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Emerging Approaches for Ocular Surface Regeneration

  • Ghasem Yazdanpanah
  • Sayena Jabbehdari
  • Ali R. DjalilianEmail author
Regenerative Medicine in Ophthalmology (D Myung, Section Editor)
  • 21 Downloads
Part of the following topical collections:
  1. Topical Collection on Regenerative Medicine in Ophthalmology
  2. Topical Collection on Regenerative Medicine in Ophthalmology

Abstract

Purpose of Review

In this manuscript, the recent advancements and novel approaches for regeneration of the ocular surface are summarized.

Recent Findings

Following severe injuries, persistent inflammation can alter the rehabilitative capability of the ocular surface environment. Limbal stem cell deficiency (LSCD) is one of the most characterized ocular surface disorders mediated by deficiency and/or dysfunction of the limbal epithelial stem cells (LESCs) located in the limbal niche. Currently, the most advanced approach for revitalizing the ocular surface and limbal niche is based on transplantation of limbal tissues harboring LESCs. Emerging approaches have focused on restoring the ocular surface microenvironment using (1) cell-based therapies including cells with capabilities to support the LESCs and modulate the inflammation, e.g., mesenchymal stem cells (MSCs), (2) bioactive extracellular matrices from decellularized tissues, and/or purified/synthetic molecules to regenerate the microenvironment structure, and (3) soluble cytokine/growth factor cocktails to revive the signaling pathways.

Summary

Ocular surface/limbal environment revitalization provides promising approaches for regeneration of the ocular surface.

Keywords

Ocular surface regeneration Corneal epithelium Limbal stem cell niche Limbal epithelial stem cell deficiency Extracellular matrix Mesenchymal stem cells 

Notes

Sources of Support

This research was supported by R01 EY024349 (ARD) and core grant EY01792 from NEI/NIH and unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

