Mimickers of anterior uveitis, scleritis and misdiagnoses- tips and tricks for the cornea specialist.

BACKGROUND: Anterior uveitis, inflammation of the anterior chamber and related structures, is a cohort of diseases that can present to almost any general or sub-specialty Ophthalmology practice. Its features classically involve anterior chamber cell and flare. Below the surface of these two signs exist a panoply of diagnoses. BODY: The purpose of this review is to provide a general framework for diagnoses of anterior uveitis that are often missed as well as non-uveitic pathologies that often mimic anterior uveitis. Diagnostic deviation in either direction can have vision-threatening and rarely life-threatening consequences for patients. Using a comprehensive literature review we have collected a broad spectrum of etiologies of anterior uveitis that are easily missed and non-uveitic pathologies that can masquerade as anterior uveitis. CONCLUSIONS: We present a focused review on specific misdiagnosed anterior uveitis pathologies and some of the conditions that can masquerade as anterior uveitis and scleritis.

Good manufacturing practice production of human corneal limbus-derived stromal stem cells and in vitro quality screening for therapeutic inhibition of corneal scarring.

BACKGROUND: Mesenchymal stem cells in the adult corneal stroma (named corneal stromal stem cells, CSSCs) inhibit corneal inflammation and scarring and restore corneal clarity in pre-clinical corneal injury models. This cell therapy could alleviate the heavy reliance on donor materials for corneal transplantation to treat corneal opacities. Herein, we established Good Manufacturing Practice (GMP) protocols for CSSC isolation, propagation, and cryostorage, and developed in vitro quality control (QC) metric for in vivo anti-scarring potency of CSSCs in treating corneal opacities. METHODS: A total of 24 donor corneal rims with informed consent were used-18 were processed for the GMP optimization of CSSC culture and QC assay development, while CSSCs from the remaining 6 were raised under GMP-optimized conditions and used for QC validation. The cell viability, growth, substrate adhesion, stem cell phenotypes, and differentiation into stromal keratocytes were assayed by monitoring the electric impedance changes using xCELLigence real-time cell analyzer, quantitative PCR, and immunofluorescence. CSSC's conditioned media were tested for the anti-inflammatory activity using an osteoclastogenesis assay with mouse macrophage RAW264.7 cells. In vivo scar inhibitory outcomes were verified using a mouse model of anterior stromal injury caused by mechanical ablation using an Algerbrush burring. RESULTS: By comparatively assessing various GMP-compliant reagents with the corresponding non-GMP research-grade chemicals used in the laboratory-based protocols, we finalized GMP protocols covering donor limbal stromal tissue processing, enzymatic digestion, primary CSSC culture, and cryopreservation. In establishing the in vitro QC metric, two parameters-stemness stability of ABCG2 and nestin and anti-inflammatory ability (rate of inflammation)-were factored into a novel formula to calculate a Scarring Index (SI) for each CSSC batch. Correlating with the in vivo scar inhibitory outcomes, the CSSC batches with SI < 10 had a predicted 50% scar reduction potency, whereas cells with SI > 10 were ineffective to inhibit scarring. CONCLUSIONS: We established a full GMP-compliant protocol for donor CSSC cultivation, which is essential toward clinical-grade cell manufacturing. A novel in vitro QC-in vivo potency correlation was developed to predict the anti-scarring efficacy of donor CSSCs in treating corneal opacities. This method is applicable to other cell-based therapies and pharmacological treatments.

Rate of fractional change in corneal tomography parameters in keratoconus using a combination of predictive parameters.

