The use of stem cells and keratoprosthesis – special surgery types for corneal disorders (a narrative review)

Martyna Dydyk; Ewa Sikorska; Piotr Sikorski; Robert Tomaszewski; Dorota Kopacz

doi:10.20883/medical.e1045

Authors

Martyna Dydyk Medical University of Warsaw, Poland https://orcid.org/0009-0005-5906-3406
Ewa Sikorska Department of Experimental and Clinical Physiology, Center for Preclinical Research, Medical University of Warsaw, Poland https://orcid.org/0000-0003-2352-650X
Piotr Sikorski Masovian Bródno Hospital, Warsaw, Poland https://orcid.org/0000-0003-1629-2784
Robert Tomaszewski University Clinical Center of Medical University of Warsaw, Poland https://orcid.org/0009-0000-0225-538X
Dorota Kopacz Department of Ophthalmology, Infant Jesus Teaching Hospital, Warsaw, Poland https://orcid.org/0000-0001-8758-4106

DOI:

https://doi.org/10.20883/medical.e1045

Keywords:

stem cells, keratoprosthesis, corneal blindness, corneal disease, boston keratoprosthesis, osteo-odonto keratoprosthesis

Abstract

Corneal disease and damage can arise from various causes, including infections, corneal dystrophies, trauma and improper contact lens use. These factors can lead to corneal blindness which greatly decreases the patient’s quality of life. Although corneal transplantation is a viable treatment option for many patients, the risk of rejection after corneal transplantation remains a concern. Severe corneal damage requires special methods of treatment, which are still sought after. This narrative review aims to summarize the use of stem cells and keratoprosthesis in the treatment of corneal diseases. Stem cell therapy, particularly limbal stem cell transplantation, shows promise in corneal regenerative therapy, especially the treatment of limbal stem cell deficiency. Additionally, induced pluripotent stem cells have been successfully used in cornea transplantation, offering a novel approach to restoring vision in patients with corneal diseases. Keratoprosthesis, such as the Boston keratoprosthesis and osteo-odonto-keratoprosthesis, provides an alternative for patients who cannot undergo traditional corneal transplantation. Artificial prostheses are also an alternative to corneal transplantation in cases of extensive trauma or in the absence of donor tissue. Continued research and development in stem cell therapy and keratoprosthesis hold the potential to improve the outcomes, accessibility of corneal disease treatment and reducing the global burden of corneal blindness.

Downloads

Download data is not yet available.

References

DelMonte DW, Kim T. Anatomy and physiology of the cornea. J Cataract Refract Surg. 2011 Mar;37(3):588-98. doi: 10.1016/j.jcrs.2010.12.037.

Eghrari AO, Riazuddin SA, Gottsch JD. Overview of the Cornea: Structure, Function, and Development. Prog Mol Biol Transl Sci. 2015;134:7-23. doi: 10.1016/bs.pmbts.2015.04.001.

Dua HS, Freitas R, Mohammed I, Ting DSJ, Said DG. The pre-Descemet's layer (Dua's layer, also known as the Dua-Fine layer and the pre-posterior limiting lamina layer): Discovery, characterisation, clinical and surgical applications, and the controversy. Prog Retin Eye Res. 2023 Nov;97:101161. doi: 10.1016/j.preteyeres.2022.101161.

Ting DSJ, Ho CS, Deshmukh R, Said DG, Dua HS. Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and antimicrobial resistance. Eye (Lond). 2021 Apr;35(4):1084-1101. doi: 10.1038/s41433-020-01339-3. Epub 2021 Jan 7. Erratum in: Eye (Lond). 2021 Oct;35(10):2908. doi: 10.1038/s41433-021-01568-0.

Bourges JL. Corneal dystrophies. J Fr Ophtalmol. 2017 Jun;40(6):e177-e192. doi: 10.1016/j.jfo.2017.05.003.

Barrientez B, Nicholas SE, Whelchel A, Sharif R, Hjortdal J, Karamichos D. Corneal injury: Clinical and molecular aspects. Exp Eye Res. 2019 Sep;186:107709. doi: 10.1016/j.exer.2019.107709.

