Skip to main content
Log in

Retinal Tissue Bioengineering, Materials and Methods for the Treatment of Glaucoma

  • Review Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Glaucoma, a characteristic type of optic nerve degeneration in the posterior pole of the eye, is a common cause of irreversible vision loss and the second leading cause of blindness worldwide. As an optic neuropathy, glaucoma is identified by increasing degeneration of retinal ganglion cells (RGCs), with consequential vision loss. Current treatments only postpone the development of retinal degeneration, and there are as yet no treatments available for this disability. Recent studies have shown that replacing lost or damaged RGCs with healthy RGCs or RGC precursors, supported by appropriately designed bio-material scaffolds, could facilitate the development and enhancement of connections to ganglion cells and optic nerve axons. The consequence may be an improved retinal regeneration. This technique could also offer the possibility for retinal regeneration in treating other forms of optic nerve ailments through RGC replacement.

Methods:

In this brief review, we describe the innovations and recent developments in retinal regenerative medicine such as retinal organoids and gene therapy which are specific to glaucoma treatment and focus on the selection of appropriate bio-engineering principles, biomaterials and cell therapies that are presently employed in this growing research area.

Results:

Identification of optimal sources of cells, improving cell survival, functional integration upon transplantation, and developing techniques to deliver cells into the retinal space without provoking immune responses are the main challenges in retinal cell replacement therapies.

Conclusion:

The restoration of visual function in glaucoma patients by the RGC replacement therapies requires appropriate protocols and biotechnology methods. Tissue-engineered scaffolds, the generation of retinal organoids, and gene therapy may help to overcome some of the challenges in the generation of clinically safe RGCs.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sluch VM, Zack DJ. Stem cells, retinal ganglion cells and glaucoma. Dev Ophthalmol. 2014;53:111–21.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kador KE, Goldberg JL. Scaffolds and stem cells: delivery of cell transplants for retinal degenerations. Expert Rev Ophthalmol. 2012;7:459–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121:2081–90.

    Article  PubMed  Google Scholar 

  5. Mantravadi AV, Vadhar N. Glaucoma, primary care–clinics in office. Practice. 2015;42:437–49.

    Google Scholar 

  6. Donegan RK, Lieberman RL. Discovery of molecular therapeutics for glaucoma: challenges, successes, and promising directions. J Med Chem. 2016;59:788–809.

    Article  CAS  PubMed  Google Scholar 

  7. Tian K, Shibata-Germanos S, Pahlitzsch M, Cordeiro MF. Current perspective of neuroprotection and glaucoma. Clin Ophthalmol. 2015;9:2109–18.

    PubMed  PubMed Central  Google Scholar 

  8. Dahlmann-Noor AH, Vijay S, Limb GA, Khaw PT. Strategies for optic nerve rescue and regeneration in glaucoma and other optic neuropathies. Drug Discov Today. 2010;15:287–99.

    Article  CAS  PubMed  Google Scholar 

  9. Young MJ. Stem cells in the mammalian eye: a tool for retinal repair. APMIS. 2005;113:845–57.

    Article  PubMed  Google Scholar 

  10. Remington LA. Visual system. In: Remington LA, Goodwin D, editors. Clinical anatomy and physiology of the visual system. 3rd ed. St. Louis: Butterworth-Heinemann, Elsvier; 2012. p. 1–9.

    Google Scholar 

  11. Doozandeh A, Yazdani S. Neuroprotection in glaucoma. J Ophthalmic Vis Res. 2016;11:209–20.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Agostinone J, Di Polo A. Retinal ganglion cell dendrite pathology and synapse loss. Prog Brain Res. 2015;220:199–216.

    Article  PubMed  Google Scholar 

  13. Mancino R, Cesareo M, Martucci A, Di Carlo E, Ciuffoletti E, Giannini C, et al. Neurodegenerative process linking the eye and the brain. 2019;26:3754–63.

  14. Huang G, Li F, Zhao X, Ma Y, Li Y, Lin M, et al. Functional and biomimetic materials for engineering of the three-dimensional cell microenvironment. Chem Rev. 2017;117:12764–850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gordon MO, Kass MA. The ocular hypertension treatment study: design and baseline description of the participants. Arch Ophthalmol. 1999;117:573–83.

    Article  CAS  PubMed  Google Scholar 

  16. Foster PJ, Alsbirk PH, Baasanhu J, Munkhbayar D, Uranchimeg D, Johnson GJ. Anterior chamber depth in mongolians: variation with age, sex, and method of measurement. Am J Ophthalmol. 1997;124:53–60.

    Article  CAS  PubMed  Google Scholar 

  17. Yamamoto T, Iwase A, Araie M, Suzuki Y, Abe H, Shirato S, et al. The tajimi study report 2: prevalence of primary angle closure and secondary glaucoma in a Japanese population. Ophthalmology. 2005;112:1661–9.

    Article  PubMed  Google Scholar 

  18. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311:1901–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Calkins DJ. Critical pathogenic events underlying progression of neurodegeneration in glaucoma. Prog Retinal Eye Res. 2012;31:702–19.

    Article  CAS  Google Scholar 

  20. Nuzzi R, Tridico F. Glaucoma: biological trabecular and neuroretinal pathology with perspectives of therapy innovation and preventive diagnosis. Front Neurosci. 2017;11:494.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet. 2004;363:1711–20.