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

  1. 1.
    • Ambroziak AM, Szaflik J, Szaflik JP, Ambroziak M, Witkiewicz J, Skopinski P. Immunomodulation on the ocular surface: a review. Cent Eur J Immunol. 2016;41(2):195–208.  https://doi.org/10.5114/ceji.2016.60995 A review summarizing the role of immune system in ocular surface physiopathology and current available treatments for impaired ocular surface immune function.Google Scholar
  2. 2.
    Galletti JG, Guzman M, Giordano MN. Mucosal immune tolerance at the ocular surface in health and disease. Immunology. 2017;150(4):397–407.  https://doi.org/10.1111/imm.12716.Google Scholar
  3. 3.
    •• Yazdanpanah G, Jabbehdari S, Djalilian AR. Limbal and corneal epithelial homeostasis. Curr Opin Ophthalmol. 2017;28(4):348–54.  https://doi.org/10.1097/ICU.0000000000000378 A leading review manuscript from our group illustrating the underlying mechanisms of ocular surface epithelial homeostasis with emphases on the vital role of limbal niche, the alterations in limbal niche following injuries and potential therapeutic approaches to restore limbal niche. Google Scholar
  4. 4.
    Eslani M, Haq Z, Movahedan A, Moss A, Baradaran-Rafii A, Mogilishetty G, et al. Late acute rejection after allograft limbal stem cell transplantation: evidence for long-term donor survival. Cornea. 2017;36(1):26–31.  https://doi.org/10.1097/ICO.0000000000000970.Google Scholar
  5. 5.
    • Nubile M, Curcio C, Dua HS, Calienno R, Lanzini M, Iezzi M, et al. Pathological changes of the anatomical structure and markers of the limbal stem cell niche due to inflammation. Mol Vis. 2013;19:516–25 An original study elucidating the three-dimensional structure of limbal niche using full-field optical coherence microscopy. It has been shown here that mesenchymal/stromal cells have projections through basement membrane leading to physical contact with limbal epithelial stem cells. Google Scholar
  6. 6.
    Notara M, Refaian N, Braun G, Steven P, Bock F, Cursiefen C. Short-term uvb-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines. Stem Cell Res. 2015;15(3):643–54.  https://doi.org/10.1016/j.scr.2015.10.008.Google Scholar
  7. 7.
    Chang JH, Putra I, Huang YH, Chang M, Han K, Zhong W, et al. Limited versus total epithelial debridement ocular surface injury: live fluorescence imaging of hemangiogenesis and lymphangiogenesis in Prox1-GFP/Flk1::Myr-mCherry mice. Biochim Biophys Acta. 2016;1860(10):2148–56.  https://doi.org/10.1016/j.bbagen.2016.05.027.Google Scholar
  8. 8.
    • Tseng SC, He H, Zhang S, Chen SY. Niche regulation of limbal epithelial stem cells: relationship between inflammation and regeneration. Ocul Surf. 2016;14(2):100–12.  https://doi.org/10.1016/j.jtos.2015.12.002 A comprehensive review summarizing the role of inflammation in ocular surface disorders and potential therapeutic approaches especially administration of amniotic membrane and its derivatives. Google Scholar
  9. 9.
    Basu S, Sureka SP, Shanbhag SS, Kethiri AR, Singh V, Sangwan VS. Simple limbal epithelial transplantation: long-term clinical outcomes in 125 cases of unilateral chronic ocular surface burns. Ophthalmology. 2016;123(5):1000–10.  https://doi.org/10.1016/j.ophtha.2015.12.042. Google Scholar
  10. 10.
    Vazirani J, Ali MH, Sharma N, Gupta N, Mittal V, Atallah M, et al. Autologous simple limbal epithelial transplantation for unilateral limbal stem cell deficiency: multicentre results. Br J Ophthalmol. 2016;100(10):1416–20.  https://doi.org/10.1136/bjophthalmol-2015-307348. Google Scholar
  11. 11.
    Ganger A, Vanathi M, Mohanty S, Tandon R. Long-term outcomes of cultivated limbal epithelial transplantation: evaluation and comparison of results in children and adults. Biomed Res Int. 2015;2015:480983.  https://doi.org/10.1155/2015/480983.Google Scholar
  12. 12.
    Shen C, Chan CC, Holland EJ. Limbal stem cell transplantation for soft contact lens wear-related limbal stem cell deficiency. Am J Ophthalmol. 2015;160(6):1142–9 e1.  https://doi.org/10.1016/j.ajo.2015.07.038.Google Scholar
  13. 13.
    Zakaria N, Possemiers T, Dhubhghaill SN, Leysen I, Rozema J, Koppen C, et al. Results of a phase I/II clinical trial: standardized, non-xenogenic, cultivated limbal stem cell transplantation. J Transl Med. 2014;12:58.  https://doi.org/10.1186/1479-5876-12-58.Google Scholar
