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Purpose: The objective of this investigation was to assess the impact of eye drops containing high molecular weight hyaluronic acid (HMW-HA) and low molecular weight hyaluronic acid (LMW-HA) on corneal nerve regeneration, dendritic cell (DC) density, corneal sensitivity (CS), and ocular surface parameters in patients with keratoconus following corneal crosslinking (CXL).
Methods: Sixty-three eyes of 55 keratoconus patients were randomized to instill eye drops containing HMW-HA (n: 20) for 12 months, LMW-HA (n:23) for 12 months and polyvinyl alcohol (n: 20) until the epithelial defect closure in the control group after CXL. Subbasal nerve plexsus (SNP) was imaged with corneal confocal microscopy (CCM) and ACCMetrics program was used to quantify corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve fiber branching density (CNBD) and corneal nerve fiber total branching density (CTBD). DC density was calculated with Image J software. CS was measured using the Cochet-Bonnet esthesiometer. Ocular Surface Disease Index (OSDI) questionnaire, non-invasive break-up time (NI-TBUT) were evaluated. All measurements were performed before CXL and postoperatively after 1, 3, 6 and 12 months.
This study assessed individuals aged 18 and above diagnosed with keratoconus and scheduled for epithelium-off CXL. A total of 63 eyes from 55 keratoconus patients were randomly assigned using computer-generated randomization (www.random.org/integers) into three groups: 20 eyes in the HMW-HA group, 23 eyes in the LMW-HA group, and 20 eyes in the control group without the administration of artificial tears.
Post-CXL, the HMW-HA group received topical HMW-HA (Comfort Shield®, i.com medical GmbH, Munich, Germany) three times daily for 12 months, the LMW-HA group received topical LMW-HA (Thealose Duo®, Thea, Clermont-Ferrand, France) three times daily for 12 months, and the control group received topical polyvinyl alcohol (Refresh, Allergan, Dublin, Ireland) three times daily until epithelial defect closure. All participants underwent accelerated epithelium-off CXL (A-CXL) for 10 minutes with 9 mW/cm² ultraviolet-A irradiation. The postoperative standard treatment regimen included topical moxifloxacin (0.5% Vigamox, Alcon Inc, USA) for one week, topical dexamethasone (0.1% Dexasine-SE, Kaysersberg Pharmaceuticals, France) for one week after epithelial closure, followed by topical loteprednol 0.5% (Lotemax, Bausch & Lomb, USA) for three weeks.
Uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and manifest spherical equivalent (SE) were recorded at all visits. The assessment was carried out in the following order: Ocular Surface Disease Index (OSDI) questionnaire, noninvasive tear break-up time (NIBUT), corneal tomography (Pentacam, OCULUS, Wetzlar, Germany), corneal sensitivity, corneal fluorescein staining, and CCM imaging. Examinations were conducted preoperatively and at the postoperative 1th, 3rd, 6th and 12th months.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control group | Nineteen patiens (20 eyes) received topical polyvinyl alcohol (Refresh, Allergan, Dublin, Ireland) three times daily until epithelial defect closure after CXL in control group. |
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| LMW-HA group | Twenty-two patiens (23 eyes) received topical LMW-HA (Thealose Duo®, Thea, Clermont-Ferrand, France) three times daily for 12 months. |
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| HMW-HA group | Seventeen patiens (20 eyes) received topical HMW-HA (Comfort Shield®, i.com medical GmbH, Munich, Germany) three times daily for 12 months. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| in vivo Corneal Confocal Microscopy | Device | CCM was performed using the Heidelberg Retinal Tomograph 3 with the Rostock Cornea Module (HRT3-RCM, Heidelberg Engineering GmbH, Germany) under topical anesthesia. A viscous gel (Viscotears, Novartis Pharmaceuticals UK) served as a coupling agent between the cornea and the applanation cap. The subjects were instructed to focus on the fixation light with the unexamined eye to ensure proper positioning. Five high-quality images of the SNP were selected and analyzed using the automated tracing of nerve fibers program (ACCMetrics, M.A. Dabbah, Imaging Science and Biomedical Engineering, Manchester, England). |