BACKGROUND: To compare the rate of fractional change for multiple corneal tomographic factors in progressive keratoconus (KC). METHODS: In this retrospective case series, 40 eyes (40 patients) with progressive KC (increase in central keratometry of 1.00 D or maximum keratometry of 1.50 D on two visits at least six months apart) were included. Cases with previous history of ocular surgery, poor scans, corneal scars, severe dry eyes, post-excimer ectasia, pellucid marginal degeneration were excluded. Medical records, corneal tomography and anterior corneal wavefront (8 mm) (Scheimpflug tomography, Pentacam, Oculus, Germany) were analyzed. Rate of fractional change (Rx = (x1 - x0)/(|x0|tm)); where, x1 = value at follow-up, x0 = value at initial visit and tm = time in months, was measured. RESULTS: The mean age of the patients was 30.0 ± 8.4 years. The mean follow-up duration was 8.9 ± 4.2 months. Coma (0.076 ± 1.4) had the largest rate of fractional change (P = 1.7 × 10-14, Kruskal-Wallis test). The rate of fractional change was higher for aberrometric parameters (anterior corneal higher-order aberrations root mean square and anterior coma) compared to pachymetric and keratometric parameters (P values ranging from 1.4 × 10-4 to 7.4 × 10-10, Mann-Whitney test, effect size ranging from 0.4-0.7). The rate of fractional change was comparable between pachymetric and keratometric factors (P > 0.05 for all comparisons, Mann-Whitney test). CONCLUSIONS: Anterior corneal wavefront, especially anterior coma, were noted to have higher rate of fractional change compared to single point keratometric and pachymetric indices in progressive KC. This information can be used for decision-making when monitoring patients with KC.

Parental Corneal Tomographic and Biomechanical Characteristics of Patients With Keratoconus.

PURPOSE: To investigate the hereditability of corneal tomographic and biomechanical parameters in keratoconus (KC). DESIGN: Prospective cohort study. METHODS: This study was conducted at Qingdao Eye Hospital of Shandong First Medical University in Qingdao, China. Forty-four patients with KC and their biological parents (n = 88) were recruited as the study group. The control group consisted of 84 healthy adults with matched age and gender. Both eyes of each participant underwent clinical examinations, and 1 eye was selected for statistical analysis. Exclusion criteria were as follows: individuals with glaucoma, ocular surgery, systemic diseases known to affect the eyes, or poor cooperation during examination. Subjects were asked to discontinue soft contact lens (CL) wear for 2 weeks and rigid gas permeable CL wear for 4 weeks before ocular examination. All participants underwent a comprehensive assessment including Pentacam Scheimpflug tomography, Corvis ST, visual acuity, refraction examination, axial length, and slitlamp examination for both eyes. Individuals presenting with KC manifestations in at least 1 eye were classified as having KC. A total of 9 Pentacam indices including keratometry in the flat/steep meridian (K1/K2), maximal keratometry (Kmax), thinnest point pachymetry (TP), and maximum/average Ambrósio relational thickness (ARTmax/ARTave), anterior and posterior surfaces elevation of the cornea (Ef/Eb) and total deviation value (Final D), and 21 biomechanical indices were collected. Associations of these factors with KC were evaluated using multiple comparison and binary logistics regression analyses. RESULTS: Two parents (2.27%) from 2 different families were diagnosed with KC. Parents of patients with KC had thinner corneas with altered corneal biomechanical parameters compared with healthy controls (P < .05). The combined tomographic and biomechanical index demonstrated the highest discriminatory power (area under the receiver operating characteristic curve 0.785) and strong specificity (84.5%). Parental corneal tomographic and biomechanical index, Corvis biomechanical index, and TP were identified as the major influential factors for KC in their offspring by logistic regression analysis, with a 73.3% accuracy in identifying offspring with KC. CONCLUSIONS: Parental corneal tomographic and biomechanical properties of patients with KC suggest a possible predisposition to KC. A combination of tomography and corneal biomechanics can be helpful in predicting the incidence rate of KC in the offspring of patients with subclinical KC.

Relationship between postoperative residual refractive error and preoperative corneal stiffness in small-incision lenticule extraction.

