New Advances in 3D Models to Improve Diabetic Keratopathy Research: A Narrative Review
Source abstract
Abstract
Diabetic keratopathy (DK) is a common ocular complication of diabetes mellitus (DM), affecting almost half of all diabetic patients. It is characterized by delayed healing of epithelial wounds, reduced corneal sensitivity, and persistent epithelial defects, which, in turn, significantly impair vision and quality of life. The limited understanding of its pathogenesis and the lack of effective treatments highlight the urgent need for more physiologically relevant experimental models. The three-dimensional (3D) models currently available provide valuable information on the pathophysiology of DK, although none of them yet fully reproduce the diabetic corneal phenotype complex. After a brief overview of corneal anatomy, the present review aims to systematically analyze the current 3D in vitro models developed for the study of DK, in terms of tissue architecture, presence of diabetic stimuli, and ability to replicate pathological traits.
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Research context
OpenAlex topics: Corneal Surgery and Treatments · Corneal surgery and disorders · Ocular Surface and Contact Lens
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Biomedical and Biotechnological Sciences, Section of Anatomy, Histology and Movement Sciences, University of Catania, 95131 Catania, Italy
Department of Drug Sciences, University of Catania, 95131 Catania, Italy
Department of Surgery, Garibaldi Hospital, 95131 Catania, Italy
Funding
BIOMETEC department, University of Catania
References (100+)
Show source-provided references
1. Diabetes mellitus, the fastest growing global public health concern: Early detection should be focused10.1002/hsr2.2004 ↗
2. A systematic review on the impact of diabetes mellitus on the ocular surface10.1038/nutd.2017.4 ↗
3. Mansoor, H., Tan, H.C., Lin, M.T., Mehta, J.S., and Liu, Y.C. (2020). Diabetic Corneal Neuropathy. J. Clin. Med., 9.10.3390/jcm9123956 ↗
4. Comprehensive Review of the Effects of Diabetes on Ocular Health10.1586/eop.10.44 ↗
5. Diabetic keratopathy
6. Overview of the Cornea: Structure, Function, and Development10.1016/bs.pmbts.2015.04.001 ↗
7. Corneal nerves in health and disease10.1016/j.survophthal.2013.09.002 ↗
8. Anatomy and physiology of the cornea10.1016/j.jcrs.2010.12.037 ↗
9. The structure and transparency of the cornea10.1113/jphysiol.1957.sp005758 ↗
10. The corneal epithelial basement membrane: Structure, function, and disease10.1167/iovs.13-12547 ↗
11. Tight junction-related protein expression and distribution in human corneal epithelium10.1016/S0014-4835(03)00054-X ↗
12. Niche Regulation of Limbal Epithelial Stem Cells: Relationship between Inflammation and Regeneration10.1016/j.jtos.2015.12.002 ↗
13. Bowman’s layer structure and function: Critical or dispensable to corneal function? A hypothesis10.1097/00003226-200007000-00001 ↗
14. Bowman’s layer in the cornea- structure and function and regeneration10.1016/j.exer.2020.108033 ↗
15. The Histopathology of Bowman’s Membrane
16. The architecture of the corneal stroma10.1136/bjo.85.4.379 ↗
17. Development of the corneal stroma, and the collagen-proteoglycan associations that help define its structure and function10.1002/dvdy.21579 ↗
18. The keratocyte: Corneal stromal cell with variable repair phenotypes10.1016/j.biocel.2006.03.010 ↗
19. The cellular basis of corneal transparency: Evidence for ‘corneal crystallins’10.1242/jcs.112.5.613 ↗
20. Corneal wound healing10.1016/j.exer.2020.108089 ↗
21. The myofibroblast, biological activities and roles in eye repair and fibrosis. A focus on healing mechanisms in avascular cornea10.1038/s41433-019-0684-8 ↗
22. Anatomy of the human corneal innervation10.1016/j.exer.2009.12.010 ↗
23. 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 controversy10.1016/j.preteyeres.2022.101161 ↗
24. Supramolecular assembly of basement membranes10.1002/bies.950180208 ↗
25. Classification of corneal endothelial disorders based on neural crest origin10.1016/S0161-6420(84)34249-X ↗
26. Role of aquaporin water channels in eye function10.1016/S0014-4835(02)00303-2 ↗