| Measure | Description | Time Frame |
|---|---|---|
| Corneal nerve fiber density (CNFD) | Automated tracing of nerve fibers program - CCMetrics (CCMetrics; M. A. Dabbah, ISBE, University of Manchester, Manchester, UK) was used to analyze CNFD. | Baseline |
| Corneal nerve fiber density (CNFD) | Automated tracing of nerve fibers program - CCMetrics (CCMetrics; M. A. Dabbah, ISBE, University of Manchester, Manchester, UK) was used to analyze CNFD. | Postoperative 1st, 3rd, 6th and 12th months |
| Corneal nerve branch density (CNBD) | Automated tracing of nerve fibers program - CCMetrics (CCMetrics; M. A. Dabbah, ISBE, University of Manchester, Manchester, UK) was used to analyze CNBD. | Baseline |
| Corneal nerve branch density (CNBD) | Automated tracing of nerve fibers program - CCMetrics (CCMetrics; M. A. Dabbah, ISBE, University of Manchester, Manchester, UK) was used to analyze CNBD. | Postoperative 1st, 3rd, 6th and 12th months |
| Corneal nerve fiber length (CNFL) | Automated tracing of nerve fibers program - CCMetrics (CCMetrics; M. A. Dabbah, ISBE, University of Manchester, Manchester, UK) was used to analyze CNFL | Baseline |
| Corneal nerve fiber length (CNFL) | Automated tracing of nerve fibers program - CCMetrics (CCMetrics; M. A. Dabbah, ISBE, University of Manchester, Manchester, UK) was used to analyze CNFL | Postoperative 1st, 3rd, 6th and 12th months |
| Corneal nerve fiber total branching density (CTBD) |
| Measure | Description | Time Frame |
|---|---|---|
| Visual Functions | Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA) by the Snellen chart, based on the logMAR scoring system and manifest spherical equivalent (SE) were assessed. | Baseline |
| Refractive Outcomes |
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Inclusion Criteria:
Exclusion Criteria:
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Fifty-five patients with keratoconus were included in the study. All participants underwent accelerated epithelium-off CXL (A-CXL) for 10 minutes with 9 mW/cm² ultraviolet-A irradiation. A total of 63 eyes from 55 keratoconus patients were assigned into three groups: 17 patiens (20 eyes) in the HMW-HA group, 22 patient (23 eyes) in the LMW-HA group, and 20 patient (20 eyes) in the control group.
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| Name | Affiliation | Role |
|---|---|---|
| Semra Akkaya Turhan, Assoc. prof. | Marmara University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Marmara University | Istanbul | Pendik | 34890 | Turkey (Türkiye) |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40157723 | Derived | Ozkan G, Turhan SA, Toker E. Effect of high and low molecular weight sodium hyaluronic acid eye drops on corneal recovery after crosslinking in keratoconus patients. BMJ Open Ophthalmol. 2025 Mar 29;10(1):e001890. doi: 10.1136/bmjophth-2024-001890. |
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| Corneal Sensitivity | Diagnostic Test | Corneal sensitivity was evaluated using a Cochet-Bonnet esthesiometer (Luneau Ophtalmologue, Chartres, France), comprising a nylon filament measuring 60 mm in length and 0.12 mm in diameter. Participants were instructed to maintain a forward gaze while the esthesiometer gently made perpendicular contact. The procedure involved gradually decreasing the filament length in 5 mm increments, starting from 60 mm, until the initial response from the subject was detected. |
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| Non invasive tear break up time | Device | Noninvasive tear break-up time (NI-TBUT) was assessed using a Sirius Scheimpflug camera (CSO, Florence, Italy) and the device automatically provided the average NI-TBUT value |
