In-depth correlation analysis between tear glucose and blood glucose using a wireless smart contact lens.

Tears have emerged as a promising alternative to blood for diagnosing diabetes. Despite increasing attempts to measure tear glucose using smart contact lenses, the controversy surrounding the correlation between tear glucose and blood glucose still limits the clinical usage of tears. Herein, we present an in-depth investigation of the correlation between tear glucose and blood glucose using a wireless and soft smart contact lens for continuous monitoring of tear glucose. This smart contact lens is capable of quantitatively monitoring the tear glucose levels in basal tears excluding the effect of reflex tears which might weaken the relationship with blood glucose. Furthermore, this smart contact lens can provide an unprecedented level of continuous tear glucose data acquisition at sub-minute intervals. These advantages allow the precise estimation of lag time, enabling the establishment of the concept called 'personalized lag time'. This demonstration considers individual differences and is successfully applied to both non-diabetic and diabetic humans, as well as in animal models, resulting in a high correlation.

Repositioned versus exchanged flanged intraocular lens fixation for intraocular lens dislocation.

This study aimed to compare the outcomes of flanged intraocular lens (IOL) fixation with new IOL exchange after dislocated IOL removal and repositioned dislocated IOL in patients with IOL dislocation. Eighty-nine eyes that underwent flanged IOL fixation were retrospectively included, with 51 eyes in the exchanged IOL group and 38 eyes in the repositioned IOL group. In both groups, best-corrected visual acuity (BCVA) improved at 1, 3, 6, and 12 months postoperatively and did not differ between the two groups at any of these time points. However, at 1 week postoperatively, BCVA in the repositioned IOL group improved compared with baseline, whereas that in the exchanged IOL group did not. Moreover, there were lesser changes in the corneal endothelial cell density (ECD) and corneal astigmatism in the repositioned IOL group than in the exchanged IOL group. The IOL positions, including IOL tilt and IOL decentration, were not different between the groups. Flanged IOL fixation with new IOL exchange and with repositioned dislocated IOL for patients with IOL dislocation had similar visual outcomes and IOL position. However, the latter had a smaller corneal ECD decrease and astigmatic change. This technique was effective in treating IOL dislocation while minimizing corneal injury.

Real-time in vivo monitoring of intraocular pressure distribution in the anterior chamber and vitreous chamber for diagnosis of glaucoma.

Glaucoma causes irreversible vision loss due to optic nerve damage and retinal cell degeneration. Since high intraocular pressure (IOP) is a major risk factor for glaucoma development, accurate IOP measurement is crucial, especially intravitreal IOP affecting the optical nerve and cells. However, conventional methods have limits in selectively and directly detecting local retina pressure. Here, we present continuous measurements of local IOP values in the anterior chamber and vitreous chamber of living animals using minimally invasive probes with pressure-sensitive transistors. After inducing glaucoma in animal models, we compared the local IOP distribution between normal and glaucomatous eyes. We also compared IOP values detected in the cornea using tonometry measurements. Our findings revealed that glaucoma induced higher IOP in the vitreous chamber than in the anterior chamber, indicating that measuring IOP in the vitreous chamber is key to the glaucoma model. This progress offers future directions for diagnosis and treatment of glaucoma.

Noninvasive Imaging of Conjunctival Goblet Cells as a Method for Diagnosing Dry Eye Disease in an Experimental Mouse Model.

Purpose: The purpose of this study was to evaluate a noninvasive conjunctival goblet cell (GC) imaging method for assessing dry eye disease (DED) in an experimental mouse model. Methods: Moxifloxacin-based fluorescence microscopy (MBFM) was used to examine GCs noninvasively in 56 mice. Forty-two (42) DED-induced mice were divided into 2 groups and treated topically for 14 days with cyclosporine (CsA) or normal saline (NS). In vivo MBFM imaging and clinical DED evaluations were performed and goblet cell density (GCD) and goblet cell area (GCA) were obtained and compared with histological GCD using periodic acid-Schiff (PAS) staining. Correlation and receiver operating characteristic (ROC) analyses showed MBFM's high diagnostic value. Results: The GCD and GCA of the DED mice obtained from in vivo MBFM imaging were highly correlated with clinical DED parameters and GCD obtained from PAS histology. The therapeutic effect of CsA, as observed by in vivo MBFM, was significant with respect to that of NS treatment. The ROC curves derived from in vivo MBFM showed high diagnostic value in assessing DED. Conclusions: The proposed noninvasive method has high diagnostic value in assessing the severity of DED and the effect of treatment for this disease. Translational Relevance: A noninvasive imaging method using moxifloxacin-based fluorescence microscopy was evaluated for assessing DED in an experimental mouse model. The method showed high diagnostic value in assessing the severity of DED and the effect of treatment, bridging the gap between basic research and clinical treatment. The study provides a promising tool for diagnosing and monitoring DED.