    Article  PubMed  Google Scholar 

  22. Chang EE, Goldberg JL. Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology. 2012;119:979–86.

    Article  PubMed  Google Scholar 

  23. Ramulu P. Glaucoma and disability: which tasks are affected, and at what stage of disease? Curr Opin Ophthalmol. 2009;20:92–8.

    Article  PubMed  PubMed Central  Google Scholar 

  24. McKean-Cowdin R, Varma R, Wu J, Hays RD, Azen SP, Los Angeles Latino Eye Study Group. Severity of visual field loss and health-related quality of life. Am J Ophthalmol. 2007;143:1013–23.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gurwitz JH, Glynn RJ, Monane M, Everitt DE, Gilden D, Smith N, et al. Treatment for glaucoma: adherence by the elderly. Am J Public Health. 1993;83:711–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kamal D, Hitchings R. Normal tension glaucoma—a practical approach. Br J Ophthalmol. 1998;82:835–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Karlstetter M, Scholz R, Rutar M, Wong WT, Provis JM, Langmann T. Retinal microglia: just bystander or target for therapy? Prog Retinal Eye Res. 2015;45:30–57.

    Article  Google Scholar 

  28. Whitmore AV, Libby RT, John SW. Glaucoma: thinking in new ways—a rôle for autonomous axonal self-destruction and other compartmentalised processes? Prog Retinal Eye Res. 2005;24:639–62.

    Article  Google Scholar 

  29. Dautriche CN, Xie Y, Sharfstein ST. Walking through trabecular meshwork biology: toward engineering design of outflow physiology. Biotechnol Adv. 2014;32:971–83.

    Article  PubMed  Google Scholar 

  30. Solomon AS, Kimron M, Holdengreber V, Nizan A, Yaakobowicz M, Harness E, et al. Up-regulation of semaphorin expression in retina of glaucomatous rabbits. Graefes Arch Clin Exp Ophthalmol. 2003;241:673–81.

    Article  CAS  PubMed  Google Scholar 

  31. Dielemans I, Vingerling JR, Wolfs RC, Hofman A, Grobbee DE, de Jong PT. The prevalence of primary open-angle glaucoma in a population-based study in the Netherlands: the Rotterdam Study. Ophthalmology. 1994;101:1851–5.

    Article  CAS  PubMed  Google Scholar 

  32. Khatib TZ, Martin KR. Protecting retinal ganglion cells. Eye (Lond). 2017;31:218–24.

    Article  CAS  Google Scholar 

  33. Danesh-Meyer HV, Levin LA. Neuroprotection: extrapolating from neurologic diseases to the eye. Am J Ophthalmol. 2009;148:186–91.e2

    Article  PubMed  Google Scholar 

  34. Kountouras J, Zavos C, Deretzi G, Polyzos SA, Gavalas E, Tsiaousi E, et al. Neuroprotection in glaucoma: is there a future role? Exp Eye Res. 2011;92:436–8.

    Article  CAS  PubMed  Google Scholar 

  35. Pearson C, Martin K. Stem cell approaches to glaucoma: from aqueous outflow modulation to retinal neuroprotection. Prog Brain Res. 2015;220:241–56.

    Article  PubMed  Google Scholar 

  36. Schwartz SD, Nagiel A, Lanza R. Cellular therapies for retinal disease: a strategic approach. Berlin: Springer; 2017.

    Book  Google Scholar 

  37. Adams CM, Stacy R, Rangaswamy N, Bigelow C, Grosskreutz CL, Prasanna G. Glaucoma—next generation therapeutics: impossible to possible. Pharm Res. 2019;36:25.

    Article  CAS  Google Scholar 

  38. Weinreb RN, Liebmann JM, Cioffi GA, Goldberg I, Brandt JD, Johnson CA, et al. Oral memantine for the treatment of glaucoma: design and results of 2 randomized, placebo-controlled, phase 3 studies. Ophthalmology. 2018;125:1874–85.

    Article  PubMed  Google Scholar 

  39. Chamling X, Sluch VM, Zack DJ. The potential of human stem cells for the study and treatment of glaucomahuman stem cell for treatment of glaucoma. Invest Ophthalmol Vis Sci. 2016;57:ORSFi1–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sluch VM, Zack DJ. Stem cells, retinal ganglion cells and glaucoma. Dev Ophthalmol. 2014;53:111–21.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Venugopalan P, Wang Y, Nguyen T, Huang A, Muller KJ, Goldberg JL. Transplanted neurons integrate into adult retinas and respond to light. Nat Commun. 2016;7:10472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Williams R, Lace R, Kennedy S, Doherty K, Levis H. Biomaterials for regenerative medicine approaches for the anterior segment of the eye. Adv Healthc Mater. 2018;7:e1701328.

    Article  PubMed  CAS  Google Scholar 

  43. Yucel YH, Gupta N. A framework to explore the visual brain in glaucoma with lessons from models and man. Exp Eye Res. 2018;7:e1701328.

    Google Scholar 

  44. Kador KE, Montero RB, Venugopalan P, Hertz J, Zindell AN, Valenzuela DA, et al. Tissue engineering the retinal ganglion cell nerve fiber layer. Biomaterials. 2013;34:4242–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li K, Zhong X, Yang S, Luo Z, Li K, Liu Y, et al. HiPSC-derived retinal ganglion cells grow dendritic arbors and functional axons on a tissue-engineered scaffold. Acta Biomater. 2017;54:117–27.