  14. 14.
    Daya SM. Conjunctival-limbal autograft. Curr Opin Ophthalmol. 2017;28(4):370–6.  https://doi.org/10.1097/ICU.0000000000000385.Google Scholar
  15. 15.
    Titiyal JS, Sharma N, Agarwal AK, Prakash G, Tandon R, Vajpayee R. Live related versus cadaveric limbal allograft in limbal stem cell deficiency. Ocul Immunol Inflamm. 2015;23(3):232–9.  https://doi.org/10.3109/09273948.2014.902076.Google Scholar
  16. 16.
    Cheung AY, Holland EJ. Keratolimbal allograft. Curr Opin Ophthalmol. 2017;28(4):377–81.  https://doi.org/10.1097/ICU.0000000000000374.Google Scholar
  17. 17.
    Yin J, Jurkunas U. Limbal stem cell transplantation and complications. Semin Ophthalmol. 2018;33(1):134–41.  https://doi.org/10.1080/08820538.2017.1353834.Google Scholar
  18. 18.
    Rama P, Ferrari G, Pellegrini G. Cultivated limbal epithelial transplantation. Curr Opin Ophthalmol. 2017;28(4):387–9.  https://doi.org/10.1097/ICU.0000000000000382.Google Scholar
  19. 19.
    Gonzalez S, Deng SX. Presence of native limbal stromal cells increases the expansion efficiency of limbal stem/progenitor cells in culture. Exp Eye Res. 2013;116:169–76.  https://doi.org/10.1016/j.exer.2013.08.020.Google Scholar
  20. 20.
    Kureshi AK, Dziasko M, Funderburgh JL, Daniels JT. Human corneal stromal stem cells support limbal epithelial cells cultured on RAFT tissue equivalents. Sci Rep. 2015;5:16186.  https://doi.org/10.1038/srep16186.Google Scholar
  21. 21.
    Ramirez BE, Sanchez A, Herreras JM, Fernandez I, Garcia-Sancho J, Nieto-Miguel T, et al. Stem cell therapy for corneal epithelium regeneration following good manufacturing and clinical procedures. Biomed Res Int. 2015;2015:408495.  https://doi.org/10.1155/2015/408495.Google Scholar
  22. 22.
    Silber PC, Ricardo JR, Cristovam PC, Hazarbassanov RM, Dreyfuss JL, Gomes JA. Conjunctival epithelial cells cultivated ex vivo from patients with total limbal stem cell deficiency. Eur J Ophthalmol. 2014.  https://doi.org/10.5301/ejo.5000511.
  23. 23.
    Jeon S, Choi SH, Wolosin JM, Chung SH, Joo CK. Regeneration of the corneal epithelium with conjunctival epithelial equivalents generated in serum- and feeder-cell-free media. Mol Vis. 2013;19:2542–50.Google Scholar
  24. 24.
    Kolli S, Ahmad S, Mudhar HS, Meeny A, Lako M, Figueiredo FC. Successful application of ex vivo expanded human autologous oral mucosal epithelium for the treatment of total bilateral limbal stem cell deficiency. Stem Cells. 2014;32(8):2135–46.  https://doi.org/10.1002/stem.1694.Google Scholar
  25. 25.
    Ilmarinen T, Laine J, Juuti-Uusitalo K, Numminen J, Seppanen-Suuronen R, Uusitalo H, et al. Towards a defined, serum- and feeder-free culture of stratified human oral mucosal epithelium for ocular surface reconstruction. Acta Ophthalmol. 2013;91(8):744–50.  https://doi.org/10.1111/j.1755-3768.2012.02523.x.Google Scholar
  26. 26.
    Zhou Q, Liu XY, Ruan YX, Wang L, Jiang MM, Wu J, et al. Construction of corneal epithelium with human amniotic epithelial cells and repair of limbal deficiency in rabbit models. Hum Cell. 2015;28(1):22–36.  https://doi.org/10.1007/s13577-014-0099-6.Google Scholar
  27. 27.
    Brzeszczynska J, Samuel K, Greenhough S, Ramaesh K, Dhillon B, Hay DC, et al. Differentiation and molecular profiling of human embryonic stem cell-derived corneal epithelial cells. Int J Mol Med. 2014;33(6):1597–606.  https://doi.org/10.3892/ijmm.2014.1714.Google Scholar
  28. 28.
    Ouyang H, Xue Y, Lin Y, Zhang X, Xi L, Patel S, et al. WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis. Nature. 2014;511(7509):358–61.  https://doi.org/10.1038/nature13465.Google Scholar
  29. 29.
    • Hayashi R, Ishikawa Y, Sasamoto Y, Katori R, Nomura N, Ichikawa T, et al. Co-ordinated ocular development from human iPS cells and recovery of corneal function. Nature. 2016;531(7594):376–80.  https://doi.org/10.1038/nature17000 An interesting study reporting generation of corneal and conjunctival epithelial cells from human iPS cells with ocular surface regeneration capabilities.Google Scholar
  30. 30.
    Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Kao WW. Extrinsic and intrinsic mechanisms by which mesenchymal stem cells suppress the immune system. Ocul Surf. 2016;14(2):121–34.  https://doi.org/10.1016/j.jtos.2015.11.004.Google Scholar
  31. 31.
    Cejkova J, Trosan P, Cejka C, Lencova A, Zajicova A, Javorkova E, et al. Suppression of alkali-induced oxidative injury in the cornea by mesenchymal stem cells growing on nanofiber scaffolds and transferred onto the damaged corneal surface. Exp Eye Res. 2013;116:312–23.  https://doi.org/10.1016/j.exer.2013.10.002.Google Scholar
  32. 32.
    Lee MJ, Ko AY, Ko JH, Lee HJ, Kim MK, Wee WR, et al. Mesenchymal stem/stromal cells protect the ocular surface by suppressing inflammation in an experimental dry eye. Mol ther. 2015;23(1):139–46.  https://doi.org/10.1038/mt.2014.159. Google Scholar
  33. 33.
    Omoto M, Katikireddy KR, Rezazadeh A, Dohlman TH, Chauhan SK. Mesenchymal stem cells home to inflamed ocular surface and suppress allosensitization in corneal transplantation. Invest Ophthalmol Vis Sci. 2014;55(10):6631–8.  https://doi.org/10.1167/iovs.14-15413.Google Scholar
  34. 34.
    Ke Y, Wu Y, Cui X, Liu X, Yu M, Yang C, et al. Polysaccharide hydrogel combined with mesenchymal stem cells promotes the healing of corneal alkali burn in rats. PLoS One. 2015;10(3):e0119725.  https://doi.org/10.1371/journal.pone.0119725.Google Scholar
  35. 35.
    Mathews S, Chidambaram JD, Lanjewar S, Mascarenhas J, Prajna NV, Muthukkaruppan V, et al. In vivo confocal microscopic analysis of normal human anterior limbal stroma. Cornea. 2015;34(4):464–70.  https://doi.org/10.1097/ICO.0000000000000369.Google Scholar
  36. 36.
    Higa K, Kato N, Yoshida S, Ogawa Y, Shimazaki J, Tsubota K, et al. Aquaporin 1-positive stromal niche-like cells directly interact with N-cadherin-positive clusters in the basal limbal epithelium. Stem Cell Res. 2013;10(2):147–55.  https://doi.org/10.1016/j.scr.2012.11.001.Google Scholar
  37. 37.
    Yamada K, Young RD, Lewis PN, Shinomiya K, Meek KM, Kinoshita S, et al. Mesenchymal-epithelial cell interactions and proteoglycan matrix composition in the presumptive stem cell niche of the rabbit corneal limbus. Mol Vis. 2015;21:1328–39.Google Scholar
  38. 38.
    Xie HT, Chen SY, Li GG, Tseng SC. Limbal epithelial stem/progenitor cells attract stromal niche cells by SDF-1/CXCR4 signaling to prevent differentiation. Stem Cells. 2011;29(11):1874–85.  https://doi.org/10.1002/stem.743.Google Scholar
  39. 39.
    Han B, Chen SY, Zhu YT, Tseng SC. Integration of BMP/Wnt signaling to control clonal growth of limbal epithelial progenitor cells by niche cells. Stem Cell Res. 2014;12(2):562–73.  https://doi.org/10.1016/j.scr.2014.01.003.Google Scholar
  40. 40.
    Notara M, Shortt AJ, Galatowicz G, Calder V, Daniels JT. IL6 and the human limbal stem cell niche: a mediator of epithelial-stromal interaction. Stem Cell Res. 2010;5(3):188–200.  https://doi.org/10.1016/j.scr.2010.07.002.Google Scholar
  41. 41.
    • Eslani M, Putra I, Shen X, Hamouie J, Afsharkhamseh N, Besharat S, et al. Corneal mesenchymal stromal cells are directly antiangiogenic via PEDF and sFLT-1. Invest Ophthalmol Vis Sci. 2017;58(12):5507–17.  https://doi.org/10.1167/iovs.17-22680 A report of therapeutic effects of human cornea-derived mesenchymal stem cells in ocular surface wounds providing data about underlying mechanisms. Google Scholar
  42. 42.
    Eslani M, Putra I, Shen X, Hamouie J, Tadepalli A, Anwar KN, et al. Cornea-derived mesenchymal stromal cells therapeutically modulate macrophage immunophenotype and angiogenic function. Stem Cells. 2018;36(5):775–84.  https://doi.org/10.1002/stem.2781.Google Scholar
  43. 43.
    Heo JS, Choi Y, Kim HS, Kim HO. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. Int J Mol Med. 2016;37(1):115–25.  https://doi.org/10.3892/ijmm.2015.2413.Google Scholar
  44. 44.
    Wegmeyer H, Broske AM, Leddin M, Kuentzer K, Nisslbeck AK, Hupfeld J, et al. Mesenchymal stromal cell characteristics vary depending on their origin. Stem Cells Dev. 2013;22(19):2606–18.  https://doi.org/10.1089/scd.2013.0016.Google Scholar
  45. 45.
