Rapid, Sensitive, and Selective "ON-OFF" Detection of Fe3+ Ions Using Novel Acetalophanes and Their Applications in Real Samples.

Three novel acetalophanes 1a-c have been designed, synthesized and characterized. The receptors 1b-c, featuring bulky anthracene groups, displayed significant selectivity for Fe3+ ions, resulting in a turn-off fluorescence mode in a DMF-buffer solution. Conversely, the non-steric probe 1a could serve as a versatile sensor for the simultaneous detection of Fe3+ and Cu2+ ions in MeOH-buffer solution. The sensing mechanism for the capability of 1a was demonstrated to be different, as evidenced by the addition of cyanide ions. The probes with Fe3+ exhibited a sensing mechanism that resulted in the deprotection of acetals to the corresponding starting materials, as confirmed by 1H NMR, IR spectra and TLC analysis. The attractive features of these practical and efficient sensors are selectivity, sensitivity (limit of detection = 0.15 µM by 1a, 0.16 µM by 1b and 0.14 µM by 1c), rapid response (less than 5 s). The on-site monitoring of various real samples, including well water, apricot, and green tea, proved to be successful for the quantitative and cost-effective detection of Fe3+. The method demonstrated good precision, even in the presence of other interfering materials.

Applications of SMILE-extracted lenticules in ophthalmology.

AIM: To review recent innovations, challenges, and applications of small incision lenticule extraction (SMILE) extracted lenticule for treating ocular disorders. METHODS: A literature review was performed in the PubMed database, which was last updated on 30 December 2021. There was no limit regarding language. The authors evaluated the reference lists of the collected papers to find any relevant research. RESULTS: Due to the simplicity and accuracy of modern femtosecond lasers and the extensive development of SMILE surgery, many healthy human corneal stromal lenticules were extracted during surgery, motivating some professionals to investigate the SMILE lenticule reusability in different ocular disorders. In addition, new approaches had been developed to preserve, modify, and bioengineer the corneal stroma, leading to the optimal use of discarded byproducts such as lenticules from SMILE surgery. The lenticules can be effectively re-implanted into the autologous or allogenic corneas of human subjects to treat refractive errors, corneal ectasia, and corneal perforation and serve as a patch graft for glaucoma drainage devices with better cosmetic outcomes. CONCLUSION: SMILE-extracted lenticules could be a viable alternative to human donor corneal tissue.

Ocular condition prognosis in Keratoconus patients after corneal ring implantation using artificial neural networks.

The common disorder, Keratoconus (KC), is distinguished by cumulative corneal slimming and steepening. The corneal ring implantation has become a successful surgical procedure to correct the KC patient's vision. The determination of suitable patients for the surgery alternative is among the paramount concerns of ophthalmologists. To reduce the burden on them and enhance the treatment, this research aims to previse the ocular condition of KC patients after the corneal ring implantation. It focuses on predicting post-surgical corneal topographic indices and visual characteristics. This study applied an efficacious artificial neural network approach to foretell the aforementioned ocular features of KC subjects 6 and 12 months after implanting KeraRing and MyoRing based on the accumulated data. The datasets are composed of sufficient numbers of corneal topographic maps and visual characteristics recorded from KC patients before and after implanting the rings. The visual characteristics under study are uncorrected visual acuity (UCVA), sphere (SPH), astigmatism (Ast), astigmatism orientation (Axe), and best corrected visual acuity (BCVA). In addition, the statistical data of multiple KC subjects were registered, including three effective indices of corneal topography (i.e., Ast, K-reading, and pachymetry) pre- and post-ring embedding. The outcomes represent the contribution of practical training of the introduced models to the estimation of ocular features of KC subjects following the implantation. The corneal topographic indices and visual characteristics were estimated with mean errors of 7.29% and 8.60%, respectively. Further, the errors of 6.82% and 7.65% were respectively realized for the visual characteristics and corneal topographic indices while assessing the predictions by the leave-one-out cross-validation (LOOCV) procedure. The results confirm the great potential of neural networks to guide ophthalmologists in choosing appropriate surgical candidates and their specific intracorneal rings by predicting post-implantation ocular features.

