Skip to main content
SpringerLink
Log in

Corneal Tissue Engineering

  • Chapter
  • First Online:
Corneal Regeneration

Part of the book series: Essentials in Ophthalmology ((ESSENTIALS))

Abstract

Mankind has been always fascinated with the idea of restoring any damaged tissue or organ. Regarding corneal functional restoration, the French ophthalmologist Pellier de Quengsy was the first one proposing in 1789 a replacement of an opaque cornea using a piece of glass surrounded by a silver ring. However, the paradigm of corneal blindness treatment does not change until 1905, when Eduard Zirm performed the first corneal transplant to a patient using a donor cornea. Corneal transplant is still the most used and reliable treatment for some corneal diseases despite their three major drawbacks: the scarcity of donors, the risk of rejection and the transmission of infectious diseases. In this milieu, corneal tissue engineering emerges with the ambition of generating artificial corneas or other type of tissue-engineered products that lead to an optimal corneal regeneration, overcoming those major disadvantages of allogeneic corneal transplants. Once we understand the structure-function relationships in the cornea, we can generate a tissue-engineered corneal substitute to restore, maintain, or improve corneal functions, using different building blocks: cells, scaffolds and bioactive molecules. In this regard, here we briefly highlight some treatment options for corneal diseases based on different tissue-engineering strategies. Moreover, we explain the concepts and regulations necessary to understand the future clinical impact of tissue engineering in corneal therapy and surgery.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Finch J. The ancient origins of prosthetic medicine. Lancet. 2011;377:548–9.

    Article  PubMed  Google Scholar 

  2. Chirila TV, Hicks CR. The origins of the artificial cornea: Pellier de Quengsy and his contribution to the modern concept of keratoprosthesis. Gesnerus. 1999;56:96–106.

    CAS  PubMed  Google Scholar 

  3. Zirm EK. Eine erfolgreiche totale Keratoplastik (a successful total keratoplasty). 1906. Refract Corneal Surg. 1989;5:258–61.

    CAS  PubMed  Google Scholar 

  4. Fagerholm P, Lagali NS, Merrett K, et al. A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study. Sci Transl Med. 2010;2:46ra61.

    Article  PubMed  CAS  Google Scholar 

  5. Oliva MS, Schottman T, Gulati M. Turning the tide of corneal blindness. Indian J Ophthalmol. 2012;60:423–7.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Burton MJ. Prevention, treatment and rehabilitation. Community Eye Health. 2009;22:33–5.

    PubMed  PubMed Central  Google Scholar 

  7. Brunette I, Roberts CJ, Vidal F, et al. Alternatives to eye bank native tissue for corneal stromal replacement. Prog Retin Eye Res. 2017;59:97–130.

    Article  PubMed  Google Scholar 

  8. Hara H, Cooper DK. Xenotransplantation–the future of corneal transplantation? Cornea. 2011;30:371–8.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Organ. 2001;79:214–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Abud TB, Di Zazzo A, Kheirkhah A, Dana R. Systemic immunomodulatory strategies in high-risk corneal transplantation. J Ophthalmic Vis Res. 2017;12:81–92.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Polisetti N, Islam MM, Griffith M. The artificial cornea. Methods Mol Biol. 2013;1014:45–52.

    Article  CAS  PubMed  Google Scholar 

  12. Pascolini D, Mariotti SP. Global estimates of visual impairment: 2010. Br J Ophthalmol. 2012;96:614–8.

    Article  PubMed  Google Scholar 

  13. O’Day DM. Diseases potentially transmitted through corneal transplantation. Ophthalmology. 1989;96:1133–7; discussion 7–8.

    Article  PubMed  Google Scholar 

  14. Remeijer L, Maertzdorf J, Doornenbal P, Verjans GM, Osterhaus AD. Herpes simplex virus 1 transmission through corneal transplantation. Lancet. 2001;357:442.

    Article  CAS  PubMed  Google Scholar 

  15. Miller TD, Maxwell AJ, Lindquist TD, Requard J 3rd. Validation of cooling effect of insulated containers for the shipment of corneal tissue and recommendations for transport. Cornea. 2013;32:63–9.

    Article  PubMed  Google Scholar 

  16. Prevention of Blindness and Visual Impairment. Accessed 11 Nov 2017, at http://www.who.int/blindness/causes/magnitude/en/.

  17. Gain P, Jullienne R, He Z, et al. Global survey of corneal transplantation and eye banking. JAMA Ophthalmol. 2016;134:167–73.

    Article  PubMed  Google Scholar 

  18. Langer R, Vacanti JP. Tissue engineering. Science. 1993;260:920–6.

    Article  CAS  PubMed  Google Scholar 

  19. Nerem RM. Cellular engineering. Ann Biomed Eng. 1991;19:529–45.

    Article  CAS  PubMed  Google Scholar 

  20. Ma Y, Xu Y, Xiao Z, et al. Reconstruction of chemically burned rat corneal surface by bone marrow-derived human mesenchymal stem cells. Stem Cells. 2006;24:315–21.

    Article  PubMed  Google Scholar 

  21. Leijten J, Seo J, Yue K, et al. Spatially and temporally controlled hydrogels for tissue engineering. Mater Sci Eng R Rep. 2017;119:1–35.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Griffith M, Osborne R, Munger R, et al. Functional human corneal equivalents constructed from cell lines. Science. 1999;286:2169–72.