27. 12. Endothelial pump and barrier function10.1016/j.exer.2020.108068 ↗
28. Proliferative capacity of corneal endothelial cells10.1016/j.exer.2011.08.014 ↗
29. Factors affecting corneal endothelial morphology10.1097/ICO.0b013e318033a6da ↗
30. Diabetic retinopathy—Ocular complications of diabetes mellitus10.4239/wjd.v6.i3.489 ↗
31. Corneal changes in diabetes mellitus10.2174/157339912800840479 ↗
32. Systemic diseases and the cornea10.1016/j.exer.2021.108455 ↗
33. In vivo confocal microscopic findings of corneal wound healing after corneal epithelial debridement in diabetic vitrectomy10.1016/j.ophtha.2009.01.002 ↗
34. Human diabetic corneas preserve wound healing, basement membrane, integrin and MMP-10 differences from normal corneas in organ culture10.1016/S0014-4835(03)00111-8 ↗
35. Sensory nerve regeneration after epithelium wounding in normal and diabetic cornea10.1586/17469899.2015.1049157 ↗
36. Prevention of diabetic keratopathy10.1136/bjo.2004.055541 ↗
37. The acceptability and feasibility of corneal confocal microscopy to detect early diabetic neuropathy in children: A pilot study10.1111/dme.12125 ↗
38. Neurotrophic keratopathy: Current challenges and future prospects10.1080/07853890.2022.2045035 ↗
39. Zhou, Q., Yang, L., Wang, Q., Li, Y., Wei, C., and Xie, L. (2022). Mechanistic investigations of diabetic ocular surface diseases. Front. Endocrinol., 13.10.3389/fendo.2022.1079541 ↗
40. Diabetic complications in the cornea10.1016/j.visres.2017.03.002 ↗
41. Reduced innervation and delayed re-innervation after epithelial wounding in type 2 diabetic Goto-Kakizaki rats10.1016/j.ajpath.2012.08.029 ↗
42. High glucose suppresses epidermal growth factor receptor/phosphatidylinositol 3-kinase/Akt signaling pathway and attenuates corneal epithelial wound healing10.2337/db08-0997 ↗
43. Diabetic keratopathy10.1016/j.disamonth.2021.101135 ↗
44. Ocular complications of diabetes mellitus10.4239/wjd.v6.i1.92 ↗
45. Vieira-Potter, V.J., Karamichos, D., and Lee, D.J. (2016). Ocular Complications of Diabetes and Therapeutic Approaches. Biomed. Res. Int., 2016.10.1155/2016/3801570 ↗
46. Effects of diabetes on the eye10.1167/iovs.13-12979 ↗
47. An overview of the eye in diabetes10.1177/014107680309600603 ↗
48. Diabetic keratopathy: Insights and challenges10.1016/j.survophthal.2020.02.005 ↗
49. Clinical observations on the corneal thickness and the corneal endothelium in diabetes mellitus10.1136/bjo.65.10.687 ↗
50. Differences in corneal thickness and corneal endothelium related to duration in diabetes10.1038/sj.eye.6701868 ↗
51. Noninvasive assessment of corneal sensitivity in young and elderly diabetic and nondiabetic subjects10.1167/iovs.03-0689 ↗
52. Clinical and pathogenetic features of neurotrophic corneal disorders in diabetes
53. Influence of diabetes mellitus on anterior segment of the eye10.2147/CIA.S190713 ↗
54. The influence of age on the fragility of the cornea10.1111/j.1755-3768.1984.tb05810.x ↗
55. Laser refractive surgery in diabetic patients: A review of the literature10.2147/OPTH.S37384 ↗
56. Corneal Sensitivity as a Potential Marker of Diabetic Neuropathy
57. Effect of diabetes mellitus on biomechanical parameters of the cornea10.1016/j.jcrs.2008.12.013 ↗
58. Collagen stiffness regulates cellular contraction and matrix remodeling gene expression10.1002/jbm.a.31423 ↗
59. Corneal biomechanical characteristics in patients with diabetes mellitus10.1016/j.jcrs.2010.08.027 ↗
60. The cornea in diabetes mellitus10.1097/00004397-199838020-00004 ↗
61. Corneal epithelial changes in diabetic rats10.1159/000265202 ↗
62. Insulin treatment ameliorates impaired corneal reepithelialization in diabetic rats10.2337/diabetes.55.04.06.db05-1581 ↗
63. Stromal-epithelial interactions in the cornea10.1016/S1350-9462(98)00017-2 ↗
64. Novel Therapy to Treat Corneal Epithelial Defects: A Hypothesis with Growth Hormone10.1016/j.jtos.2014.12.005 ↗
65. Extracellular matrix and wound healing10.1097/00055735-200108000-00001 ↗
66. An Update on Corneal Biomechanics and Architecture in Diabetes
67. The impact of hyperglycemia on the corneal epithelium: Molecular mechanisms and insight10.1016/j.jtos.2019.06.007 ↗
