Smart contact lens containing hyaluronate-rose bengal conjugate for biophotonic myopia vision correction.

As the collagen layer weakens with increasing age or certain diseases such as keratoconus and myopia, the mechanical property of the collagen layer decreases with corneal deformation. To circumvent these problems, the corneal collagen has been crosslinked with the photosensitizer riboflavin under UV light after de-epithelialization. However, this treatment with riboflavin and UV light can cause notable damage to the eye. Here, the biocompatible rose bengal (RB) dye was conjugated to hyaluronic acid (HA) to enhance the corneal permeability, which can be activated by safe green light with a wavelength of 530 nm. Two-photon microscopy revealed the deep tissue penetration of the HA-RB conjugate in comparison with RB. Collagen fibrillogenesis, ex vivo tensile test, and ex vivo histological analysis confirmed the effective collagen crosslinking by HA-RB conjugate and the light irradiation. Furthermore, we developed a smart contact lens for on-demand HA-RB conjugate delivery from the reservoir embedded in the contact lens. Taken together, we could envision the feasibility of a smart contact lens for biophotonic myopia vision correction.

A Smartphone-Based Near-Vision Testing System: Design, Accuracy, and Reproducibility Compared With Standard Clinical Measures.

BACKGROUND AND OBJECTIVE: Ophthalmologic telemedicine has emerged during the COVID-19 pandemic. The objective of this study is to assess the accuracy and reproducibility of a smartphone-based home vision monitoring system (Sightbook) and to compare it with existing clinical standards. PATIENTS AND METHODS: Near Snellen visual acuity (VA) was measured with Sightbook and compared with conventional measurements for distance and near VA at an academic medical center ophthalmology clinic in 200 patients with a variety of different specified preexisting ocular conditions. Measurements of contrast sensitivity were also compared by using an existing commercially available chart system in 15 normal patients and 15 patients with age-related macular degeneration. RESULTS: Sightbook VA tests were reproducible (SD = ±0.054 logMAR), and correlation with standard VA methods was significant (R > 0.87 and P < .001). Sightbook contrast sensitivity measurements were reproducible (SD/mean ratio, 0.02 to 0.04), yielding results similar to those of standard tests (R2 > 0.87 and P < .001). CONCLUSIONS: Smartphone-based VA and contrast sensitivity are highly correlated with standard charts and may be useful in augmenting limited inoffice care. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:79-84.].

Mucin-Like Glycoproteins Modulate Interfacial Properties of a Mimetic Ocular Epithelial Surface.

Dry eye disease (DED) has high personal and societal costs, but its pathology remains elusive due to intertwined biophysical and biochemical processes at the ocular surface. Specifically, mucin deficiency is reported in a subset of DED patients, but its effects on ocular interfacial properties remain unclear. Herein a novel in vitro mucin-deficient mimetic ocular surface (Mu-DeMOS) with a controllable amount of membrane-tethered mucin molecules is developed to represent the diseased ocular surfaces. Contact angle goniometry on mimetic ocular surfaces reveals that high surface roughness, but not the presence of hydrophilic mucin molecules, delivers constant hydration over native ocular surface epithelia. Live-cell rheometry confirms that the presence of mucin-like glycoproteins on ocular epithelial cells reduces shear adhesive strength at cellular interfaces. Together, optimal surface roughness and surface chemistry facilitate sustainable lubrication for healthy ocular surfaces, while an imbalance between them contributes to lubrication-related dysfunction at diseased ocular epithelial surfaces. Furthermore, the restoration of low adhesive strength at Mu-DeMOS interfaces through a mucin-like glycoprotein, recombinant human lubricin, suggests that increased frictional damage at mucin-deficient cellular surfaces may be reversible. More broadly, these results demonstrate that Mu-DeMOS is a promising platform for drug screening assays and fundamental studies on ocular physiology.

Effect of mesenchymal stromal cells encapsulated within polyethylene glycol-collagen hydrogels formed in situ on alkali-burned corneas in an ex vivo organ culture model.