Callegan MC. Checks and balances: the ocular response to infection. Virulence. 2010 Jul-Aug;1(4):222. doi: 10.4161/viru.1.4.12317.

Cabrera-Aguas M, Khoo P, Watson SL. Infectious keratitis: A review. Clin Exp Ophthalmol. 2022 Jul;50(5):543-562. doi: 10.1111/ceo.14113.

Nosrati H, Alizadeh Z, Nosrati A, Ashrafi-Dehkordi K, Banitalebi-Dehkordi M, Sanami S, Khodaei M. Stem cell-based therapeutic strategies for corneal epithelium regeneration. Tissue Cell. 2021 Feb;68:101470. doi: 10.1016/j.tice.2020.101470.

Singh R, Gupta N, Vanathi M, Tandon R. Corneal transplantation in the modern era. Indian J Med Res. 2019 Jul;150(1):7-22. doi: 10.4103/ijmr.IJMR_141_19.

Arora A, Pandey SK, Roychoudhury A, Bhutia O, Tandon R, Gagnani SP, Yadav R. Piezoelectric harvest of osteo-odonto-lamina in modified osteo-odonto keratoprosthesis: A maxillofacial perspective. Natl J Maxillofac Surg. 2018 Jul-Dec;9(2):167-173. doi: 10.4103/njms.NJMS_32_16.

Ple-Plakon PA, Shtein RM. Trends in corneal transplantation: indications and techniques. Curr Opin Ophthalmol. 2014 Jul;25(4):300-5. doi: 10.1097/ICU.0000000000000080.

Tan DT, Dart JK, Holland EJ, Kinoshita S. Corneal transplantation. Lancet. 2012 May 5;379(9827):1749-61. doi: 10.1016/S0140-6736(12)60437-1.

Iyer G, Srinivasan B, Agarwal S, Talele D, Rishi E, Rishi P, Krishnamurthy S, Vijaya L, Subramanian N, Somasundaram S. Keratoprosthesis: Current global scenario and a broad Indian perspective. Indian J Ophthalmol. 2018 May;66(5):620-629. doi: 10.4103/ijo.IJO_22_18.

Md Noh UK, Then KY. Spontaneous bilateral corneal perforation in stevens- johnsons syndrome-a challenge in management. Malays J Med Sci. 2013 Jan;20(1):84-7.

Inoue K, Amano S, Oshika T, Tsuru T. Risk factors for corneal graft failure and rejection in penetrating keratoplasty. Acta Ophthalmol Scand. 2001 Jun;79(3):251-5. doi: 10.1034/j.1600-0420.2001.790308.x.

Kaur J. Osteo-odonto keratoprosthesis: Innovative dental and ophthalmic blending. J Indian Prosthodont Soc. 2018 Apr-Jun;18(2):89-95. doi: 10.4103/jips.jips_283_17.

Pellier de Quengsy G. Précis ou cours d'opérations sur la chirurgie des yeux : puisé dans le sein de la pratique, & enrichi de figures en taille-douce, qui représentent les instrumens qui leur sont propres, avec des observations de pratique très-intéressantes. Paris 1789.

Maghsoudlou P, Sood G, Gurnani B, et al. Cornea Transplantation. [Updated 2024 Feb 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539690.

Salvador-Culla B, Kolovou PE. Keratoprosthesis: A Review of Recent Advances in the Field. J Funct Biomater. 2016 May 19;7(2):13. doi: 10.3390/jfb7020013.

Magalhães FP, Sousa LB, Oliveira LA. Boston type I keratoprosthesis: Review. Arq Bras Oftalmol. 2012 May-Jun;75(3):218-22. doi: 10.1590/s0004-27492012000300016.

Nonpassopon M, Niparugs M, Cortina MS. Boston Type 1 Keratoprosthesis: Updated Perspectives. Clin Ophthalmol. 2020 Apr 29;14:1189-1200. doi: 10.2147/OPTH.S219270.