    Li G, Zhang Y, Cai S, Sun M, Wang J, Li S, et al. Human limbal niche cells are a powerful regenerative source for the prevention of limbal stem cell deficiency in a rabbit model. Sci Rep. 2018;8(1):6566.  https://doi.org/10.1038/s41598-018-24862-6. Google Scholar
  46. 46.
    Funderburgh J, Basu S, Damala M, Tavakkoli F, Sangwan V, Singh V. Limbal stromal stem cell therapy for acute and chronic superficial corneal pathologies: one-year outcomes. Invest Ophthalmol Vis Sci. 2018;59(9):3455.Google Scholar
  47. 47.
    Basu S, Damala M, Singh V. Limbal stromal stem cell therapy for acute and chronic superficial corneal pathologies: early clinical outcomes of the Funderburgh technique. Invest Ophthalmol Vis Sci. 2017;58(8):3371.Google Scholar
  48. 48.
    Dziasko MA, Tuft SJ, Daniels JT. Limbal melanocytes support limbal epithelial stem cells in 2D and 3D microenvironments. Exp Eye Res. 2015;138:70–9.  https://doi.org/10.1016/j.exer.2015.06.026.Google Scholar
  49. 49.
    • Polisetti N, Zenkel M, Menzel-Severing J, Kruse FE, Schlotzer-Schrehardt U. Cell adhesion molecules and stem cell-niche-interactions in the limbal stem cell niche. Stem Cells. 2016;34(1):203–19.  https://doi.org/10.1002/stem.2191 In this study, the adhesion molecules mediating the cell-cell and cell-extracellular matrix interaction/cross talk in limbal niche were identified. Google Scholar
  50. 50.
    Schlotzer-Schrehardt U, Polisetti N, Zenkel M, Naschberger E, Heger L, Dudziak D, et al. Melanocytes as an emerging key player in niche regulation of limbal stem cells. Invest Ophthalmol Vis Sci. 2018;59(9):3453.Google Scholar
  51. 51.
    • Grieve K, Ghoubay D, Georgeon C, Thouvenin O, Bouheraoua N, Paques M, et al. Three-dimensional structure of the mammalian limbal stem cell niche. Exp Eye Res. 2015;140:75–84.  https://doi.org/10.1016/j.exer.2015.08.003 An original study elucidating the three-dimensional structure of limbal niche using full-field optical coherence microscopy. It has been shown here that mesenchymal/stromal cells have projections through basement membrane leading to physical contact with limbal epithelial stem cells. Google Scholar
  52. 52.
    Notara M, Lentzsch A, Coroneo M, Cursiefen C. The role of limbal epithelial stem cells in regulating corneal (lymph)angiogenic privilege and the micromilieu of the limbal niche following UV exposure. Stem Cells Int. 2018;2018:8620172.  https://doi.org/10.1155/2018/8620172. Google Scholar
  53. 53.
    Deihim T, Yazdanpanah G, Niknejad H. Different light transmittance of placental and reflected regions of human amniotic membrane that could be crucial for corneal tissue engineering. Cornea. 2016;35(7):997–1003.  https://doi.org/10.1097/ICO.0000000000000867.Google Scholar
  54. 54.
    Niknejad H, Yazdanpanah G, Ahmadiani A. Induction of apoptosis, stimulation of cell-cycle arrest and inhibition of angiogenesis make human amnion-derived cells promising sources for cell therapy of cancer. Cell Tissue Res. 2016;363(3):599–608.  https://doi.org/10.1007/s00441-016-2364-3.Google Scholar
  55. 55.
    Ma DH, Chen HC, Ma KS, Lai JY, Yang U, Yeh LK, et al. Preservation of human limbal epithelial progenitor cells on carbodiimide cross-linked amniotic membrane via integrin-linked kinase-mediated Wnt activation. Acta Biomater. 2016;31:144–55.  https://doi.org/10.1016/j.actbio.2015.11.042.Google Scholar
  56. 56.
    Levis HJ, Daniels JT. Recreating the human Limbal epithelial stem cell niche with bioengineered limbal crypts. Curr Eye Res. 2016;41(9):1153–60.  https://doi.org/10.3109/02713683.2015.1095932.Google Scholar
  57. 57.
    • Ahearne M, Lynch AP. Early observation of extracellular matrix-derived hydrogels for corneal stroma regeneration. Tissue Eng Part C Methods. 2015;21(10):1059–69.  https://doi.org/10.1089/ten.TEC.2015.0008 The protocol of producing solubilized extracellular matrix from porcine corneas applicable in ocular surface regeneration. Google Scholar
  58. 58.
    Lu Y, Yao QK, Feng B, Yan CX, Zhu MY, Chen JZ et al. Characterization of a hydrogel derived from decellularized corneal extracellular matrix. 2015;5(12):951–60.Google Scholar
  59. 59.
    Tidu A, Ghoubay-Benallaoua D, Lynch B, Haye B, Illoul C, Allain JM, et al. Development of human corneal epithelium on organized fibrillated transparent collagen matrices synthesized at high concentration. Acta Biomater. 2015;22:50–8.  https://doi.org/10.1016/j.actbio.2015.04.018.Google Scholar
