Journal of Clinical Medicine · 7 authors, 4 centres
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This study found that adding plasma rich in growth factors (PRGF) to standard dry eye therapy significantly improved corneal nerve regeneration and tear film stability in patients with dry eye disease, especially in the aqueous-deficient subtype. Standard treatment alone did not improve corneal nerve parameters. These findings suggest PRGF may be a valuable adjunct for restoring corneal innervation in dry eye disease.
**Background:** Dry eye disease (DED) is a common multifactorial condition involving tear film instability, hyperosmolarity, inflammation, and neurosensory abnormalities. Corneal nerves are essential for ocular surface integrity, and their damage contributes to DED pathology. Plasma rich in growth factors (PRGF) is a blood-derived eye drop containing growth factors like NGF, EGF, and PDGF, which may promote corneal nerve regeneration. However, its effect on corneal innervation in DED was not well studied. This study aimed to analyze changes in corneal innervation in patients with evaporative (EDE) and aqueous-deficient dry eye (ADDE) treated with standard therapy plus PRGF versus standard therapy alone.
**Methods:** This observational, retrospective, longitudinal study included 83 DED patients (OSDI >13, tear break-up time <10 s) from the Fernández-Vega Ophthalmological Institute (January 2020–April 2022). Patients were divided into two groups: 32 received standard treatment (fluorometholone 0.1% tapering over 4 weeks, trehalose 3%/sodium hyaluronate 0.15% 4 times daily, eyelid hygiene once daily) and 51 received the same standard treatment plus PRGF eye drops 4 times daily for 3 months. PRGF was prepared from autologous blood, centrifuged at 580×g for 8 min, and the plasma column was collected avoiding leukocytes. In vivo confocal microscopy (IVCM) was performed using a Heidelberg Retina Tomograph III with Rostock Cornea Module. Images were analyzed automatically with ACCMetrics software for corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL), total branch density (CTBD), area (CNFA), width (CNFW), and fractal dimension (CNFrD). Semi-automatic analysis with FIJI software quantified neuromas, beaded axons, and dendritic cells per frame. Tear film stability was assessed by fluorescein break-up time (FBUT), tear production by Schirmer test, and symptoms by OSDI and SANDE questionnaires. Statistical analysis used paired t-tests or Wilcoxon tests, and effect size was calculated with Cohen's d.
**Key Results:** Baseline demographics were similar between groups. In the standard treatment group, no significant changes were observed in any corneal nerve parameter (CNFD: 19.572±1.188 to 19.340±1.615, p=0.859; CNFL: 13.087±0.590 to 12.965±0.677, p=0.832). In the PRGF group, significant increases were found in CNFD (13.827±1.019 to 17.556±1.162, p<0.001), CNFL (10.177±0.537 to 11.863±0.603, p<0.001), CNBD (17.440±2.092 to 23.796±2.762, p=0.002), CTBD (32.257±3.158 to 40.925±4.148, p=0.012), CNFA (0.0053±0.0003 to 0.0057±0.0003, p=0.004), and CNFrD (1.4331±0.010 to 1.4500±0.009, p=0.004). CNFW did not change significantly. Dendritic cells decreased significantly in the standard group (4.9519±1.810 to 2.3541±1.252, p=0.039) but not in the PRGF group (3.1908±0.549 to 2.5806±0.545, p=0.077). Axonal beads decreased significantly in both groups (standard: 0.6694±0.147 to 0.1669±0.561, p=0.002; PRGF: 0.3890±0.078 to 0.1278±0.052, p=0.008). Neuromas did not change significantly. FBUT improved significantly only in the PRGF group (4.935±0.468 to 6.106±0.463 sec, p=0.003). Schirmer test showed no significant changes. OSDI and SANDE scores improved significantly in both groups (p<0.005 for OSDI, p<0.001 for SANDE). Subgroup analysis revealed that in ADDE, PRGF significantly increased CNFD, CNBD, and CNFL (p<0.05 for all), while standard treatment showed non-significant increases. In EDE, PRGF showed non-significant increases in nerve parameters, while standard treatment showed significant decreases in CNFD (p<0.05) and CNFL (p=0.01). Effect size analysis showed moderate-to-large positive effects for PRGF on nerve parameters in ADDE (Cohen's d: CNFD 0.413, CNBD 0.308, CNFL 0.322) and large effects on SANDE scores (frequency 0.874, intensity 0.948).
**Clinical Implications:** This study demonstrates that adding PRGF to standard DED therapy significantly improves corneal nerve regeneration, particularly in aqueous-deficient dry eye, and enhances tear film stability. The findings support the use of PRGF as a regenerative treatment for DED, especially in patients with ADDE who may have more severe nerve loss. IVCM is a valuable non-invasive tool for monitoring corneal innervation and guiding personalized treatment. Limitations include the retrospective design, small sample size, lack of eyelid monitoring, and all patients having an evaporative component (BUT <10 s). Future prospective studies with larger samples and longer follow-up are needed to confirm these results and explore the role of PRGF in different DED subtypes.