    Article  CAS  PubMed  Google Scholar 

  46. Laha B, Stafford BK, Huberman AD. Regenerating optic pathways from the eye to the brain. Science. 2017;356:1031–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nazari H, Zhang L, Zhu D, Chader GJ, Falabella P, Stefanini F, et al. Stem cell based therapies for age-related macular degeneration: the promises and the challenges. Prog Retinal Eye Res. 2015;48:1–39.

    Article  CAS  Google Scholar 

  48. Davis DM, Dyer MA. Retinal progenitor cells, differentiation, and barriers to cell cycle reentry. Curr Top Dev Biol. 2010;93:175–88.

    Article  PubMed  Google Scholar 

  49. Cepko C. Intrinsically different retinal progenitor cells produce specific types of progeny. Nat Rev Neurosci. 2014;15:615–27.

    Article  CAS  PubMed  Google Scholar 

  50. Divya MS, Rasheed VA, Schmidt T, Lalitha S, Hattar S, James J. Intraocular injection of ES cell-derived neural progenitors improve visual function in retinal ganglion cell-depleted mouse models. Front Cell Neurosci. 2017;11:295.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Dahlmann-Noor A, Vijay S, Jayaram H, Limb A, Khaw PT. Current approaches and future prospects for stem cell rescue and regeneration of the retina and optic nerve. Can J Ophthalmol. 2010;45:333–41.

    Article  PubMed  Google Scholar 

  52. Miltner AM, La Torre A. Retinal ganglion cell replacement: current status and challenges ahead. Dev Dyn. 2019;248:118–28.

    Article  PubMed  Google Scholar 

  53. Pillai RG. Stem cells for ocular tissue engineering and regeneration. Curr Top Med Chem. 2011;11:1606–20.

    Article  CAS  PubMed  Google Scholar 

  54. Silva GA, Silva NF, Fortunato TM. Stem cell and tissue engineering therapies for ocular regeneration. Curr Stem Cell Res Ther. 2011;6:255–72.

    Article  CAS  PubMed  Google Scholar 

  55. Treharne AJ, Grossel MC, Lotery AJ, Thomson HA. The chemistry of retinal transplantation: the influence of polymer scaffold properties on retinal cell adhesion and control. Br J Ophthalmol. 2011;95:768–73.

    Article  PubMed  Google Scholar 

  56. Blenkinsop TA, Corneo B, Temple S, Stern JH. Ophthalmologic stem cell transplantation therapies. Regen Med. 2012;7:32–9.

    Article  CAS  PubMed  Google Scholar 

  57. Dalton PD, Harvey AR, Oudega M, Plant GW. Tissue engineering of the nervous system. In: van Blitterswijk CA, de Boer J, editors. Tissue engineering: 2nd ed. Elsevier, Academic Press; 2014. p. 583–625.

  58. MacHalińska A, Baumert B, Kuprjanowicz L, Wiszniewska B, Karczewicz D, MacHaliński B. Potential application of adult stem cells in retinal repair-challenge for regenerative medicine. Curr Eye Res. 2009;34:748–60.

    Article  PubMed  CAS  Google Scholar 

  59. Mason SL, Stewart RM, Kearns VR, Williams RL, Sheridan CM. Ocular epithelial transplantation: current uses and future potential. Regen Med. 2011;6:767–82.

    Article  PubMed  Google Scholar 

  60. Aoki H, Hara A, Nakagawa S, Motohashi T, Hirano M, Takahashi Y, et al. Embryonic stem cells that differentiate into RPE cell precursors in vitro develop into RPE cell monolayers in vivo. Exp Eye Res. 2006;82:265–74.

    Article  CAS  PubMed  Google Scholar 

  61. Nistor G, Seiler MJ, Yan F, Ferguson D, Keirstead HS. Three-dimensional early retinal progenitor 3D tissue constructs derived from human embryonic stem cells. J Neurosci Methods. 2010;190:63–70.

    Article  PubMed  Google Scholar 

  62. Osakada F, Ikeda H, Mandai M, Wataya T, Watanabe K, Yoshimura N, et al. Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nat Biotechnol. 2008;26:215–24.

    Article  CAS  PubMed  Google Scholar 

  63. Peng S, Gan G, Qiu C, Zhong M, An H, Adelman RA, et al. Engineering a blood-retinal barrier with human embryonic stem cell-derived retinal pigment epithelium: transcriptome and functional analysis. Stem Cells Transl Med. 2013;2:534–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jasty S, Suriyanarayanan S, Krishnakumar S. Influence of self-assembling peptide nanofibre scaffolds on retinal differentiation potential of stem/progenitor cells derived from ciliary pigment epithelial cells. J Tissue Eng Regen Med. 2017;11:509–18.

    Article  CAS  PubMed  Google Scholar 

  65. Kundu J, Michaelson A, Talbot K, Baranov P, Young MJ, Carrier RL. Decellularized retinal matrix: natural platforms for human retinal progenitor cell culture. Acta Biomater. 2016;31:61–70.

    Article  CAS  PubMed  Google Scholar 

  66. Lawley E, Baranov P, Young M. Hybrid vitronectin-mimicking polycaprolactone scaffolds for human retinal progenitor cell differentiation and transplantation. J Biomater Appl. 2015;29:894–902.