  60. 60.
    Sorkio A, Koch L, Koivusalo L, Deiwick A, Miettinen S, Chichkov B, et al. Human stem cell based corneal tissue mimicking structures using laser-assisted 3D bioprinting and functional bioinks. Biomaterials. 2018;171:57–71.  https://doi.org/10.1016/j.biomaterials.2018.04.034. Google Scholar
  61. 61.
    • Dehghani S, Rasoulianboroujeni M, Ghasemi H, Keshel SH, Nozarian Z, Hashemian MN, et al. 3D-printed membrane as an alternative to amniotic membrane for ocular surface/conjunctival defect reconstruction: an in vitro & in vivo study. Biomaterials. 2018;174:95–112.  https://doi.org/10.1016/j.biomaterials.2018.05.013 In this study, development of a bio-ink for three-dimensional printing of structures for ocular surface applications with suturing potential and proper degradation properties has been reported. Google Scholar
  62. 62.
    Rama P, Bonini S, Lambiase A, Golisano O, Paterna P, De Luca M, et al. Autologous fibrin-cultured limbal stem cells permanently restore the corneal surface of patients with total limbal stem cell deficiency. Transplantation. 2001;72(9):1478–85.Google Scholar
  63. 63.
    Bray LJ, George KA, Hutmacher DW, Chirila TV, Harkin DG. A dual-layer silk fibroin scaffold for reconstructing the human corneal limbus. Biomaterials. 2012;33(13):3529–38.  https://doi.org/10.1016/j.biomaterials.2012.01.045.Google Scholar
  64. 64.
    Palchesko RN, Carrasquilla SD, Feinberg AW. Natural biomaterials for corneal tissue engineering, repair, and regeneration. Adv Healthc Mater. 2018;7(16):e1701434.  https://doi.org/10.1002/adhm.201701434. Google Scholar
  65. 65.
    Abdel-Naby W, Cole B, Liu A, Liu J, Wan P, Guaiquil VH, et al. Silk-derived protein enhances corneal epithelial migration, adhesion, and proliferation. Invest Ophthalmol Vis Sci. 2017;58(3):1425–33.  https://doi.org/10.1167/iovs.16-19957.Google Scholar
  66. 66.
    Kang KB, Lawrence BD, Gao XR, Luo Y, Zhou Q, Liu A, et al. Micro- and nanoscale topographies on silk regulate gene expression of human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2017;58(14):6388–98.  https://doi.org/10.1167/iovs.17-22213.Google Scholar
  67. 67.
    Lee HJ, Fernandes-Cunha GM, Na KS, Hull SM, Myung D. Bio-orthogonally crosslinked, in situ forming corneal stromal tissue substitute. Adv Healthc Mater. 2018;7(19):e1800560.  https://doi.org/10.1002/adhm.201800560. Google Scholar
  68. 68.
    Lynch AP, Ahearne M. Strategies for developing decellularized corneal scaffolds. Exp Eye Res. 2013;108:42–7.  https://doi.org/10.1016/j.exer.2012.12.012.Google Scholar
  69. 69.
    Oh JY, Kim MK, Lee HJ, Ko JH, Wee WR, Lee JH. Comparative observation of freeze-thaw-induced damage in pig, rabbit, and human corneal stroma. Vet Ophthalmol. 2009;12(Suppl 1):50–6.  https://doi.org/10.1111/j.1463-5224.2009.00723.x. Google Scholar
  70. 70.
    Shafiq MA, Gemeinhart RA, Yue BY, Djalilian AR. Decellularized human cornea for reconstructing the corneal epithelium and anterior stroma. Tissue Eng Part C Methods. 2012;18(5):340–8.  https://doi.org/10.1089/ten.TEC.2011.0072.Google Scholar
  71. 71.
    Shafiq MA, Milani BY, Djalilian AR. In vivo evaluation of a decellularized limbal graft for limbal reconstruction. 2014;2014.Google Scholar
  72. 72.
    Zhang X, M VJ, Qu Y, He X, Ou S, Bu J, et al. Dry eye management: targeting the ocular surface microenvironment. Int J Mol Sci. 2017;18(7).  https://doi.org/10.3390/ijms18071398.
  73. 73.
    • Azari AA, Rapuano CJ. Autologous serum eye drops for the treatment of ocular surface disease. Eye Contact Lens. 2015;41(3):133–40.  https://doi.org/10.1097/ICL.0000000000000104 A systematic review based on PubMed, the ISI Web of Knowledge database, and the Cochrane library, evaluating the superiority of autologous serum tears over conventional eye lubricants for treatment of ocular surface diseases. Google Scholar
  74. 74.
    Giannaccare G, Versura P, Buzzi M, Primavera L, Pellegrini M, Campos EC. Blood derived eye drops for the treatment of cornea and ocular surface diseases. Transfus Apher Sci. 2017;56(4):595–604.  https://doi.org/10.1016/j.transci.2017.07.023.Google Scholar
