Current state of endothelial cell therapy.

PURPOSE OF REVIEW: Currently, there is heightened interest surrounding endothelial cell therapy for the treatment of corneal edema. The purpose of this review article is to describe and summarize the background information as well as the research surrounding the emerging treatment modalities for endothelial cell therapy. RECENT FINDINGS: Marked advancements have been made in the translational research in this area, and increasing refinements have been demonstrated in the treatment protocols for cell therapy. Human clinical trials in this field are ongoing, specifically, in the area of injected human corneal endothelial cells (HCECs), with early results showing favorable safety and efficacy profiles. SUMMARY: Efficient and effective delivery of HCECs to patients with corneal edema and dysfunction now appears feasible, and the results from ongoing human clinical trials are much anticipated. Adjunct therapeutics-in the form of pharmacological agents and/or surgical techniques, such as descemetorhexis-will likely continue to play an important role in defining the future of endothelial cell therapy.

Corneal Hydrops - Aetiology and Advanced Therapeutic Strategies. / Der korneale Hydrops ­ Ursachen und moderne Therapieansätze.

Acute hydrops refers to sudden corneal edema caused by rupture of Descemet's membrane (DM) - often in progressive keratectasia. It leads to a sudden decrease in visual acuity, pain, and foreign body sensation as well as an increased glare sensation. Acute hydrops usually heals with scarring within months, but complications such as corneal perforation, infectious keratitis, and corneal vascularization may occur. The prevalence in keratoconus patients is 2.6 to 2.8%. Risk factors include keratoconjunctivitis vernalis, atopic dermatitis, high keratometry, male gender, and eye rubbing. Keratoplasty should be avoided in the acute phase. The prognosis of the graft is reduced, and after scar healing of the hydrops, wearing contact lenses or glasses may be possible again. Conservative therapy alone with lubricants and hyperosmolar eye drops, prophylactic antibiotic eye drops to prevent superinfection, and topical steroids was long considered the only possible form of treatment. However, healing under conservative therapy takes an average of over 100 days. In the meantime, there are different surgical strategies that rapidly shorten the healing and thus the recovery phase of the patients to a few days. If the DM is detached without tension, a simple injection of gas into the anterior chamber can already lead to reattachment and thus to almost immediate deswelling of the cornea. If the DM is under tension, predescemetal sutures combined with a gas injection into the anterior chamber can flatten the cornea and reattach the DM. Mini-Descemet membrane endothelial keratoplasty (mini-DMEK) allows for sutureless closure of the DM defect by transplantation of a small (< 5 mm) graft. In cases of particularly large DM tears and very pronounced hydrops, suture loosening and relapse may occur after the placement of predescemetal sutures. Mini-DMEK can then lead to permanent healing, but in contrast to simple corneal sutures, it is usually performed under general anesthesia and by aid of intraoperative optical coherence tomography. The very good results with regard to the rapid healing prove that surgical therapy makes sense in the vast majority of patients with acute hydrops and should be initiated quickly.

Corneal Oedema: Aetiology, Diagnostic Testing, and Treatment.

Corneal oedema results from an underlying pathology, which can be diverse in origin, and may be mechanical, dystrophic, or inflammatory, and affect any layer of the cornea. Diagnostic tools such as Scheimpflug imaging and anterior segment optical coherence tomography have standardised quantification of corneal oedema and have become important aids in clinical practice. Timely diagnosis and treatment are key to preventing irreversible damage to the corneal ultrastructure, such as anterior corneal fibrosis or endothelial cell damage. The oedema usually resolves quickly when the underlying cause has been addressed. Symptomatic treatment using hyperosmolar agents has failed to show any benefits in oedema resolution or improvement in visual acuity compared to placebo. In contrast, rho-associated protein kinase (ROCK) inhibitors offer a promising option for medical treatment in cases of endothelial dysfunction, but their safety and efficacy must be further validated in large scale clinical trials. Until then, endothelial or penetrating keratoplasties remain the mainstay treatment where structural changes to the cornea have occurred.

Five-Year Follow-up of First 11 Patients Undergoing Injection of Cultured Corneal Endothelial Cells for Corneal Endothelial Failure.

