Assessment of the Predictive Ability of Theranostics for Corneal Cross-linking in Treating Keratoconus: A Randomized Clinical Trial.

PURPOSE: To validate the ability of theranostic imaging biomarkers in assessing corneal cross-linking (CXL) efficacy in flattening the maximum keratometry (Kmax) index. DESIGN: Prospective, randomized, multicenter, masked clinical trial (ClinicalTrails.gov identifier, NCT05457647). PARTICIPANTS: Fifty patients with progressive keratoconus. INTERVENTION: Participants were stratified to undergo epithelium-off (25 eyes) and epithelium-on (25 eyes) CXL protocols using an ultraviolet A (UV-A) medical device with theranostic software. The device controlled UV-A light both for performing CXL and assessing the corneal riboflavin concentration (riboflavin score) and treatment effect (theranostic score). A 0.22% riboflavin formulation was applied onto the cornea for 15 minutes and 20 minutes in epithelium-off and epithelium-on protocols, respectively. All eyes underwent 9 minutes of UV-A irradiance at 10 mW/cm2. MAIN OUTCOME MEASURES: The primary outcome measure was validation of the combined use of theranostic imaging biomarkers through measurement of their accuracy (proportion of correctly classified eyes) and precision (positive predictive value) to classify eyes correctly and predict a Kmax flattening at 1 year after CXL. Other outcome measures included change in Kmax, endothelial cell density, uncorrected and corrected distance visual acuity, manifest spherical equivalent refraction and central corneal thickness 1 year after CXL. RESULTS: Accuracy and precision of the theranostic imaging biomarkers in predicting eyes that had >0.1 diopter (D) of Kmax flattening at 1 year were 91% and 95%, respectively. The Kmax value significantly flattened by a median of -1.3 D (IQR, -2.11 to -0.49 D; P < 0.001); both the uncorrected and corrected distance visual acuity improved by a median of -0.1 logarithm of the minimum angle of resolution (logMAR; IQR, -0.3 to 0.0 logMAR [P < 0.001] and -0.2 to 0.0 logMAR [P < 0.001], respectively). No significant changes in endothelial cell density (P = 0.33) or central corneal thickness (P = 0.07) were noted 1 year after surgery. CONCLUSIONS: The study demonstrated the efficacy of integrating theranostics in a UV-A medical device for the precise and predictive treatment of keratoconus with epithelium-off and epithelium-on CXL protocols. Concentration of riboflavin and its UV-A light mediated photoactivation in the cornea are the primary factors determining CXL efficacy. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A Systematic Quality Assessment of Online Resources on Eyelid Ptosis Using the Modified Ensuring Quality Information for Patients (mEQIP) Tool.

BACKGROUND: Eyelid ptosis is an underestimated pathology deeply affecting patients' quality of life. Internet has increasingly become the major source of information regarding health care, and patients often browse on websites to acquire an initial knowledge on the subject. However, there is lack of data concerning the quality of available information focusing on the eyelid ptosis and its treatment. We systematically evaluated online information quality on eyelid ptosis by using the "Ensuring Quality Information for Patients" (EQIP) scale. MATERIALS AND METHODS: Google, Yahoo and Bing have been searched for the keywords "Eyelid ptosis," "Eyelid ptosis surgery" and "Blepharoptosis." The first 50 hits were included, evaluating the quality of information with the expanded EQIP tool. Websites in English and intended for general non-medical public use were included. Irrelevant documents, videos, pictures, blogs and articles with no access were excluded. RESULTS: Out of 138 eligible websites, 79 (57,7%) addressed more than 20 EQIP items, with an overall median score of 20,2. Only 2% discussed procedure complication rates. The majority fail to disclose severe complications and quantifying risks, fewer than 18% clarified the potential need for additional treatments. Surgical procedure details were lacking, and there was insufficient information about pre-/postoperative precautions for patients. Currently, online quality information has not improved since COVID-19 pandemic. CONCLUSIONS: This study highlights the urgent requirement for improved patient-oriented websites adhering to international standards for plastic and oculoplastic surgery. Healthcare providers should effectively guide their patients in finding trustworthy and reliable eyelid ptosis correction information. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A randomized clinical trial assessing theranostic-guided corneal cross-linking for treating keratoconus: the ARGO protocol.

The Assessment of theranostic guided riboflavin/UV-A corneal cross-linking for treatment of keratoconus (ARGO; registration number NCT05457647) clinical trial tests the hypothesis that theranostic-guided riboflavin/UV-A corneal cross-linking (CXL) can provide predictable clinical efficacy for halting keratoconus progression, regardless of treatment protocol, i.e., either with or without epithelial removal. Theranostics is an emerging therapeutic paradigm of personalized and precision medicine that enables real-time monitoring of image-guided therapy. In this trial, the theranostic software module of a novel UV-A medical device will be validated in order to confirm its accuracy in estimating corneal cross-linking efficacy in real time. During CXL procedure, the theranostic UV-A medical device will provide the operator with an imaging biomarker, i.e., the theranostic score, which is calculated by non-invasive measurement of corneal riboflavin concentration and its UV-A light mediated photo-degradation. ARGO is a randomized multicenter clinical trial in patients aged between 18 and 40 years with progressive keratoconus aiming to validate the theranostic score by assessing the change of the maximum keratometry point value at 1-year postoperatively. A total of 50 participants will be stratified with allocation ratio 1:1 using a computer-generated stratification plan with blocks in two treatment protocols, such as epithelium-off or epithelium-on CXL. Following treatment, participants will be monitored for 12 months. Assessment of safety and performance of theranostic-guided corneal cross-linking treatment modality will be determined objectively by corneal tomography, corneal endothelial microscopy, visual acuity testing and slit-lamp eye examination.

Outcomes of serial sessions of Activa mask combined with intense pulsed light therapy in patients with Meibomian gland dysfunction.

BACKGROUND: To evaluate the effects on ocular surface signs and symptoms of serial sessions of heating and vibrating eye mask followed by intense pulsed light (IPL) therapy for the treatment of dry eye disease owing to meibomian gland dysfunction (MGD). METHODS: Consecutive patients with MGD whose signs and symptoms were not satisfactorily controlled with conventional therapy were included. Patients received 3 treatments performed at day 1, 15, and 45 incorporating a session with a newly-developed eye mask (Activa, SBS Sistemi, Turin, Italy) immediately followed by IPL therapy (E > Eye device, E-Swin, Paris, France). Patients were examined before the first session (T0) and 30 days after the last session (T1) for the measurement of: noninvasive break-up time (NIBUT); lipid layer thickness (LLT); tear meniscus height (TMH); meibomian gland loss (MGL); tear osmolarity. Ocular discomfort symptoms were ascertained by ocular surface disease index (OSDI) questionnaire. RESULTS: Thirty patients were ultimately included in the study. At T1, all objective ocular surface parameters improved significantly, except for TMH: NIBUT and LLT increased from 6.4 ± 1.7 to 8.6 ± 1.7 s and from 57.7 ± 15.5 to 81.3 ± 12.0 µm (all P < 0.001), while MGL and tear osmolarity decreased from 21.1 ± 17.3 to 17.0 ± 14.1% and from 302.0 ± 8.5 to 295.7 ± 6.9 mOsm/L (respectively, P = 0.004 and P < 0.001). In parallel, OSDI score decreased significantly from 49.8 ± 13.5 to 29.8 ± 10.6 (P < 0.001). In the historical control group of patients who underwent only IPL, NIBUT, LLT, tear osmolarity and OSDI improved significantly but not MGL and TMH. CONCLUSIONS: Serial sessions incorporating the application of an eye mask producing heating and vibration immediately followed by IPL therapy are able to improve all ocular surface parameters as well as ocular discomfort symptoms in MGD patients.

Retinal microcirculation abnormalities in patients with systemic sclerosis: an explorative optical coherence tomography angiography study.

OBJECTIVES: To investigate subclinical and clinical abnormalities in retinal and choroidal vascular plexuses in patients with SSc by means of optical coherence tomography angiography (OCT-A). METHODS: A total of 20 consecutive SSc patients were recruited and compared with 20 healthy subjects. Quantitative analysis of vessel density (VD), choriocapillaris plexus flow index (CCP-FI) and choroidal vascularity index were performed on OCT-A images in the superficial capillary plexus (SCP), deep capillary plexus (DCP) and CCP for all patients. Images were further reviewed by two independent readers for the assessment of qualitative abnormalities, including tortuosity, rarefaction areas, megacapillaries and macular-foveal capillaries. RESULTS: The DCP-VD in the whole scan and in the perifoveal, superior, inferior, nasal and temporal regions was significantly lower in the SSc group. The CCP-FI was significantly higher in SSc patients. When comparing SSc patients with and without digital ulcers, significantly decreased SCP-VD was demonstrated in the whole, perifoveal, superior, inferior, temporal and nasal regions. No difference in any of the OCT-A parameters was observed when comparing patients with and without interstitial lung disease. Qualitative analysis of OCT-A revealed at least one abnormality in 95% of patients. CONCLUSION: We showed the ability of OCT-A to disclose early ocular vascular abnormalities in patients with SSc. Our results may represent a hypothesis-generating basis for exploring the potential role of OCT-A in diagnosis, monitoring and prognosis stratification in SSc.

Automated digital analysis of intraoperative keratoscopy and its correlation with postoperative astigmatism after big-bubble deep anterior lamellar keratoplasty.

PURPOSE: To investigate the correlation between postoperative corneal astigmatism (PCA) and values of intraoperative keratoscopy analyzed with a newly developed automated technique in patients undergoing big-bubble (BB) deep anterior lamellar keratoplasty (DALK). METHODS: Photographs of keratoscope rings taken at the end of BB-DALK were analyzed using ImageJ for the calculation of "roundness" (R): values = 1 indicate a perfect circle. Pearson's correlation was used to evaluate the relationship between R and PCA that measured 1 week (V1), 3 months (V2), and 18 months (V3), postoperatively. The area under the curve (AUC) of receiver operating characteristic (ROC) curve was used to evaluate the accuracy of R for identifying patients with PCA < 3 diopters (D). The point on the ROC curve nearest to the coordinate (0,100) was used as a cutoff to determine sensitivity and specificity. RESULTS: Data from 121 patients were included. The mean value of R*was 0.93 ± 0.04 (range 0.76-0.99). R showed a significant correlation with PA at V3 (R = - 0.42, P < 0.01). The ROC curve had an AUC of 0.69 (95% CI 0.59-0.79). A cutoff value of R = 0.93 had a sensitivity of 70.3% and specificity of 61.0% for identifying patients with PA < 3D at V3. CONCLUSIONS: This new digital analysis of keratoscope rings allows to identify with reasonably good diagnostic accuracy patients with low values of post-DALK astigmatism correctable with spectacles.

Short-term choroidal vascular changes after aflibercept therapy for neovascular age-related macular degeneration.

INTRODUCTION: The purpose of this study was to evaluate choroidal vascular changes in patients with neovascular age-related macular degeneration (nAMD) treated with aflibercept injection over a 3-month period. METHODS: Enhanced depth imaging optical coherence tomography scans of 60 eyes with treatment-naïve nAMD and 60 unaffected fellow eyes were retrospectively analyzed. Data was collected at baseline and after 3 monthly intravitreal injections of aflibercept. The ImageJ software was used to binarize OCT scans and measure total choroid area (TCA), luminal area (LA), and stromal area (SA). Choroidal vascularity index (CVI) was defined as the ratio of LA to TCA. RESULTS: After treatment, subfoveal choroidal thickness (CT) in nAMD eyes significantly decreased from 210. 6 ± 61.6 to 194.6 ± 58.7 µm (P < 0.001), TCA from 1.620 ± 0.502 to 1.500 ± 0.451 mm2 (P < 0.001), LA from 1.075 ± 0.335 to 0.985 ± 0.307 mm2 (P < 0.001), SA from 0.545 ± 0.176 to 0.516 ± 0.153 mm2 (P = 0.005), and CVI from 66.36 ± 2.89 to 65.46 ± 2.87% (P = 0.009). The decrease of CVI after treatment was significantly correlated with baseline CVI (Rs = 0.466, P < 0.001), but not with the change in BCVA and presence of dry macula after treatment (always P > 0.05). CONCLUSION: Choroidal thickness and vascularity significantly decreased after treatment with aflibercept in nAMD eyes. Besides the pharmacologic effect on the neovascular lesion, aflibercept may induce vascular changes also on the underlying choroid.

Multimodal imaging of Hypotrichosis with juvenile macular dystrophy: a case report.

BACKGROUND: To report the first Italian case of hypotrichosis with juvenile macular dystrophy complicated by macular neovascularization diagnosed through multimodal imaging. CASE PRESENTATION: An 11-year-old boy was referred to our Institution for bilateral maculopathy of unknown origin. Multimodal imaging helps the diagnosis of Juvenile Macular Dystrophy with Hypotrichosis (HJMD). Fundus examination showed several alterations of the retinal pigment epithelium and circular pigmented area of chorioretinal atrophy. Structural spectral domain optical coherence tomography (OCT) showed some backscattering phenomenon with several alterations of retinal pigment epithelium and photoreceptor layer in both eyes. Moreover, OCT showed hyperreflective lesion beneath the neuroepithelium in left eye. OCT angiography (OCT-A) revealed a pathologic neovascular network in choriocapillaris plexus, probably the result of a fibrovascular membrane. Multifocal electroretinograms (MfERGs) showed functional alterations in 12.22° of the central retina. In order to confirm the suspicion of HJMD, the child and both parents underwent genetic testing. Both parents resulted to be heterozygous healthy carriers of a single variation. CONCLUSION: Multimodal imaging, in particular OCT-A, is a useful aid, along to clinical findings and genetics, for the diagnosis of inherited retinal dystrophies.

Clinical Applications of Astaxanthin in the Treatment of Ocular Diseases: Emerging Insights.

Astaxanthin is a naturally occurring red carotenoid pigment belonging to the family of xanthophylls, and is typically found in marine environments, especially in microalgae and seafood such as salmonids, shrimps and lobsters. Due to its unique molecular structure, astaxanthin features some important biologic properties, mostly represented by strong antioxidant, anti-inflammatory and antiapoptotic activities. A growing body of evidence suggests that astaxanthin is efficacious in the prevention and treatment of several ocular diseases, ranging from the anterior to the posterior pole of the eye. Therefore, the present review aimed at providing a comprehensive evaluation of current clinical applications of astaxanthin in the management of ocular diseases. The efficacy of this carotenoid in the setting of retinal diseases, ocular surface disorders, uveitis, cataract and asthenopia is reported in numerous animal and human studies, which highlight its ability of modulating several metabolic pathways, subsequently restoring the cellular homeostatic balance. To maximize its multitarget therapeutic effects, further long-term clinical trials are warranted in order to define appropriate dosage, route of administration and exact composition of the final product.

Therapeutic Effects of Lactoferrin in Ocular Diseases: From Dry Eye Disease to Infections.

Lactoferrin is a naturally occurring iron-binding glycoprotein, produced and secreted by mucosal epithelial cells and neutrophils in various mammalian species, including humans. It is typically found in fluids like saliva, milk and tears, where it reaches the maximum concentration. Thanks to its unique anti-inflammatory, antioxidant and antimicrobial activities, topical application of lactoferrin plays a crucial role in the maintenance of a healthy ocular surface system. The present review aims to provide a comprehensive evaluation of the clinical applications of lactoferrin in ocular diseases. Besides the well-known antibacterial effect, novel interest has been rising towards its potential application in the field of dry eye and viral infections. A growing body of evidence supports the antimicrobial efficacy of lactoferrin, which is not limited to its iron-chelating properties but also depends on its capability to directly interact with pathogen particles while playing immunomodulatory effects. Nowadays, lactoferrin antiviral activity is of special interest, since lactoferrin-based eye drops could be adopted to treat/prevent the new severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, which has conjunctivitis among its possible clinical manifestations. In the future, further data from randomized controlled studies are desirable to confirm the efficacy of lactoferrin in the wide range of ocular conditions where it can be used.

Ocular surface system alterations in ocular graft-versus-host disease: all the pieces of the complex puzzle.

PURPOSE: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cells transplantation, occurring in about half of transplanted patients. This condition seems to be the result of a progressive immune-mediated damage that can involve various tissues, including the eyes. The ocular surface system is the ocular structure most frequently impaired, and dry eye disease is considered the hallmark of ocular GVHD. Given the increasing prevalence and the frequent severe involvement of the ocular surface with vision-threatening complications, ocular GVHD represents a current diagnostic and therapeutic challenge. The purpose of this literature review is to describe all the clinical manifestations occurring in the setting of ocular GVHD, and to further report the outcomes of conventional and novel therapies. METHODS: A literature search about ocular GVHD was performed in PubMed, Scopus, Medline databases, and ClinicalTrials.gov as well as through the reference lists of identified publications until January 2019. We have included RCTs, prospective observational studies, prospective and retrospective cohort studies, pilot studies, and review articles. RESULTS: Overall, 107 articles, 3 book chapters, and 6 ongoing registered clinical trials were collected and analyzed. Ocular GVHD can affect all the structures of the entire ocular surface system, including lacrimal and meibomian glands, cornea, conjunctiva, eyelids, nasolacrimal duct, and tears. Current medical treatment is mainly focused on lubrication and control of drainage, tear evaporation, and ocular surface inflammation. Surgical treatment may be necessary in severe, recalcitrant, or complicated cases. Amniotic membrane and tectonic keratoplasty can be valid options to restore the integrity of the cornea. Recently, conjunctival and limbal transplantation from the same living-related bone marrow donor has been proposed to manage both dry eye and limbal stem cell deficiency, without any risk of immunologic rejection. CONCLUSION: This review provides an up-to-date analysis on clinical findings and current and future management of ocular GVHD. A correct and prompt diagnosis along with an appropriate and aggressive treatment are fundamental for avoiding the occurrence of vision-threatening complications.

Large (9 mm) Deep Anterior Lamellar Keratoplasty with Clearance of a 6-mm Optical Zone Optimizes Outcomes of Keratoconus Surgery.

PURPOSE: To evaluate the outcomes of a 9-mm deep anterior lamellar keratoplasty (DALK) with removal of the deep stroma limited to the central 6-mm optical zone. DESIGN: Prospective, noncomparative, interventional case series. PARTICIPANTS: A total of 80 consecutive keratoconic eyes without deep stromal scarring, with at least 1 postoperative examination 1 month after complete suture removal. INTERVENTION: A standardized DALK was performed, including (1) deep trephination of the recipient bed 450 to 550 µm in depth and 9 mm in diameter; (2) pneumatic dissection; (3) debulking of approximately 80% of the anterior stroma; (4) removal of the deep stroma (bubble roof) from a central 6-mm optical zone; and (5) transplantation of a 9-mm anterior corneal lamella cut by microkeratome-assisted dissection (400-µm head) and sutured with a double running 10-0 nylon suture. MAIN OUTCOME MEASURES: Success rate and type of pneumatic dissection obtained; best spectacle-corrected visual acuity (BSCVA), refractive astigmatism (RA), and topographic astigmatism (TA), central corneal thickness (CCT) and endothelial cell density 12 months postoperatively; and intraoperative and postoperative complications. RESULTS: Pneumatic dissection created a "big bubble" in 67 of 80 eyes (83.7%), all of them but 1 (1.5%) being of type 1 according to the classification by Dua et al. After complete suture removal, BSCVA averaged 0.09±0.72 logarithm of the minimum angle of resolution (logMAR) and was ≥20/20 in 28 eyes (35%), ≥20/25 in 54 eyes (67.5%), and ≥20/40 in 76 eyes (95%); RA averaged 3.10±1.30 diopters (D), with 73 eyes (91%) within 4.5 D and none above 6 D; regular TA was detected in 72 eyes (90%); mean CCT was 492±62.10 µm; postoperative endothelial cell density averaged 2026±397cells/mm2 with a mean cell loss of 11.2%. Intraoperative complications included loss of suction (n = 1) and perforation (n = 4). No conversion to penetrating keratoplasty was necessary. After surgery, double anterior chamber was observed in 2 cases (2.5%), both managed successfully by air filling of the anterior chamber. Stromal rejection was observed in 6 eyes (7.5%) and was reversed with topical steroids in all cases. CONCLUSIONS: In keratoconic eyes without deep stromal scars, the combination of a graft larger than conventional ones with limited removal of deep stroma can improve visual and refractive outcomes of DALK, while minimizing the rate of complications.

CLINICAL SPECTRUM OF MACULAR-FOVEAL CAPILLARIES EVALUATED WITH OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To describe macular-foveal capillaries (MFC) by means of optical coherence tomography angiography and to identify the clinical spectrum of this angiographic feature. METHODS: Patients with MFC presenting at the Medical Retina & Imaging Unit of the Department of Ophthalmology, University Vita-Salute San Raffaele in Milan were recruited. Patients underwent a complete ophthalmologic examination that included slit-lamp examination, fundus examination, measurement of best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany). Fluorescein angiography was performed in selected cases. Optical coherence tomography angiography was performed through Zeiss prototype (AngioPlex, CIRRUS HD-OCT models 5000; Carl Zeiss Meditec, Inc, Dublin, OH). RESULTS: Twelve eyes of 10 consecutive white patients (5 men and 5 women; 50%) presenting MFC were included. Mean age was 66.2 ± 10.2 years (range, 53-79 years); mean best-corrected visual acuity was 0.1 ± 0.13 logarithm of the minimum angle of resolution (range, 0-0.4 logarithm of the minimum angle of resolution, corresponding to 20/20 to 20/50). Mean central macular thickness was 348 ± 57.6 µm. Two patients were affected by macular pucker, two by postsurgical macular edema, two by age-related macular degeneration, one by diabetic retinopathy, one by dome-shaped macula, one presented with chronic serous chorioretinopathy, and one with branch artery occlusion. Six eyes disclosed a complete absence of the foveal avascular zone, whereas the six other cases showed a partial foveal avascularity. No significant difference was found between complete and incomplete MFC with regards to best-corrected visual acuity (P = 0.272) and central macular thickness (P = 0.870). CONCLUSION: Cases of persistent MFC are heterogeneous in demographic characteristics, fundus appearance, and visual function. However, MFC, presenting either as complete absence of the foveal avascular zone or only partial foveal avascularity, may complicate different retinal abnormalities or represents a coincident finding.

Contact Lens-Assisted Pull-Through Technique for Delivery of Tri-Folded (Endothelium in) DMEK Grafts Minimizes Surgical Time and Cell Loss.

PURPOSE: To evaluate the feasibility and outcomes of contact lens-assisted bimanual pull-through delivery of Descemet membrane endothelial keratoplasty (DMEK) tissue trifolded with the endothelium inward. DESIGN: Prospective, noncomparative, interventional case series. PARTICIPANTS: Forty-two consecutive eyes of 42 patients with Fuchs endothelial dystrophy with or without cataract. INTERVENTION: Standardized DMEK was performed as a single procedure (n = 9) or in combination with phacoemulsification and implantation of a posterior chamber intraocular lens (n = 33) using prestripped donor tissue punched to a diameter of 8.25 mm and then trifolded with the endothelium in. Using a sterile soft contact lens as scaffold, the tissue was loaded in this configuration into a disposable cartridge and delivered into the anterior chamber under continuous irrigation using a bimanual pull-through technique to facilitate spontaneous proper unfolding. MAIN OUTCOME MEASURES: Surgical time, intraoperative and postoperative complications, visual acuity 3 and 6 months after surgery, and endothelial cell loss 6 months after surgery. RESULTS: Surgery was uneventful in all cases and the time required for the DMEK procedure (from Descemet scoring until final air filling) never exceeded 20 minutes (average, 17.1±1.6 minutes). The only complication observed after surgery was graft detachment (10 of 42 eyes [23.8%]), successfully managed in all cases by single rebubbling within 6 days from surgery. In all eyes with a minimum postoperative follow-up of 6 months (n = 20), best spectacle-corrected visual acuity was 20/25 or better and the average endothelial cell density (±standard deviation) was 2363.8±82.7 cells/mm(2) (range, 2258-2490 cells/mm(2)). The cell loss calculated as a percentage of the preoperative value determined at the eye bank (range, 2500-2700 cells/mm(2)) was 9.9±2.1% (range, 4.1%-11.9%). CONCLUSIONS: Delivering DMEK tissue, trifolded with the endothelium inward, reduces surgical trauma to donor cells and facilitates spontaneous unfolding, thus minimizing surgical time.