{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:19:18Z","timestamp":1789712358830,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T00:00:00Z","timestamp":1700870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The purpose of the research project was to extensively review the efficacy and safety of a trehalose tear-substitute treatment in cases of dry eye disease (DED). A systematic review that included only full-length randomized controlled studies (RCTs) reporting the effects of trehalose tear-substitute treatment in three databases, PubMed, Scopus and Web of Science, was performed according to the PRISMA statement. The search period included papers published before 8 August 2023. The Cochrane risk-of-bias tool was used to analyze the quality of the studies selected. A total of 10 RCTs were included in this systematic review. Trehalose tear-substitute treatments achieved a higher improvement than did control group interventions in all reported variables. The mean differences between both groups were in favor of trehalose, and were as follows: ocular surface disease index (OSDI) questionnaire score of \u22128.5 \u00b1 7 points, tear film breakup time (TBUT) of 1.9 \u00b1 1 s, tear film thickness (TFT) of 0.25 \u00b1 0.1 \u03bcm, tear meniscus height (TMH) of 0.02 \u00b1 0.02 mm, Schirmer test (ST) of 0.8 \u00b1 1.4 mm, corneal fluorescein staining (CFS) of \u22120.7 \u00b1 0.1 points and visual acuity (VA) of 0.3 \u00b1 2.1 letters. No adverse events after trehalose tear-substitute treatments were reported. Trehalose tear substitutes are a safe and effective treatment for DED. Therefore, trehalose tear substitutes should be recommended for patients with dry eye disease. In addition, there is specific evidence to support its use in the preoperative cataract surgery period.<\/jats:p>","DOI":"10.3390\/jcm12237301","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T03:48:17Z","timestamp":1701056897000},"page":"7301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Trehalose and Dry Eye Disease: A Comprehensive Systematic Review of Randomized Controlled Trials"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9248-8685","authenticated-orcid":false,"given":"Antonio","family":"Ballesteros-S\u00e1nchez","sequence":"first","affiliation":[{"name":"Department of Physics of Condensed Matter, Optics Area, University of Seville, 41004 Seville, Spain"},{"name":"Department of Ophthalmology, Cl\u00ednica Novovisi\u00f3n, 30008 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0996-5007","authenticated-orcid":false,"given":"Clara","family":"Martinez-Perez","sequence":"additional","affiliation":[{"name":"ISEC LISBOA (Instituto Superior de Educa\u00e7\u00e3o e Ci\u00eancias), 1750-142 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1097-4581","authenticated-orcid":false,"given":"Cristina","family":"Alvarez-Peregrina","sequence":"additional","affiliation":[{"name":"Optometry and Vision Department, Faculty of Optics and Optometry, Complutense University of Madrid, 28037 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2583-1789","authenticated-orcid":false,"given":"Miguel \u00c1ngel","family":"S\u00e1nchez-Tena","sequence":"additional","affiliation":[{"name":"Optometry and Vision Department, Faculty of Optics and Optometry, Complutense University of Madrid, 28037 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concepci\u00f3n","family":"De-Hita-Cantalejo","sequence":"additional","affiliation":[{"name":"Department of Physics of Condensed Matter, Optics Area, University of Seville, 41004 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9453-8615","authenticated-orcid":false,"given":"Mar\u00eda Carmen","family":"S\u00e1nchez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Physics of Condensed Matter, Optics Area, University of Seville, 41004 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0450-7717","authenticated-orcid":false,"given":"Jos\u00e9-Mar\u00eda","family":"S\u00e1nchez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Physics of Condensed Matter, Optics Area, University of Seville, 41004 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","article-title":"TFOS DEWS II Definition and Classification Report","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.jtos.2017.05.003","article-title":"TFOS DEWS II Epidemiology Report","volume":"15","author":"Stapleton","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.jtos.2017.05.011","article-title":"TFOS DEWS II Pathophysiology Report","volume":"15","author":"Bron","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1097\/ICU.0b013e32833a8c15","article-title":"Impact of Dry Eye Disease and Treatment on Quality of Life","volume":"21","author":"Friedman","year":"2010","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s40135-013-0009-1","article-title":"Dry Eye Disease: Impact on Quality of Life and Vision","volume":"1","author":"Uchino","year":"2013","journal-title":"Curr. Ophthalmol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jtos.2017.05.006","article-title":"TFOS DEWS II Management and Therapy Report","volume":"15","author":"Jones","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/eye.2017.289","article-title":"Assessment and Management of Dry Eye Disease","volume":"32","author":"Buckley","year":"2018","journal-title":"Eye"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e000697","DOI":"10.1136\/bmjophth-2020-000697","article-title":"Dry Eye: Why Artificial Tears Are Not Always the Answer","volume":"6","author":"Kim","year":"2021","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1016\/S0161-6420(02)01219-8","article-title":"Trehalose