PURPOSE: To explore the relationship between postoperative residual refractive error and preoperative corneal stiffness after small-incision lenticule extraction (SMILE). SETTING: Hospital clinic. DESIGN: Retrospective cohort study. METHODS: Corneal stiffness was evaluated using the stress-strain index (SSI). Associations between postoperative spherical equivalent (SE) and corneal stiffness were determined using longitudinal regression analysis after adjustment for sex, age, preoperative SE, and other variables. The cohort was divided into halves to compare risk ratios for residual refraction in corneas with different SSI values. Low SSI values were defined as having less-stiff corneas and others as having stiffer corneas. RESULTS: 287 patients (287 eyes) were included. Greater undercorrection was found in less-stiff corneas across all follow-up timepoints (less-stiff corneas: 1 day: -0.36 ± 0.45 diopters [D], 1 month: -0.22 ± 0.36 D, and 3 months: -0.13 ± 0.15 D; stiffer corneas: -0.22 ± 0.37 D, -0.14 ± 0.35 D, and -0.05 ± 0.11 D, respectively). Postoperative refraction exhibited a mean 0.05 D undercorrection for every 0.1-unit decrease in the SSI after adjustment for variables. The SSI accounted for nearly 10% of the variance in refractive outcomes. Less-stiff corneas increased the risk ratio of postoperative absolute SE >0 D and ≥0.25 D by 2.242 (95% CI, 1.334-3.768) and 3.023 (95% CI, 1.466-6.233), respectively, compared with stiffer corneas. CONCLUSIONS: Postoperative residual refractive error was associated with preoperative corneal stiffness. Patients with less-stiff corneas had a 2- to 3-fold increased risk of residual refractive error after SMILE. Preoperative analysis of corneal stiffness can help modify nomogram algorithms of surgery and improve the predictability of refractive outcomes.

Crosslinking for post-laser-assisted in situ keratomileusis corneal ectasia: Transepithelial flap-on 30 minute and flap-lift 4 minute protocol.

Purpose: To evaluate the outcomes of transepithelial corneal collagen crosslinking (CXL) for management of corneal ectasia after laser-assisted in situ keratomileusis (LASIK). Methods: CXL was performed on 18 eyes of 16 patients either with LASIK flap lift (n = 9; 365 nm, 30 mW/cm2, 4 minutes, pulse) or with transepithelial flap-on (n = 9 eyes; 365 nm, 3 mW/cm2, 30 minutes) technique. Postoperative change in maximum keratometry (Kmax), anterior elevation, posterior elevation, spherical equivalent (SE), logMAR uncorrected distance visual acuity (UDVA), aberrations, and central corneal thickness (CCT) were evaluated at 12 months postoperatively. Results: A total of 18 eyes of 16 patients (11 males, 5 females) were included. Overall, Kmax flattened more after flap-on CXL (P = 0.014) compared to flap-lift CXL. The endothelial cell density and posterior elevation were stable throughout the follow-up period. Index of vertical asymmetry (IVA), keratoconus index (KI), and central keratoconus index (CKI) decreased after flap-on CXL at 12 months, postoperatively (P < 0.05), whereas there were no statistically significant changes in these parameters after flap-off CXL group. The spherical aberrations and total root mean square decreased after flap-lift CXL at 12 months, postoperatively (P < 0.05). Conclusion: In our study, transepithelial collagen crosslinking was successfully used to halt disease progression in post-LASIK keratectasia. We recommend flap-on surgical technique for these cases.

A review on drug-induced dry eye disease.

Dry eye disease encompasses a broad range of etiologies and disease subtypes which have similar clinical manifestations. Medications can cause dry eye disease or symptoms of dryness as a side effect by either interfering with the lacrimal gland or meibomian gland function, or both, and by other mechanisms that affect the ocular surface homeostasis. This is important to know and recognize as eliminating the offending medication can reverse the symptoms and, in many cases, prevent further deterioration of the ocular surface inflammation. This review focuses on drugs like systemic isotretinoin and taxanes, which cause meibomian gland dysfunction; immune checkpoint inhibitors that cause lacrimal gland dysfunction; gliptins and topical antiglaucoma medications that cause cicatrizing conjunctivitis; and epidermal growth factor receptor inhibitors, fibroblast growth factor receptor inhibitors, and belantamab mafodotin, which cause mucosal epitheliopathy. Many of these medications, particularly the newer anticancer agents, have only recently been introduced for clinical use, and knowledge and awareness of their ocular side effects are still evolving. This review aims to update ophthalmologists on the drug-induced causes of dry eye disease or symptoms of dryness, which is avoidable by discontinuation of the incriminating agent or can be mitigated by reducing the dose or frequency of usage.

The association between altered intestinal microbiome, impaired systemic and ocular surface immunity, and impaired wound healing response after corneal alkaline-chemical injury in diabetic mice.