An inspired microenvironment of cell replicas to induce stem cells into keratocyte-like dendritic cells for corneal regeneration.

Corneal stromal disorders due to the loss of keratocytes can affect visual impairment and blindness. Corneal cell therapy is a promising therapeutic strategy for healing corneal tissue or even enhancing corneal function upon advanced disorders, however, the sources of corneal keratocytes are limited for clinical applications. Here, the capacity of cell-imprinted substrates fabricated by molding human keratocyte templates to induce differentiation of human adipose-derived stem cells (hADSCs) into keratocytes, is presented. Keratocytes are isolated from human corneal stroma and grown to transmit their ECM architecture and cell-like topographies to a PDMS substrate. The hADSCs are then seeded on cell-imprinted substrates and their differentiation to keratocytes in DMEM/F12 (with and without chemical factors) are evaluated by real-time PCR and immunocytochemistry. The mesenchymal stem cells grown on patterned substrates present gene and protein expression profiles similar to corneal keratocytes. In contrast, a negligible expression of myofibroblast marker in the hADSCs cultivated on the imprinted substrates, is observed. Microscopic analysis reveals dendritic morphology and ellipsoid nuclei similar to primary keratocytes. Overall, it is demonstrated that biomimetic imprinted substrates would be a sufficient driver to solely direct the stem cell fate toward target cells which is a significant achievement toward corneal regeneration.

Combination of natural scaffolds and conditional medium to induce the differentiation of adipose-derived mesenchymal stem cells into keratocyte-like cells and its safety evaluation in the animal cornea.

Keratocytes are the main cellular components of the corneal stroma. This cell is quiescent and cannot be cultured easily. The aim of this study was to investigate differentiate human adipose mesenchymal stem cells (hADSCs) into corneal keratocyte cells by combining natural scaffolds and conditioned medium (CM) and evaluating their safety in the rabbit's cornea. Keratocytes were cultured in an optimal culture medium and this medium was collected and kept as a CM. hADSCs were cultured on the decellularized human small incision lenticule extraction (SMILE) lenticule (SL), amniotic membrane (AM), and collagen-coated plates, and were exposed to keratocyte-CM (KCM) for 7, 14, and 21 days. Differentiation was evaluated using Real-time PCR and immunocytochemistry (ICC). hADSCs were cultured on the SL scaffolds and implanted in the corneal stroma of 8 New Zealand male rabbits. Rabbits were followed for 3 months and the safety was evaluated by clinical and histological variables. Real-time PCR results showed a significant increase in the expression of keratocyte-specific markers on the 21 day of differentiation compared to the control group. ICC also confirmed the induction of differentiation. Implantation of SLs containing differentiated cells in the cornea of animals showed no serious complications including neovascularization, corneal opacity, inflammation, or signs of tissue rejection. Furthermore, the evaluation of the presence of keratocyte-like cells after three months in the rabbit stroma was confirmed by Real-time PCR and immunohistochemistry (IHC) analysis. Our results showed that combination of combination of corneal extracellular matrix and KCM can induced keratocytes differentiation of hADSC and can be introduced as a alternative method to supply the required keratocytes in corneal tissue engineering.

Novel pathogenic CERKL variant in Iranian familial with inherited retinal dystrophies: genotype-phenotype correlation.

Inherited retinal dystrophies (IRDs) include a large chronic heterogeneity genetic disease. While many disease-causing pathogenic variants were involved in the progression of IRD, the Ceramide Kinase Like (CERKL) gene variant in Iranian patients is not well characterized. In this study, a consanguineous Iranian family with three generations was recruited whom presented with the clinical diagnosis of autosomal recessive IRD. By targeted next-generation sequencing (TGS) and Sanger sequencing, the proband was found to have a novel, pathological homozygous deletion variant c.560_568del (p.187_190del) of the CERKL gene (NM_001030311.2) that co-segregated with the disease in all affected family members. The Cerkl is highly expressed in the later four developmental retinal stages, playing a vital role in retina degeneration. Therefore, the identification of a novel, homozygous deletion CERKL variant c.560_568del (p.187_190del) in an IRD familial cohort descent provides insights into the molecular pathogenesis of IRD and facilitates genetic counseling and disease prediction.