  75. 75.
    Tseng CL, Chen ZY, Renn TY, Hsiao SH, Burnouf T. Solvent/detergent virally inactivated serum eye drops restore healthy ocular epithelium in a rabbit model of dry-eye syndrome. PLoS One. 2016;11(4):e0153573.  https://doi.org/10.1371/journal.pone.0153573.Google Scholar
  76. 76.
    Yeh SI, Ho TC, Chen SL, Chen CP, Cheng HC, Lan YW, et al. Pigment epithelial-derived factor peptide regenerated limbus serves as regeneration source for limbal regeneration in rabbit limbal deficiency. Invest Ophthalmol Vis Sci. 2016;57(6):2629–36.  https://doi.org/10.1167/iovs.15-17171.Google Scholar
  77. 77.
    Baradaran-Rafii A, Asl NS, Ebrahimi M, Jabbehdari S, Bamdad S, Roshandel D, et al. The role of amniotic membrane extract eye drop (AMEED) in in vivo cultivation of limbal stem cells. Ocul Surf. 2018;16(1):146–53.  https://doi.org/10.1016/j.jtos.2017.11.001.Google Scholar
  78. 78.
    Gabriella. Fernandes-Cunha, Kyung-Sun Na, Ilham Putra, Hyun Jong Lee, Sarah Hull, Yu-Chia Cheng et al. Corneal wound healing effects of mesenchymal stem cell secretome delivered within a viscoelastic gel carrier. Stem Cells Transl Med. 2018.Google Scholar
  79. 79.
    Akcam HT, Unlu M, Karaca EE, Yazici H, Aydin B, Hondur AM. Autologous serum eye-drops and enhanced epithelial healing time after photorefractive keratectomy. Clin Exp Optom. 2018;101(1):34–7.  https://doi.org/10.1111/cxo.12574.Google Scholar
  80. 80.
    Harritshoj LH, Nielsen C, Ullum H, Hansen MB, Julian HO. Ready-made allogeneic ABO-specific serum eye drops: production from regular male blood donors, clinical routine, safety and efficacy. Acta Ophthalmol. 2014;92(8):783–6.  https://doi.org/10.1111/aos.12386.Google Scholar
  81. 81.
    Semeraro F, Forbice E, Braga O, Bova A, Di Salvatore A, Azzolini C. Evaluation of the efficacy of 50% autologous serum eye drops in different ocular surface pathologies. Biomed Res Int. 2014;2014:826970.  https://doi.org/10.1155/2014/826970.Google Scholar
  82. 82.
    Lekhanont K, Jongkhajornpong P, Anothaisintawee T, Chuckpaiwong V. Undiluted serum eye drops for the treatment of persistent corneal epitheilal defects. Sci Rep. 2016;6:38143.  https://doi.org/10.1038/srep38143.Google Scholar
  83. 83.
    Anitua E, de la Fuente M, Muruzabal F, Riestra A, Merayo-Lloves J, Orive G. Plasma rich in growth factors (PRGF) eye drops stimulates scarless regeneration compared to autologous serum in the ocular surface stromal fibroblasts. Exp Eye Res. 2015;135:118–26.  https://doi.org/10.1016/j.exer.2015.02.016.Google Scholar
  84. 84.
    Freire V, Andollo N, Etxebarria J, Hernaez-Moya R, Duran JA, Morales MC. Corneal wound healing promoted by 3 blood derivatives: an in vitro and in vivo comparative study. Cornea. 2014;33(6):614–20.  https://doi.org/10.1097/ICO.0000000000000109.Google Scholar
  85. 85.
    Lee JH, Kim MJ, Ha SW, Kim HK. Autologous platelet-rich plasma eye drops in the treatment of recurrent corneal erosions. Korean J Ophthalmol. 2016;30(2):101–7.  https://doi.org/10.3341/kjo.2016.30.2.101.Google Scholar
  86. 86.
    Avila MY, Igua AM, Mora AM. Randomised, prospective clinical trial of platelet-rich plasma injection in the management of severe dry eye. Br J Ophthalmol. 2018.  https://doi.org/10.1136/bjophthalmol-2018-312072.
  87. 87.
    Eslani M, Putra I, Shen X, Hamouie J, Tadepalli A, Movahedan A, et al. Corneal-limbal mesenchymal stromal cell secretome is antiangiogenic in vitro. Invest Ophthalmol Vis Sci. 2017;58(8):997.Google Scholar
  88. 88.
    Zhou Q, Chen P, Di G, Zhang Y, Wang Y, Qi X, et al. Ciliary neurotrophic factor promotes the activation of corneal epithelial stem/progenitor cells and accelerates corneal epithelial wound healing. Stem Cells. 2015;33(5):1566–76.  https://doi.org/10.1002/stem.1942.Google Scholar
  89. 89.
    Fok E, Sandeman SR, Guildford AL, Martin YH. The use of an IL-1 receptor antagonist peptide to control inflammation in the treatment of corneal limbal epithelial stem cell deficiency. Biomed Res Int. 2015;2015:516318.  https://doi.org/10.1155/2015/516318.Google Scholar
  90. 90.
    Tirassa P, Rosso P, Iannitelli A. Ocular nerve growth factor (NGF) and NGF eye drop application as paradigms to investigate NGF neuroprotective and reparative actions. Methods Mol Biol. 2018;1727:19–38.  https://doi.org/10.1007/978-1-4939-7571-6_2.Google Scholar