    Article  CAS  PubMed  Google Scholar 

  23. Boote C, Dennis S, Newton RH, Puri H, Meek KM. Collagen fibrils appear more closely packed in the prepupillary cornea: optical and biomechanical implications. Invest Ophthalmol Vis Sci. 2003;44:2941–8.

    Article  PubMed  Google Scholar 

  24. Marfurt CF, Cox J, Deek S, Dvorscak L. Anatomy of the human corneal innervation. Exp Eye Res. 2010;90:478–92.

    Article  CAS  PubMed  Google Scholar 

  25. Sweeney DF, Xie RZ, O'Leary DJ, et al. Nutritional requirements of the corneal epithelium and anterior stroma: clinical findings. Invest Ophthalmol Vis Sci. 1998;39:284–91.

    CAS  PubMed  Google Scholar 

  26. DiMattio J. In vivo entry of glucose analogs into lens and cornea of the rat. Invest Ophthalmol Vis Sci. 1984;25:160–5.

    CAS  PubMed  Google Scholar 

  27. Holden BA, Mertz GW. Critical oxygen levels to avoid corneal edema for daily and extended wear contact lenses. Invest Ophthalmol Vis Sci. 1984;25:1161–7.

    CAS  PubMed  Google Scholar 

  28. Apte RS, Niederkorn JY. Isolation and characterization of a unique natural killer cell inhibitory factor present in the anterior chamber of the eye. J Immunol. 1996;156:2667–73.

    CAS  PubMed  Google Scholar 

  29. Niederkorn JY. Role of innate immune system in corneal transplantation. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2013.

    Google Scholar 

  30. Foulsham W, Marmalidou A, Amouzegar A, Coco G, Chen Y, Dana R. Review: the function of regulatory T cells at the ocular surface. Ocul Surf. 2017;15:652–9.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Qazi Y, Hamrah P. Corneal allograft rejection: Immunopathogenesis to therapeutics. J Clin Cell Immunol. 2013;2013:pii: 006.

    Google Scholar 

  32. Kruse FE. Stem cells and corneal epithelial regeneration. Eye. 1994;8(Pt 2):170–83.

    Article  PubMed  Google Scholar 

  33. Du Y, Funderburgh ML, Mann MM, SundarRaj N, Funderburgh JL. Multipotent stem cells in human corneal stroma. Stem Cells. 2005;23:1266–75.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Funderburgh ML, Du Y, Mann MM, SundarRaj N, Funderburgh JL. PAX6 expression identifies progenitor cells for corneal keratocytes. FASEB J: Off Publication Fed Am Soc Exp Biol. 2005;19:1371–3.

    Article  CAS  Google Scholar 

  35. Pellegrini G, Traverso CE, Franzi AT, Zingirian M, Cancedda R, De Luca M. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet. 1997;349:990–3.

    Article  CAS  PubMed  Google Scholar 

  36. Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med. 2010;363:147–55.

    Article  CAS  PubMed  Google Scholar 

  37. Sangwan VS, Basu S, Vemuganti GK, et al. Clinical outcomes of xeno-free autologous cultivated limbal epithelial transplantation: a 10-year study. Br J Ophthalmol. 2011;95:1525–9.

    Article  PubMed  Google Scholar 

  38. Nakamura T, Inatomi T, Sotozono C, et al. Transplantation of autologous serum-derived cultivated corneal epithelial equivalents for the treatment of severe ocular surface disease. Ophthalmology. 2006;113:1765–72.

    Article  PubMed  Google Scholar 

  39. Rama P, Bonini S, Lambiase A, et al. Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation. 2001;72:1478–85.

    Article  CAS  PubMed  Google Scholar 

  40. Dravida S, Gaddipati S, Griffith M, et al. A biomimetic scaffold for culturing limbal stem cells: a promising alternative for clinical transplantation. J Tissue Eng Regen Med. 2008;2:263–71.

    Article  CAS  PubMed  Google Scholar 

  41. Sangwan VS, Basu S, MacNeil S, Balasubramanian D. Simple limbal epithelial transplantation (SLET): a novel surgical technique for the treatment of unilateral limbal stem cell deficiency. Br J Ophthalmol. 2012;96:931–4.

    Article  PubMed  Google Scholar 

  42. Di Girolamo N, Bosch M, Zamora K, Coroneo MT, Wakefield D, Watson SL. A contact lens-based technique for expansion and transplantation of autologous epithelial progenitors for ocular surface reconstruction. Transplantation. 2009;87:1571–8.

    Article  PubMed  Google Scholar 

  43. Sehic A, Utheim OA, Ommundsen K, Utheim TP. Pre-clinical cell-based therapy for Limbal stem cell deficiency. J Funct Biomater. 2015;6:863–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chun YS, Park IK, Kim JC. Technique for autologous nasal mucosa transplantation in severe ocular surface disease. Eur J Ophthalmol. 2011;21:545–51.

    Article  PubMed  Google Scholar 

  45. Kim JH, Chun YS, Lee SH, et al. Ocular surface reconstruction with autologous nasal mucosa in cicatricial ocular surface disease. Am J Ophthalmol. 2010;149:45–53.