Substrate-Controlled Diastereo- and Enantiodivergent Synthesis of Bis-Spirocyclopropyloxindoles from Available Isatin as a Single Starting Material.

The first diastereo- and enantiodivergent asymmetric synthesis of new bis-spirocyclopropyloxindole scaffolds has been accomplished from the readily available isatin as a single starting material. Four rel-(1R,2R,3R), rel-(1S,2S,3R), rel-(1R,2R,3S), and rel-(1S,2S,3S) configurations of desired products were constructed in excellent enantiopurity via a simple switch in substrates using the chiral auxiliary-controlled method. The absolute configuration of cycloadducts with three contiguous quaternary/tertiary stereogenic centers was confirmed through X-ray diffraction analysis. A facile synthesis of versatile precursor 3-chlorooxindoles was also introduced.

Regioselective synthesis of enantiopure 1,2- and 1,3-dispirooxindoles along with a DFT study.

In the present study, a library of important enantiopure dispirooxindole [indolizidine, pyrrolizidine, and pyrrolidine] derivatives with three or four contiguous and two quaternary stereogenic centers using different amino acids (pipecolic acid, sarcosine, proline and hydroxyproline) were synthesized in high yields (up to 96%) through a regio- and diastereoselective (up to 99 : 1) multicomponent 1,3-dipolar cycloaddition strategy. Based on the results, the alteration of amino acids led to a change in the regioselectivity and unusual regioisomers (pyrrolizidine versus indolizidine/pyrrolidine) were obtained to construct a novel enantiopure 1,3-dispirooxindole skeleton. The stereochemical outcome of the cycloaddition was determined by single crystal X-ray diffraction analysis and the self-disproportionation of enantiomers (SDE) test confirmed the enantiomeric purity of the desired products. The mechanism and differences in the regioselectivity of the 1,3-dipolar cycloaddition reactions between the stable azomethane ylides obtained from ninhydrin, pipecolinic acid, and proline with (E)-2-oxoindolin-3-ylideneacetyl sultam were theoretically studied through DFT calculations at the M06-2X/6-31G(d,p) level in methanol.

Sublimation of Benign Conjunctival Nevi Using Plasma-Assisted Noninvasive Surgery: A Clinical Case Series.

Background: Conjunctival nevi (CN) are common benign ocular tumors. Given their low risk of malignancy, surgical removal of nevi is primarily requested by patients. Herein, we introduce Atmospheric Low-temperature Plasma (ALTP) as a novel noninvasive method for the removal of CN. Methods: A clinical case series was conducted from 2020 to 2021 at the Vision Health Ophthalmic Center in Tehran, Iran. CN in one of the eyes of seven patients was treated. In all patients, the benignity of CN was confirmed by ocular oncologists. The white handpiece of the Plexr device, which generates plasma with the lowest output, was used to apply plasma spots on the nevi. In addition, the Ocular Surface Disease Index (OSDI) questionnaire was completed by all patients before and six months after the treatment. Results: In all patients, the nevi outside the limbus area completely disappeared. The mean size of pre- and post-operative nevi was 3.89×11.7 and 0.54×1.69 mm, respectively. Results of the OSDI questionnaire showed significantly lower scores after the surgery in all patients. Conclusion: The ALTP method is a simple, cost-effective, and office-based surgery to remove CN safely and effectively.

Changes in Stress-Strain Index and Corneal Biomechanics in Granular Corneal Dystrophy.