PURPOSE: To report the safety and efficacy of a novel cell injection therapy using cultured human corneal endothelial cells (hCECs) for endothelial failure conditions via the report of the long-term 5-year postoperative clinical data from a first-in-humans clinical trial group. DESIGN: Prospective observational study. PARTICIPANTS: This study involved 11 eyes of 11 patients with pseudophakic endothelial failure conditions who underwent hCEC injection therapy between December 2013 and December 2014. METHODS: All patients underwent follow-up examinations at 1 week, 4 weeks, 12 weeks, and 24 weeks and 1 year, 2 years, 3 years, 4 years, and 5 years after surgery. Specific corneal endothelial cell parameters (i.e., corneal endothelial cell density [ECD], coefficient of variation of area, and percentage of hexagonal cells) and central corneal thickness, best-corrected visual acuity (BCVA) on a Landolt C eye chart, and intraocular pressure (IOP) were recorded. MAIN OUTCOME MEASURES: The primary outcome was the change in central ECD after cell injection therapy, and the secondary outcome was corneal thickness, BCVA, and IOP during the 5-year-postoperative follow-up period. RESULTS: At 5 years after surgery, normal corneal endothelial function was restored in 10 of the 11 eyes, the mean ± standard deviation central corneal ECD was 1257 ± 467 cells/mm2 (range, 601-2067 cells/mm2), BCVA improved significantly in 10 treated eyes, the mean visual acuity changed from 0.876 logarithm of the minimum angle of resolution before surgery to 0.046 logarithm of the minimum angle of resolution after surgery, and no major adverse reactions directly related to the hCEC injection therapy were observed. CONCLUSIONS: The findings in this study confirmed the safety and efficacy of cultured hCEC injection therapy for up to 5 years after surgery.

Efficacy of Anterior Stromal Puncture Surgery with Corneal Bandage Lens for Bullous Keratopathy.

Objective: To investigate the safety and efficacy of the combination therapy of anterior stromal puncture (ASP) with bandage contact lens for bullous keratopathy (BK). Methods: Twelve cases (12 eyes) with vision acuity no better than light perception were treated with ASP surgery and bandage contact lens. 200 points punctures were made through the corneal epithelium and Bowman's layer vertically, using fine needles. A soft bandage contact lens was applied immediately and removed 2 weeks later. The severity of irrigating symptoms including pain, photophobia and tearing was graded and calculated before treatment and 1, 2, 4, 12 weeks after the surgery, slit-lamp microscope examination was used to quantify the time for corneal epithelial blisters disappearing, optical coherence tomography (OCT) was used to monitor the central corneal thickness. Results: No cornea infection was observed during the following up period. The average grade scores of the irrigating symptoms was 8.3 ± 2.1 before surgery, while it was reduced to 4.8 ±1.9 two weeks after the surgery (p=0.0003). Slit-lamp microscope examination showed that corneal edema relieved obviously after the operation, the average time for epithelial blisters disappearing was 15.6 ± 4.0 days. The average central corneal thickness of the eyes was 999.3 ±278.0 µm before the treatment, while it was 805.1 ± 145.0 µm four weeks after the treatment, with a statistically significant difference (p=0.043). Conclusions: ASP with bandage contact lens is an effective and safe treatment for patients with BK and low vision that not suitable for corneal transplantation.

Recurrent Corneal Erosions in Corneal Dystrophies: a Review of the Pathogenesis, Differential Diagnosis, and Therapy.

INTRODUCTION: Recurrent corneal erosions in corneal dystrophies are visually significant and bothersome to patients. The goal of this article is to review the pathogenesis, differential diagnosis, and management of recurrent corneal erosions in corneal dystrophies. PATIENTS AND METHODS: Forty-eight articles and 1 textbook recently published on corneal erosions in corneal dystrophies were reviewed. The findings on the pathogenesis and clinical characteristics of erosions in each dystrophy were summarized. Any contradicting opinions for which the literature was unclear were either omitted or recorded as lacking strong evidence. RESULTS AND CONCLUSIONS: The epithelial-stromal complex plays an important role in the pathogenesis of erosions in corneal dystrophies. The clinical features of each corneal dystrophy guide their diagnosis and management. A better understanding of the pathogenesis and clinical features of erosions in corneal dystrophies can lead to better clinical outcomes.

Characterization and Prospective of Human Corneal Endothelial Progenitors.

Corneal endothelial cells play a critical role in maintaining corneal transparency and dysfunction of these cells caused by aging, diseases (such as Fuch's dystrophy), injury or surgical trauma, which can lead to corneal edema and blindness. Due to their limited proliferative capacity in vivo, the only treatment method is via transplantation of a cadaver donor cornea. However, there is a severe global shortage of donor corneas. To circumvent such issues, tissue engineering of corneal tissue is a viable option thanks to the recent discoveries in this field. In this review, we summarize the recent advances in reprogramming adult human corneal endothelial cells into their progenitor status, the expansion methods and characteristics of human corneal endothelial progenitors, and their potential clinical applications as corneal endothelial cell grafts.

Management of corneal decompensation 4 decades after Sputnik intraocular lens implantation.

OBJECTIVES: We report an unusual case of corneal decompensation occurring four decades after complicated cataract extraction with implantation of a Sputnik intraocular lens (IOL) and highlight the clinical and practical issues faced in managing corneal decompensation with a Sputnik IOL. METHODS: A 72-year-old woman presented with deterioration of the vision in her left eye, four decades after intracapsular cataract extraction with Sputnik IOL implantation. Ocular examination revealed diffuse corneal edema and thickened vitreous strands in the anterior chamber. Her best-corrected visual acuity (BCVA) worsened to 6/60 within 3 months. Anterior vitrectomy and inferior iridectomy combined with Desçemet-stripping automated endothelial keratoplasty was performed. RESULTS: The procedure was successful, with the patient achieving best-corrected visual acuity of 6/6 at 8 months postoperatively. CONCLUSION: Corneal decompensation after Sputnik IOL implantation can occur four decades later. When the historical preoperative visual acuity is good in such cases, careful anterior vitrectomy with Desçemet-stripping automated endothelial keratoplasty provides good visual rehabilitation.

Toxic anterior segment syndrome (TASS): A review and update.

Toxic anterior segment syndrome (TASS) is an acute, sterile, postoperative inflammatory reaction of the anterior segment without vitreous involvement, following an uncomplicated and uneventful ocular surgery, having broad and multiple etiologies. The symptoms of decreased visual acuity and ocular discomfort generally occur within the first 12-48 h after intraocular surgery. The clinical signs include prominent limbus-to-limbus corneal edema, anterior chamber cells, aqueous flare, fibrinous inflammation, and/or keratic precipitates. There can be sight-threatening complications of TASS, such as permanent corneal decompensation, intractable glaucoma, and cystoid macular edema. The causes of TASS are emerging and being reported, so are the newer treatment options for managing the inflammation and its complications. Prevention guidelines for TASS are being updated, and a traceability system for surgical instruments and intraocular fluids used during the surgery is being perpetually developed. It is important to recognize TASS and start treatment on an immediate effect. Hereby, we review the literature on TASS, emphasizing its etiology, pathophysiology, management, prognosis, complications, and the importance of prevention as well as prompt recognition.

Management of acute corneal hydrops - Current perspectives.

Acute corneal hydrops (ACH) is a rare but sight-threatening complication of corneal ectasias. We aim to review the current literature on etiopathogenesis, histology, role of ancillary investigations, management, and outcomes of ACH by classifying the various management strategies based on their site of action and the underlying mechanism. A review of the literature was conducted by searching the following databases: PubMed (United States National Library of Medicine), Embase (Reed Elsevier Properties SA), Web of Science (Thomson Reuters), and Scopus (Elsevier BV) till April 2023. The literature search used various combinations of the following keywords: acute corneal hydrops, keratoconus, ectasia, management, keratoplasty. Nine hundred eighty-three articles were identified based on the above searches. Case reports which did not add any new modality of treatment to the existing literature, articles unrelated to management, those with no full text available, and foreign-language articles with no translation available were excluded. Eventually, 75 relevant articles that pertained to the management of ACH were shortlisted and reviewed. Recent studies have described newer surgical interventions like full-thickness or pre-Descemetic sutures, thermokeratoplasty, and plasma injection that aim to close the posterior stromal break. Posterior lamellar keratoplasties act by replacing the posterior torn Descemet's membrane (DM), and early deep anterior lamellar keratoplasty (DALK) has been attempted to combine the correction of the anatomical defect and visual rehabilitation in a single surgery. These surgical interventions may help by reducing the scarring and increasing the number of patients who can be visually rehabilitated with contact lenses rather than keratoplasty.

The impact of postoperative nasal oxygen therapy on early-stage corneal edema in cataract patients with dynamic Scheimpflug analyze: A retrospective study.

This study aimed to assess the impact of 6 hours of postoperative nasal oxygen therapy on early-stage corneal edema in patients with nuclear cataracts of grades 3 to 4. A retrospective study involved 49 patients (49 eyes) with grades 3 to 4 nuclear cataracts undergoing phacoemulsification and intraocular lens implantation from September 2021 to September 2022. The oxygen group (27 cases) received postoperative nasal oxygen therapy for 6 hours, while the control group (22 cases) received no additional treatment. Corneal edema was evaluated 24 hours postoperatively using a slit lamp microscope, recording the edema degree. The Pentacam anterior segment analyzer measured central corneal thickness (CCT), corneal volume (CV), and corneal optical density (COD) values preoperatively and 24 hours postoperatively. The study enrolled 49 patients. Preoperatively, there were no significant differences between the 2 groups. The oxygen group and the control group exhibited significant differences in CCT, CV, and corneal optical density values before and after surgery for intragroup comparison (all P < .05). At 24 hours postoperatively, the proportion of grade 0 corneal edema in the oxygen therapy group was 59.3%, compared to 31.8% in the control group, with no statistically significant difference (P > .05). The postoperative logMAR visual acuity in the oxygen therapy group was 0.0969 (0.0969, 0.2218), and in the control group it was 0.0969 (0.2218, 0.3979), with a statistically significant difference (P < .05). In oxygen group, the CCT, CV were 585.00 (553.00, 604.00), 68.0 (61.9, 71.3) respectively, all significantly lower than 603.50 (578.50, 788.25), 73.05 (65.3, 75.73) (all P < .05). Statistically significant differences were found in overall COD, COD within specific depth and thickness ranges, and COD within the anterior layer (120 µm thickness) at 24 hours postoperatively (all P < .05). No significant difference was observed in COD values within the central and posterior layers (60 µm thickness) between the 2 groups (all P > .05). Postoperative nasal oxygen therapy for 6 hours immediately after surgery could alleviate the severity of early-stage corneal edema in patients with nuclear cataracts of grades 3 to 4.

[Personalized cell therapy for early postoperative bullous keratopathy (experimental proof and clinical results)].

The article presents the results of a long-term research on development and clinical application of personalized cell therapy (PCT) for treatment of early postoperative (manifesting within the first 3 months after surgery) bullous keratopathy (BK). The method of intracameral PCT implies in vitro incubation of the patient's blood sample with poly(A:U) stimulator, separation of the serum with activated leukocytes, and injection of the final cell preparation into the anterior chamber. The fundamental part of the research was aimed at a detailed description of the cell preparation and investigation of its possible mechanisms of action. Cytokine and growth factor level in the cell preparation suggested that its high clinical efficacy might be due to its ability to improve regeneration of damaged corneal endothelium. The clinical study was conducted on a group of 52 patients with early BK. A significant effect (smoothing of the Descement's membrane folds, complete resorption of corneal edema, improvement of corneal transparency, reduction of corneal thickness and increase of visual acuity by 0.49 +/- 0.27) was achieved in 44.2% of patients, while partial effect was seen in 21.1% of patients. There was no clinical effect in 34.6% of patients. In those patients who developed significant or partial clinical effect after the PCT, many endotheliocytes appeared to have multiple nuclei (2 and more). In some patients polyploid nuclei persisted for 3-5 years after the treatment. Polyploidy results from incomplete mitosis which might be due to regenerative processes in the endothelium stimulated by the PCT. Obviously, high efficacy and relative simplicity of the method should promote its further clinical introduction.