    Article  PubMed  Google Scholar 

  46. Monteiro BG, Serafim RC, Melo GB, et al. Human immature dental pulp stem cells share key characteristic features with limbal stem cells. Cell Prolif. 2009;42:587–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gomes JA, Geraldes Monteiro B, Melo GB, et al. Corneal reconstruction with tissue-engineered cell sheets composed of human immature dental pulp stem cells. Invest Ophthalmol Vis Sci. 2010;51:1408–14.

    Article  PubMed  Google Scholar 

  48. Meyer-Blazejewska EA, Call MK, Yamanaka O, et al. From hair to cornea: toward the therapeutic use of hair follicle-derived stem cells in the treatment of limbal stem cell deficiency. Stem Cells. 2011;29:57–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Garzon I, Martin-Piedra MA, Alfonso-Rodriguez C, et al. Generation of a biomimetic human artificial cornea model using Wharton’s jelly mesenchymal stem cells. Invest Ophthalmol Vis Sci. 2014;55:4073–83.

    Article  PubMed  Google Scholar 

  50. Reza HM, Ng BY, Gimeno FL, Phan TT, Ang LP. Umbilical cord lining stem cells as a novel and promising source for ocular surface regeneration. Stem Cell Rev. 2011;7:935–47.

    Article  Google Scholar 

  51. Omoto M, Miyashita H, Shimmura S, et al. The use of human mesenchymal stem cell-derived feeder cells for the cultivation of transplantable epithelial sheets. Invest Ophthalmol Vis Sci. 2009;50:2109–15.

    Article  PubMed  Google Scholar 

  52. Rohaina CM, Then KY, Ng AM, et al. Reconstruction of limbal stem cell deficient corneal surface with induced human bone marrow mesenchymal stem cells on amniotic membrane. Transl Res. 2014;163:200–10.

    Article  CAS  PubMed  Google Scholar 

  53. Lin KJ, Loi MX, Lien GS, et al. Topical administration of orbital fat-derived stem cells promotes corneal tissue regeneration. Stem Cell Res Ther. 2013;4:72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Hayashi R, Ishikawa Y, Ito M, et al. Generation of corneal epithelial cells from induced pluripotent stem cells derived from human dermal fibroblast and corneal limbal epithelium. PLoS One. 2012;7:e45435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ang LP, Tanioka H, Kawasaki S, et al. Cultivated human conjunctival epithelial transplantation for total limbal stem cell deficiency. Invest Ophthalmol Vis Sci. 2010;51:758–64.

    Article  PubMed  Google Scholar 

  56. Sangwan VS, Vemuganti GK, Singh S, Balasubramanian D. Successful reconstruction of damaged ocular outer surface in humans using limbal and conjunctival stem cell culture methods. Biosci Rep. 2003;23:169–74.

    Article  CAS  PubMed  Google Scholar 

  57. Sangwan VS, Vemuganti GK, Iftekhar G, Bansal AK, Rao GN. Use of autologous cultured limbal and conjunctival epithelium in a patient with severe bilateral ocular surface disease induced by acid injury: a case report of unique application. Cornea. 2003;22:478–81.

    Article  PubMed  Google Scholar 

  58. Subramaniam SV, Sejpal K, Fatima A, Gaddipati S, Vemuganti GK, Sangwan VS. Coculture of autologous limbal and conjunctival epithelial cells to treat severe ocular surface disorders: long-term survival analysis. Indian J Ophthalmol. 2013;61:202–7.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Tan DT, Ang LP, Beuerman RW. Reconstruction of the ocular surface by transplantation of a serum-free derived cultivated conjunctival epithelial equivalent. Transplantation. 2004;77:1729–34.

    Article  PubMed  Google Scholar 

  60. Burillon C, Huot L, Justin V, et al. Cultured autologous oral mucosal epithelial cell sheet (CAOMECS) transplantation for the treatment of corneal limbal epithelial stem cell deficiency. Invest Ophthalmol Vis Sci. 2012;53:1325–31.

    Article  PubMed  Google Scholar 

  61. Inatomi T, Nakamura T, Kojyo M, Koizumi N, Sotozono C, Kinoshita S. Ocular surface reconstruction with combination of cultivated autologous oral mucosal epithelial transplantation and penetrating keratoplasty. Am J Ophthalmol. 2006;142:757–64.

    Article  PubMed  Google Scholar 

  62. Nakamura T, Takeda K, Inatomi T, Sotozono C, Kinoshita S. Long-term results of autologous cultivated oral mucosal epithelial transplantation in the scar phase of severe ocular surface disorders. Br J Ophthalmol. 2011;95:942–6.

    Article  PubMed  Google Scholar 

  63. Nishida K, Yamato M, Hayashida Y, et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med. 2004;351:1187–96.

    Article  CAS  PubMed  Google Scholar 

  64. Takeda K, Nakamura T, Inatomi T, Sotozono C, Watanabe A, Kinoshita S. Ocular surface reconstruction using the combination of autologous cultivated oral mucosal epithelial transplantation and eyelid surgery for severe ocular surface disease. Am J Ophthalmol. 2011;152:195–201. e1

    Article  PubMed  Google Scholar 

  65. Utheim TP. Concise review: transplantation of cultured oral mucosal epithelial cells for treating limbal stem cell deficiency-current status and future perspectives. Stem Cells. 2015;33:1685–95.