Eye Drops in the Treatment of Dry Eye Syndrome","volume":"109","author":"Matsuo","year":"2002","journal-title":"Ophthalmology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s10384-004-0085-8","article-title":"Trehalose versus Hyaluronan or Cellulose in Eyedrops for the Treatment of Dry Eye","volume":"48","author":"Matsuo","year":"2004","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e307","DOI":"10.1111\/aos.13342","article-title":"Effect of Different Lubricant Eye Gels on Tear Film Thickness as Measured with Ultrahigh-Resolution Optical Coherence Tomography","volume":"95","author":"Wozniak","year":"2017","journal-title":"Acta Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1097\/ICO.0000000000000358","article-title":"Tear Film Thickness After Treatment with Artificial Tears in Patients with Moderate Dry Eye Disease","volume":"34","author":"Schmidl","year":"2015","journal-title":"Cornea"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1007\/s10792-021-01869-z","article-title":"Trehalose\/Sodium Hyaluronate Eye Drops in Post-Cataract Ocular Surface Disorders","volume":"41","author":"Cagini","year":"2021","journal-title":"Int. Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1007\/s10792-021-01897-9","article-title":"Comparison of Efficacy of Trehalose-Based Eye Drops versus Topical 0.1% Hyaluronic Acid for Management of Clinically Significant Dry Eye Using Non-Invasive Investigational Modalities","volume":"41","author":"Brar","year":"2021","journal-title":"Int. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1097\/j.jcrs.0000000000000652","article-title":"Dry Eye and Inflammation of the Ocular Surface after Cataract Surgery: Effectiveness of a Tear Film Substitute Based on Trehalose\/Hyaluronic Acid vs Hyaluronic Acid to Resolve Signs and Symptoms","volume":"47","author":"Cagini","year":"2021","journal-title":"J. Cataract Refract. Surg."},{"key":"ref_16","first-page":"89","article-title":"The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews","volume":"46","author":"Page","year":"2022","journal-title":"Rev. Panam. Salud Publica Pan Am. J. Public Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"n160","DOI":"10.1136\/bmj.n160","article-title":"PRISMA 2020 Explanation and Elaboration: Updated Guidance and Exemplars for Reporting Systematic Reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_18","unstructured":"DistillerSR Inc (2022). DistillerSR, Version 2.35, DistillerSR Inc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.jtos.2017.05.001","article-title":"TFOS DEWS II Diagnostic Methodology Report","volume":"15","author":"Wolffsohn","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8630","DOI":"10.1167\/iovs.11-8027","article-title":"Rasch Analysis of the Ocular Surface Disease Index (OSDI)","volume":"52","author":"Dougherty","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1097\/00003226-200310000-00008","article-title":"Grading of Corneal and Conjunctival Staining in the Context of Other Dry Eye Tests","volume":"22","author":"Bron","year":"2003","journal-title":"Cornea"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"d5928","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane Collaboration\u2019s Tool for Assessing Risk of Bias in Randomised Trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.2147\/OPTH.S208256","article-title":"Efficacy of Carbomer Sodium Hyaluronate Trehalose vs Hyaluronic Acid to Improve Tear Film Instability and Ocular Surface Discomfort after Cataract Surgery","volume":"13","author":"Caretti","year":"2019","journal-title":"Clin. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mencucci, R., Favuzza, E., Decandia, G., Cennamo, M., and Giansanti, F. (2021). Hyaluronic Acid\/Trehalose Ophthalmic Solution in Reducing Post-Cataract Surgery Dry Eye Signs and Symptoms: A Prospective, Interventional, Randomized, Open-Label Study. J. Clin. Med., 10.","DOI":"10.3390\/jcm10204699"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5301\/ejo.5000836","article-title":"A Randomized, Controlled Study of the Efficacy and Safety of a New Eyedrop Formulation for Moderate to Severe Dry Eye Syndrome","volume":"27","author":"Chiambaretta","year":"2017","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1080\/03007995.2018.1434496","article-title":"Comparison of the Effect of a Hyaluronate\u2013Trehalose Solution to Hyaluronate Alone on Ocular Surface Disease Index in Patients with Moderate to Severe Dry Eye Disease","volume":"34","author":"Doan","year":"2018","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.clae.2019.10.001","article-title":"Comparison Study of Two Different Topical Lubricants on Tear Meniscus and Tear Osmolarity in Dry Eye","volume":"43","author":"Karaca","year":"2020","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"161","DOI":"10.4103\/tjo.tjo_58_20","article-title":"Randomized Controlled Trial of Trehalose: An Efficient Autophagic Bioprotectant in the Management of Dry Eye Disease","volume":"11","author":"Morya","year":"2021","journal-title":"Taiwan J. Ophthalmol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/jrsm.1411","article-title":"Risk-of-Bias VISualization (Robvis): An R Package and Shiny Web App for Visualizing Risk-of-Bias Assessments","volume":"12","author":"McGuinness","year":"2021","journal-title":"Res. Synth. Methods"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Labetoulle, M., Benitez-Del-castillo, J.M., Barabino, S., Vanrell, R.H., Daull, P., Garrigue, J.S., and Rolando, M. (2022). Artificial Tears: Biological Role of Their Ingredients in the