Management of acute corneal hydrops in ectatic corneal disorders.

PURPOSE OF REVIEW: The purpose of this review is to outline the risk factors, clinical features, diagnosis, and management of acute corneal hydrops in corneal ectatic disorders. RECENT FINDINGS: The advent of newer investigative modalities aids in diagnosis and planning of treatment in cases of acute hydrops. Although visual outcome does not differ with intervention such as intracameral air/gas injection the duration of symptoms and the risk of complications decrease in comparison with medical therapy alone. SUMMARY: The intent of this article is to highlight the various risk factors and the newer diagnostic modalities such as ultra biomicroscopy, anterior segment optical coherence tomography and confocal microscopy in cases of acute corneal hydrops. Further, the conventional as well as the newer treatment modalities are also described. Although newer diagnostic and treatment modalities are found to be useful, the available information in literature is limited. This article will encourage future prospective studies and randomized controlled trials, which may help in finding novel diagnostic and effective therapeutic techniques.

[Vital confocal microscopy in evaluation of efficacy of personalized cell therapy in management of early postoperative bullous keratopathy].

The results of vital confocal microscopy (VCM) of 5 patients with early postoperative bullous keratopathy after cataract phakoemulsification (PE) treated with author's technique of personalized cell therapy (PCT, intracameral injection of activated patient's leukocytes in autologous serum) are presented. In 3 of all presented cases endothelial loss after PE was more than 50%. Before PCT using of VCM was not possible due to corneal edema. After 2-3 PCT sessions corneal clarity recovery was observed and signs of regenerative processes in cornea were captured by VCM: activation of keratocytes (hyperreflective nuclei) and endothelial cells (multinucleated cells), descemet membrane folds smoothening, normalization of epithelium. Results of VCM correlate with biomicroscopic signs of corneal edema resolution, corneal clarity recovery, improvement of visual acuity after PCT.

Successful treatment of recurrent epithelial ingrowth associated with interface fluid syndrome, flap necrosis, and epithelial defects following LASIK.

PURPOSE: to report the successful treatment of two patients who developed flap necrosis preceded by recurrent epithelial ingrowth and interface fluid syndrome after LASIK. METHODS: patient 1 was treated with epithelial debridement and flap suturing. Patient 2 was initially treated with epithelial debridement and flap suturing, but developed recurrent epithelial ingrowth in the right eye and 2 weeks later in the left eye. RESULTS: patient 1 developed diffuse interface fluid accumulation in the left eye after epithelial debridement and flap suturing and was treated with timolol meleate 0.5% solution and methazolamide. The interface fluid resolved and the cornea and flap became clear. Slit-lamp examination identified a small area of epithelial ingrowth recurrence, which has remained stable for 3 years. Patient 2 was successfully retreated with epithelial debridement followed by fibrin tissue adhesive application. Five months after debridement and fibrin tissue adhesive, no recurrence of epithelial ingrowth or interface fluid accumulation was noted. CONCLUSIONS: epithelial ingrowth and interface fluid syndrome may be associated with secondary flap necrosis following LASIK, which can be effectively treated with debridement and flap suturing or fibrin tissue adhesive application.

[The value of anterior stromal puncture in the treatment of bullous keratopathy].

Results of anterior stromal puncture (ASP) in treatment of painful bullous keratopathy (PBK) are presented and its mechanism of action is hypothesized. ASP is an effective, simple, safe and low-cost procedure for symptomatic relief in patients with PBK.

Transplantation of iPSC-derived corneal endothelial substitutes in a monkey corneal edema model.

OBJECTIVE: In order to provide regenerative therapy for millions of patients suffering from corneal blindness globally, we derived corneal endothelial cell substitute (CECSi) cells from induced pluripotent stem cells (iPSCs) to treat corneal edema due to endothelial dysfunction (bullous keratopathy). METHODS AND RESULTS: We developed an efficient xeno-free protocol to produce CECSi cells from both research grade (Ff-MH09s01 and Ff-I01s04) and clinical grade (QHJI01s04) iPSCs. CECSi cells formed a hexagonal confluent monolayer with Na, K-ATPase alpha 1 subunit expression (ATP1A1), tight junctions, N-cadherin adherence junction formation, and nuclear PITX2 expression, which are all characteristics of corneal endothelial cells. CECSi cells can be cryopreserved, and thawed CECSi cell suspensions also expressed N-cadherin and ATP1A1. Residual undifferentiated iPSCs in QHJI01s04-derived CECSi cells was below 0.01%. Frozen stocks of Ff-I01s04- and QHJI01s04-derived CECSi cells were transported, thawed and transplanted into a monkey corneal edema model. CECSi-transplanted eyes significantly reduced corneal edema compared to control group. CONCLUSION: Our results show a promising approach to provide bullous keratopathy patients with an iPS-cell-based cell therapy to recover useful vision.

Treatment strategies for the management of acute hydrops.

Acute corneal hydrops is a condition characterized by marked stromal edema attributable to leakage of aqueous humor through a rupture in Descemet's membrane. In addition to the clinical examination, imaging options include ultrasound biomicroscopy, anterior segment optical coherence tomography and in vivo confocal microscopy. While it is a self-limiting condition, the duration of acute hydrops is an important factor linked to complications such as neovascularization. Therapeutic options may relieve symptoms and/or reduce healing time; these include conservative, medical and/or surgical therapies. Several new medical and surgical management options have been reported in the past few years and will be discussed in this article.

Effectiveness of Pulmonary Surfactant in the Treatment of Corneal Edema.

Purpose: To compare the effectiveness of topical surfactant and 3% sodium chloride (NaCl) in the treatment of corneal edema occurring after cataract surgery. Methods: Ninety eyes of 90 patients with no corneal disease who underwent cataract surgery were included in the study. Thirty eyes without corneal edema comprised group 1. Patients with corneal edema were divided into two groups: those treated with 3% NaCl (group 2, 30 eyes) and those treated with surfactant drop (group 3, 30 eyes). Results: The mean age was 70.8 ± 6.6 years, with no significant age difference between the groups. Preoperatively, there was no significant difference in mean central corneal thickness (CCT) or mean endothelial cell count (ECC) among the groups (P = 0.999). On postoperative day 1, CCT was significantly lower in group 1 (P < 0.001) but did not differ between groups 2 and 3 (P = 0.999). There was no significant difference between groups in terms of ECC (P > 0.05). At postoperative day 7 and 14, CCT differed significantly between groups 1 and 2 (P < 0.001) and between groups 2 and 3 (P = 0.001), with no significant difference between groups 1 and 3 (P = 0.474). ECC was significantly higher in group 1 (P < 0.05), whereas there was no significant difference between groups 2 and 3 (P > 0.05). Conclusion: Topical pulmonary surfactant may be a more effective treatment option than 3% hypertonic NaCl for the treatment of corneal edema that develops after cataract surgery.

[When cataracts lead to a corneal transplant]. / Quand la cataracte conduit à une greffe de la cornée.

The eye has two converging lenses arranged in series: the cornea and the lens. They combine their powers. The image, which is naturally defocused ad infinitum, by crossing them successively, focuses on the retina to be seen clearly. Edema can cause the cornea to lose transparency while the clouding of lens leads to cataract. The loss of transparency of one or both lenses significantly affects the vision. Treating cataracts is a common practice. However, this can lead to the permanent loss of transparency of the cornea. A graft of the latter must then be carried out. How does this sometimes come about?

TITLE: Quand la cataracte conduit à une greffe de la cornée. ABSTRACT: L'œil possède deux lentilles convergentes disposées en série : la cornée et le cristallin. Elles associent leurs puissances. L'image qui est naturellement défocalisée à l'infini, en les traversant successivement, se focalise sur la rétine pour être vue nette (Figure 1). Un œdème peut faire perdre sa transparence à la cornée tandis que le cristallin qui s'opacifie constitue la cataracte. La perte de transparence de l'une ou des deux lentilles affecte la vue significativement. Traiter la cataracte est une pratique banale. Cependant, ceci peut conduire à la perte définitive de transparence de la cornée. Il faut alors réaliser une greffe de cette dernière. Comment en vient-on parfois à cela ?