ, Chakravarti S. Cornea organoids from human induced pluripotent stem cells. Sci Rep. 2017;7(1):1–8 The first generation of 3D cornea organoids with expression of key epithelial, stromal, and endothelial cell markers.

    Google Scholar 

  30. Susaimanickam PJ, Maddileti S, Pulimamidi VK, Boyinpally SR, Naik RR, Naik MN, et al. Generating minicorneal organoids from human induced pluripotent stem cells. Development. 2017;144(13):2338–51.

    CAS  PubMed  Google Scholar 

  31. Wagoner MD, Bohrer LR, Aldrich BT, Greiner MA, Mullins RF, Worthington KS, et al. Feeder-free differentiation of cells exhibiting characteristics of corneal endothelium from human induced pluripotent stem cells. Biol Open. 2018;7(5):bio032102.

    PubMed  PubMed Central  Google Scholar 

  32. Shao C, Fu Y, Lu W, Fan X. Bone marrow-derived endothelial progenitor cells: a promising therapeutic alternative for corneal endothelial dysfunction. Cells Tissues Organs. 2011;193(4):253–63.

    PubMed  Google Scholar 

  33. Shao C, Chen J, Chen P, Zhu M, Yao Q, Gu P, et al. Targeted transplantation of human umbilical cord blood endothelial progenitor cells with immunomagnetic nanoparticles to repair corneal endothelium defect. Stem Cells Dev. 2015;24(6):756–67.

    CAS  PubMed  Google Scholar 

  34. Inagaki E, Hatou S, Higa K, Yoshida S, Shibata S, Okano H, et al. Skin-derived precursors as a source of progenitors for corneal endothelial regeneration. Stem Cells Transl Med. 2017;6(3):788–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Shen L, Sun P, Zhang C, Yang L, Du L, Wu X. Therapy of corneal endothelial dysfunction with corneal endothelial cell-like cells derived from skin-derived precursors. Sci Rep. 2017;7(1):1–13.

    Google Scholar 

  36. Joyce NC, Harris DL, Markov V, Zhang Z, Saitta B. Potential of human umbilical cord blood mesenchymal stem cells to heal damaged corneal endothelium. Mol Vis. 2012;18:547–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Lachaud CC, Soria F, Escacena N, Quesada-Hernández E, Hmadcha A, Alió J, et al. Mesothelial cells: a cellular surrogate for tissue engineering of corneal endothelium. Invest Ophthalmol Vis Sci. 2014;55(9):5967–78.

    CAS  PubMed  Google Scholar 

  38. Yamashita K, Inagaki E, Hatou S, Higa K, Ogawa A, Miyashita H, et al. Corneal endothelial regeneration using mesenchymal stem cells derived from human umbilical cord. Stem Cells Dev. 2018;27(16):1097–108.

    CAS  PubMed  Google Scholar 

  39. Gutermuth A, Maassen J, Harnisch E, Kuhlen D, Sauer-Budge A, Skazik-Voogt C, et al. Descemet’s membrane biomimetic microtopography differentiates human mesenchymal stem cells into corneal endothelial-like cells. Cornea. 2019;38(1):110–9.

    PubMed  Google Scholar 

  40. Palchesko RN, Lathrop KL, Funderburgh JL, Feinberg AW. In vitro expansion of corneal endothelial cells on biomimetic substrates. Sci Rep. 2015;5:7955.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Vazquez N, Chacón M, Rodriguez-Barrientos CA, Merayo-Lloves J, Naveiras M, Baamonde B, et al. Human bone derived collagen for the development of an artificial corneal endothelial graft. In vivo results in a rabbit model. PLoS One. 2016;11(12):e0167578.

    PubMed  PubMed Central  Google Scholar 

  42. • Parikumar P, Haraguchi K, Senthilkumar R, Abraham SJ. Human corneal endothelial cell transplantation using nanocomposite gel sheet in bullous keratopathy. Am J Stem Cells. 2018;7(1):18–24 The first case report evaluating the bioengineering-based cell injection therapy for patients with bullous keratopathy.

    PubMed  PubMed Central  Google Scholar 

  43. • Kim KW, Lee SJ, Park SH, Kim JC. Ex vivo functionality of 3D bioprinted corneal endothelium engineered with ribonuclease 5-overexpressing human corneal endothelial cells. Adv Healthc Mater. 2018;7(18):1800398 The first using the 3D bioprinted technique into the generation of corneal endothelial graft with high consistency.