  91. 91.
    Lambiase A, Bonini S, Manni L, Ghinelli E, Tirassa P, Rama P, et al. Intraocular production and release of nerve growth factor after iridectomy. Invest Ophthalmol Vis Sci. 2002;43(7):2334–40.Google Scholar
  92. 92.
    Lambiase A, Sacchetti M, Bonini S. Nerve growth factor therapy for corneal disease. Curr Opin Ophthalmol. 2012;23(4):296–302.  https://doi.org/10.1097/ICU.0b013e3283543b61.Google Scholar
  93. 93.
    Qi H, Li DQ, Shine HD, Chen Z, Yoon KC, Jones DB, et al. Nerve growth factor and its receptor TrkA serve as potential markers for human corneal epithelial progenitor cells. Exp Eye Res. 2008;86(1):34–40.  https://doi.org/10.1016/j.exer.2007.09.003.Google Scholar
  94. 94.
    Lambiase A, Coassin M, Costa N, Lauretti P, Micera A, Ghinelli E, et al. Topical treatment with nerve growth factor in an animal model of herpetic keratitis. Graefes Arch Clin Exp Ophthalmol. 2008;246(1):121–7.  https://doi.org/10.1007/s00417-007-0593-6. Google Scholar
  95. 95.
    Lambiase A, Micera A, Sacchetti M, Cortes M, Mantelli F, Bonini S. Alterations of tear neuromediators in dry eye disease. Arch Ophthalmol. 2011;129(8):981–6.  https://doi.org/10.1001/archophthalmol.2011.200.Google Scholar
  96. 96.
    Bonini S, Lambiase A, Rama P, Sinigaglia F, Allegretti M, Chao W, et al. Phase II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor for neurotrophic keratitis. Ophthalmology. 2018;125(9):1332–43.  https://doi.org/10.1016/j.ophtha.2018.02.022.Google Scholar
  97. 97.
    Dudok DV, Nagdee I, Cheung K, Liu H, Vedovelli L, Ghinelli E, et al. Effects of amniotic membrane extract on primary human corneal epithelial and limbal cells. Clin Exp Ophthalmol. 2015;43(5):443–8.  https://doi.org/10.1111/ceo.12480.Google Scholar
  98. 98.
    Murri MS, Moshirfar M, Birdsong OC, Ronquillo YC, Ding Y, Hoopes PC. Amniotic membrane extract and eye drops: a review of literature and clinical application. Clin Ophthalmol. 2018;12:1105–12.  https://doi.org/10.2147/OPTH.S165553.Google Scholar
  99. 99.
    Tseng SC. HC-HA/PTX3 purified from amniotic membrane as novel regenerative matrix: insight into relationship between inflammation and regeneration. Invest Ophthalmol Vis Sci. 2016;57(5):ORSFh1–8.  https://doi.org/10.1167/iovs.15-17637.Google Scholar
  100. 100.
    Chen SY, Han B, Zhu YT, Mahabole M, Huang J, Beebe DC, et al. HC-HA/PTX3 purified from amniotic membrane promotes BMP signaling in limbal niche cells to maintain quiescence of limbal epithelial progenitor/stem cells. Stem Cells. 2015;33(11):3341–55.  https://doi.org/10.1002/stem.2091. Google Scholar
  101. 101.
    Jeong WY, Kim JH, Kim CW. Co-culture of human bone marrow mesenchymal stem cells and macrophages attenuates lipopolysaccharide-induced inflammation in human corneal epithelial cells. Biosci Biotechnol Biochem. 2018;82(5):800–9.  https://doi.org/10.1080/09168451.2018.1438167.Google Scholar
  102. 102.
    Bai L, Shao H, Wang H, Zhang Z, Su C, Dong L, et al. Effects of mesenchymal stem cell-derived exosomes on experimental autoimmune uveitis. Sci Rep. 2017;7(1):4323.  https://doi.org/10.1038/s41598-017-04559-y. Google Scholar
  103. 103.
    Han KY, Tran JA, Chang JH, Azar DT, Zieske JD. Potential role of corneal epithelial cell-derived exosomes in corneal wound healing and neovascularization. Sci Rep. 2017;7:40548.  https://doi.org/10.1038/srep40548.Google Scholar
  104. 104.
    • Samaeekia R, Rabiee B, Putra I, Shen X, Park YJ, Hematti P, et al. Effect of human corneal mesenchymal stromal cell-derived exosomes on corneal epithelial wound healing. Invest Ophthalmol Vis Sci. 2018;59(12):5194–200.  https://doi.org/10.1167/iovs.18-24803 The report of potential corneal epithelial wound healing effects of corneal mesenchymal stem cell-derived exosomes by our group.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ghasem Yazdanpanah
    • 1
  • Sayena Jabbehdari
    • 1
  • Ali R. Djalilian
    • 1
    Email author
  1. 1.Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear InfirmaryUniversity of Illinois at ChicagoChicagoUSA

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