    Article  CAS  PubMed  Google Scholar 

  66. Ahmad S, Stewart R, Yung S, et al. Differentiation of human embryonic stem cells into corneal epithelial-like cells by in vitro replication of the corneal epithelial stem cell niche. Stem Cells. 2007;25:1145–55.

    Article  CAS  PubMed  Google Scholar 

  67. Zhang C, Du L, Pang K, Wu X. Differentiation of human embryonic stem cells into corneal epithelial progenitor cells under defined conditions. PLoS One. 2017;12:e0183303.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Reza HM, Ng BY, Phan TT, Tan DT, Beuerman RW, Ang LP. Characterization of a novel umbilical cord lining cell with CD227 positivity and unique pattern of P63 expression and function. Stem Cell Rev. 2011;7:624–38.

    Article  CAS  Google Scholar 

  69. Zieske JD. Corneal development associated with eyelid opening. Int J Dev Biol. 2004;48:903–11.

    Article  PubMed  Google Scholar 

  70. Meek KM, Knupp C. Corneal structure and transparency. Prog Retin Eye Res. 2015;49:1–16.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Carlson EC, Wang IJ, Liu CY, Brannan P, Kao CW, Kao WW. Altered KSPG expression by keratocytes following corneal injury. Mol Vis. 2003;9:615–23.

    CAS  PubMed  Google Scholar 

  72. Jester JV, Petroll WM, Cavanagh HD. Corneal stromal wound healing in refractive surgery: the role of myofibroblasts. Prog Retin Eye Res. 1999;18:311–56.

    Article  CAS  PubMed  Google Scholar 

  73. Fini ME. Keratocyte and fibroblast phenotypes in the repairing cornea. Prog Retin Eye Res. 1999;18:529–51.

    Article  CAS  PubMed  Google Scholar 

  74. Buss DG, Giuliano EA, Sharma A, Mohan RR. Isolation and cultivation of equine corneal keratocytes, fibroblasts and myofibroblasts. Vet Ophthalmol. 2010;13:37–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Patel DV, McKelvie J, Sherwin T, McGhee C. Keratocyte progenitor cell transplantation: a novel therapeutic strategy for corneal disease. Med Hypotheses. 2013;80:122–4.

    Article  CAS  PubMed  Google Scholar 

  76. Basu S, Hertsenberg AJ, Funderburgh ML, et al. Human limbal biopsy-derived stromal stem cells prevent corneal scarring. Sci Transl Med. 2014;6:266ra172.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Wu J, Rnjak-Kovacina J, Du Y, Funderburgh ML, Kaplan DL, Funderburgh JL. Corneal stromal bioequivalents secreted on patterned silk substrates. Biomaterials. 2014;35:3744–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Du Y, Sundarraj N, Funderburgh ML, Harvey SA, Birk DE, Funderburgh JL. Secretion and organization of a cornea-like tissue in vitro by stem cells from human corneal stroma. Invest Ophthalmol Vis Sci. 2007;48:5038–45.

    Article  PubMed  Google Scholar 

  79. Naylor RW, McGhee CN, Cowan CA, Davidson AJ, Holm TM, Sherwin T. Derivation of corneal Keratocyte-like cells from human induced pluripotent stem cells. PLoS One. 2016;11:e0165464.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Bahn CF, Falls HF, Varley GA, Meyer RF, Edelhauser HF, Bourne WM. Classification of corneal endothelial disorders based on neural crest origin. Ophthalmology. 1984;91:558–63.

    Article  CAS  PubMed  Google Scholar 

  81. Hatou S, Yamada M, Mochizuki H, Shiraishi A, Joko T, Nishida T. The effects of dexamethasone on the Na,K-ATPase activity and pump function of corneal endothelial cells. Curr Eye Res. 2009;34:347–54.

    Article  CAS  PubMed  Google Scholar 

  82. Kinoshita S, Koizumi N, Ueno M, Okumura N, Imai K, Tanaka H, Yamamoto Y, Nakamura T, Inatomi T, Bush J, Toda M, Hagiya M, Yokota I, Teramukai S, Sotozono C, Hamuro J. Injection of cultured cells with a ROCK inhibitor for bullous keratopathy. N Engl J Med. 2018;378(11):995–1003. https://doi.org/10.1056/NEJMoa1712770. PMID:29539291.

    Article  CAS  PubMed  Google Scholar 

  83. Chan BP, Leong KW. Scaffolding in tissue engineering: general approaches and tissue-specific considerations. Eur Spine J. 2008;17(Suppl 4):467–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Grinstaff MW. Designing hydrogel adhesives for corneal wound repair. Biomaterials. 2007;28:5205–14.

    Article  CAS  PubMed  Google Scholar 

  85. Rafat M, Li F, Fagerholm P, et al. PEG-stabilized carbodiimide crosslinked collagen-chitosan hydrogels for corneal tissue engineering. Biomaterials. 2008;29:3960–72.

    Article  CAS  PubMed  Google Scholar 

  86. Aldave AJ, Kamal KM, Vo RC, Yu F. The Boston type I keratoprosthesis: improving outcomes and expanding indications. Ophthalmology. 2009;116:640–51.

