The cornea and the skin are both organs that provide the outer barrier of the body. Both tissues have developed intrinsic mechanisms that protect the organism from a wide range of external threats, ...but at the same time also enable rapid restoration of tissue integrity and organ-specific function. The easy accessibility makes the skin an attractive model system to study tissue damage and repair. Findings from skin research have contributed to unravelling novel fundamental principles in regenerative biology and the repair of other epithelial-mesenchymal tissues, such as the cornea. Following barrier disruption, the influx of inflammatory cells, myofibroblast differentiation, extracellular matrix synthesis and scar formation present parallel repair mechanisms in cornea and skin wound healing. Yet, capillary sprouting, while pivotal in proper skin wound healing, is a process that is rather associated with pathological repair of the cornea. Understanding the parallels and differences of the cellular and molecular networks that coordinate the wound healing response in skin and cornea are likely of mutual importance for both organs with regard to the development of regenerative therapies and understanding of the disease pathologies that affect epithelial-mesenchymal interactions. Here, we review the principal events in corneal wound healing and the mechanisms to restore corneal transparency and barrier function. We also refer to skin repair mechanisms and their potential implications for regenerative processes in the cornea.
The purpose of this retrospective panel study was to provide an overview of absolute numbers and of trends in the types of and indications for corneal transplantation in Germany from 2001 to 2016.
A ...questionnaire about absolute numbers, types of transplantation, and indications was sent to 111 ophthalmologic departments in Germany, out of which 94 (85%) provided their data.
Since the year 2001, the number of corneal transplantations has increased by 1.5-fold, from 4730 penetrating keratoplasties (PKPs) in 2001 to 7325 penetrating and lamellar keratoplasties in 2016. The shift from penetrating to lamellar procedures began in 2006. In 2014, lamellar procedures (231 4% anterior and 2883 49% posterior lamellar keratoplasties) surpassed PKPs (2721, 47%) for the first time. Main indications for keratoplasty in Germany (2016) are Fuchs endothelial corneal dystrophy (46%), pseudophakic corneal decompensation (bullous keratopathy, 13%), repeated keratoplasty after graft failure (11%), keratoconus (8%), and corneal scarring (6%; others: 16%). The number of Descemet membrane endothelial keratoplasties (DMEKs) was 12 times higher (3850, 53%) than Descemet stripping automated endothelial keratoplasties (DSAEKs, 319, 4.4%) in 2016. The proportion of deep anterior lamellar keratoplasties (DALKs) never exceeded 6% (269 in 2011).
The number of keratoplasties in Germany has increased from 2001 to 2016. Since 2014, posterior lamellar keratoplasties have surpassed PKPs. There was a constant increase of DMEKs, with a 12-fold higher number compared to DSAEKs in 2016. The shorter recovery time after DMEK seems to contribute to the trend toward earlier operative intervention in corneal endothelial diseases.
To assess the evolution of clinical outcomes of more than 1300 Descemet membrane endothelial keratoplasties (DMEKs) alone or in combination with cataract surgery (triple DMEK) throughout a 5-year ...period at a single center, performed by 2 already experienced DMEK surgeons.
Retrospective trend study.
Review of charts between July 2011 and July 2016 at the Department of Ophthalmology, University of Cologne, Germany.
A total of 1340 out of 1340 eyes with sufficient information were included. Six-month and 12-month best spectacle-corrected visual acuity (logMAR) had already reached high levels for the surgeries performed in 2011 (0.10 ± 0.06 and 0.09 ± 0.07, respectively) and did not further improve in later years (P = .272). Likewise, endothelial cell loss (ECL) and central corneal thickness (CCT) reached comparable levels independently of the year of surgery (average 12-month ECL was 38% ± 15% and average 6-month CCT decrease was 19% ± 11%). However, there was a decrease in the rebubbling rate, from 68% in 2011, 67% in 2012, and 70% in 2013 to 53% in 2014, 29% in 2015, and 16% in 2016, which was associated with the introduction of 20% sulfur hexafluoride (SF6) instead of room air for anterior chamber tamponade in 2015 (n = 986; P < .001). The percentage of severe complications after DMEK surgery also decreased significantly with surgeons' growing experience (P < .001; 95% confidence interval 0.09; 0.12) over the years.
After an initial learning curve in DMEK surgery, results of visual acuity and ECL do not seem to further improve. However, the complication rate continuously declines, at least over the subsequent 5-year period analyzed herein.