Clinical Evaluation of a Hydrophobic Intraocular Lens Using a Preloaded Automated Injector in a Korean Population.

Purpose: This study assessed post-market clinical outcomes of the Clareon monofocal intraocular lens (IOL) preloaded in the AutonoMe Delivery System in a real-world setting of Korean patients. Methods: This prospective, multicenter, single-arm study in Korea was conducted from July 2020 to December 2021. Patients were ≥20 years old with unilateral or bilateral cataracts who received Clareon IOLs (CNA0T0) preloaded in an automated injector system. Best corrected distance visual acuity (BCDVA) and uncorrected distance visual acuity (UCDVA) were evaluated under photopic conditions. Surgeon delivery system preference was assessed using a survey questionnaire. Glistenings, surface haze, adverse events, posterior capsule opacification (PCO), and Nd:YAG capsulotomy rates were also assessed during the 12-month postoperative follow-up. Results: Mean ± SD monocular BCDVA was 0.02 ± 0.11 and 0.00 ± 0.10 logMAR at 1 month and 12 months, respectively. BCDVA of 0.2 logMAR or better was achieved by 94.4% and 99.1% of eyes at 1 month and 12 months after implantation, respectively. Mean monocular UCDVA was 0.11 ± 0.14 and 0.07 ± 0.13 logMAR at 1 month and 12 months, respectively. UCDVA of 0.3 logMAR or better was achieved by 97.4% of eyes at 12 months after implantation. Preparation of the automated injector system was rated as "very easy" or "easy" and CNA0T0 IOL delivery was rated as "very controllable" or "controllable" by all surgeons. Only grade 0 glistenings and no surface haze were observed during the 12-month follow-up. No clinically significant PCO or Nd:YAG capsulotomy were reported throughout the study; clinically nonsignificant PCO was reported in 23% of eyes. Conclusion: This 12-month real-world study of the CNA0T0 IOL and the automated injector system demonstrated excellent visual outcomes and high surgeon satisfaction.

Efficacy and safety of 1% and 2% rebamipide clear solution in dry eye disease: a multicenter randomized trial.

BACKGROUND: To evaluate the efficacy of 1% and 2% rebamipide clear solution in the treatment of dry eye disease (DED). METHODS: Two hundred twenty patients with DED were randomly assigned to one of three groups: the 1% rebamipide, 2% rebamipide, or placebo (eye drops containing the same ingredients, except for the active components). Each eye drop was instilled four times daily for 12 weeks. Changes in tear film break-up time (TBUT), corneal and conjunctival staining score, Schirmer 1 test, and the Ocular Surface Disease Index (OSDI) from baseline to 12-week visit between the study groups were compared for efficacy assessment. RESULTS: The mean age of study patients was 43.8±14.2 years. The 1% and 2% rebamipide groups showed greater improvement in TBUT (1.99±1.87 and 2.02±2.21 s) at 12 weeks from baseline than the placebo group (1.25±2.93 s). The 2% rebamipide group showed greater improvement in the corneal staining score (- 3.15±2.00) at 12 weeks from baseline than the placebo group (- 2.85±1.80). The 1% and 2% rebamipide groups showed improvement in Schirmer 1 test (1.27±3.86 and 1.50±4.14 mm) at 12 weeks of treatment, but not the placebo group (0.55±2.99 mm). Both the rebamipide groups and the placebo group showed significantly improved OSDI after treatment for 12 weeks; however, there was no significant difference among the three groups. CONCLUSIONS: 1% and 2% rebamipide clear solutions are an effective therapeutic option for improving TBUT and tear volume, and stabilizing the corneal staining score in DED.

The subjective controllability of exotropia and its effect on surgical outcomes in patients with intermittent exotropia.

BACKGROUND/AIMS: We evaluate the clinical characteristics of intermittent exotropia with controllability and compare surgical outcomes between patients with and without controllability. METHODS: We reviewed the medical records of patients aged 6-18 years with intermittent exotropia who underwent surgery between September 2015 and September 2021. Controllability was defined as the patient's subjective awareness of exotropia or diplopia associated with the presence of exotropia and ability to instinctively correct the ocular exodeviation. Surgical outcomes were compared between patients with and without controllability, with a favorable surgical outcome defined as an ocular deviation between ≤ 10 PD of exotropia and ≤ 4 PD of esotropia at distance and near. RESULTS: Among 521 patients, 130 (25%, 130/521) had controllability. The mean age of onset (7.7 years) and surgery (9.9 years) were higher in patients with controllability than in those without controllability (p < 0.001). The mean control scores of patients with controllability (distance: 1.9, near: 1.5) were lower compared with patients without controllability (distance: 3.0, near: 2.2), reflecting a better level of control. Patients with controllability had a better surgical outcome than those without controllability, as analyzed by log-rank test (p < 0.001). Larger preoperative ocular exodeviation at distance (hazard ratio [HR] = 1.083, confidence interval [CI] = 1.018-1.151, p = 0.012) and near (HR = 1.102, CI = 1.037-1.172, p = 0.002) were significantly related to recurrence in patients with controllability. CONCLUSIONS: Patients with controllability showed better surgical outcomes, later exotropia onset, and better level of control than patients without controllability. Preoperative ocular exodeviation was a significant factor influencing favorable outcomes in patients with controllable exotropia.

A Multicenter, Randomized, Double-Blind Evaluation of the Efficacy of TJO-087 Versus 0.05% Cyclosporine A in Moderate to Severe Dry Eye.

Purpose: To compare the efficacy and ocular tolerability of a 0.08% nanoemulsion cyclosporine A (CsA) (TJO-087) once daily versus a conventional 0.05% emulsion CsA twice daily in dry eye disease. Methods: 178 patients with dry eye disease were randomly assigned to one of two groups: the TJO-087 or CsA0.05% group. Changes in the Ocular Surface Disease Index (OSDI), tear film break-up time (TBUT), corneal and conjunctival staining scores, and Schirmer test scores from baseline to the 32-week visit were compared between both groups. To evaluate ocular tolerability of the study formulations, 7 symptoms (stinging/burning, itching, blurred vision, sandiness/grittiness, dryness, light sensitivity, and pain or soreness) were evaluated (the higher the score, the lower the tolerability) at each follow-up visit. Results: A total of 155 eyes of 155 patients were enrolled. The TJO-087 and CsA0.05% groups showed significant improvement in OSDI, TBUT, ocular surface staining, and Schirmer test scores at 32 weeks from baseline. There was no difference in the extent of improvement in all efficacy parameters. There were no differences in the ocular tolerability scores between the 2 groups at all visits, except that the itching score was higher in the TJO-087 group than in the CsA0.05% group at week 8. Conclusions: Using topical 0.08% CsA once daily is an effective therapeutic option for improving the symptoms and signs in dry eye disease, with a tolerability comparable with that of conventional 0.05% CsA. This trial was registered at the US National Library of Medicine ClinicalTrials.gov (http://clinicaltrial.gov) as NCT05245604 (registration date: 19/06/2020).

Development of Müller cell-based 3D biomimetic model using bioprinting technology.

Müller cells are the principal glial cells for the maintenance of structural stability and metabolic homeostasis in the human retina. Although variousin vitroexperiments using two-dimensional (2D) monolayer cell cultures have been performed, the results provided only limited results because of the lack of 3D structural environment and different cellular morphology. We studied a Müller cell-based 3D biomimetic model for use in experiments on thein vivo-like functions of Müller cells within the sensory retina. Isolated primary Müller cells were bioprinted and a 3D-aligned architecture was induced, which aligned Müller cell structure in retinal tissue. The stereographic and functional characteristics of the biomimetic model were investigated and compared to those of the conventional 2D cultured group. The results showed the potential to generate Müller cell-based biomimetic models with characteristic morphological features such as endfeet, soma, and microvilli. Especially, the 3D Müller cell model under hyperglycemic conditions showed similar responses as observed in thein vivodiabetic model with retinal changes, whereas the conventional 2D cultured group showed different cytokine and growth factor secretions. These results show that our study is a first step toward providing advanced tools to investigate thein vivofunction of Müller cells and to develop complete 3D models of the vertebrate retina.

Wireless Non-Invasive Monitoring of Cholesterol Using a Smart Contact Lens.

Herein, a wireless and soft smart contact lens that enables real-time quantitative recording of cholesterol in tear fluids for the monitoring of patients with hyperlipidemia using a smartphone is reported. This contact lens incorporates an electrochemical biosensor for the continuous detection of cholesterol concentrations, stretchable antenna, and integrated circuits for wireless communication, which makes a smartphone the only device required to operate this lens remotely without obstructing the wearer's vision. The hyperlipidemia rabbit model is utilized to confirm the correlation between cholesterol levels in tear fluid and blood and to confirm the feasibility of this smart contact lens for diagnostic application of cholesterol-related diseases. Further in vivo tests with human subjects demonstrated its good biocompatibility, wearability, and reliability as a non-invasive healthcare device.

Target ischemic stroke model creation method using photoacoustic microscopy with simultaneous vessel monitoring and dynamic photothrombosis induction.

The ischemic stroke animal model evaluates the efficacy of reperfusion and neuroprotective strategies for ischemic injuries. Various conventional methods have been reported to induce the ischemic models; however, controlling specific neurological deficits, mortality rates, and the extent of the infarction is difficult as the size of the affected region is not precisely controlled. In this paper, we report a single laser-based localized target ischemic stroke model development method by simultaneous vessel monitoring and photothrombosis induction using photoacoustic microscopy (PAM), which has minimized the infarct size at precise location with high reproducibility. The proposed method has significantly reduced the infarcted region by illuminating the precise localization. The reproducibility and validity of suggested method have been demonstrated through repeated experiments and histological analyses. These results demonstrate that our method can provide the ischemic stroke model closest to the clinical pathology for brain ischemia research from inducement, occurrence mechanisms to the recovery process.

Moxifloxacin-Based Extended Depth-of-Field Fluorescence Microscopy for Real-Time Conjunctival Goblet Cell Examination.

Conjunctival goblet cells (CGCs) are mucin-secreting cells in the eye and play essential roles for ocular surface homeostasis. Since various ocular surface pathologies are related to CGC dysfunction, CGC examination is important for the evaluation of ocular surface conditions. Recently we introduced moxifloxacin-based fluorescence microscopy (MBFM) for non-invasive CGC imaging. However, the imaging speed was up to 1 frame per second (fps) and needed to be improved for clinical applications. In this study, we developed a high-speed moxifloxacin-based, extended depth-of-field (EDOF) microscopy system that operates at a maximum imaging speed of 15 fps. The system used a deformable mirror for the high-speed axial sweeping of focal plane during single-frame acquisitions. The acquired images contained both in-focus and out-of-focus information, and deconvolution was used to filter the in-focus information. The system had a DOF of 800 [Formula: see text], field-of-view of 1.2 mm ×1.2 mm, and resolution of [Formula: see text]. Its performance was demonstrated by real-time, breathing-motion-insensitive CGC imaging of mouse and rabbit models, in vivo. High-speed EDOF microscopy has potentials for non-invasive, real-time CGC examinations of human subjects.

Comparison of a preservative-free nonsteroidal anti-inflammatory drug and preservative-free corticosteroid after uneventful cataract surgery: multicenter, randomized, evaluator-blinded clinical trial.

PURPOSE: To compare the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) and steroidal eyedrops for inflammation management after cataract surgery using slitlamp indicators. SETTING: 11 eye centers in South Korea. DESIGN: Randomized prospective multicenter study with a blinded evaluator. METHOD: In 125 (250 eyes) patients who underwent cataract surgery, bromfenac sodium hydrate 0.1% (NSAID group) was applied twice a day in 1 eye, whereas the other eye was treated with fluorometholone 0.1% (steroid group), 4 times a day for 4 weeks postoperatively. The primary efficacy outcome was the presence of anterior chamber cells and flare at 1 week postoperatively. Anterior chamber cells and flare at 4 to 8 weeks, corrected distance visual acuity, central corneal thickness, conjunctival hyperemia, dry eye parameters, foveal thickness, and ocular and visual discomfort were evaluated as secondary outcomes. RESULTS: At week 1, residual anterior chamber inflammation was not statistically significantly different between the groups (-1.03 ± 1.27 vs -0.95 ± 1.24, P = .4850). However, the NSAID group recovered from conjunctival hyperemia more rapidly than the steroid group (0.30 ± 0.52 vs 0.44 ± 0.81, P = .0144 at week 1). The increase in central corneal thickness in the NSAID group was less than that in the steroid group 1 week postoperatively (7.87 ± 22.46 vs 29.47 ± 46.60 µm, P < .0001). The change in foveal thickness in the NSAID group was significantly less than that in the steroid group (18.11 ± 68.19 vs 22.25 ± 42.37 µm, P = .0002). Lower levels of postoperative ocular and visual discomfort were reported in the NSAID group than in the steroid group under treatment. CONCLUSIONS: Preservative-free bromfenac was as effective as preservative-free fluorometholone eyedrops in anterior chamber inflammation control and showed better signs and symptoms after cataract surgery.

A randomized multicenter clinical evaluation of sequential application of 0.3% and 0.15% hyaluronic acid for treatment of dry eye.

PURPOSE: We report the clinical efficacy of sequential applications of 0.3% and 0.15% unpreserved hyaluronic acid (HA) for the treatment of dry eye disease (DED). STUDY DESIGN: Randomized clinical trial. METHODS: Patients over 19 years of age with DED level 2 or higher, corneal fluorescein staining (CFS) score > 1, and tear break-up time (TBUT) < 10 s were included. Seventy-six patients were randomly assigned to the 0.15% HA group, 0.3% HA group, or combination group. Each group applied two drops of 0.15% or 0.3% HA, or a single drop of both 0.3% and 0.15% HA. Patients were evaluated using the ocular surface disease index (OSDI), CFS and conjunctival fluorescein stain score, TBUT, and blurring/discomfort after application at baseline, 4 weeks, and 8 weeks. RESULTS: The combination group had the greatest improvement in CFS score from baseline to 8 weeks, compared with the 0.15% and 0.3% HA group (p < 0.001). The combined CFS-OSDI responder rates of the combination group (CFS score = 0 and OSDI ≥ 50% improvement at 8 weeks) were significantly higher than those of the 0.15% and 0.3% groups (p = 0.037). At 4 and 8 weeks, blurring after application in both the 0.3% and combination groups was significantly higher than in the 0.15% group, despite no difference between the 0.3% and combination groups. There were no differences in CFS and conjunctival staining score, TBUT, or OSDI within the three groups at baseline, 4 weeks, and 8 weeks. CONCLUSIONS: Sequential application of 0.3% and 0.15% HA improved symptoms/signs in moderate to severe DED patients.

Real-time measurement of intraocular pressure variation during automatic intravitreal injections: An ex-vivo experimental study using porcine eyes.

PURPOSE: To measure needle insertion force and change in intraocular pressure (IOP) in real-time during intravitreal injection (IVI). The effects of needle size, insertion speed, and injection rate to IOP change were investigated. METHODS: Needle insertion and fluid injection were performed on 90 porcine eyeballs using an automatic IVI device. The IVI conditions were divided according to needle sizes of 27-gauge (G), 30G, and 33G; insertion speeds of 1, 2, and 5 mm/s; and injection rates of 0.01, 0.02, and 0.05 mL/s. Insertion force and IOP were measured in real-time using a force sensor and a pressure transducer. RESULTS: The peak IOP was observed when the needle penetrated the sclera; the average IOP elevation was 96.3, 67.1, and 59.4 mmHg for 27G, 30G, and 33G needles, respectively. An increase in insertion speed caused IOP elevation at the moment of penetration, but this effect was reduced as needle size decreased: 109.8-85.9 mmHg in 27G for 5-1 mm/s (p = 0.0149) and 61.8-60.7 mmHg in 33G for 5-1 mm/s (p = 0.8979). Injection speed was also related to IOP elevation during the stage of drug injection: 16.65 and 11.78 mmHg for injection rates of 0.05 and 0.01 mL/s (p < 0.001). CONCLUSION: The presented data offers an understanding of IOP changes during each step of IVI. Slow needle insertion can reduce IOP elevation when using a 27G needle. Further, the injection rate must be kept low to avoid IOP elevations during the injection stage.

A soft and transparent contact lens for the wireless quantitative monitoring of intraocular pressure.

Continuous detection of raised intraocular pressure (IOP) could benefit the monitoring of patients with glaucoma. Current contact lenses with embedded sensors for measuring IOP are rigid, bulky, partially block vision or are insufficiently sensitive. Here, we report the design and testing in volunteers of a soft and transparent contact lens for the quantitative monitoring of IOP in real time using a smartphone. The contact lens incorporates a strain sensor, a wireless antenna, capacitors, resistors, stretchable metal interconnects and an integrated circuit for wireless communication. In rabbits, the lens provided measurements that match those of a commercial tonometer. In ten human participants, the lens proved to be safe, and reliably provided accurate quantitative measurements of IOP without inducing inflammation.

Smart contact lens and transparent heat patch for remote monitoring and therapy of chronic ocular surface inflammation using mobiles.

Wearable electronic devices that can monitor physiological signals of the human body to provide biomedical information have been drawing extensive interests for sustainable personal health management. Here, we report a human pilot trial of a soft, smart contact lens and a skin-attachable therapeutic device for wireless monitoring and therapy of chronic ocular surface inflammation (OSI). As a diagnostic device, this smart contact lens enables real-time measurement of the concentration of matrix metalloproteinase-9, a biomarker for OSI, in tears using a graphene field-effect transistor. As a therapeutic device, we also fabricated a stretchable and transparent heat patch attachable on the human eyelid conformably. Both diagnostic and therapeutic devices can be incorporated using a smartphone for their wireless communications, thereby achieving instantaneous diagnosis of OSI and automated hyperthermia treatments. Furthermore, in vivo tests using live animals and human subjects confirm their good biocompatibility and reliability as a noninvasive, mobile health care solution.

Sensor-Embedded Automatic Grasping Forceps for Precise Corneal Suture in Penetrating Keratoplasty.

In penetrating keratoplasty (PKP), the proper corneal suture placement is very important for successful transplantation and restoring functional vision. Generating sutures with accurate depth is difficult for the surgeon because of the tissue's softness, lack of depth information, and hand tremors. In this paper, an automatic cornea grasping device is proposed, which detects when the device reaches the target suture depth. When the device reaches the target depth, the device rapidly grasps the cornea to prevent error induced by human hand tremors. In the paper, the performance of the proposed sensor, the actuator, and the device are experimentally verified with ex vivo experiment. The result showed that the proposed device could enhance the accuracy and precision of the corneal suture depth.

Quadruple ultrasound, photoacoustic, optical coherence, and fluorescence fusion imaging with a transparent ultrasound transducer.

Ultrasound and optical imagers are used widely in a variety of biological and medical applications. In particular, multimodal implementations combining light and sound have been actively investigated to improve imaging quality. However, the integration of optical sensors with opaque ultrasound transducers suffers from low signal-to-noise ratios, high complexity, and bulky form factors, significantly limiting its applications. Here, we demonstrate a quadruple fusion imaging system using a spherically focused transparent ultrasound transducer that enables seamless integration of ultrasound imaging with photoacoustic imaging, optical coherence tomography, and fluorescence imaging. As a first application, we comprehensively monitored multiparametric responses to chemical and suture injuries in rats' eyes in vivo, such as corneal neovascularization, structural changes, cataracts, and inflammation. As a second application, we successfully performed multimodal imaging of tumors in vivo, visualizing melanomas without using labels and visualizing 4T1 mammary carcinomas using PEGylated gold nanorods. We strongly believe that the seamlessly integrated multimodal system can be used not only in ophthalmology and oncology but also in other healthcare applications with broad impact and interest.