    Google Scholar 

  44. Nakahara M, Okumura N, Nakano S, Koizumi N. Effect of a p38 mitogen-activated protein kinase inhibitor on corneal endothelial cell proliferation. Invest Ophthalmol Vis Sci. 2018;59(10):4218–27.

    CAS  PubMed  Google Scholar 

  45. Le-Bel G, Giasson CJ, Deschambeault A, Carrier P, Germain L, Guérin SL. The presence of a feeder layer improves human corneal endothelial cell proliferation by altering the expression of the transcription factors Sp1 and NFI. Exp Eye Res. 2018;176:161–73.

    CAS  PubMed  Google Scholar 

  46. Cen YJ, Feng Y. Constructing a novel three-dimensional biomimetic corneal endothelium graft by culturing corneal endothelium cells on compressed collagen gels. Chin Med J. 2018;131(14):1710–4.

    PubMed  PubMed Central  Google Scholar 

  47. Okumura N, Ueno M, Koizumi N, Sakamoto Y, Hirata K, Hamuro J, et al. Enhancement on primate corneal endothelial cell survival in vitro by a ROCK inhibitor. Invest Ophthalmol Vis Sci. 2009;50(8):3680–7.

    PubMed  Google Scholar 

  48. Okumura N, Koizumi N, Ueno M, Sakamoto Y, Takahashi H, Tsuchiya H, et al. ROCK inhibitor converts corneal endothelial cells into a phenotype capable of regenerating in vivo endothelial tissue. Am J Pathol. 2012;181(1):268–77.

    CAS  PubMed  Google Scholar 

  49. Guo Y, Liu Q, Yang Y, Guo X, Lian R, Li S, et al. The effects of ROCK inhibitor Y-27632 on injectable spheroids of bovine corneal endothelial cells. Cellular Reprogramming (Formerly “Cloning and Stem Cells”). 2015;17(1):77–87.

  50. Peh GS, Adnan K, George BL, Ang HP, Seah XY, Tan DT, et al. The effects of rho-associated kinase inhibitor Y-27632 on primary human corneal endothelial cells propagated using a dual media approach. Sci Rep. 2015;5(1):1–10.

    Google Scholar 

  51. Lee W, Miyagawa Y, Long C, Zhang M, Cooper DK, Hara H. Effect of rho-kinase inhibitor, Y27632, on porcine corneal endothelial cell culture, inflammation and immune regulation. Ocul Immunol Inflamm. 2016;24(5):579–93.

    CAS  PubMed  Google Scholar 

  52. Meekins LC, Rosado-Adames N, Maddala R, Zhao JJ, Rao PV, Afshari NA. Corneal endothelial cell migration and proliferation enhanced by rho kinase (ROCK) inhibitors in in vitro and in vivo models. Invest Ophthalmol Vis Sci. 2016;57(15):6731–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Okumura N, Sakamoto Y, Fujii K, Kitano J, Nakano S, Tsujimoto Y, et al. Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction. Sci Rep. 2016;6(1):26113.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Parekh M, Ahmad S, Ruzza A, Ferrari S. Human corneal endothelial cell cultivation from old donor corneas with forced attachment. Sci Rep. 2017;7(1):142.

    PubMed  PubMed Central  Google Scholar 

  55. •• Kinoshita S, Koizumi N, Ueno M, Okumura N, Imai K, Tanaka H, et al. Injection of cultured cells with a ROCK inhibitor for bullous keratopathy. N Engl J Med. 2018;378(11):995–1003 The first clinical trial of the bioengineering-based cell injection therapy for the treatment of corneal endothelial diseases.

    CAS  PubMed  Google Scholar 

  56. Yin X, Mead Benjamin E, Safaee H, Langer R, Karp Jeffrey M, Levy O. Engineering stem cell organoids. Cell Stem Cell. 2016;18(1):25–38. https://doi.org/10.1016/j.stem.2015.12.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chakradhar S. An eye to the future: researchers debate best path for stem cell–derived therapies. Nat Med. 2016;22(2):116–9. https://doi.org/10.1038/nm0216-116.