    Article  PubMed  Google Scholar 

  87. Zorlutuna P, Tezcaner A, Kiyat I, Aydinli A, Hasirci V. Cornea engineering on polyester carriers. J Biomed Mater Res A. 2006;79:104–13.

    Article  CAS  PubMed  Google Scholar 

  88. Liu L, Sheardown H. Glucose permeable poly (dimethyl siloxane) poly (N-isopropyl acrylamide) interpenetrating networks as ophthalmic biomaterials. Biomaterials. 2005;26:233–44.

    Article  CAS  PubMed  Google Scholar 

  89. Deng ZX, Zhang ZX, Li LH, Zhou CR. Biocompatibility evaluation of chitosan-g-polyvinylpyrrolidone. Di Yi Jun Yi Da Xue Xue Bao. 2004;24:639–41.

    CAS  PubMed  Google Scholar 

  90. Bae SR, Park C, Choi JC, Poo H, Kim CJ, Sung MH. Effects of ultra high molecular weight poly-gamma-glutamic acid from Bacillus subtilis (chungkookjang) on corneal wound healing. J Microbiol Biotechnol. 2010;20:803–8.

    CAS  PubMed  Google Scholar 

  91. Sharma CP. Biointegration of medical implant materials: science and design. New York: Elsevier Science; 2010.

    Book  Google Scholar 

  92. Li F, Griffith M, Li Z, et al. Recruitment of multiple cell lines by collagen-synthetic copolymer matrices in corneal regeneration. Biomaterials. 2005;26:3093–104.

    Article  CAS  PubMed  Google Scholar 

  93. Duan X, Sheardown H. Dendrimer crosslinked collagen as a corneal tissue engineering scaffold: mechanical properties and corneal epithelial cell interactions. Biomaterials. 2006;27:4608–17.

    Article  CAS  PubMed  Google Scholar 

  94. McLaughlin CR, Acosta MC, Luna C, et al. Regeneration of functional nerves within full thickness collagen-phosphorylcholine corneal substitute implants in guinea pigs. Biomaterials. 2010;31:2770–8.

    Article  CAS  PubMed  Google Scholar 

  95. Liu W, Deng C, McLaughlin CR, et al. Collagen-phosphorylcholine interpenetrating network hydrogels as corneal substitutes. Biomaterials. 2009;30:1551–9.

    Article  CAS  PubMed  Google Scholar 

  96. Duan X, McLaughlin C, Griffith M, Sheardown H. Biofunctionalization of collagen for improved biological response: scaffolds for corneal tissue engineering. Biomaterials. 2007;28:78–88.

    Article  CAS  PubMed  Google Scholar 

  97. Lai JY, Li YT. Functional assessment of cross-linked porous gelatin hydrogels for bioengineered cell sheet carriers. Biomacromolecules. 2010;11:1387–97.

    Article  CAS  PubMed  Google Scholar 

  98. Alaminos M, Del Carmen Sanchez-Quevedo M, Munoz-Avila JI, et al. Construction of a complete rabbit cornea substitute using a fibrin-agarose scaffold. Invest Ophthalmol Vis Sci. 2006;47:3311–7.

    Article  PubMed  Google Scholar 

  99. Lawrence BD, Marchant JK, Pindrus MA, Omenetto FG, Kaplan DL. Silk film biomaterials for cornea tissue engineering. Biomaterials. 2009;30:1299–308.

    Article  CAS  PubMed  Google Scholar 

  100. Grolik M, Szczubialka K, Wowra B, et al. Hydrogel membranes based on genipin-cross-linked chitosan blends for corneal epithelium tissue engineering. J Mater Sci Mater Med. 2012;23:1991–2000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Vrana NE, Builles N, Justin V, et al. Development of a reconstructed cornea from collagen-chondroitin sulfate foams and human cell cultures. Invest Opthalmol Vis Sci. 2008;49:5325–31.

    Article  Google Scholar 

  102. Maia J, Ribeiro MP, Ventura C, Carvalho RA, Correia IJ, Gil MH. Ocular injectable formulation assessment for oxidized dextran-based hydrogels. Acta Biomater. 2009;5:1948–55.

    Article  CAS  PubMed  Google Scholar 

  103. Fiorica C, Senior RA, Pitarresi G, et al. Biocompatible hydrogels based on hyaluronic acid cross-linked with a polyaspartamide derivative as delivery systems for epithelial limbal cells. Int J Pharm. 2011;414:104–11.

    Article  CAS  PubMed  Google Scholar 

  104. Tonsomboon K, Oyen ML. Composite electrospun gelatin fiber-alginate gel scaffolds for mechanically robust tissue engineered cornea. J Mech Behav Biomed. 2013;21:185–94.

    Article  CAS  Google Scholar 

  105. Hamley IW, Dehsorkhi A, Castelletto V, et al. Self-assembly and collagen-stimulating activity of a peptide Amphiphile incorporating a peptide sequence from Lumican. Langmuir. 2015;31:4490–5.