BACKGROUND AIMS: Corneal inflammation after alkali burns often results in vision loss due to corneal opacification and neovascularization. Mesenchymal stem cells (MSCs) and their secreted factors (secretome) have been studied for their anti-inflammatory and anti-angiogenic properties with encouraging results. However, topical instillation of MSCs or their secretome is often accompanied by issues related to delivery or rapid washout. Polyethylene glycol (PEG) and collagen are well-known biomaterials used extensively in scaffolds for tissue engineering. To effectively suppress alkaline burn-induced corneal injury, the authors proposed encapsulating MSCs within collagen gels cross-linked with multi-functional PEG-succinimidyl esters as a means to deliver the secretome of immobilized MSCs. METHODS: Human MSCs were added to a neutralized collagen solution and mixed with a solution of four-arm PEG-N-hydroxysuccinimide. An ex vivo organ culture was conducted using rabbit corneas injured by alkali burn. MSCs were encapsulated within PEG-collagen hydrogels and injected onto the wounded cornea immediately following alkali burn and washing. Photographs of the ocular surface were taken over a period of 7 days after the alkali burn and processed for immunohistochemical evaluation. Samples were split into three groups: injury without treatment, MSCs alone, and MSCs encapsulated within PEG-collagen hydrogels. RESULTS: All corneas in ex vivo organ culture lost their transparency immediately after alkali burn, and only the groups treated with MSCs and MSCs encapsulated within PEG-collagen hydrogels recovered some transparency after 7 days. Immunohistochemical analysis revealed increased expression of vimentin in the anterior corneal stroma of the group without treatment indicative of fibrotic healing, whereas less stromal vimentin was detected in the group containing MSCs encapsulated within the PEG-collagen hydrogels. CONCLUSIONS: PEG-collagen hydrogels enable the encapsulation of viable MSCs capable of releasing secreted factors onto the ocular surface. Encapsulating MSCs within PEG-collagen hydrogels may be a promising method for delivering their therapeutic benefits in cases of ocular inflammatory diseases, such as alkali burn injuries.

Gold nanoparticles to enhance ophthalmic imaging.

The use of gold nanoparticles as diagnostic tools is burgeoning, especially in the cancer community with a focus on theranostic applications to both cancer diagnosis and treatment. Gold nanoparticles have also demonstrated great potential for use in diagnostic and therapeutic approaches in ophthalmology. Although many ophthalmic imaging modalities are available, there is still a considerable unmet need, in particular for ophthalmic molecular imaging for the early detection of eye disease before morphological changes are more grossly visible. An understanding of how gold nanoparticles are leveraged in other fields could inform new ways they could be utilized in ophthalmology. In this paper, we review current ophthalmic imaging techniques and then identify optical coherence tomography (OCT) and photoacoustic imaging (PAI) as the most promising technologies amenable to the use of gold nanoparticles for molecular imaging. Within this context, the development of gold nanoparticles as OCT and PAI contrast agents are reviewed, with the most recent developments described in detail.

Management of acute corneal hydrops with intracameral gas injection.

PURPOSE: To report two cases of severe acute corneal hydrops that were resolved by intracameral gas injection alone. OBSERVATIONS: Case 1 is a 27-year-old woman with bilateral severe keratoconus who developed sequential acute corneal hydrops in the right eye followed by the left eye that were each successfully treated using intracameral 20% sulfur hexafluoride gas injection. Case 2 is a 62-year-old man that developed a large fluid cleft beneath a pre-existing LASIK flap, which resolved with intracameral 20% sulfur hexafluoride gas injection without the need for corneal transplantation. CONCLUSIONS AND IMPORTANCE: In acute corneal hydrops, intracameral gas injection to tamponade Descemet's membrane tears with decompression of stromal fluid can be an effective intervention to delay or avoid keratoplasty in individuals whose corneal hydrops does not improve with conventional medical management.

Assessment of Eye Disease and Visual Impairment in the Nursing Home Population Using Mobile Health Technology.