    Article  CAS  PubMed  Google Scholar 

  58. Pellegrini G, Lambiase A, Macaluso C, Pocobelli A, Deng S, Cavallini GM, et al. From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU. Regen Med. 2016;11(4):407–20. https://doi.org/10.2217/rme-2015-0051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Navaratnam J, Utheim TP, Rajasekhar VK, Shahdadfar A. Substrates for expansion of corneal endothelial cells towards bioengineering of human corneal endothelium. J Funct Biomater. 2015;6(3):917–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Jumblatt MM, Maurice DM, McCulley JP. Transplantation of tissue-cultured corneal endothelium. Invest Ophthalmol Vis Sci. 1978;17(12):1135–41.

    CAS  PubMed  Google Scholar 

  61. Gospodarowicz D, Greenburg G, Alvarado J. Transplantation of cultured bovine corneal endothelial cells to rabbit cornea: clinical implications for human studies. Proc Natl Acad Sci. 1979;76(1):464–8.

    CAS  PubMed  Google Scholar 

  62. Chen HC, Zhu YT, Chen SY, Tseng SC. Wnt signaling induces epithelial–mesenchymal transition with proliferation in ARPE-19 cells upon loss of contact inhibition. Lab Investig. 2012;92(5):676–87.

    CAS  PubMed  Google Scholar 

  63. Chen HC, Zhu YT, Chen SY, Tseng SC. Selective activation of p120ctn-Kaiso signaling to unlock contact inhibition of ARPE-19 cells without epithelial-mesenchymal transition. PLoS One. 2012;7(5):e36864.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Zhu YT, Chen HC, Chen SY, Tseng SC. Nuclear p120 catenin unlocks mitotic block of contact-inhibited human corneal endothelial monolayers without disrupting adherent junctions. J Cell Sci. 2012;125(15):3636–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Feng Y, LoGrasso PV, Defert O, Li R. Rho kinase (ROCK) inhibitors and their therapeutic potential. J Med Chem. 2016;59(6):2269–300.

    CAS  PubMed  Google Scholar 

  66. Ricker E, Chowdhury L, Yi W, Pernis AB. The RhoA-ROCK pathway in the regulation of T and B cell responses. F1000Research. 2016;5.

  67. Zhang C, Wang H-J, Bao QC, Wang L, Guo TK, Chen WL, et al. NRF2 promotes breast cancer cell proliferation and metastasis by increasing RhoA/ROCK pathway signal transduction. Oncotarget. 2016;7(45):73593–606.

    PubMed  PubMed Central  Google Scholar 

  68. Yan Q, Wang X, Zha M, Yu M, Sheng M, Yu J. The RhoA/ROCK signaling pathway affects the development of diabetic nephropathy resulting from the epithelial to mesenchymal transition. Int J Clin Exp Pathol. 2018;11(9):4296–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Shimizu T, Liao JK. Rho kinases and cardiac remodeling. Circ J. 2016;CJ-16-0433.

  70. Koizumi N, Okumura N, Ueno M, Kinoshita S. New therapeutic modality for corneal endothelial disease using rho-associated kinase inhibitor eye drops. Cornea. 2014;33:S25–31.

    PubMed  Google Scholar 

  71. Yao T, Asayama Y. Animal-cell culture media: history, characteristics, and current issues. Reprod Med Biol. 2017;16(2):99–117. https://doi.org/10.1002/rmb2.1202.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Zhu C, Joyce NC. Proliferative response of corneal endothelial cells from young and older donors. Invest Ophthalmol Vis Sci. 2004;45(6):1743–51.

    PubMed  Google Scholar 

  73. Jäckel T, Knels L, Valtink M, Funk RH, Engelmann K. Serum-free corneal organ culture medium (SFM) but not conventional minimal essential organ culture medium (MEM) protects human corneal endothelial cells from apoptotic and necrotic cell death. Br J Ophthalmol. 2011;95(1):123–30.

    PubMed  Google Scholar 

  74. Peh GS, Chng Z, Ang HP, Cheng TY, Adnan K, Seah XY, et al. Propagation of human corneal endothelial cells: a novel dual media approach. Cell Transplant. 2015;24(2):287–304.

    PubMed  Google Scholar 

  75. Shima N, Kimoto M, Yamaguchi M, Yamagami S. Increased proliferation and replicative lifespan of isolated human corneal endothelial cells with L-ascorbic acid 2-phosphate. Invest Ophthalmol Vis Sci. 2011;52(12):8711–7.