    Article  CAS  PubMed  Google Scholar 

  67. Liu Y, Wang R, Zarembinski TI, Doty N, Jiang C, Regatieri C, et al. The application of hyaluronic acid hydrogels to retinal progenitor cell transplantation. Tissue Eng Part A. 2013;19:135–42.

    Article  PubMed  CAS  Google Scholar 

  68. Sorkio A, Haimi S, Verdoold V, Juuti-Uusitalo K, Grijpma D, Skottman H. Poly(trimethylene carbonate) as an elastic biodegradable film for human embryonic stem cell-derived retinal pigment epithelial cells. J Tissue Eng Regen Med. 2017;11:3134–44.

    Article  CAS  PubMed  Google Scholar 

  69. Subrizi A, Hiidenmaa H, Ilmarinen T, Nymark S, Dubruel P, Uusitalo H, et al. Generation of hESC-derived retinal pigment epithelium on biopolymer coated polyimide membranes. Biomaterials. 2012;33:8047–54.

    Article  CAS  PubMed  Google Scholar 

  70. Yip HK. Retinal stem cells and regeneration of vision system. Anat Rec (Hoboken). 2014;297:137–60.

    Article  CAS  Google Scholar 

  71. Hunt NC, Hallam D, Karimi A, Mellough CB, Chen J, Steel DHW, et al. 3D culture of human pluripotent stem cells in RGD-alginate hydrogel improves retinal tissue development. Acta Biomater. 2017;49:329–43.

    Article  CAS  PubMed  Google Scholar 

  72. Parvini M, Satarian L, Parivar K, Javan M, Tondar M, Ahmad S, et al. Human pluripotent stem cell-derived retinal pigmented epithelium in retinal treatment: from bench to bedside. Mol Neurobiol. 2014;50:597–612.

    Article  CAS  PubMed  Google Scholar 

  73. Roozafzoon R, Lashay A, Vasei M, Ai J, Khoshzaban A, Keshel SH, et al. Dental pulp stem cells differentiation into retinal ganglion-like cells in a three dimensional network. Biochem Biophys Res Commun. 2015;457:154–60.

    Article  CAS  PubMed  Google Scholar 

  74. Song MJ, Bharti K. Looking into the future: using induced pluripotent stem cells to build two and three dimensional ocular tissue for cell therapy and disease modeling. Brain Res. 2016;1638:2–14.

    Article  CAS  PubMed  Google Scholar 

  75. Worthington KS, Green BJ, Rethwisch M, Wiley LA, Tucker BA, Guymon CA, et al. Neuronal differentiation of induced pluripotent stem cells on surfactant templated chitosan hydrogels. Biomacromolecules. 2016;17:1684–95.

    Article  CAS  PubMed  Google Scholar 

  76. Yam GH, Peh GS, Singhal S, Goh BT, Mehta JS. Dental stem cells: a future asset of ocular cell therapy. Expert Rev Mol Med. 2015;17:e20.

    Article  PubMed  CAS  Google Scholar 

  77. Yun C, Oh J, Lee B, Lee JM, Ariunaa T, Huh K. Generation of retinal progenitor cells from human induced pluripotent stem cell-derived spherical neural mass. Tissue Eng Regen Med. 2017;14:39–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhong X, Gutierrez C, Xue T, Hampton C, Vergara MN, Cao LH, et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun. 2014;5:4047.

    Article  CAS  PubMed  Google Scholar 

  79. Pearson RA. Advances in repairing the degenerate retina by rod photoreceptor transplantation. Biotechnol Adv. 2014;32:485–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hentze H, Soong PL, Wang ST, Phillips BW, Putti TC, Dunn NR. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res. 2009;2:198–210.

    Article  PubMed  Google Scholar 

  81. Enzmann V, Yolcu E, Kaplan HJ, Ildstad ST. Stem cells as tools in regenerative therapy for retinal degeneration. Arch Ophthalmol. 2009;127:563–71.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Aoki H, Hara A, Niwa M, Motohashi T, Suzuki T, Kunisada T. Transplantation of cells from eye-like structures differentiated from embryonic stem cells in vitro and in vivo regeneration of retinal ganglion-like cells. Graefes Arch Clin Exp Ophthalmol. 2008;246:255–65.

    Article  PubMed  Google Scholar 

  83. Hsiung J, Zhu D, Hinton DR. Polarized human embryonic stem cell-derived retinal pigment epithelial cell monolayers have higher resistance to oxidative stress-induced cell death than nonpolarized cultures. Stem Cells Transl Med. 2015;4:10–20.

    Article  CAS  PubMed  Google Scholar 

  84. Levenberg S, Burdick JA, Kraehenbuehl T, Langer R. Neurotrophin-induced differentiation of human embryonic stem cells on three-dimensional polymeric scaffolds. Tissue Eng. 2005;11:506–12.

    Article  CAS  PubMed  Google Scholar 

  85. Sluch VM, Davis CH, Ranganathan V, Kerr JM, Krick K, Martin R, et al. Differentiation of human ESCs to retinal ganglion cells using a CRISPR engineered reporter cell line. Sci Rep. 2015;5:16595.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Li JY, Christophersen NS, Hall V, Soulet D, Brundin P. Critical issues of clinical human embryonic stem cell therapy for brain repair. Trends Neurosci. 2008;31:146–53.