Management of Dry Eye Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052434"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1089\/jop.2017.0080","article-title":"Impact of Hyaluronic Acid-Containing Artificial Tear Products on Reepithelialization in an In Vivo Corneal Wound Model","volume":"34","author":"Carlson","year":"2018","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1089\/jop.2018.0151","article-title":"Cross-Linked Hyaluronic Acid as Tear Film Substitute","volume":"35","author":"Posarelli","year":"2019","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1152\/physrev.1992.72.1.101","article-title":"Physiological Actions of Taurine","volume":"72","author":"Huxtable","year":"1992","journal-title":"Physiol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1167\/tvst.8.6.2","article-title":"Physicochemical Properties of Hyaluronic Acid-Based Lubricant Eye Drops","volume":"8","author":"Aragona","year":"2019","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"118006","DOI":"10.1016\/j.carbpol.2021.118006","article-title":"Hyaluronic Acid in Ocular Drug Delivery","volume":"264","author":"Zhang","year":"2021","journal-title":"Carbohydr. Polym."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Guarise, C., Acquasaliente, L., Pasut, G., Pavan, M., Soato, M., Garofolin, G., Beninatto, R., Giacomel, E., Sartori, E., and Galesso, D. (2023). The Role of High Molecular Weight Hyaluronic Acid in Mucoadhesion on an Ocular Surface Model. J. Mech. Behav. Biomed. Mater., 143.","DOI":"10.1016\/j.jmbbm.2023.105908"},{"key":"ref_37","first-page":"478","article-title":"Comparison of the Schirmer I Test with and without Topical Anesthesia for Diagnosing Dry Eye","volume":"5","author":"Li","year":"2012","journal-title":"Int. J. Ophthalmol."},{"key":"ref_38","first-page":"577","article-title":"Trehalose: An Intriguing Disaccharide with Potential for Medical Application in Ophthalmology","volume":"5","author":"Luyckx","year":"2011","journal-title":"Clin. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1136\/bjo.85.5.610","article-title":"Trehalose Protects Corneal Epithelial Cells from Death by Drying","volume":"85","author":"Matsuo","year":"2001","journal-title":"Br. J. Ophthalmol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Hill-Bator, A., Misiuk-Hoj\u0142o, M., Marycz, K., and Grzesiak, J. (2014). Trehalose-Based Eye Drops Preserve Viability and Functionality of Cultured Human Corneal Epithelial Cells during Desiccation. Biomed Res. Int., 2014.","DOI":"10.1155\/2014\/292139"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.jtos.2013.07.003","article-title":"Role of Hyperosmolarity in the Pathogenesis and Management of Dry Eye Disease: Proceedings of the OCEAN Group Meeting","volume":"11","author":"Baudouin","year":"2013","journal-title":"Ocul. Surf."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/ICU.0b013e3283414284","article-title":"The Impact of Cataract Surgery on Quality of Life","volume":"22","author":"Lamoureux","year":"2011","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17273","DOI":"10.1038\/s41598-020-72846-2","article-title":"Changes in Patient Subjective Happiness and Satisfaction with Cataract Surgery","volume":"10","author":"Yotsukura","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.jtos.2017.05.004","article-title":"TFOS DEWS II Iatrogenic Report","volume":"15","author":"Gomes","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S25","DOI":"10.1097\/ICO.0000000000002125","article-title":"Management of Postoperative Inflammation and Dry Eye After Cataract Surgery","volume":"38","author":"Kato","year":"2019","journal-title":"Cornea"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s10384-012-0117-8","article-title":"Changes in the Tear Film and Ocular Surface after Cataract Surgery","volume":"56","author":"Oh","year":"2012","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s40123-021-00332-7","article-title":"Iatrogenic Dry Eye Disease: Dealing with the Conundrum of Post-Cataract Discomfort. A P.I.C.A.S.S.O. Board Narrative Review","volume":"10","author":"Mencucci","year":"2021","journal-title":"Ophthalmol. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Villani, E., Catania, A.G., Luccarelli, S.V., Magnani, F., Martone, G., Zanzottera, E., and Lagali, N. (2023). Dry Eye and Cataract Surgery: Narrative Review and Recommendations for Management. Eur. J. Ophthalmol.","DOI":"10.1177\/11206721231174060"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1007\/s40123-022-00513-y","article-title":"Prevalence and Characteristics of Dry Eye Disease After Cataract Surgery: A Systematic Review and Meta-Analysis","volume":"11","author":"Miura","year":"2022","journal-title":"Ophthalmol. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1097\/ICU.0000000000000227","article-title":"Mechanisms and Management of Dry Eye in Cataract Surgery Patients","volume":"27","author":"Sutu","year":"2016","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_51","first-page":"611","article-title":"Trehalose in Ophthalmology","volume":"34","author":"Cejka","year":"2019","journal-title":"Histol. Histopathol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/23\/7301\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:29:56Z","timestamp":1760131796000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/23\/7301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,25]]},"references-count":51,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["jcm12237301"],"URL":"https:\/\/doi.org\/10.3390\/jcm12237301","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,25]]}}}