    CAS  PubMed  Google Scholar 

  76. Hongo A, Okumura N, Nakahara M, Kay EP, Koizumi N. The effect of a p38 mitogen-activated protein kinase inhibitor on cellular senescence of cultivated human corneal endothelial cells. Invest Ophthalmol Vis Sci. 2017;58(9):3325–34.

    CAS  PubMed  Google Scholar 

  77. Peh GS, Ang HP, Lwin CN, Adnan K, George BL, Seah XY, et al. Regulatory compliant tissue-engineered human corneal endothelial grafts restore corneal function of rabbits with bullous keratopathy. Sci Rep. 2017;7(1):14149.

    PubMed  PubMed Central  Google Scholar 

  78. Sun P, Shen L, Zhang C, Du L, Wu X. Promoting the expansion and function of human corneal endothelial cells with an orbital adipose-derived stem cell-conditioned medium. Stem Cell Res Ther. 2017;8(1):287.

    PubMed  PubMed Central  Google Scholar 

  79. Choi JS, Kim EY, Kim MJ, Khan FA, Giegengack M, D’Agostino R Jr, et al. Factors affecting successful isolation of human corneal endothelial cells for clinical use. Cell Transplant. 2014;23(7):845–54.

    PubMed  Google Scholar 

  80. Kim E, Kim JJ, Hyon JY, Chung E-S, Chung TY, Yi K, et al. The effects of different culture media on human corneal endothelial cells. Invest Ophthalmol Vis Sci. 2014;55(8):5099–108.

    PubMed  Google Scholar 

  81. Bružauskaitė I, Bironaitė D, Bagdonas E, Bernotienė E. Scaffolds and cells for tissue regeneration: different scaffold pore sizes—different cell effects. Cytotechnology. 2016;68(3):355–69. https://doi.org/10.1007/s10616-015-9895-4.

    Article  CAS  PubMed  Google Scholar 

  82. Wang TJ, Wang IJ, Hu FR, Young TH. Applications of biomaterials in corneal endothelial tissue engineering. Cornea. 2016;35:S25–30.

    PubMed  Google Scholar 

  83. Parekh M, Ferrari S, Sheridan C, Kaye S, Ahmad S. Concise review: an update on the culture of human corneal endothelial cells for transplantation. Stem Cells Transl Med. 2016;5(2):258–64.

    PubMed  Google Scholar 

  84. Okumura N, Kakutani K, Numata R, Nakahara M, Schlötzer-Schrehardt U, Kruse F, et al. Laminin-511 and-521 enable efficient in vitro expansion of human corneal endothelial cells. Invest Ophthalmol Vis Sci. 2015;56(5):2933–42.

    CAS  PubMed  Google Scholar 

  85. Van den Bogerd B, Ni Dhubhghaill S, Zakaria N. Characterizing human decellularized crystalline lens capsules as a scaffold for corneal endothelial tissue engineering. J Tissue Eng Regen Med. 2018;12(4):e2020–e8.

    PubMed  PubMed Central  Google Scholar 

  86. Huang YH, Tseng FW, Chang WH, Peng IC, Hsieh DJ, Wu SW, et al. Preparation of acellular scaffold for corneal tissue engineering by supercritical carbon dioxide extraction technology. Acta Biomater. 2017;58:238–43.

    CAS  PubMed  Google Scholar 

  87. Zhang Z, Niu G, San Choi J, Giegengack M, Atala A, Soker S. Bioengineered multilayered human corneas from discarded human corneal tissue. Biomed Mater. 2015;10(3):035012.

    PubMed  Google Scholar 

  88. Parekh M, Van den Bogerd B, Zakaria N, Ponzin D, Ferrari S. Fish scale-derived scaffolds for culturing human corneal endothelial cells. Stem Cells Int. 2018;29:8146834.

    Google Scholar 

  89. Xue J, Wu T, Dai Y, Xia Y. Electrospinning and electrospun nanofibers: methods, materials, and applications. Chem Rev. 2019;119(8):5298–415. https://doi.org/10.1021/acs.chemrev.8b00593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Li XX, He JH. Nanoscale adhesion and attachment oscillation under the geometric potential. Part 1: the formation mechanism of nanofiber membrane in the electrospinning. Results Phys. 2019;12:1405–10.