    Article  PubMed  CAS  Google Scholar 

  87. Yamanaka S. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell. 2012;10:678–84.

    Article  CAS  PubMed  Google Scholar 

  88. Jin ZB, Okamoto S, Mandai M, Takahashi M. Induced pluripotent stem cells for retinal degenerative diseases: a new perspective on the challenges. J Genet. 2009;88:417–24.

    Article  PubMed  Google Scholar 

  89. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  CAS  PubMed  Google Scholar 

  90. Green DI, Ou Y. Towards the development of a human glaucoma disease-in-a-dish model using stem cells. Expert Rev Ophthalmol. 2015;10:267–80.

    Article  CAS  Google Scholar 

  91. Gill KP, Hewitt AW, Davidson KC, Pébay A, Wong RC. Methods of retinal ganglion cell differentiation from pluripotent stem cells. Transl Vis Sci Technol. 2014;3:7.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Tanaka T, Yokoi T, Tamalu F, Watanabe S, Nishina S, Azuma N. Generation of retinal ganglion cells with functional axons from human induced pluripotent stem cells. Sci Rep. 2015;5:8344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ohlemacher SK, Sridhar A, Xiao Y, Hochstetler AE, Sarfarazi M, Cummins TR, et al. Stepwise differentiation of retinal ganglion cells from human pluripotent stem cells enables analysis of glaucomatous neurodegeneration. Stem Cells. 2016;34:1553–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chen J, Riazifar H, Guan MX, Huang T. Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets. Stem Cell Res Ther. 2016;7:2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Sridhar A, Ohlemacher SK, Langer KB, Meyer JS. Robust differentiation of mRNA-reprogrammed human induced pluripotent stem cells toward a retinal lineage. Stem Cells Transl Med. 2016;5:417–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Deng F, Chen M, Liu Y, Hu H, Xiong Y, Xu C, et al. Stage-specific differentiation of iPSCs toward retinal ganglion cell lineage. Mol Vis. 2016;22:536–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Aftab U, Jiang C, Tucker B, Kim JY, Klassen H, Miljan E, et al. Growth kinetics and transplantation of human retinal progenitor cells. Exp Eye Res. 2009;89:301–10.

    Article  CAS  PubMed  Google Scholar 

  98. Wu N, Wang Y, Yang L, Cho KS. Signaling networks of retinal ganglion cell formation and the potential application of stem cell-based therapy in retinal degenerative diseases. Hum Gene Ther. 2016;27:609–20.

    Article  CAS  PubMed  Google Scholar 

  99. Wang Y, Zhang D, Shen B, Zhang Y, Gu P. Stem/progenitor cells and biodegradable scaffolds in the treatment of retinal degenerative diseases. Curr Stem Cell Res Ther. 2018;13:160–73.

    Article  CAS  PubMed  Google Scholar 

  100. Singh R, Cuzzani O, Binette F, Sternberg H, West MD, Nasonkin IO. Pluripotent stem cells for retinal tissue engineering: current status and future prospects. Stem Cell Rev Rep. 2018;14:463–83.

    Article  PubMed  Google Scholar 

  101. Harrison RG. The cultivation of tissues in extraneous media as a method of morpho-genetic study. Anat Rec (Hoboken). 1912;6:181–93.

    Article  Google Scholar 

  102. Weiss P. The problem of specificity in growth and development. Yale J Biol Med. 1947;19:235–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Curtis ASG, Varde M. Control of cell behavior: topological factors fot retinal repair. J Natl Cancer Inst. 1964;33:15–26.

    CAS  PubMed  Google Scholar 

  104. West EL, Pearson RA, MacLaren RE, Sowden JC, Ali RR. Cell transplantation strategies for retinal repair. Prog Brain Res. 2009;175:3–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tomita M, Lavik E, Klassen H, Zahir T, Langer R, Young MJ. Biodegradable polymer composite grafts promote the survival and differentiation of retinal progenitor cells. Stem Cells. 2005;23:1579–88.

    Article  PubMed  Google Scholar 

  106. Gater R, Khoshnaw N, Nguyen D, El Haj AJ, Yang Y. OCT as a convenient tool to assess the quality and application of organotypic retinal samples. In: Tuchin VV, Larin KV, Leahy MJ, Wang RK, editors. Dynamics and fluctuations in biomedical photonics Xiii. SPIE BiOS; 2016. p. 97071C.

  107. Dutta RC, Dey M, Dutta AK, Basu B. Competent processing techniques for scaffolds in tissue engineering. Biotechnol Adv. 2017;35:240–50.

    Article  CAS  PubMed  Google Scholar 

  108. Farrell K, Kothapalli CR, Axonal regeneration, biomimetic polymeric substrates for. 2014.

  109. Zhang N, Yan H, Wen X. Tissue-engineering approaches for axonal guidance. Brain Res Rev. 2005;49:48–64.

    Article  CAS  PubMed  Google Scholar 

  110. Young MJ, Borrás T, Walter M, Ritch R. Tissue bioengineering: potential applications to glaucoma. Arch Ophthalmol. 2005;123:1725–31.

    Article  PubMed  Google Scholar 

  111. Yoon DM, Fisher JP. Polymeric scaffolds for tissue engineering applications. In: Fisher JP, editor. Tissue Engineering. 2nd ed. Boca Raton: Taylor & Francis; 2007.

    Google Scholar 

  112. Trese M, Regatieri CV, Young MJ. Advances in retinal tissue engineering. Materials (Basel). 2012;5:108–20.

    Article  Google Scholar 

  113. Yao J, Tao SL, Young MJ. Synthetic polymer scaffolds for stem cell transplantation in retinal tissue engineering. Polymers (Basel). 2011;3:899–914.

    Article  CAS  Google Scholar 

  114. Kador KE, Alsehli HS, Zindell AN, Lau LW, Andreopoulos FM, Watson BD, et al. Retinal ganglion cell polarization using immobilized guidance cues on a tissue-engineered scaffold. Acta Biomater. 2014;10:4939–46.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Kador KE, Grogan SP, Dorthé EW, Venugopalan P, Malek MF, Goldberg JL, et al. Control of retinal ganglion cell positioning and neurite growth: combining 3D printing with radial electrospun scaffolds. Tissue Eng Part A. 2016;22:286–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Warnke PH, Alamein M, Skabo S, Stephens S, Bourke R, Heiner P, et al. Primordium of an artificial Bruch’s membrane made of nanofibers for engineering of retinal pigment epithelium cell monolayers. Acta Biomater. 2013;9:9414–22.

    Article  CAS  PubMed  Google Scholar 

  117. Hotaling NA, Khristov V, Wan Q, Sharma R, Jha BS, Lotfi M, et al. Nanofiber scaffold-based tissue-engineered retinal pigment epithelium to treat degenerative eye diseases. J Ocul Pharmacol Ther. 2016;32:272–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Sharifi F, Patel BB, Dzuilko AK, Montazami R, Sakaguchi DS, Hashemi N. Polycaprolactone microfibrous scaffolds to navigate neural stem cells. Biomacromolecules. 2016;17:3287–97.

    Article  CAS  PubMed  Google Scholar 

  119. Sepahvandi A, Eskandari M, Mortarzadeh F. Fabrication and characterization of SrAl2O4: Eu(2+)Dy(3+)/CS-PCL electrospun nanocomposite scaffold for retinal tissue regeneration. Mater Sci Eng C Mater Biol Appl. 2016;66:306–14.

    Article  CAS  PubMed  Google Scholar 

  120. Yao J, Ko CW, Baranov PY, Regatieri CV, Redenti S, Tucker BA, et al. Enhanced differentiation and delivery of mouse retinal progenitor cells using a micropatterned biodegradable thin-film polycaprolactone scaffold. Tissue Eng Part A. 2015;21:1247–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Redenti S, Tao S, Yang J, Gu P, Klassen H, Saigal S, et al. Retinal tissue engineering using mouse retinal progenitor cells and a novel biodegradable, thin-film poly(e-caprolactone) nanowire scaffold. J Ocul Biol Dis Infor. 2008;1:19–29.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Steedman MR, Tao SL, Klassen H, Desai TA. Enhanced differentiation of retinal progenitor cells using microfabricated topographical cues. Biomed Microdevices. 2010;12:363–9.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Xiang P, Wu KC, Zhu Y, Xiang L, Li C, Chen DL, et al. A novel Bruch’s membrane-mimetic electrospun substrate scaffold for human retinal pigment epithelium cells. Biomaterials. 2014;35:9777–88.

    Article  CAS  PubMed  Google Scholar 

  124. Redenti S, Neeley WL, Rompani S, Saigal S, Yang J, Klassen H, et al. Engineering retinal progenitor cell and scrollable poly(glycerol-sebacate) composites for expansion and subretinal transplantation. Biomaterials. 2009;30:3405–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. de Lima S, Koriyama Y, Kurimoto T, Oliveira JT, Yin Y, Li Y, et al. Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors. Proc Natl Acad Sci U S A. 2012;109:9149–54.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Zhang D, Ni N, Chen J, Yao Q, Shen B, Zhang Y, et al. Electrospun SF/PLCL nanofibrous membrane: a potential scaffold for retinal progenitor cell proliferation and differentiation. Sci Rep. 2015;5:14326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Bolbasov EN, Rybachuk M, Golovkin AS, Antonova LV, Shesterikov EV, Malchikhina AI, et al. Surface modification of poly(l-lactide) and polycaprolactone bioresorbable polymers using RF plasma discharge with sputter deposition of a hydroxyapatite target. Mater Lett. 2014;132:281–4.

    Article  CAS  Google Scholar 

  128. Kearns V, Mistry A, Mason S, Krishna Y, Sheridan C, Short R, et al. Plasma polymer coatings to aid retinal pigment epithelial growth for transplantation in the treatment of age related macular degeneration. J Mater Sci Mater Med. 2012;23:2013–21.

    Article  CAS  PubMed  Google Scholar 

  129. Petlin DG, Tverdokhlebov SI, Anissimov YG. Plasma treatment as an efficient tool for controlled drug release from polymeric materials: a review. J Control Release. 2017;266:57–74.

    Article  CAS  PubMed  Google Scholar 

  130. Liu ZP, Yu N, Holz FG, Yang F, Stanzel BV. Enhancement of retinal pigment epithelial culture characteristics and subretinal space tolerance of scaffolds with 200 nm fiber topography. Biomaterials. 2014;35:2837–50.

    Article  CAS  PubMed  Google Scholar 

  131. Kundu J, Michaelson A, Baranov P, Young MJ, Carrier RL. Approaches to cell delivery: substrates and scaffolds for cell therapy. Dev Ophthalmol. 2014;53:143–54.

    Article  PubMed  Google Scholar 

  132. Gamm DM, Wong R, The AGI Workshop Panelists. Report on the national eye institute audacious goals initiative: photoreceptor regeneration and integration workshop. Transl Vis Sci Technol. 2015;4:2.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Laboissonniere LA, Goetz JJ, Martin GM, Bi R, Lund TJ, Ellson L, et al. Molecular signatures of retinal ganglion cells revealed through single cell profiling. Sci Rep. 2019;9:15778.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Rheaume BA, Jereen A, Bolisetty M, Sajid MS, Yang Y, Renna K, et al. Single cell transcriptome profiling of retinal ganglion cells identifies cellular subtypes. Nat Commun. 2018;9:2759.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Barak Y, Heroman WJ, Tezel TH. The past, present, and future of exudative age-related macular degeneration treatment. Middle East Afr J Ophthalmol. 2012;19:43–51.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Hynes SR, Lavik EB. A tissue-engineered approach towards retinal repair: scaffolds for cell transplantation to the subretinal space. Graefes Arch Clin Exp Ophthalmol. 2010;248:763–78.

    Article  PubMed  Google Scholar 

  137. Cordeiro MF, Erskine L. Back to basics—ephrins, axonal guidance, neuroprotection and glaucoma. Br J Ophthalmol. 2007;91:1106.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Du J, Tran T, Sretavan DW. Axon guidance molecules upregulated at the optic nerve head of DBA/2 J glaucomatous mice alter RGC intra-axonal calcium levels in vitro. Invest Ophthalmol Vis Sci. 2005;46:1288.

    Google Scholar 

  139. Carreras FJ, Medina J, Ruiz-Lozano M, Carreras I, Castro JL. Virtual tissue engineering and optic pathways: plotting the course of the axons in the retinal nerve fiber layer. Invest Ophthalmol Vis Sci. 2014;55:3107–19.

    Article  PubMed  Google Scholar 

  140. Bartfeld S, Clevers H. Stem cell-derived organoids and their application for medical research and patient treatment. J Mol Med (Berl). 2017;95:729–38.

    Article  CAS  Google Scholar 

  141. Achberger K, Haderspeck JC, Kleger A, Liebau S. Stem cell-based retina models. Adv Drug Deliv Rev. 2019;140:33–50.

    Article  CAS  PubMed  Google Scholar 

  142. Lowe A, Harris R, Bhansali P, Cvekl A, Liu W. Intercellular adhesion-dependent cell survival and ROCK-regulated actomyosin-driven forces mediate self-formation of a retinal organoid. Stem Cell Reports. 2016;6:743–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Mazerik JN, Becker S, Sieving PA. 3-D retina organoids: building platforms for therapies of the future. Cell Med. 2018;10:1–6.

    Article  Google Scholar 

  144. Lou YR, Leung AW. Next generation organoids for biomedical research and applications. Biotechnol Adv. 2018;36:132–49.

    Article  CAS  PubMed  Google Scholar 

  145. Clevers H. Modeling development and disease with organoids. Cell. 2016;165:1586–97.

    Article  CAS  PubMed  Google Scholar 

  146. Kaewkhaw R, Swaroop M, Homma K, Nakamura J, Brooks M, Kaya KD, et al. Treatment paradigms for retinal and macular diseases using 3-D retina cultures derived from human reporter pluripotent stem cell lines. Invest Ophthalmol Vis Sci. 2016;57:ORSFl1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Luo Z, Zhong X, Li K, Xie B, Liu Y, Ye M, et al. An optimized system for effective derivation of three-dimensional retinal tissue via wnt signaling regulation. Stem Cells. 2018;36:1709–22.

    Article  CAS  PubMed  Google Scholar 

  148. Browne AW, Arnesano C, Harutyunyan N, Khuu T, Martinez JC, Pollack HA, et al. Structural and functional characterization of human stem-cell-derived retinal organoids by live imaging. Invest Ophthalmol Vis Sci. 2017;58:3311–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Ito SI, Onishi A, Takahashi M. Chemically-induced photoreceptor degeneration and protection in mouse iPSC-derived three-dimensional retinal organoids. Stem Cell Res. 2017;24:94–101.

    Article  CAS  PubMed  Google Scholar 

  150. Felemban M, Dorgau B, Hunt NC, Hallam D, Zerti D, Bauer R, et al. Extracellular matrix component expression in human pluripotent stem cell-derived retinal organoids recapitulates retinogenesis in vivo and reveals an important role for IMPG1 and CD44 in the development of photoreceptors and interphotoreceptor matrix. Acta Biomater. 2018;74:207–21.

    Article  CAS  PubMed  Google Scholar 

  151. DiStefano T, Chen HY, Panebianco C, Kaya KD, Brooks MJ, Gieser L, et al. Accelerated and improved differentiation of retinal organoids from pluripotent stem cells in rotating-wall vessel bioreactors. Stem Cell Reports. 2018;10:300–13.