68. Reins, R.Y., Hanlon, S.D., Magadi, S., and McDermott, A.M. (2016). Effects of Topically Applied Vitamin D during Corneal Wound Healing. PLoS ONE, 11.10.1371/journal.pone.0152889 ↗
69. The corneal endothelium and thickness in type II diabetes mellitus10.1016/S0021-5155(01)00458-0 ↗
70. Dysfunctional tear syndrome: Dry eye disease and associated tear film disorders—New strategies for diagnosis and treatment10.1097/01.icu.0000512373.81749.b7 ↗
71. Atopic ocular surface disease: Implications on tear function and ocular surface mucins10.1097/01.ico.0000178741.14212.53 ↗
72. Dry Eye Syndrome in Patients with Diabetes Mellitus: Prevalence, Etiology, and Clinical Characteristics10.1155/2016/8201053 ↗
73. Effect of Omega-3 Fatty Acids Dietary Supplementation on Ocular Surface and Tear Film in Diabetic Patients with Dry Eye10.1080/07315724.2016.1170643 ↗
74. Biomechanical Diagnostics of the Cornea10.1097/IIO.0000000000000172 ↗
75. Advanced glycation end products and ultrastructural changes in corneas of long-term streptozotocin-induced diabetic monkeys10.1097/ICO.0b013e3182490907 ↗
76. Evaluation of the corneal endothelium in patients with diabetes mellitus type I and II
77. The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas10.1016/j.preteyeres.2021.101039 ↗
78. Buonfiglio, F., Wasielica-Poslednik, J., Pfeiffer, N., and Gericke, A. (2024). Diabetic Keratopathy: Redox Signaling Pathways and Therapeutic Prospects. Antioxidants, 13.10.3390/antiox13010120 ↗
79. Interleukin-1beta and tumor necrosis factor-alpha have opposite effects on fibroblasts and epithelial cells during basement membrane formation10.1016/j.matbio.2008.02.005 ↗
80. IL-1β Impaired Diabetic Wound Healing by Regulating MMP-2 and MMP-9 through the p38 Pathway10.1155/2021/6645766 ↗
81. A PEDF peptide mimetic effectively relieves dry eye in a diabetic murine model by restoring corneal nerve, barrier, and lacrimal gland function10.1016/j.jtos.2023.12.002 ↗
82. Insulin facilitates corneal wound healing in the diabetic environment through the RTK-PI3K/Akt/mTOR axis in vitro10.1016/j.mce.2022.111611 ↗
83. Topical Recombinant Human Nerve Growth Factor (Cenegermin) for Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial10.1016/j.ophtha.2019.08.020 ↗
84. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors10.1089/adt.2014.573 ↗
85. Modeling Physiological Events in 2D vs. 3D Cell Culture10.1152/physiol.00036.2016 ↗
86. Deconstructing the third dimension: How 3D culture microenvironments alter cellular cues
87. Cell viability assessment using the Alamar blue assay: A comparison of 2D and 3D cell culture models10.1016/j.tiv.2014.09.014 ↗
88. 3D in vitro corneal models: A review of current technologies10.1016/j.exer.2020.108213 ↗
89. Assembly and Application of a Three-Dimensional Human Corneal Tissue Model10.1002/cptx.84 ↗
90. Morphologic characterization of organized extracellular matrix deposition by ascorbic acid-stimulated human corneal fibroblasts10.1167/iovs.06-1216 ↗
91. Corneal Tissue Engineering: An In Vitro Model of the Stromal-nerve Interactions of the Human Cornea
92. Deardorff, P.M., McKay, T.B., Wang, S., Ghezzi, C.E., Cairns, D.M., Abbott, R.D., Funderburgh, J.L., Kenyon, K.R., and Kaplan, D.L. (2018). Modeling Diabetic Corneal Neuropathy in a 3D In Vitro Cornea System. Sci. Rep., 8.10.1038/s41598-018-35917-z ↗
93. Silk film biomaterials for cornea tissue engineering10.1016/j.biomaterials.2008.11.018 ↗
94. Tensile mechanical properties of three-dimensional type I collagen extracellular matrices with varied microstructure10.1115/1.1449904 ↗
95. Water-Stable Silk Films with Reduced β-Sheet Content10.1002/adfm.200400405 ↗
96. In vitro degradation of silk fibroin10.1016/j.biomaterials.2004.09.020 ↗
97. In vitro 3D corneal tissue model with epithelium, stroma, and innervation10.1016/j.biomaterials.2016.09.030 ↗
98. Coculture of dorsal root ganglion neurons and differentiated human corneal stromal stem cells on silk-based scaffolds10.1002/jbm.a.35465 ↗
99. Corneal stromal bioequivalents secreted on patterned silk substrates10.1016/j.biomaterials.2013.12.078 ↗
100. Nerve growth factor promotes corneal epithelial migration by enhancing expression of matrix metalloprotease-910.1167/iovs.12-10816 ↗