    Article  CAS  PubMed  Google Scholar 

  106. Gouveia RM, González-Andrades E, Cardona JC, González-Gallardo C, Ionescu AM, Garzon I, Alaminos M, González-Andrades M, Connon CJ. Controlling the 3D architecture of Self-Lifting Auto-generated Tissue Equivalents (SLATEs) for optimized corneal graft composition and stability. Biomaterials. 2017;121:205–19. https://doi.org/10.1016/j.biomaterials.2016.12.023. Epub 2016 Dec 23. PMID: 28092777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Islam MM, Ravichandran R, Olsen D, et al. Self-assembled collagen-like-peptide implants as alternatives to human donor corneal transplantation. RSC Adv. 2016;6:55745–9.

    Article  CAS  Google Scholar 

  108. Jangamreddy JR, Haagdorens MKC, Mirazul Islam M, et al. Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants. Acta Biomaterialia. 2018. pii: S1742–7061(18)30022–9; https://doi.org/10.1016/j.actbio.2018.01.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kumano Y, Sakamoto T, Egawa M, Tanaka M, Yamamoto I. Enhancing effect of 2-O-alpha-D-glucopyranosyl-L-ascorbic acid, a stable ascorbic acid derivative, on collagen synthesis. Biol Pharm Bull. 1998;21:662–6.

    Article  CAS  PubMed  Google Scholar 

  110. Saika S. Ultrastructural effect of L-ascorbic acid 2-phosphate on cultured keratocytes. Cornea. 1992;11:439–45.

    Article  CAS  PubMed  Google Scholar 

  111. Cissell DD, Hu JC, Griffiths LG, Athanasiou KA. Antigen removal for the production of biomechanically functional, xenogeneic tissue grafts. J Biomech. 2014;47:1987–96.

    Article  PubMed  Google Scholar 

  112. Gilbert TW, Sellaro TL, Badylak SF. Decellularization of tissues and organs. Biomaterials. 2006;27:3675–83.

    CAS  PubMed  Google Scholar 

  113. Vorotnikova E, McIntosh D, Dewilde A, et al. Extracellular matrix-derived products modulate endothelial and progenitor cell migration and proliferation in vitro and stimulate regenerative healing in vivo. Matrix Biol. 2010;29:690–700.

    Article  CAS  PubMed  Google Scholar 

  114. Barkan D, Green JE, Chambers AF. Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth. Eur J Cancer. 2010;46:1181–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Petersen TH, Calle EA, Zhao L, et al. Tissue-engineered lungs for in vivo implantation. Science. 2010;329:538–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials. 2011;32:3233–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gonzalez-Andrades M, de la Cruz Cardona J, Ionescu AM, Campos A, Del Mar Perez M, Alaminos M. Generation of bioengineered corneas with decellularized xenografts and human keratocytes. Invest Ophthalmol Vis Sci. 2011;52:215–22.

    Article  CAS  Google Scholar 

  118. Brown BN, Valentin JE, Stewart-Akers AM, McCabe GP, Badylak SF. Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. Biomaterials. 2009;30:1482–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhang MC, Liu X, Jin Y, Jiang DL, Wei XS, Xie HT. Lamellar Keratoplasty treatment of fungal corneal ulcers with acellular porcine corneal stroma. Am J Transplant. 2015;15:1068–75.

    Article  PubMed  Google Scholar 

  120. Nishida T, Nakamura M, Ofuji K, Reid TW, Mannis MJ, Murphy CJ. Synergistic effects of substance P with insulin-like growth factor-1 on epithelial migration of the cornea. J Cell Physiol. 1996;169:159–66.

    Article  CAS  PubMed  Google Scholar 

  121. Holan V, Trosan P, Krulova M, Zajicova A. Identification of factors regulating differentiation and growth of limbal stem cells for corneal surface regeneration. Acta Ophthalmologica. 2012;90:0.

    Article  Google Scholar 

  122. Zieske JD, Takahashi H, Hutcheon AE, Dalbone AC. Activation of epidermal growth factor receptor during corneal epithelial migration. Invest Ophthalmol Vis Sci. 2000;41:1346–55.

    CAS  PubMed  Google Scholar 

  123. Wilson SE, Walker JW, Chwang EL, He YG. Hepatocyte growth factor, keratinocyte growth factor, their receptors, fibroblast growth factor receptor-2, and the cells of the cornea. Invest Ophthalmol Vis Sci. 1993;34:2544–61.

    CAS  PubMed  Google Scholar 

  124. Daniels JT, Limb GA, Saarialho-Kere U, Murphy G, Khaw PT. Human corneal epithelial cells require MMP-1 for HGF-mediated migration on collagen I. Invest Ophthalmol Vis Sci. 2003;44:1048–55.

    Article  PubMed  Google Scholar 

  125. Kakazu A, Chandrasekher G, Bazan HE. HGF protects corneal epithelial cells from apoptosis by the PI-3K/Akt-1/Bad- but not the ERK1/2-mediated signaling pathway. Invest Ophthalmol Vis Sci. 2004;45:3485–92.

    Article  PubMed  Google Scholar 

  126. Wilson SE, Li Q, Mohan RR, et al. Lacrimal gland growth factors and receptors: lacrimal fibroblastic cells are a source of tear HGF. Adv Exp Med Biol. 1998;438:625–8.

    Article  CAS  PubMed  Google Scholar 

  127. Haber M, Cao Z, Panjwani N, Bedenice D, Li WW, Provost PJ. Effects of growth factors (EGF, PDGF-BB and TGF-beta 1) on cultured equine epithelial cells and keratocytes: implications for wound healing. Vet Ophthalmol. 2003;6:211–7.