Background: The aim of this study was to assess stress-strain index (SSI) and corneal biomechanical parameters in eyes with granular corneal dystrophy (GCD). Methods: This case-control study included 12 eyes of 12 patients with GCD (mean age 45.2 ± 18.7 years) and 20 eyes of 20 healthy individuals (mean age 54.4 ± 3.8 years). In addition to SSI, dynamic corneal response (DCR) parameters were assessed at the first and second applanation, including length (AL1, AL2), velocity (AV1, AV2), time (AT1, AT2), and deformation amplitude (DA A1, DA A2), and at the highest concavity (HC) phase, including DA, peak distance (PD), radius (HCR), and DA ratio (DAR 1 and 2 mm), by Corvis ST. Central corneal thickness (CCT) and biomechanically corrected intraocular pressure (bIOP) were considered covariates in comparing DCR parameters between the two groups. Results: SSI was statistically significantly lower in eyes with GCD than in normal eyes (p = 0.04). The corneal velocity towards the first applanation was 0.02 m/s faster in the GCD eyes AV1 (0.15 ± 0.02 vs. 0.13 ± 0.02 m/s, p < 0.001) and IR (7.48 ± 1.01 vs. 6.80 ± 1.22 mm, p = 0.003) parameters were significantly higher in the GDC group, while AT1 (7.33 ± 0.66 vs. 7.47 ± 0.36 ms, p = 0.002) and HCR (7.42 ± 0.76 vs. 8.20 ± 1.08 mm, p = 0.014) were significantly lower in the normal group. Conclusions: GCD led to a change in biomechanical properties of the cornea. SSI refers to fewer stiff corneas in GDC than normal.

Histopathology Study of Patients with Delayed Mustard Gas Keratopathy 30 Years After Exposure.

Background & Objective: Delayed mustard gas keratopathy (DMGK) is the main chronic outcome in eye-chemical injured patients. The aim of this study was the histopathological evaluation of mustard-exposed cornea after more than 30 years. Methods: Fourteen corneas after Lamellar keratoplasty were evaluated in this study. Corneal tissues were prepared by histologic methods and stained by H&E. Results: The main histopathological findings in these cases were the presence of severe stromal edema and corneal scar. In the sections with visible superficial epithelium, subepithelial bullae formation was observed. Focal or diffuse disruption of Bowman's membrane and replacement with fibrosis were also seen. There was no evidence of stromal vascularization and inflammation in all specimens. Conclusion: After more than 30 years, an extensive corneal scar is seen in sulfur mustard exposed patients. Scar tissue without vascularization and fibroblastic proliferation is the main finding in the sulfur mustard exposed cornea. This pathology result is different from other scars. No evidence of inflammation or immune cell infiltration should be considered in managing DMGK.

Tear proteomics analysis of patient suffered from delayed mustard gas keratopathy.

Understanding the molecular and cellular mechanisms involved in the pathogenesis of ocular injured induced by mustard gas can help better identify complications and discover appropriate therapies. This study aimed to analyze the proteomics of tears of chemical warfare victims with mustard gas ocular injuries and compare it with healthy individuals. In this case-control research, 10 mustard gas victims with long-term ocular difficulties (Chronic) were included in the patient group, while 10 healthy persons who were age and sex matched to the patients were included in the control group. Schirmer strips were used to collect the tears of the participants. Proteomics experiments were performed using the high-efficiency TMT10X method to evaluate the tear protein profile, and statistical bioinformatics methods were used to identify the differently expressed proteins. 24 proteins had different expressions between the two groups. Among these 24 proteins, 8 proteins had increased expression in veterans' tears, while the remaining 16 proteins had decreased expression. Reactome pathways were used to look at proteins with various expressions, and 13 proteins were found to be engaged in the immune system, 9 of which were effective in the innate immune system, and 5 proteins were effective in the complement cascade. Ocular mustard gas exposure may cause a compromised immune system on the eye's surface, exposing the cornea to external and endogenous infections, and eventually causing corneal opacity and reduced vision.

Innovative intra-corneal ring-supported graft surgery for treatment of keratoconus and cornea regeneration: Surgical technique and case report.

Therapeutic options for corneal ectasia are evolving, with emphasis on the intra-stromal corneal ring for delaying or eliminating the need for penetrating keratoplasty. A 33-year-old man with grade 4 keratoconus and rising intolerance of the hard contact lens underwent a combination of a new innovative ring and graft with suture in the left eye. Excellent structural support and stability of the cornea were observed immediately post-operatively and 12 months after surgery. It appears as a feasible and safe therapy option for keratoconus eyes with reference to the instability and asymmetry of the cornea. Hence, as a safe and effective technique, it can be performed easily.

Emerging tissue engineering strategies for the corneal regeneration.

Cornea as the outermost layer of the eye is at risk of various genetic and environmental diseases that can damage the cornea and impair vision. Corneal transplantation is among the most applicable surgical procedures for repairing the defected tissue. However, the scarcity of healthy tissue donations as well as transplantation failure has remained as the biggest challenges in confront of corneal grafting. Therefore, alternative approaches based on stem-cell transplantation and classic regenerative medicine have been developed for corneal regeneration. In this review, the application and limitation of the recently-used advanced approaches for regeneration of cornea are discussed. Additionally, other emerging powerful techniques such as 5D printing as a new branch of scaffold-based technologies for construction of tissues other than the cornea are highlighted and suggested as alternatives for corneal reconstruction. The introduced novel techniques may have great potential for clinical applications in corneal repair including disease modeling, 3D pattern scheming, and personalized medicine.

Unusual presentation of corneal laceration in a post-LASIK eye following blunt trauma.

PURPOSE: To report a case with full thickness corneal laceration behind the intact LASIK flap after blunt trauma. OBSERVATIONS: A 48-year-old man with a history of LASIK surgery was hit by a shovel. Slit-lamp examination showed 4+ corneal edema. The anterior chamber (AC) was deep and the Seidel test was negative. Uncorrected distance visual acuity (UDVA) was hand motion. A more accurate evaluation was performed with an anterior segment optical coherence tomography (OCT) and it was found that the paracentral corneal tissue was ruptured while the flap remained completely intact. Under the surgical procedure, the rupture site was sutured, and then the flap was replaced, and two U-shaped sutures were performed to ensure the flap stability. Three months after surgery, corrected distance visual acuity (CDVA) was 9/10 decimal with a manifest refraction of +1-3 x 60°. CONCLUSIONS AND IMPORTANCE: In a traumatic post-LASIK eye, the posterior part of the flap should be carefully evaluated. The role of the OCT device in the diagnosis and management of complication is also very valuable.

The Role of Inflammatory Cytokines in Neovascularization of Chemical Ocular Injury.

AIM: Chemical injuries can potentially lead to the necrosis anterior segment of the eye, and cornea in particular. Inflammatory cytokines are the first factors produced after chemical ocular injuries. Inflammation via promoting the angiogenesis factor tries to implement the wound healing mechanism in the epithelial and stromal layer of the cornea. METHODS: Narrative review. RESULTS: In our review, we described the patterns of chemical injuries in the cornea and their molecular mechanisms associated with the expression of inflammatory cytokines. Moreover, the effects of inflammation signals on angiogenesis factors and CNV were explained. CONCLUSION: The contribution of inflammation and angiogenesis causes de novo formation of blood vessels that is known as the corneal neovascularization (CNV). The new vascularity interrupts cornea clarity and visual acuity. Inflammation also depleted the Limbal stem cells (LSCs) in the limbus causing the failure of normal corneal epithelial healing and conjunctivalization of the cornea.

Comparison of the effect of removing bandage contact lens on the days 3 and 5 following photorefractive keratectomy.

AIM: To compare the outcomes of removing bandage contact lens (BCL) on days 3 and 5 after photorefractive keratectomy (PRK). METHODS: One hundred patients who underwent PRK (a total of 200 eyes) were enrolled in the present study. The subjects were assigned to two groups. Group 1 consisted of the right eyes of subjects and bandage contact lenses removal were on the 3rd day; Group 2 consisted of the fellow eyes of same subjects and removed bandage contact lenses on the 5th day after PRK. Then, data obtained from both groups were compared. To evaluate complications, the subjects underwent a slit-lamp examination in all visits. RESULTS: Filamentary keratitis was observed in one eye in both groups. The frequency of haze was higher in group 1; however, it was not significant between the two groups. Using mixed model analysis, significant differences were observed in the rate of complications as well as pain and eye discomfort scores between the groups (P < 0.05). No major complication was reported. CONCLUSION: Majority of post-PRK corneal epithelial defect is healed on day 3. However, keeping BCL for 5 days postoperatively instead of the three days produces a slightly lower rate of total complication.