Purpose To evaluate visual outcome and endothelial cell survival after Descemet membrane endothelial keratoplasty (DMEK) in comparison with Descemet stripping automated endothelial keratoplasty ...(DSAEK). Design Single-center, retrospective, consecutive case series. Methods Thirty-eight eyes of 38 consecutive patients undergoing DMEK, who completed a 6-month follow-up, were compared with 35 eyes of 35 consecutive patients undergoing DSAEK for Fuchs endothelial dystrophy or pseudophakic bullous keratopathy. Main outcome measures included best-corrected visual acuity (in logarithm of the minimal angle of resolution logMAR units) and endothelial cell density within a 6-month follow-up. Results Best-corrected visual acuity increased from 0.70 ± 0.48 logMAR and 0.75 ± 0.32 logMAR before surgery to 0.21 ± 0.14 logMAR and 0.48 ± 0.19 logMAR 3 months after DMEK and DSAEK ( P < .001), respectively, and to 0.17 ± 0.12 logMAR and 0.36 ± 0.15 logMAR 6 months after DMEK and DSAEK ( P < .001), respectively. Endothelial cell density decreased from 2575 ± 260 cells/mm2 and 2502 ± 220 cells/mm2 before surgery to 1498 ± 244 cells/mm2 and 1778 ± 420 cells/mm2 3 months after DMEK and DSAEK ( P < .001), respectively, and to 1520 ± 299 cells/mm2 and 1532 ± 495 cells/mm2 6 months after DMEK and DSAEK ( P = .483), respectively. Central corneal thickness decreased from 652 ± 92 μm before surgery to 517 ± 45 μm 6 months after DMEK, and from 698 ± 137 μm before surgery to 618 ± 66 μm 6 months after DSAEK. Conclusions DMEK provided faster and more complete visual rehabilitation when compared with DSAEK. However, there were no significant differences concerning endothelial cell survival within a 6-month follow-up.
The cornea, essential for vision, is normally avascular, transparent, and immune-privileged. However, injuries or infections can break this privilege, allowing blood and lymphatic vessels to invade, ...potentially impairing vision and causing immune responses. This review explores the complex role of corneal lymphangiogenesis in health and diseases. Traditionally, the cornea was considered devoid of lymphatic vessels, a phenomenon known as "corneal (lymph)angiogenic privilege." Recent advances in molecular markers have enabled the discovery of lymphatic vessels in the cornea under certain conditions. Several molecules contribute to preserving both immune and lymphangiogenic privileges. Lymphangiogenesis, primarily driven by VEGF family members, can occur directly or indirectly through macrophage recruitment. Corneal injuries and diseases disrupt these privileges, reducing graft survival rates following transplantation. However, modulation of lymphangiogenesis offers potential interventions to promote graft survival and expedite corneal edema resolution.
This review underscores the intricate interplay between lymphatic vessels, immune privilege, and corneal pathologies, highlighting innovative therapeutic possibilities. Future investigations should explore the modulation of lymphangiogenesis to enhance corneal health and transparency, as well as corneal graft survival, and this benefits patients with various corneal conditions.
This study aimed to identify the risk factors for endothelial cell density (ECD) loss after Descemet membrane endothelial keratoplasty (DMEK) and analyse whether donor tissues from cold versus organ ...culture differ in terms of ECD loss after DMEK. Consecutive DMEK cases from a prospective database for Fuchs' endothelial corneal dystrophy were retrospectively analysed between 2011 and 2016 at the University of Cologne, and the possible risk factors for ECD loss, including patient-related factors, type of tamponade (air or 20% sulphur hexafluoride gas), type of surgery (triple DMEK or DMEK alone), re-bubbling, immune rejection, and donor-related factors were determined. Eight hundred and forty-one eyes were selected. There was no significant difference in the best-corrected visual acuity (logarithm of the minimal angle of resolution) and corneal thickness (P = 0.540 and P = 0.667) between groups. Immune reactions were more common in cold cultures (P = 0.019), but ECD loss (1 year after DMEK) was greater in organ cultures (38.3 ± 0.8%) than in cold cultures (34.7 ± 1.4%) (P = 0.022). Only re-bubbling was significantly associated with ECD loss (P < 0.001). Re-bubbling was found to be a key factor for ECD loss at 1 year after DMEK.
To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting ...from impaired corneal innervation.
Phase II multicenter, randomized, double-masked, vehicle-controlled trial.
Patients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye.
The REPARO phase II study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study treatment, whereas efficacy was by intention to treat.
Corneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining).
At week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) versus 54.9% receiving rhNGF 10 μg/ml (+35.3%; 97.06% confidence interval CI, 15.88–54.71; P < 0.001) and 58.0% receiving rhNGF 20 μg/ml (+38.4%; 97.06% CI, 18.96–57.83; P < 0.001). At week 8 (key secondary end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 74.5% receiving rhNGF 10 μg/ml (+31.4%; 97.06% CI, 11.25–51.49; P = 0.001) and 74.0% receiving rhNGF 20 μg/ml (+30.9%; 97.06% CI, 10.60–51.13; P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled rhNGF treatment remained recurrence free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient.
Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK.
Abstract
The efficacy of deep learning in predicting successful big-bubble (SBB) formation during deep anterior lamellar keratoplasty (DALK) was evaluated. Medical records of patients undergoing DALK ...at the University of Cologne, Germany between March 2013 and July 2019 were retrospectively analyzed. Patients were divided into two groups: (1) SBB or (2) failed big-bubble (FBB). Preoperative images of anterior segment optical coherence tomography and corneal biometric values (corneal thickness, corneal curvature, and densitometry) were evaluated. A deep neural network model, Visual Geometry Group-16, was selected to test the validation data, evaluate the model, create a heat map image, and calculate the area under the curve (AUC). This pilot study included 46 patients overall (11 women, 35 men). SBBs were more common in keratoconus eyes (KC eyes) than in corneal opacifications of other etiologies (non KC eyes) (
p
= 0.006). The AUC was 0.746 (95% confidence interval CI 0.603–0.889). The determination success rate was 78.3% (18/23 eyes) (95% CI 56.3–92.5%) for SBB and 69.6% (16/23 eyes) (95% CI 47.1–86.8%) for FBB. This automated system demonstrates the potential of SBB prediction in DALK. Although KC eyes had a higher SBB rate, no other specific findings were found in the corneal biometric data.
Purpose
To investigate a possible correlation between established imaging biomarkers for age-related macular degeneration and local complement system activation, measured in aqueous humor (AH) of ...patients with early stages of age-related macular degeneration (AMD) and controls.
Methods
This analysis included prospectively acquired AH samples of 106 eyes (35 with early/intermediate AMD, 71 controls). The levels of complement protein 3 (C3), 4 (C4), 5 (C5); activation products of complement factor 3a (C3a) and Ba, C3b/iC3b; complement factors B, D, H, I (CFB, CFD, CFH, CFI); and total protein concentration were analyzed. Quantitative levels of complement factors were correlated to the presence of reticular pseudodrusen (RPD), the presence of hyperreflective foci (HRF), and total drusen volume (DV) graded on imaging by spectral-domain optical coherence tomography and using Spearman’s rank correlation test.
Results
DV correlated with C3b/iC3b (
r
= 0.285;
P
= 0.034), C3a (
r
= 0.200;
P
= 0.047), Ba (
r
= 0.262;
P
= 0.009), and C5 (
r
= 430;
P
= 0.005), and showed a tendency towards correlation with C3a (
r
= 0.198;
P
= 0.057). HRF correlated significantly with C5 (
r
= 0.388;
P
= 0.011) and RPD showed a tendency towards correlation with CFB (
r
= 0.196;
P
= 0.050).
Conclusion
In patients with early AMD, HRF and drusen parameters but not RPD show low to fair levels of correlation with local complement activation in patients’ AH. Better understanding of complement activation could provide some insights into the pathogenesis of AMD. Imaging biomarkers could be useful to identify suitable patients for future clinical trials with complement-modulating therapies.
Immunologic graft rejection is the main complication after corneal transplant into pathologically prevascularized so‐called high‐risk eyes. The aim of this study was to evaluate whether ultraviolet ...(UV) light crosslinking can regress pathologic corneal blood and lymphatic vessels and thereby improve subsequent graft survival. Using the murine model of suture‐induced corneal neovascularization, we found that corneal crosslinking with UVA light and riboflavin regressed both preexisting blood and lymphatic vessels significantly via induction of apoptosis in vascular endothelial cells. In addition, macrophages and CD45+ cell counts were significantly reduced. Consistently, corneal crosslinking reduced keratocyte density and corneal thickness without affecting corneal nonvascular endothelial cells, iris, and lens depending on the crosslinking duration. Furthermore, using the murine model of corneal transplant, long‐term graft survival was significantly promoted (P < .05) and CD4+CD25+FoxP3+ T regulatory cells were upregulated (P < .01) in high‐risk eyes preoperatively treated with crosslinking. Our results suggest UV light crosslinking as a novel method to regress both pathologic corneal blood and lymphatic vessels and to reduce CD45+ inflammatory cells. Furthermore, this study demonstrates for the first time that preoperative corneal crosslinking in prevascularized high‐risk eyes can significantly improve subsequent graft survival and may become a promising novel therapy in the clinic.
Corneal crosslinking with ultraviolet‐A light and riboflavin can regress mature pathological corneal blood and lymphatic vessels, thereby promoting graft survival of a prevascularized high‐risk corneal transplantation.
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