Purpose: We aim to investigate the effect of sustained hyperglycemia on corneal epithelial wound healing, ocular surface and systemic immune response, and microbiome indices in diabetic mice compared to controls after alkaline chemical injury of the eye. Methods: Corneal alkaline injury was induced in the right eye of Ins2Akita (Akita) mice and wild-type mice. The groups were observed at baseline and subsequently days 0, 3, and 7 after injury. Corneal re-epithelialization was observed under slit lamp with fluorescein staining using a cobalt blue light filter. Enucleated cornea specimens were compared at baseline and after injury for changes in cornea thickness under hematoxylin and eosin staining. Tear cytokine and growth factor levels were measured using protein microarray assay and compared between groups and time points. Flow cytometry was conducted on peripheral blood and ocular surface samples to determine CD3+CD4+ cell count. Fecal samples were collected, and gut microbiota composition and diversity pattern were measured using shotgun sequencing. Results: Akita mice had significantly delayed corneal wound healing compared to controls. This was associated with a reduction in tear levels of vascular endothelial growth factor A, angiopoietin 2, and insulin growth factor 1 on days 0, 3, and 7 after injury. Furthermore, there was a distinct lack of upregulation of peripheral blood and ocular surface CD3+CD4+ cell counts in response to injury in Akita mice compared to controls. This was associated with a reduction in intestinal microbiome diversity indices in Akita mice compared to controls after injury. Specifically, there was a lower abundance of Firmicutes bacterium M10-2 in Akita mice compared to controls after injury. Conclusion: In diabetic mice, impaired cornea wound healing was associated with an inability to mount systemic and local immune response to ocular chemical injury. Baseline and post-injury differences in intestinal microbial diversity and abundance patterns between diabetic mice and controls may potentially play a role in this altered response.

Human corneal stromal stem cells express anti-fibrotic microRNA-29a and 381-5p - A robust cell selection tool for stem cell therapy of corneal scarring.

INTRODUCTION: Corneal blindness due to scarring is treated with corneal transplantation. However, a global problem is the donor material shortage. Preclinical and clinical studies have shown that cell-based therapy using corneal stromal stem cells (CSSCs) suppresses corneal scarring, potentially mediated by specific microRNAs transported in extracellular vesicles (EVs). However, not every CSSC batch from donors achieves similar anti-scarring effects. OBJECTIVES: To examine miRNA profiles in EVs from human CSSCs showing "healing" versus "non-healing" effects on corneal scarring and to design a tool to select CSSCs with strong healing potency for clinical applications. METHODS: Small RNAs from CSSC-EVs were extracted for Nanostring nCounter Human miRNA v3 assay. MicroRNAs expressed > 20 folds in "healing" EVs (P < 0.05) were subject to enriched gene ontology (GO) term analysis. MiRNA groups with predictive regulation on inflammatory and fibrotic signalling were studied by mimic transfection to (1) mouse macrophages (RAW264.7) for M1 phenotype assay; (2) human corneal keratocytes for cytokine-induced fibrosis, and (3) human CSSCs for corneal scar prevention in vivo. The expression of miR-29a was screened in additional CSSC batches and the anti-scarring effect of cells was validated in mouse corneal wounds. RESULTS: Twenty-one miRNAs were significantly expressed in "healing" CSSC-EVs and 9 miRNA groups were predicted to associate with inflammatory and fibrotic responses, and tissue regeneration (P <10-6). Overexpression of miR-29a and 381-5p significantly prevented M1 phenotype transition in RAW264.7 cells after lipopolysaccharide treatment, suppressed transforming growth factor ß1-induced fibrosis marker expression in keratocytes, and reduced scarring after corneal injury. High miR-29a expression in EV fractions distinguished human CSSCs with strong healing potency, which inhibited corneal scarring in vivo. CONCLUSION: We characterized the anti-inflammatory and fibrotic roles of miR-29a and 381-5p in CSSCs, contributing to scar prevention. MiR-29a expression in EVs distinguished CSSCs with anti-scarring quality, identifying good quality cells for a scarless corneal healing.

Descemet Stripping Automated Endothelial Keratoplasty in Thick Corneas.