The assessment of the concentration of candidate cytokines in response to conjunctival-exposure of atmospheric low-temperature plasma in an animal model.

BACKGROUND: Atmospheric Low-Temperature Plasma (ALTP) can be used as an effective tool in conjunctival cyst ablation, but little is known about how conjunctival ALTP-exposure affects the concentration of inflammatory mediators and also the duration of inflammatory responses. METHODS: We used 8 female adult Lewis rats that were followed up in 4 groups. The right eye of each rat was selected for the test, whereas the left eye was considered as a control. The ALTP was generated and used to target 3 spots of the conjunctiva. The digital camera examinations were performed to follow-up the clinical outcomes after ALTP exposure. Tear and serum samples were isolated-at 2 days, 1 week, 1 month, and 6 months after treatment-from each rat and the concentration of candidate pro-inflammatory (i.e. IL-1α, IL-2, IL-6, IFN-γ, and TNF-α) and anti-inflammatory cytokines (i.e. IL-4 and IL-10) were measured using flow cytometry. RESULTS: The external and digital camera examinations showed no ocular surface complications in all ALTP-exposed rats after 1 week. The analyses revealed that the ALTP transiently increases the concentration of pro-inflammatory cytokines-IL-1α and IL-2 in tear samples in 1 week and 2 days after exposure, respectively; no differences were observed regarding other pro- and anti-inflammatory cytokines in the tear or serum samples. CONCLUSIONS: ALTP can probably be used as a minimally-invasive therapeutic method that triggers no permanent or continual inflammatory responses. The results of this study might help the patients to shorten the consumption of immunosuppressive drugs, e.g. corticosteroids, that are prescribed to mitigate the inflammation after ALTP-surgery.

Safety evaluation of the atmospheric low-temperature plasma (ALTP) on the conjunctiva: an animal study and histopathological findings; 6-month follow-up.

BACKGROUND: Plasma medicine is an innovative research field focused on the application of atmospheric-pressure low-temperature plasmas (ALTP) for therapeutic purposes. Considering the potentials of plasma in ophthalmology, in this study, we evaluated the safety of plasma on the conjunctival tissue in animal models for 6 months. METHODS: Twelve adult male New Zealand albino rabbits were divided into four groups. The right eye of each rabbit was chosen for the test and the left eye was considered as the control. Experiments were performed using the Plexr device (GMV, Rocca Priora, RM, Italy). Four plasma spots were applied on the superior part of the conjunctiva (from 10 to 2 o'clock positions) using the continuous mode and a low power level (white handpiece) of the Plexr. For evaluation of the plasma safety, the histopathological changes were assessed 1 week (A), 1 month (B), 3 months (C), and 6 months (D) after the intervention. RESULTS: According to the histopathological findings, a mild decrease in blood vessels and severe stromal edema, as well as a superficial epithelium loss, were observed in group A. No chronic inflammation, scar tissue, deposition, and hemorrhage were found in group B. Epithelialization was confirmed by the histological examinations after 1 month. There was no evidence of atypia or dysplasia after 3 and 6 months. CONCLUSION: In conclusion, there were no persistent histopathological changes on conjunctival tissue after plasma exposure. Then, plasma can be considered as a minimally invasive alternative method for treating some ocular surface disorders.

Application of mesenchymal stem cells in corneal regeneration.

Due to delicate its structure, the cornea is susceptible to physical, chemical, and genetic damages. Corneal transplantation is the main treatment for serious corneal damage, but it faces significant challenges, including donor shortages and severe complications. In recent years, cell therapy is suggested as a novel alternative method for corneal regeneration. Regarding the unique characteristics of Mesenchymal stem cells including the potential to differentiate into discrete cell types, secretion of growth factors, mobilization potency, and availability from different sources; special attention has been paid to these cells in corneal engineering. Differentiation of MSCs into specialized corneal cells such as keratocytes, epithelial and endothelial cells is reported. Potential for Treatment of keratitis, reducing inflammation, and inhibition of neovascularization by MSCs, introducing them as novel agents for corneal repairing. In this review, various types of MSCs used to treat corneal injuries as well as their potential for restoring different corneal layers was investigated.