Hui PC, Pereira LA, Dore R, Chen S, Taniguchi E, Chodosh J, et al. Intrinsic Optical Properties of Boston Keratoprosthesis. Trans. Vis. Sci. Tech. 2020;9(12):10. https://doi.org/10.1167/tvst.9.12.10.

Al Arfaj K. Boston keratoprosthesis - Clinical outcomes with wider geographic use and expanding indications - A systematic review. Saudi J Ophthalmol. 2015 Jul-Sep;29(3):212-21. doi: 10.1016/j.sjopt.2015.02.001.

Kang KB, Karas FI, Rai R, Hallak JA, Kang JJ, de la Cruz J, Cortina MS. Five year outcomes of Boston type I keratoprosthesis as primary versus secondary penetrating corneal procedure in a matched case control study. PLoS One. 2018 Feb 6;13(2):e0192381. doi: 10.1371/journal.pone.0192381.

Ahmad S, Mathews PM, Lindsley K, Alkharashi M, Hwang FS, Ng SM, Aldave AJ, Akpek EK. Boston Type 1 Keratoprosthesis versus Repeat Donor Keratoplasty for Corneal Graft Failure: A Systematic Review and Meta-analysis. Ophthalmology. 2016 Jan;123(1):165-77. doi: 10.1016/j.ophtha.2015.09.028.

Priddy J, Bardan AS, Tawfik HS, Liu C. Systematic Review and Meta-Analysis of the Medium- and Long-Term Outcomes of the Boston Type 1 Keratoprosthesis. Cornea. 2019 Nov;38(11):1465-1473. doi: 10.1097/ICO.0000000000002098.

Krysik K, Miklaszewski P, Dobrowolski D, Lyssek-Boroń A, Grabarek BO, Wylęgała E. Ocular Surface Preparation Before Keratoprosthesis Implantation. Ophthalmol Ther. 2022 Feb;11(1):249-259. doi: 10.1007/s40123-021-00420-8.

Sharifi S, Sharifi H, Guild C, Islam MM, Tran KD, Patzer C, Dohlman CH, Paschalis EI, Gonzalez-Andrades M, Chodosh J. Toward electron-beam sterilization of a pre-assembled Boston keratoprosthesis. Ocul Surf. 2021 Apr;20:176-184. doi: 10.1016/j.jtos.2021.02.009.

Park J, Phrueksaudomchai P, Cortina MS. Retroprosthetic membrane: A complication of keratoprosthesis with broad consequences. Ocul Surf. 2020 Oct;18(4):893-900. doi: 10.1016/j.jtos.2020.09.004.

Sivaraman KR, Hou JH, Allemann N, de la Cruz J, Cortina MS. Retroprosthetic membrane and risk of sterile keratolysis in patients with type I Boston Keratoprosthesis. Am J Ophthalmol. 2013 May;155(5):814-22. doi: 10.1016/j.ajo.2012.11.019.

Wang JC, Rudnisky CJ, Belin MW, Ciolino JB; Boston Type 1 Keratoprosthesis Study Group. Outcomes of Boston keratoprosthesis type 1 reimplantation: multicentre study results. Can J Ophthalmol. 2018 Jun;53(3):284-290. doi: 10.1016/j.jcjo.2017.10.021.

Kamyar R, Weizer JS, de Paula FH, Stein JD, Moroi SE, John D, Musch DC, Mian SI. Glaucoma associated with Boston type I keratoprosthesis. Cornea. 2012 Feb;31(2):134-9. doi: 10.1097/ICO.0b013e31820f7a32.

Lee R, Khoueir Z, Tsikata E, Chodosh J, Dohlman CH, Chen TC. Long-term Visual Outcomes and Complications of Boston Keratoprosthesis Type II Implantation. Ophthalmology. 2017 Jan;124(1):27-35. doi: 10.1016/j.ophtha.2016.07.011.

Netland PA, Terada H, Dohlman CH. Glaucoma associated with keratoprosthesis. Ophthalmology. 1998 Apr;105(4):751-7. doi: 10.1016/S0161-6420(98)94034-9.