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| Ocular Surface Disease Index Qestionnaire | Diagnostic Test | The Ocular surface disease index (OSDI) questionnaire consists of a total of 12 questions categorized into three subscales as follows: ocular symptoms, vision-related function, and environmental triggers. Each patient is asked to rate the symptoms on a 5-point scale ranging from never (0 score) to always (4 score) for every question in the questionnaire. The fourth and fifth questions in the first section, concerning blurred vision and reduced vision symptoms, were excluded from the questionnaire as these symptoms may already be present in patients with keratoconus disease. The total OSDI score was calculated according to the formula: OSDI = [(sum of scores for all questions answered) × 100] / [(total number of questions answered) × 4]. |
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| Corneal tomography | Device | Scheimpflug-tomography device (Pentacam, OCULUS, Wetzlar, Germany) was used for measurement of keratometric values. |
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Automated tracing of nerve fibers program - CCMetrics (CCMetrics; M. A. Dabbah, ISBE, University of Manchester, Manchester, UK) was used to analyze CTBD. |
| Baseline |
| Corneal nerve fiber total branching density (CTBD) | Automated tracing of nerve fibers program - CCMetrics (CCMetrics; M. A. Dabbah, ISBE, University of Manchester, Manchester, UK) was used to analyze CTBD. | Postoperative 1st, 3rd, 6th and 12th months |
| Corneal Sensitivity | Corneal sensitivity was assessed using a Cochet-Bonnet esthesiometer (Luneau Ophtalmologue, Chartes, France). | Baseline |
| Corneal Sensitivity | Corneal sensitivity was assessed using a Cochet-Bonnet esthesiometer (Luneau Ophtalmologue, Chartes, France). | Postoperative 1st, 3rd, 6th and 12th months |
| Dendritic cell density | The Density of dendritic cells was calculated using ImageJ software (Image V.1.31; National Institutes of Health) | Baseline |
| Dendritic cell density | The Density of dendritic cells was calculated using ImageJ software (Image V.1.31; National Institutes of Health) | Postoperative 1st, 3rd, 6th and 12th months |
| Ocular surface disease Index (OSDI) questionnaire | The Turkish validated version of the OSDI, a questionnaire assesing the clinical symptoms of the ocular surface disease, was used. The 4th and 5th questions in the first section, which inquire about blurred vision and reduced vision symptoms, were excluded from the questionnaire as they could already be present in patients with keratoconus disease. | Baseline |
| Ocular surface disease Index (OSDI) questionnaire | The Turkish validated version of the OSDI, a questionnaire assesing the clinical symptoms of the ocular surface disease, was used. The 4th and 5th questions in the first section, which inquire about blurred vision and reduced vision symptoms, were excluded from the questionnaire as they could already be present in patients with keratoconus disease. | Postoperative 1st, 3rd, 6th and 12th months |
| Non invaziv tear break-up time (NI-TBUT) | The tear break-up time (TBUT) was evaluated non-invasively using a Sirius Scheimpflug camera (CSO, Florence, Italy). | Baseline |
| Non invaziv tear break-up time (NI-TBUT) | The tear break-up time (TBUT) was evaluated non-invasively using a Sirius Scheimpflug camera (CSO, Florence, Italy). | Postoperative 1st, 3rd, 6th and 12th months |
Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA) by the Snellen chart, based on the logMAR scoring system and manifest spherical equivalent (SE) were assessed.
| Postoperative 1st, 3rd and 6th months |
| Keratometric Findings | Corneal tomography (Pentacam, OCULUS, Wetzlar Germany) was used to obtain the data for K1, K2, Kmean, Kmax, and the Thinnest point (TP). | Baseline |
| Keratometric Findings | Corneal tomography (Pentacam, OCULUS, Wetzlar Germany) was used to obtain the data for K1, K2, Kmean, Kmax, and the Thinnest point (TP). | Postoperative 1st, 3rd and 6th months |
| ID | Term |
|---|---|
| D007640 | Keratoconus |
| ID | Term |
|---|---|
| D003316 | Corneal Diseases |
| D005128 | Eye Diseases |
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