Purpose: To evaluate the outcomes of Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) in corneas > 820 microns in thickness. Methods: This retrospective study included 30 eyes of 30 patients who underwent DSAEK. Endothelial cell destiny (ECD) and corneal thickness were recorded before surgery and at 1 and 12 months postoperatively. Patients were divided into two groups (≤ 820 microns and > 820 microns) based on median preoperative corneal thickness. Linear regression analyses were used to investigate the correlations between ECD and preoperative corneal thickness. Results: Recipient corneal thickness (RCT) and postoperative central cornea thickness had a statistically significant difference 1 month after surgery (p = 0.03, p = 0.08, respectively). BCVA and ECD did not have a statistical difference in the two groups at 1 month and 12 months after DSAEK. Conclusions: BCVA, ECD and corneal thickness were similar at 12 months after DSAEK in thick corneas. DSAEK is a viable surgical option in thick corneas.

Vector analysis of astigmatic correction after single-step transepithelial photorefractive keratectomy and femtosecond-assisted laser in-situ keratomileusis for low to moderate myopic astigmatism.

Purpose: This study aimed to evaluate the outcomes of astigmatic correction by single-step transepithelial photorefractive keratectomy (TransPRK) and femtosecond-assisted laser in-situ keratomileusis (Femto-LASIK) surgeries. Methods: A total of 218 subjects received TransPRK or Femto-LASIK surgery for the treatment of myopia and astigmatism (-2.25 to -0.25 D). Refraction errors and uncorrected (UDVA) and corrected distance visual acuity (CDVA) were examined before and at 3 months after surgery. Astigmatism changes were assessed by vector analysis. Results: Preoperative parameters of the TransPRK group were similar to the Femto-LASIK group. UDVA and CDVA at 3 months were similar between both groups. Manifest refraction (MR) spherical equivalent in the TransPRK group (0 ± 0.20 D) was slightly lower compared with the Femto-LASIK group at 3 months (0.11 ± 0.25 D, P = 0.001). MR cylinder was -0.06 ± 0.19 D in the TransPRK group and -0.02 ± 0.15 D in the Femto-LASIK group at 3 months (P = 0.135). The index of success (IS) was 0.15 ± 0.36 in the TransPRK group and 0.06 ± 0.17 in the Femto-LASIK group (P = 0.125). The correction index (CI) was 1.03 ± 0.19 in the TransPRK group and 1.01 ± 0.11 in the Femto-LASIK group (P = 0.815). Conclusion: For low to moderate myopic astigmatism, TransPRK provided a comparable astigmatic treatment effect as Femto-LASIK. Myopic astigmatism was both slightly overcorrected after TransPRK and Femto-LASIK surgeries.

A Randomized Trial of Topical Fibrinogen-Depleted Human Platelet Lysate Treatment of Dry Eye Secondary to Chronic Graft-versus-Host Disease.

Purpose: The purpose of the study was to evaluate, as a pilot trial, safety and tolerability of CAM-101 10% and 30% topical ophthalmic fibrinogen-depleted human platelet lysate (FD hPL) solution in patients with dry eye disease (DED) secondary to graft-versus-host disease (GvHD) after 6 weeks of treatment. Design: A phase I/II, pilot, prospective, multicenter, randomized, double-masked clinical trial. Participants: Patients with DED secondary to GvHD. Methods: Sixty-four adult patients were stratified by "symptom severity" (Ocular Surface Disease Index [OSDI], ocular discomfort Visual Analog Scale (VAS), ocular symptom frequency, and use of artificial tears) and then randomized 1:1:1 to CAM-101 (FD hPL) at 10% or 30% concentration or an electrolyte (Plasma-Lyte A) vehicle control, 1 drop in both eyes, 4 times daily, for 42 days. After 42 days, control patients were offered 42 days of open-label treatment with 30% FD hPL. Main Outcome Measures: Primary outcome safety measures were ocular and systemic adverse events and the number of patients in each group with clinically significant change from normal to abnormal in any ocular findings. Secondary outcomes were changes from baseline to day 42 in ocular discomfort, OSDI, fluorescein corneal staining, and lissamine green conjunctival staining relative to the vehicle control. The ocular symptom frequency was assessed on a 100-point VAS. Results: FD hPL 10% and 30% were safe and well tolerated. Relative to the vehicle control, significant decreases from baseline to day 42 were seen in the FD hPL 30% group with regard to ocular discomfort (mean decrease = -18.04; P = 0.018), frequency of burning/stinging (-20.23; P = 0.022), eye discomfort (-32.97; P < 0.001), eye dryness (-21.61; P = 0.020), pain (-15.12; P = 0.044), photophobia (-24.33; P = 0.0125), and grittiness (-20.08; P = 0.0185). Decreases were also seen for itching and foreign body sensation, though not statistically significant. Improvements were seen in tear breakup time (mean increase = 1.30 seconds; P = 0.082) and the investigator's global evaluation 4-point scale (mean decrease = -0.86; P = 0.026). Corneal fluorescein staining was not improved. The OSDI had a mean decrease of -8.88 compared to the vehicle, although not statistically significant. Conclusions: Fibrinogen-depleted human platelet lysate appears to be well tolerated, with no significant toxicity at concentrations of 10% and 30%. These initial data suggest some efficacy, especially for subjective outcome measures relative to baseline assessments and treatment with the vehicle, but larger studies are needed to confirm these effects.