Gu J, Zhang Y, Zhai J, Lin L, Ou Z, Huang T, Chen M, Zhou J, Zeng L, Xu Y, Chen J. Clinical Experience in Patients with Ocular Burns Treated with Boston Type I Keratoprosthesis Implantation with or Without Prophylactic Ahmed Glaucoma Valve Implantation. Ophthalmol Ther. 2022 Feb;11(1):421-434. doi: 10.1007/s40123-021-00446-y.

Jabbour S, Harissi-Dagher M, Agoumi Y, Singh H, Robert MC. Cyclophotocoagulation in the Control of Glaucoma in Patients With the Boston Keratoprosthesis Type 1. Cornea. 2020 Feb;39(2):181-185. doi: 10.1097/ICO.0000000000002064.

Orive Bañuelos A, Arana Larrea B, Crnej A, Arce Soto A, Andollo Victoriano N, Etxebarria Ecenarro J. Transscleral Cyclophotocoagulation for the Treatment of Uncontrolled Glaucoma in a Boston Keratoprosthesis Type II Patient. Case Rep Ophthalmol. 2022 Mar 17;13(1):158-165. doi: 10.1159/000522440.

Poon LY, Chodosh J, Vavvas DG, Dohlman CH, Chen TC. Endoscopic Cyclophotocoagulation for the Treatment of Glaucoma in Boston Keratoprosthesis Type II Patient. J Glaucoma. 2017 Apr;26(4):e146-e149. doi: 10.1097/IJG.0000000000000626.

Fu L, Hollick EJ. Artificial Cornea Transplantation. 2023 Apr 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 33760451.

Tan A, Tan DT, Tan XW, Mehta JS. Osteo-odonto keratoprosthesis: systematic review of surgical outcomes and complication rates. Ocul Surf. 2012 Jan;10(1):15-25. doi: 10.1016/j.jtos.2012.01.003.

Avadhanam V, Ingavle G, Zheng Y, Kumar S, Liu C, Sandeman S. Biomimetic bone-like composites as osteo-odonto-keratoprosthesis skirt substitutes. J Biomater Appl. 2021 Mar;35(8):1043-1060. doi: 10.1177/0885328220972219.

Charoenrook V, Michael R, de la Paz MF, Ding A, Barraquer RI, Temprano J. Osteokeratoprosthesis Using Tibial Bone: Surgical Technique and Outcomes. Ocul Surf. 2016 Oct;14(4):495-506. doi: 10.1016/j.jtos.2016.07.002.

Myung D, Duhamel PE, Cochran JR, Noolandi J, Ta CN, Frank CW. Development of hydrogel-based keratoprostheses: a materials perspective. Biotechnol Prog. 2008 May-Jun;24(3):735-41. doi: 10.1021/bp070476n.

Viitala R, Franklin V, Green D, Liu C, Lloyd A, Tighe B. Towards a synthetic osteo-odonto-keratoprosthesis. Acta Biomater. 2009 Jan;5(1):438-52. doi: 10.1016/j.actbio.2008.07.008.

Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019 Feb 26;10(1):68. doi: 10.1186/s13287-019-1165-5.

Wang X. Stem cells in tissues, organoids, and cancers. Cell Mol Life Sci. 2019 Oct;76(20):4043-4070. doi: 10.1007/s00018-019-03199-x.

Ratajczak MZ, Zuba-Surma EK, Wysoczynski M, Wan W, Ratajczak J, Wojakowski W, Kucia M. Hunt for pluripotent stem cell -- regenerative medicine search for almighty cell. J Autoimmun. 2008 May;30(3):151-62. doi: 10.1016/j.jaut.2007.12.003.

Suman S, Domingues A, Ratajczak J, Ratajczak MZ. Potential Clinical Applications of Stem Cells in Regenerative Medicine. Adv Exp Med Biol. 2019;1201:1-22. doi: 10.1007/978-3-030-31206-0_1.