    Article  CAS  PubMed  Google Scholar 

  128. Andresen JL, Ledet T, Ehlers N. Keratocyte migration and peptide growth factors: the effect of PDGF, bFGF, EGF, IGF-I, aFGF and TGF-beta on human keratocyte migration in a collagen gel. Curr Eye Res. 1997;16:605–13.

    Article  CAS  PubMed  Google Scholar 

  129. Jester JV, Huang J, Fisher S, et al. Myofibroblast differentiation of normal human keratocytes and hTERT, extended-life human corneal fibroblasts. Invest Ophthalmol Vis Sci. 2003;44:1850–8.

    Article  PubMed  Google Scholar 

  130. Daniels JT, Khaw PT. Temporal stimulation of corneal fibroblast wound healing activity by differentiating epithelium in vitro. Invest Ophthalmol Vis Sci. 2000;41:3754–62.

    CAS  PubMed  Google Scholar 

  131. Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. 2000;107:1347–51; discussion 51–2.

    Article  CAS  PubMed  Google Scholar 

  132. Cellini M, Bendo E, Bravetti GO, Campos EC. The use of nerve growth factor in surgical wound healing of the cornea. Ophthalmic Res. 2006;38:177–81.

    Article  CAS  PubMed  Google Scholar 

  133. Ma K, Yan N, Huang Y, Cao G, Deng J, Deng Y. Effects of nerve growth factor on nerve regeneration after corneal nerve damage. Int J Clin Exp Med. 2014;7:4584–9.

    PubMed  PubMed Central  Google Scholar 

  134. McLaughlin PJ, Sassani JW, Klocek MS, Zagon IS. Diabetic keratopathy and treatment by modulation of the opioid growth factor (OGF)-OGF receptor (OGFr) axis with naltrexone: a review. Brain Res Bull. 2010;81:236–47.

    Article  CAS  PubMed  Google Scholar 

  135. Nakamura Y, Sotozono C, Kinoshita S. The epidermal growth factor receptor (EGFR): role in corneal wound healing and homeostasis. Exp Eye Res. 2001;72:511–7.

    Article  CAS  PubMed  Google Scholar 

  136. Yanai R, Yamada N, Inui M, Nishida T. Correlation of proliferative and anti-apoptotic effects of HGF, insulin, IGF-1, IGF-2, and EGF in SV40-transformed human corneal epithelial cells. Exp Eye Res. 2006;83:76–83.

    Article  CAS  PubMed  Google Scholar 

  137. Chandrasekher G, Kakazu AH, Bazan HE. HGF- and KGF-induced activation of PI-3K/p70 s6 kinase pathway in corneal epithelial cells: its relevance in wound healing. Exp Eye Res. 2001;73:191–202.

    Article  CAS  PubMed  Google Scholar 

  138. Lee JG, Kay EP. FGF-2-induced wound healing in corneal endothelial cells requires Cdc42 activation and Rho inactivation through the phosphatidylinositol 3-kinase pathway. Invest Ophthalmol Vis Sci. 2006;47:1376–86.

    Article  PubMed  Google Scholar 

  139. Trosan P, Svobodova E, Chudickova M, Krulova M, Zajicova A, Holan V. The key role of insulin-like growth factor I in limbal stem cell differentiation and the corneal wound-healing process. Stem Cells Dev. 2012;21:3341–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Pancholi S, Tullo A, Khaliq A, Foreman D, Boulton M. The effects of growth factors and conditioned media on the proliferation of human corneal epithelial cells and keratocytes. Graefes Arch Clin Exp Ophthalmol. 1998;236:1–8.

    Article  CAS  PubMed  Google Scholar 

  141. Kay EP, Lee MS, Seong GJ, Lee YG. TGF-beta s stimulate cell proliferation via an autocrine production of FGF-2 in corneal stromal fibroblasts. Curr Eye Res. 1998;17:286–93.

    Article  CAS  PubMed  Google Scholar 

  142. Denk PO, Knorr M. The in vitro effect of platelet-derived growth factor isoforms on the proliferation of bovine corneal stromal fibroblasts depends on cell density. Graefes Arch Clin Exp Ophthalmol. 1997;235:530–4.

    Article  CAS  PubMed  Google Scholar 

  143. Kamiyama K, Iguchi I, Wang X, Imanishi J. Effects of PDGF on the migration of rabbit corneal fibroblasts and epithelial cells. Cornea. 1998;17:315–25.

    Article  CAS  PubMed  Google Scholar 

  144. Sosne G, Siddiqi A, Kurpakus-Wheater M. Thymosin-beta4 inhibits corneal epithelial cell apoptosis after ethanol exposure in vitro. Invest Ophthalmol Vis Sci. 2004;45:1095–100.

    Article  PubMed  Google Scholar 

  145. Sosne G, Qiu P, Ousler GW 3rd, Dunn SP, Crockford D. Thymosin beta4: a potential novel dry eye therapy. Ann N Y Acad Sci. 2012;1270:45–50.

    Article  CAS  PubMed  Google Scholar 

  146. Dunn SP, Heidemann DG, Chow CY, et al. Treatment of chronic nonhealing neurotrophic corneal epithelial defects with thymosin beta4. Ann N Y Acad Sci. 2010;1194:199–206.