    Article  CAS  PubMed  Google Scholar 

  152. Chen HY, Kaya KD, Dong L, Swaroop A. Three-dimensional retinal organoids from mouse pluripotent stem cells mimic in vivo development with enhanced stratification and rod photoreceptor differentiation. Mol Vis. 2016;22:1077–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Lakowski J, Welby E, Budinger D, Di Marco F, Di Foggia V, Bainbridge JWB, et al. Isolation of human photoreceptor precursors via a cell surface marker panel from stem cell-derived retinal organoids and fetal retinae. Stem Cells. 2018;36:709–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kobayashi W, Onishi A, Tu HY, Takihara Y, Matsumura M, Tsujimoto K, et al. Culture systems of dissociated mouse and human pluripotent stem cell-derived retinal ganglion cells purified by two-step immunopanning. Invest Ophthalmol Vis Sci. 2018;59:776–87.

    Article  CAS  PubMed  Google Scholar 

  155. Reichman S, Slembrouck A, Gagliardi G, Chaffiol A, Terray A, Nanteau C, et al. Generation of storable retinal organoids and retinal pigmented epithelium from adherent human iPS cells in xeno-free and feeder-free conditions. Stem Cells. 2017;35:1176–88.

    Article  CAS  PubMed  Google Scholar 

  156. Calkins DJ, Horner PJ. The cell and molecular biology of glaucoma: axonopathy and the brain. Invest Ophthalmol Vis Sci. 2012;53:2482–4.

    Article  CAS  PubMed  Google Scholar 

  157. Lamba DA, Karl MO, Ware CB, Reh TA. Efficient generation of retinal progenitor cells from human embryonic stem cells. Proc Natl Acad Sci U S A. 2006;103:12769–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Maekawa Y, Onishi A, Matsushita K, Koide N, Mandai M, Suzuma K, et al. Optimized culture system to induce neurite outgrowth from retinal ganglion cells in three-dimensional retinal aggregates differentiated from mouse and human embryonic stem cells. Curr Eye Res. 2016;41:558–68.

    CAS  PubMed  Google Scholar 

  159. Riazifar H, Jia Y, Chen J, Lynch G, Huang T. Chemically induced specification of retinal ganglion cells from human embryonic and induced pluripotent stem cells. Stem Cells Transl Med. 2014;3:424–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Tucker BA, Anfinson KR, Mullins RF, Stone EM, Young MJ. Use of a synthetic xeno-free culture substrate for induced pluripotent stem cell induction and retinal differentiation. Stem Cells Transl Med. 2013;2:16–24.

    Article  CAS  PubMed  Google Scholar 

  161. Xie BB, Zhang XM, Hashimoto T, Tien AH, Chen A, Ge J, et al. Differentiation of retinal ganglion cells and photoreceptor precursors from mouse induced pluripotent stem cells carrying an Atoh7/Math5 lineage reporter. PLoS One. 2014;9:e112175.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Tamalu F, Chiba C, Ishida A, Saito T. Functional differentiation of ganglion cells from multipotent progenitor cells in sliced retina of adult goldfish. J Comp Neurol. 2000;419:297–305.

    Article  CAS  PubMed  Google Scholar 

  163. Pitt CG, Gu ZW. Modification of the rates of chain cleavage of poly(ϵ-caprolactone) and related polyesters in the solid state. J Control Release. 1987;4:283–92.

    Article  CAS  Google Scholar 

  164. Della Santina L, Inman DM, Lupien CB, Horner PJ, Wong RO. Differential progression of structural and functional alterations in distinct retinal ganglion cell types in a mouse model of glaucoma. J Neurosci. 2013;33:17444–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. El-Danaf RN, Huberman AD. Characteristic patterns of dendritic remodeling in early-stage glaucoma: evidence from genetically identified retinal ganglion cell types. J Neurosci. 2015;35:2329–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Drummond ES, Rodger J, Penrose M, Robertson D, Hu Y, Harvey AR. Effects of intravitreal injection of a Rho-GTPase inhibitor (BA-210), or CNTF combined with an analogue of cAMP, on the dendritic morphology of regenerating retinal ganglion cells. Restor Neurol Neurosci. 2014;32:391–402.

    CAS  PubMed  Google Scholar 

  167. Lorenzetto E, Ettorre M, Pontelli V, Bolomini-Vittori M, Bolognin S, Zorzan S, et al. Rac1 selective activation improves retina ganglion cell survival and regeneration. PLoS One. 2013;8:e64350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Morquette B, Morquette P, Agostinone J, Feinstein E, McKinney R, Kolta A, et al. REDD2-mediated inhibition of mTOR promotes dendrite retraction induced by axonal injury. Cell Death Differ. 2015;22:612–25.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

S.B. acknowledges the Royan Institute for Biotechnology for the visiting doctoral training support.

Author information

Authors and Affiliations

Authors

Contributions

SB designed and conceptualised the study, carried out the search and collection of review data, carried out data analysis, drafted the manuscript; AÖ and YGA critically revised the manuscript; MR designed, conceptualised and coordinated the study, drafted and critically revised the manuscript. All authors gave final approval for publication and agree to be held accountable for the work performed therein.

Corresponding author

Correspondence to Maksym Rybachuk.

Ethics declarations

Conflict of interest

The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support of this work that could have influenced its outcome.

Ethical statement

The authors confirm that material presented in this publication is exempt from formal institutional review and/or national ethical committee approval.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Behtaj, S., Öchsner, A., Anissimov, Y.G. et al. Retinal Tissue Bioengineering, Materials and Methods for the Treatment of Glaucoma. Tissue Eng Regen Med 17, 253–269 (2020). https://doi.org/10.1007/s13770-020-00254-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-020-00254-8

Keywords

Navigation