Elahimehr R, Scheinok AT, McKay DB. Hematopoietic stem cells and solid organ transplantation. Transplant Rev (Orlando). 2016 Oct;30(4):227-34. doi: 10.1016/j.trre.2016.07.005.

Song Y, Du H, Dai C, Zhang L, Li S, Hunter DJ, Lu L, Bao C. Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections. Regen Med. 2018 Apr;13(3):295-307. doi: 10.2217/rme-2017-0152.

Singh V, Tiwari A, Kethiri AR, Sangwan VS. Current perspectives of limbal-derived stem cells and its application in ocular surface regeneration and limbal stem cell transplantation. Stem Cells Transl Med. 2021 Aug;10(8):1121-1128. doi: 10.1002/sctm.20-0408.

Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell. 1989 Apr 21;57(2):201-9. doi: 10.1016/0092-8674(89)90958-6.

Funderburgh JL, Funderburgh ML, Du Y. Stem Cells in the Limbal Stroma. Ocul Surf. 2016 Apr;14(2):113-20. doi: 10.1016/j.jtos.2015.12.006.

Deng SX, Borderie V, Chan CC, Dana R, Figueiredo FC, Gomes JAP, Pellegrini G, Shimmura S, Kruse FE; and The International Limbal Stem Cell Deficiency Working Group. Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency. Cornea. 2019 Mar;38(3):364-375. doi: 10.1097/ICO.0000000000001820.

Ruan Y, Jiang S, Musayeva A, Pfeiffer N, Gericke A. Corneal Epithelial Stem Cells-Physiology, Pathophysiology and Therapeutic Options. Cells. 2021 Sep 3;10(9):2302. doi: 10.3390/cells10092302.

Deng SX, Kruse F, Gomes JAP, Chan CC, Daya S, Dana R, Figueiredo FC, Kinoshita S, Rama P, Sangwan V, Slomovic AR, Tan D; and the International Limbal Stem Cell Deficiency Working Group. Global Consensus on the Management of Limbal Stem Cell Deficiency. Cornea. 2020 Oct;39(10):1291-1302. doi: 10.1097/ICO.0000000000002358.

Jurkunas U, Johns L, Armant M. Cultivated Autologous Limbal Epithelial Cell Transplantation: New Frontier in the Treatment of Limbal Stem Cell Deficiency. Am J Ophthalmol. 2022 Jul;239:244-268. doi: 10.1016/j.ajo.2022.03.015.

Massachusetts E, Ear I, Dana-Farber Cancer I. Limbal Stem Cell Deficiency (LSCD) Treatment With Cultivated Stem Cell (CALEC) Graft 2023 [updated April 1]. Available from: https://ClinicalTrials.gov/show/NCT02592330.

Cyranoski D. Woman is first to receive cornea made from 'reprogrammed' stem cells. Nature. 2019 Sep 2. doi: 10.1038/d41586-019-02597-2.

Oh JY, Lee RH, Yu JM, Ko JH, Lee HJ, Ko AY, Roddy GW, Prockop DJ. Intravenous mesenchymal stem cells prevented rejection of allogeneic corneal transplants by aborting the early inflammatory response. Mol Ther. 2012 Nov;20(11):2143-52. doi: 10.1038/mt.2012.165.

Mansoor H, Ong HS, Riau AK, Stanzel TP, Mehta JS, Yam GH. Current Trends and Future Perspective of Mesenchymal Stem Cells and Exosomes in Corneal Diseases. Int J Mol Sci. 2019 Jun 12;20(12):2853. doi: 10.3390/ijms20122853.

Nieto-Nicolau N, Martín-Antonio B, Müller-Sánchez C, Casaroli-Marano RP. In vitro potential of human mesenchymal stem cells for corneal epithelial regeneration. Regen Med. 2020 Mar;15(3):1409-1426. doi: 10.2217/rme-2019-0067.

Azmi SM, Salih M, Abdelrazeg S, Roslan FF, Mohamed R, Tan JJ, Shaharuddin B. Human umbilical cord-mesenchymal stem cells: a promising strategy for corneal epithelial regeneration. Regen Med. 2020 Mar;15(3):1381-1397. doi: 10.2217/rme-2019-0103. Epub 2020 Apr 7. Erratum in: Regen Med. 2020 Jul;15(7):1935. doi: 10.2217/rme-2019-0103c1.