    Google Scholar 

  91. Chen J, Yan C, Zhu M, Yao Q, Shao C, Lu W, et al. Electrospun nanofibrous SF/P (LLA-CL) membrane: a potential substratum for endothelial keratoplasty. Int J Nanomedicine. 2015;10:3337.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kruse M, Walter P, Bauer B, Rütten S, Schaefer K, Plange N, et al. Electro-spun membranes as scaffolds for human corneal endothelial cells. Curr Eye Res. 2018;43(1):1–11.

    CAS  PubMed  Google Scholar 

  93. Hsueh YJ, Chen HC, Wu SE, Wang TK, Chen JK, Ma DHK. Lysophosphatidic acid induces YAP-promoted proliferation of human corneal endothelial cells via PI3K and ROCK pathways. Mol Ther Methods Clin Dev. 2015;2:15014.

    PubMed  PubMed Central  Google Scholar 

  94. Hsueh YJ, Meir YJJ, Lai JY, Chen HC, Ma DHK, Huang CC, et al. Lysophosphatidic acid improves corneal endothelial density in tissue culture by stimulating stromal secretion of interleukin-1β. J Cell Mol Med. 2020. https://doi.org/10.1111/jcmm.15307.

  95. Jeang L, Cha BJ, Birk DE, Espana EM. Endothelial–stromal communication in murine and human corneas. Anat Rec (Hoboken). 2020 Jun;303(6):1717–26. https://doi.org/10.1002/ar.24393.

    Article  CAS  Google Scholar 

  96. Tamay DG, Usal TD, Alagoz AS, Yucel D, Hasirci N, Hasirci V. 3D and 4D printing of polymers for tissue engineering applications. Front Bioengi Biotechnol. 2019;7:164.

    Google Scholar 

  97. Kim H, Jang J, Park J, Lee KP, Lee S, Lee DM, et al. Shear-induced alignment of collagen fibrils using 3D cell printing for corneal stroma tissue engineering. Biofabrication. 2019;11(3):035017.

    CAS  PubMed  Google Scholar 

  98. Ruskowitz ER, DeForest CA. Photoresponsive biomaterials for targeted drug delivery and 4D cell culture. Nat Rev Mater. 2018;3(2):1–17.

    Google Scholar 

  99. Hilderbrand AM, Ovadia EM, Rehmann MS, Kharkar PM, Guo C, Kloxin AM. Biomaterials for 4D stem cell culture. Curr Opinion Solid State Mater Sci. 2016;20(4):212–24.

    CAS  Google Scholar 

  100. Zheng Y, Han MKL, Jiang Q, Li B, Feng J, del Campo A. 4D hydrogel for dynamic cell culture with orthogonal, wavelength-dependent mechanical and biochemical cues. Mater Horiz. 2020;7:111–1116.

    CAS  Google Scholar 

  101. •• Miotto M, Gouveia RM, Ionescu AM, Figueiredo F, Hamley IW, Connon CJ. 4D corneal tissue engineering: achieving time-dependent tissue self-curvature through localized control of cell actuators. Adv Funct Mater. 2019;29(8):1807334 The first introduction of the 4D scaffold technique into corneal tissue engineering.

    Google Scholar 

  102. Gladman AS, Matsumoto EA, Nuzzo RG, Mahadevan L, Lewis JA. Biomimetic 4D printing. Nat Mater. 2016;15(4):413–8.

    PubMed  Google Scholar 

  103. Momeni FM, Mehdi Hassani NS, Liu X, Ni J. A review of 4D printing. Mater Des. 2017;122:42–79. https://doi.org/10.1016/j.matdes.2017.02.068.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank the advice from Dr. Scheffer C.G. Tseng at the Ocular Surface Center, Miami, FL, USA.

Funding

The research was funded by the Chang Gung Memorial Hospital (CMRPG3J0511 and CMRPG3G0031~3) and the Ministry of Science and Technology (MOST 107-2314-B-182A-088-MY3).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hung-Chi Chen.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consents

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Additional information

Publisher’s Note

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

This article is part of the Topical Collection on Cornea

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsao, YT., Cheng, CM., Wu, WC. et al. Bioengineering of Human Corneal Endothelial Cells from Single- to Four-Dimensional Cultures. Curr Ophthalmol Rep 8, 172–184 (2020). https://doi.org/10.1007/s40135-020-00244-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40135-020-00244-y

Keywords

Navigation