Artificial Intelligence-Based Diagnostic Model for Detecting Keratoconus Using Videos of Corneal Force Deformation.

Purpose: To develop a novel method based on biomechanical parameters calculated from raw corneal dynamic deformation videos to quickly and accurately diagnose keratoconus using machine learning. Methods: The keratoconus group was included according to Rabinowitz's criteria, and the normal group included corneal refractive surgery candidates. Independent biomechanical parameters were calculated from dynamic corneal deformation videos. A novel neural network model was trained to diagnose keratoconus. Tenfold cross-validation was performed, and the sample set was divided into a training set for training, a validation set for parameter validation, and a testing set for performance evaluation. External validation was performed to evaluate the model's generalizability. Results: A novel intelligent diagnostic model for keratoconus based on a five-layer feedforward network was constructed by calculating four biomechanical characteristics, including time of the first applanation, deformation amplitude at the highest concavity, central corneal thickness, and radius at the highest concavity. The model was able to diagnose keratoconus with 99.6% accuracy, 99.3% sensitivity, 100% specificity, and 100% precision in the sample set (n = 276), and it achieved an accuracy of 98.7%, sensitivity of 97.4%, specificity of 100%, and precision of 100% in the external validation set (n = 78). Conclusions: In the absence of corneal topographic examination, rapid and accurate diagnosis of keratoconus is possible with the aid of machine learning. Our study provides a new potential approach and sheds light on the diagnosis of keratoconus from a purely corneal biomechanical perspective. Translational Relevance: Our findings could help improve the diagnosis of keratoconus based on corneal biomechanical properties.

Fungal Keratitis: Clinical Features, Risk Factors, Treatment, and Outcomes.

Fungal keratitis (FK) can be challenging to diagnose and treat. In this retrospective case series, FK cases presenting at the University of Pittsburgh Medical Center, Pennsylvania, USA, from 2015 to 2021 were reviewed for ocular risk factors, clinical presentation, management, and outcomes. Twenty-eight cases of FK were included. The median presenting age was 58.5 (18.5) years, and the median symptom duration prior to presentation was 10 (35.8) days. Predisposing ocular risk factors included contact lens use (67.9%), recent ocular trauma/abrasion (42.9%), and history of ocular surgery (42.9%). The median presenting visual acuity (VA) was 1.35 (1.72) LogMAR. About half presented with a central ulcer (42.9%), large infiltrate (6.7 (6.3) mm2), corneal thinning (50.0%), and hypopyon (32.1%). The majority of isolated fungal species were filamentous (75.0%). Most common antifungal medications included topical voriconazole (71.4%) and natamycin (53.6%) drops and oral voriconazole (64.3%). Surgical management was necessary in 32.1% of cases and enucleation in one case. Defect resolution occurred in 42.5 (47.0) days, and median final VA was 0.5 (1.84) LogMAR. Features associated with poor final visual outcomes included poor initial VA (p < 0.001) and larger defect size (p = 0.002). In conclusion, unlike prior studies in the northeast region of the USA, FK was commonly caused by filamentous fungi, and antifungal management most often consisted of topical and oral voriconazole.

Human SMILE-Derived Stromal Lenticule Scaffold for Regenerative Therapy: Review and Perspectives.

A transparent cornea is paramount for vision. Corneal opacity is one of the leading causes of blindness. Although conventional corneal transplantation has been successful in recovering patients' vision, the outcomes are challenged by a global lack of donor tissue availability. Bioengineered corneal tissues are gaining momentum as a new source for corneal wound healing and scar management. Extracellular matrix (ECM)-scaffold-based engineering offers a new perspective on corneal regenerative medicine. Ultrathin stromal laminar tissues obtained from lenticule-based refractive correction procedures, such as SMall Incision Lenticule Extraction (SMILE), are an accessible and novel source of collagen-rich ECM scaffolds with high mechanical strength, biocompatibility, and transparency. After customization (including decellularization), these lenticules can serve as an acellular scaffold niche to repopulate cells, including stromal keratocytes and stem cells, with functional phenotypes. The intrastromal transplantation of these cell/tissue composites can regenerate native-like corneal stromal tissue and restore corneal transparency. This review highlights the current status of ECM-scaffold-based engineering with cells, along with the development of drug and growth factor delivery systems, and elucidates the potential uses of stromal lenticule scaffolds in regenerative therapeutics.

Changes in effective optical zone after small-incision lenticule extraction in high myopia.

PURPOSE: To evaluate the four measurement approaches on the determination of effective optical zone (EOZ) using Scheimpflug tomography after small-incision lenticule extraction surgery in eyes with high myopia. SETTING: Corneal refractive surgery conducted in an eye hospital in southern China. DESIGN: This is a retrospective cohort study. METHODS: In total, 74 subjects were recruited. EOZ was measured at 3 months postoperatively using vertex-based (EOZV), pupil-based (EOZP), 4 mm-ring-based total corneal refraction method (EOZ4) and tangential curvature difference map method (EOZD), and their consistencies were compared. EOZs and planned optical zone (POZ) were compared and analyzed with eccentricity, ablation degree (AD) and total corneal aberrations. RESULTS: At 3 months after surgery, the mean root mean square of ΔHOA, ΔComa, ΔTrefoil and ΔSA were 0.53 ± 0.27 µm, 0.36 ± 0.20 µm, 0.01 ± 0.84 µm and 0.16 ± 0.14 µm, respectively. EOZV, EOZP, EOZ4 and EOZD were 5.87 ± 0.44 mm, 5.85 ± 0.45 mm, 4.78 ± 0.40 mm and 5.29 ± 0.27 mm, respectively, which were significantly smaller than POZ 6.48 ± 0.16 mm. Bland-Altman plots showed a good consistency among the four EOZs. The difference between the EOZV and EOZP was 0.02 mm within the range of clinically acceptable difference. In addition, the eccentricity was positively correlated with ΔHOA, ΔComa and ΔSA. CONCLUSIONS: All 4 measurement approaches demonstrated the reduction of EOZs compared to POZ. The EOZV was the closest to POZ, followed by EOZP. The ΔEOZs showed no significant difference with eccentricity, AD and corneal aberrations.

Combined Therapy Using Human Corneal Stromal Stem Cells and Quiescent Keratocytes to Prevent Corneal Scarring after Injury.

Corneal blindness due to scarring is conventionally treated by corneal transplantation, but the shortage of donor materials has been a major issue affecting the global success of treatment. Pre-clinical and clinical studies have shown that cell-based therapies using either corneal stromal stem cells (CSSC) or corneal stromal keratocytes (CSK) suppress corneal scarring at lower levels. Further treatments or strategies are required to improve the treatment efficacy. This study examined a combined cell-based treatment using CSSC and CSK in a mouse model of anterior stromal injury. We hypothesize that the immuno-regulatory nature of CSSC is effective to control tissue inflammation and delay the onset of fibrosis, and a subsequent intrastromal CSK treatment deposited collagens and stromal specific proteoglycans to recover a native stromal matrix. Using optimized cell doses, our results showed that the effect of CSSC treatment for suppressing corneal opacities was augmented by an additional intrastromal CSK injection, resulting in better corneal clarity. These in vivo effects were substantiated by a further downregulated expression of stromal fibrosis genes and the restoration of stromal fibrillar organization and regularity. Hence, a combined treatment of CSSC and CSK could achieve a higher clinical efficacy and restore corneal transparency, when compared to a single CSSC treatment.