    Article  CAS  PubMed  Google Scholar 

  147. Lambiase A, Bonini S, Micera A, Rama P, Bonini S, Aloe L. Expression of nerve growth factor receptors on the ocular surface in healthy subjects and during manifestation of inflammatory diseases. Invest Ophthalmol Vis Sci. 1998;39:1272–5.

    CAS  PubMed  Google Scholar 

  148. Lambiase A, Bonini S, Aloe L, Rama P, Bonini S. Anti-inflammatory and healing properties of nerve growth factor in immune corneal ulcers with stromal melting. Arch Ophthalmol. 2000;118:1446–9.

    Article  CAS  PubMed  Google Scholar 

  149. Joo M, Yuhan KR, Hyon J, et al. The effect of nerve growth factor on corneal sensitivity after laserin situ keratomileusis. Arch Ophthalmol. 2004;122:1338–41.

    Article  PubMed  Google Scholar 

  150. Zagon IS, Sassani JW, McLaughlin PJ. Opioid growth factor modulates corneal epithelial outgrowth in tissue culture. Am J Phys. 1995;268:R942–50.

    CAS  Google Scholar 

  151. Wang L, Gonzalez S, Dai W, Deng S, Lu L. Effect of hypoxia-regulated polo-like kinase 3 (Plk3) on human Limbal stem cell differentiation. J Biol Chem. 2016;291:16519–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Hu N, Zhang YY, Gu HW, Guan HJ. Effects of bone marrow mesenchymal stem cells on cell proliferation and growth factor expression of limbal epithelial cells in vitro. Ophthalmic Res. 2012;48:82–8.

    Article  CAS  PubMed  Google Scholar 

  153. Gonfiotti A, Jaus MO, Barale D, et al. The first tissue-engineered airway transplantation: 5-year follow-up results. Lancet. 2014;383:238–44.

    Article  PubMed  Google Scholar 

  154. Hibino N, McGillicuddy E, Matsumura G, et al. Late-term results of tissue-engineered vascular grafts in humans. J Thorac Cardiovasc Surg. 2010;139:431–6. 6.e1–2.

    Article  PubMed  Google Scholar 

  155. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006;367:1241–6.

    Article  PubMed  Google Scholar 

  156. Alió del Barrio JL, El Zarif M, Azaar A, et al. Corneal stroma enhancement with decellularized stromal laminas with or without stem cell recellularization for advanced keratoconus. Am J Ophthalmol. 2018;186:47–58.

    Article  PubMed  Google Scholar 

  157. Fagerholm P, Lagali NS, Ong JA, et al. Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold. Biomaterials. 2014;35:2420–7.

    Article  CAS  PubMed  Google Scholar 

  158. Buznyk O, Pasyechnikova N, Islam MM, Iakymenko S, Fagerholm P, Griffith M. Bioengineered corneas grafted as alternatives to human donor corneas in three high-risk patients. Clin Transl Sci. 2015;8:558–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Islam MM, Buznyk O, Reddy JC, et al. Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation. NPJ Regen Med. 2018;3:2.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Gonzalez-Andrades M, Mata R, Gonzalez-Gallardo MDC, et al. A study protocol for a multicentre randomised clinical trial evaluating the safety and feasibility of a bioengineered human allogeneic nanostructured anterior cornea in patients with advanced corneal trophic ulcers refractory to conventional treatment. BMJ Open. 2017;7:e016487.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Massey LK. Chapter 38 – acrylic polycarbonate alloy (Acrylic PC). In: The effect of sterilization methods on plastics and elastomers. 2nd ed. Norwich: William Andrew Publishing; 2005. p. 241–4.

    Chapter  Google Scholar 

  162. U.S. FDA: Tissue & tissue products. Accessed 13 Dec 2017, at https://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/.

  163. U.S. FDA: Combination product definition. Accessed 13 Dec 2017, at https://www.fda.gov/CombinationProducts/AboutCombinationProducts/ucm118332.htm.

  164. FDA announces comprehensive regenerative medicine policy framework. November 16, 2017. Accessed 11 Dec 2017, at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585345.htm.

Download references

Author information

Authors and Affiliations

  1. Massachusetts Eye and Ear and Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA

    Mohammad Mirazul Islam, Roholah Sharifi & Miguel Gonzalez-Andrades

Authors
  1. Mohammad Mirazul Islam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roholah Sharifi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miguel Gonzalez-Andrades
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Miguel Gonzalez-Andrades .

Editor information

Editors and Affiliations

  1. Miguel Hernández University , Alicante, Spain

    Jorge L. Alió

  2. Vissum-Instituto Oftalmologico de Alica, University Miguel Hernandez, Alicante, Alicante, Spain

    Jorge L. Alió del Barrio

  3. Vissum Corporation, Madrid, Spain

    Francisco Arnalich-Montiel

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Islam, M.M., Sharifi, R., Gonzalez-Andrades, M. (2019). Corneal Tissue Engineering. In: Alió, J., Alió del Barrio, J., Arnalich-Montiel, F. (eds) Corneal Regeneration . Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-030-01304-2_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-01304-2_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-01303-5

  • Online ISBN: 978-3-030-01304-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation