Research progress on the detection of tear markers and application in fundus diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Kaiyan ¹ , Zhang Shuyuan ² ,  Chen Yingying ¹

1. Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou 570311, China;
2. Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou 570311, China;

Corresponding author：

Chen Yingying, Email: ping_guo_183@126.com

Keywords：

Tear fluid; Biomarkers; Fundus diseases; Review

DOI：

10.3760/cma.j.cn511434-20250612-00265

Video：

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Abstract Full text Figures/Tables Video References Cited by

Tear fluid, as an important ocular surface fluid, can effectively reflect both ocular and systemic metabolic states through its compositional changes, making it an ideal source for discovering disease biomarkers. Current tear collection methods mainly include the Schirmer strip test and microcapillary collection, while detection technologies encompass enzyme-linked immunosorbent assay, protein chip technology, mass spectrometry, Olink targeted proteomics, and bead-based multiplex assays. Studies have shown that various biomarkers in tear fluid—such as proteins, cytokines, and chemokines that are closely associated with the pathophysiological processes of fundus diseases including diabetic retinopathy, retinal vein occlusion, age-related macular degeneration, retinopathy of prematurity, and uveitis, demonstrating potential as indicators for early diagnosis, disease assessment, and therapeutic monitoring. As a non-invasive and convenient detection tool, tear analysis shows broad application prospects in the diagnosis and treatment of fundus diseases. However, further optimization of collection and detection techniques, along with large-scale clinical studies to validate the clinical utility of tear biomarkers, is still needed to promote their standardization and widespread adoption in clinical practice.

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1. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands[J]. Cornea, 1998, 17(6): 584-589. DOI: 10.1097/00003226-199811000-00002.
2. Zhou L, Beuerman RW. Tear analysis in ocular surface diseases[J]. Prog Retin Eye Res, 2012, 31(6): 527-550. DOI: 10.1016/j.preteyeres.2012.06.002.
3. Adigal SS, Rizvi A, Rayaroth NV, et al. Human tear fluid analysis for clinical applications: progress and prospects[J]. Expert Rev Mol Diagn, 2021, 21(8): 767-787. DOI: 10.1080/14737159.2021.1941879.
4. Altman J, Jones G, Ahmed S, et al. Tear film microRNAs as potential biomarkers: a review[J/OL]. Int J Mol Sci, 2023, 24(4): 3694[2023-02-12]. https://pubmed.ncbi.nlm.nih.gov/36835108/. DOI: 10.3390/ijms24043694.
5. Zhan X, Li J, Guo Y, et al. Mass spectrometry analysis of human tear fluid biomarkers specific for ocular and systemic diseases in the context of 3P medicine[J]. EPMA J, 2021, 12(4): 449-475. DOI: 10.1007/s13167-021-00265-y.
6. Król-Grzymała A, Sienkiewicz-Szłapka E, Fiedorowicz E, et al. Tear biomarkers in Alzheimer's and Parkinson's diseases, and multiple sclerosis: implications for diagnosis (systematic review)[J/OL]. Int J Mol Sci, 2022, 23(17): 10123[2022-09-04]. https://pubmed.ncbi.nlm.nih.gov/36077520/. DOI: 10.3390/ijms231710123.
7. Kumar A, Sharma SP, Agarwal A, et al. Tear IL-6 and IL-10 levels in HLA-B27-associated uveitis and its clinical implications[J]. Ocul Immunol Inflamm, 2021, 29(2): 237-243. DOI: 10.1080/09273948.2019.1704022.
8. Tomosugi N, Kitagawa K, Takahashi N, et al. Diagnostic potential of tear proteomic patterns in Sjögren's syndrome[J]. J Proteome Res, 2005, 4(3): 820-825. DOI: 10.1021/pr0497576.
9. Pieragostino D, Bucci S, Agnifili L, et al. Differential protein expression in tears of patients with primary open angle and pseudoexfoliative glaucoma[J]. Mol Biosyst, 2012, 8(4): 1017-1028. DOI: 10.1039/c1mb05357d.
10. Choi W, Li Z, Oh HJ, et al. Expression of CCR5 and its ligands CCL3, -4, and -5 in the tear film and ocular surface of patients with dry eye disease[J]. Curr Eye Res, 2012, 37(1): 12-17. DOI: 10.3109/02713683.2011.622852.
11. Fauquert JL, Kowalski ML. Glycomics in tears: seeking for new biomarkers for ocular allergy diagnosis[J]. Allergy, 2021, 76(8): 2335-2336. DOI: 10.1111/all.14846.
12. 张丽, 李建桥. 重视全身疾病的眼部表现[J]. 眼科学报, 2023, 38(5): 365-370. DOI: 10.12419/j.issn.1000-4432.2023.05.01.Zhang L, Li JQ. Attach importance to ocular manifestations of systemic diseases[J]. Eye Science, 2023, 38(5): 365-370. DOI: 10.12419/j.issn.1000-4432.2023.05.01.
13. Ghasemi H, Yaraee R, Faghihzadeh S, et al. Tear and serum MMP-9 and serum TIMPs levels in the severe sulfur mustard eye injured exposed patients[J/OL]. Int Immunopharmacol, 2019, 77: 105812[2019-10-31]. https://pubmed.ncbi.nlm.nih.gov/31677500/. DOI: 10.1016/j.intimp.2019.105812.
14. Waszczykowska A, Goś R, Waszczykowska E, et al. The role of angiogenesis factors in the formation of vascular changes in scleroderma by assessment of the concentrations of VEGF and sVEGFR2 in blood serum and tear fluid[J/OL]. Mediators Inflamm, 2020, 2020: 7649480[2020-01-24]. https://pubmed.ncbi.nlm.nih.gov/32410862/. DOI: 10.1155/2020/7649480.
15. Chen Y, Meng Y, Tan M, et al. Changes in expression of inflammatory cytokines and ocular indicators in pre-diabetic patients with cataract[J/OL]. BMC Ophthalmol, 2025, 25(1): 119[2025-03-10]. https://pubmed.ncbi.nlm.nih.gov/40065310/. DOI: 10.1186/s12886-025-03892-5.
16. Ponzini E. Tear biomarkers[J]. Adv Clin Chem, 2024, 120: 69-115. DOI: 10.1016/bs.acc.2024.03.002.
17. Beisel A, Jones G, Glass J, et al. Comparative analysis of human tear fluid and aqueous humor proteomes[J]. Ocul Surf, 2024, 33: 16-22. DOI: 10.1016/j.jtos.2024.03.011.
18. Pieczyński J, Szulc U, Harazna J, et al. Tear fluid collection methods: review of current techniques[J]. Eur J Ophthalmol, 2021, 31(5): 2245-2251. DOI: 10.1177/1120672121998922.
19. Rodney WM, Louie J, Puffer JC. Schirmer's test of lacrimation[J]. Am Fam Physician, 1981, 24(5): 161-164.
20. Stuchell RN, Feldman JJ, Farris RL, et al. The effect of collection technique on tear composition[J]. Invest Ophthalmol Vis Sci, 1984, 25(3): 374-377.
21. Ablamowicz AF, Nichols JJ. Concentrations of MUC16 and MUC5AC using three tear collection methods[J]. Mol Vis, 2017, 23: 529-537.
22. Posa A, Bräuer L, Schicht M, et al. Schirmer strip vs. capillary tube method: non-invasive methods of obtaining proteins from tear fluid[J]. Ann Anat, 2013, 195(2): 137-142. DOI: 10.1016/j.aanat.2012.10.001.
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