Ghiasi M, Jadidi K, Hashemi M, Zare H, Salimi A, Aghamollaei H. Application of mesenchymal stem cells in corneal regeneration. Tissue Cell. 2021 Dec;73:101600. doi: 10.1016/j.tice.2021.101600.

Marta CM, Adrian M, Jorge FD, Francisco AM, De Miguel MP. Improvement of an Effective Protocol for Directed Differentiation of Human Adipose Tissue-Derived Adult Mesenchymal Stem Cells to Corneal Endothelial Cells. Int J Mol Sci. 2021 Nov 5;22(21):11982. doi: 10.3390/ijms222111982.

Karimian F, Hassanpour K. En Bloc Keratolimbal Allograft and Central Penetrating Keratoplasty: A Novel Surgical Technique in Severe Limbal Stem Cell Deficiency. Cornea. 2023 May 1;42(5):656-661. doi: 10.1097/ICO.0000000000003199.

Li Z, Yang K, Zhou Y, Wu T, Zhang H, Yang Q, Wang Q, Huang Y, Wang L. Outcome of keratolimbal allograft transplantation with deep anterior lamellar keratoplasty for bilateral limbal stem cell deficiency. Front Med (Lausanne). 2022 Nov 15;9:986194. doi: 10.3389/fmed.2022.986194.

Karimian F, Jafarinasab MR, Feizi S, Javadi M, Ansari MH, Hassanpour K. Long-Term Clinical Outcomes of Keratolimbal Allograft Alone or in Combination With Keratoplasty in Chronic and Delayed-Onset Mustard Gas Keratopathy. Cornea. 2023 May 1;42(5):536-543. doi: 10.1097/ICO.0000000000003066.

Le Q, Chauhan T, Yung M, Tseng CH, Deng SX. Outcomes of Limbal Stem Cell Transplant: A Meta-analysis. JAMA Ophthalmol. 2020 Jun 1;138(6):660-670. doi: 10.1001/jamaophthalmol.2020.1120.

Krysik K, Dobrowolski D, Tarnawska D, Wylegala E, Lyssek-Boroń A. Long-Term Outcomes of Allogeneic Ocular Surface Reconstruction: Keratolimbal Allograft (KLAL) Followed by Penetrating Keratoplasty (PK). J Ophthalmol. 2020 Apr 14;2020:5189179. doi: 10.1155/2020/5189179.

Hou JH, de la Cruz J, Djalilian AR. Outcomes of Boston keratoprosthesis implantation for failed keratoplasty after keratolimbal allograft. Cornea. 2012 Dec;31(12):1432-5. doi: 10.1097/ICO.0b013e31823e2ac6.

de Farias CC, Bezerra FM, Lamazales LL, Nosé W, Pereira Gomes JÁ. KeraKlear Artificial Cornea Implantation Assisted by Femtosecond Laser in Eyes With Aniridia. Cornea. 2022 May 1;41(5):635-639. doi: 10.1097/ICO.0000000000002998.

Shanbhag SS, Saeed HN, Paschalis EI, Chodosh J. Keratolimbal allograft for limbal stem cell deficiency after severe corneal chemical injury: a systematic review. Br J Ophthalmol. 2018 Aug;102(8):1114-1121. doi: 10.1136/bjophthalmol-2017-311249.

Ganger A, Singh A, Kalaivani M, Gupta N, Vanathi M, Mohanty S, Tandon R. Outcomes of surgical interventions for the treatment of limbal stem cell deficiency. Indian J Med Res. 2021 Jul;154(1):51-61. doi: 10.4103/ijmr.IJMR_1139_18.

Atallah MR, Palioura S, Perez VL, Amescua G. Limbal stem cell transplantation: current perspectives. Clin Ophthalmol. 2016 Apr 1;10:593-602. doi: 10.2147/OPTH.S83676.