Lirentelimab for severe and chronic forms of allergic conjunctivitis.

BACKGROUND: Allergic conjunctivitis (AC) is an ocular inflammatory disease with symptoms driven by eosinophils and mast cells. Allergic comorbidities are common. Current treatments are often ineffective in severe AC and limited by potential side effects. Lirentelimab is an anti-sialic acid-binding immunoglobulin-like lectin-8 mAb that depletes eosinophils and inhibits mast cells. OBJECTIVE: We sought to determine safety and preliminary efficacy of lirentelimab in an open-label, phase 1b study. METHODS: Patients with chronic, severely symptomatic atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC, and who had history of topical or systemic corticosteroid use, were enrolled to receive up to 6 monthly lirentelimab infusions (dose 1: 0.3 mg/kg, dose 2: 1 mg/kg, subsequent doses: 1 or 3 mg/kg). Changes from baseline in peripheral blood eosinophils, changes in patient-reported symptoms (measured by daily Allergic Conjunctivitis Symptom Questionnaire, including atopic comorbidities), changes in investigator-reported ocular signs and symptoms (Ocular Symptom Scores), changes in quality of life, and changes in tear cytokine and chemokine levels were assessed. RESULTS: Thirty patients were enrolled (atopic keratoconjunctivitis n = 13, vernal keratoconjunctivitis n = 1, perennial AC n = 16), 87% of whom had atopic comorbidities. After lirentelimab treatment, mean improvement was observed in Allergic Conjunctivitis Symptom Questionnaire score (-61%; 95% CI, -75% to -48%) and Ocular Symptom Scores (-53%; 95% CI, -76% to -31%), consistent across atopic keratoconjunctivitis, vernal keratoconjunctivitis, and perennial AC groups. There was substantial improvement in atopic comorbidities, with -55% (95% CI, -78% to -31%), -50% (95% CI, -82% to -19%), and -63% (95% CI, -87% and -38%) reduction in symptoms of atopic dermatitis, asthma, and rhinitis, respectively. Levels of key mediators of inflammation were reduced in patient tears after lirentelimab treatment. The most common adverse effects were mild to moderate infusion-related reactions. CONCLUSIONS: Lirentelimab was well tolerated, improved severe AC and concomitant atopic symptoms, and reduced inflammatory mediators in patient tears.

Predictive factors of posterior corneal shift after small incision lenticule extraction: a 5-year follow-up study.

PURPOSE: The aim of this study was to determine risk factors affecting changes in posterior corneal elevation (PCE) and predict the 5-year stability after small incision lenticule extraction (SMILE). METHODS: This retrospective, longitudinal study enrolled 161 patients post-SMILE. The PCE values were measured at the apex, thinnest, maximal and 24 other prespecified preoperative points and at 6 months, 1 year and 5 years postoperatively. RESULTS: Posterior corneas exhibited time-dependent, region-dependent and angle-dependent changes. For every dioptre increase in the absolute preoperative spherical equivalent (SE), 10-µm decrease in the central corneal thickness (CCT), 10-µm increase in the maximum lenticule thickness (MLT), 10-µm decrease in the residual bed thickness (RBT), 10% increase in the percentage ablation depth (PAD, MLT divided by CCT) and 10% decrease in the percentage stromal bed thickness (PSBT, RBT divided by CCT), PCE exhibited average forward displacements of 0.2-0.4, 0.2-0.7, 0.1-0.2, 0.1-0.3, 0.6-1.0 and 0.5-1.1 µm, respectively (p < 0.05). PSBT was the variable with the highest accuracy in predicting 5-year stability of posterior corneas (area under curve = 0.75). The cut-off values of SE, CCT, MLT, RBT, PAD and PSBT for increased PCE were -8.00 to -8.31 D, 481.0-498.5 µm, 139.5-144.5 µm, 255.5-263.5 µm, 26.9-28.3% and 48.9-52.6%, respectively. CONCLUSION: Eyes with thinner corneas, higher myopia requiring greater MLT and lower RBT exhibited greater predispositions towards posterior protrusion. The thresholds for preventing forward posterior corneal displacement were 26.9-28.3% for PAD and 48.9-52.6% for PSBT. Prediction of posterior corneal stability is useful for assessing surgical risks post-SMILE.