BACKGROUND AND OBJECTIVE: To characterize the burden of eye disease and the utility of teleophthalmology in nursing home patients, a population with ophthalmic needs not commensurate with care received. PATIENTS AND METHODS: Informed consent was obtained from 78 California Bay Area skilled nursing facility patients. Near visual acuity (VA) and anterior/posterior segment photographs were taken with a smartphone-based VA app and ophthalmic camera system. The Nursing Home Vision-Targeted Health-Related Quality of Life questionnaire was also administered. Risk factors for visual impairment were assessed. Institutional review board approval was obtained from Stanford University. RESULTS: Cataracts (51%), diabetic retinopathy (DR) (12%), optic neuropathy (12%), and age-related macular degeneration (AMD) (10%) were common findings; 11.7% had other referral-warranted findings. AMD and DR correlated with a higher risk of poor VA, with adjusted odds ratios of 22 (P = .01) and 43 (P = .004). CONCLUSIONS: This study demonstrated a high prevalence of poor VA and ophthalmic disease in the nursing home population impacting quality of life. Smartphone-based teleophthalmology platforms have the potential to increase access to eye care for nursing home patients. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:262-270.].

Utility and Feasibility of Teleophthalmology Using a Smartphone-Based Ophthalmic Camera in Screening Camps in Nepal.

PURPOSE: To determine whether use of a mobile device-based ophthalmic camera by ophthalmic technicians (OTs) in village screening camps in Nepal followed by remote image interpretation by an ophthalmologist can improve detection of ocular pathology and medical decision-making. DESIGN: Evaluation of mobile device-based ophthalmic camera through study of before and after clinical decision-making. METHODS: One hundred forty patients over 18 years of age presenting to remote screening camps with best-corrected visual acuity ≤20/60 in one or both eyes were enrolled. Participants were examined by an OT with direct ophthalmoscopy. The technician recorded a diagnosis for each eye and a disposition for each patient. Patients then had anterior segment and fundus photos and/or videos taken using a smartphone-based ophthalmic camera system. Photos and videos were uploaded to a secure, HIPAA-compliant, cloud-based server, and interpreted by masked ophthalmologists from XXX, who independently recorded diagnoses and a disposition for each patient. RESULTS: The diagnoses given by OTs and ophthalmologists differed in 42.4% of eyes. Diagnosis agreement was highest for cataract [k = 0.732, 95% confidence interval (CI) 0.65-0.81], but much lower for posterior segment (retina/optic nerve) pathology (k = 0.057, 95% CI -0.03-0.14). Ophthalmologists and OTs suggested different dispositions for 68.6% of patients. Agreement was highest for cataract extraction (k = 0.623, 95% CI 0.49-0.75), whereas agreement for referral to XXX was lower (k = 0.12, 95% CI 0.00-0.24). CONCLUSIONS: Remote ophthalmologist consultation utilizing a mobile device ophthalmic camera system is logistically feasible, easily scalable, and capable of capturing high-quality images in the setting of rural eye screening camps. Although OTs are well equipped to identify and triage anterior segment pathology, this technology may be helpful in the detection of and referral for posterior segment pathology.

Characterizing the impact of 2D and 3D culture conditions on the therapeutic effects of human mesenchymal stem cell secretome on corneal wound healing in vitro and ex vivo.

The therapeutic effects of secreted factors (secretome) produced by bone marrow-derived human mesenchymal stem cells (MSCs) were evaluated as a function of their growth in 2D culture conditions and on 3D electrospun fiber scaffolds. Electrospun fiber scaffolds composed of polycaprolactone and gelatin were fabricated to provide a 3D microenvironment for MSCs, and their mechanical properties were optimized to be similar to corneal tissue. The secretome produced by the MSCs cultured on 3D fiber matrices versus 2D culture dishes were analyzed using a Luminex immunoassay, and the secretome of MSCs cultured on the 3D versus 2D substrates showed substantial compositional differences. Concentrations of factors such as HGF and ICAM-1 were increased over 5 times in 3D cultures compared to 2D cultures. In vitro proliferation and scratch-based wound healing assays were performed to compare the effects of the secretome on corneal fibroblast cells (CFCs) when delivered synchronously from co-cultured MSCs through a trans-well co-culture system versus asynchronously after harvesting the factors separately and adding them to the media. Cell viability of CFCs was sustained for 6 days when co-cultured with MSCs seeded on the fibers but decreased with time under other conditions. Scratch assays showed 95% closure at 48 h when CFCs were co-cultured with MSCs seeded on fibers, while the control group only exhibited 50% closure at 48 h. Electrospun fibers seeded with MSCs were then applied to a rabbit corneal organ culture system, and MSCs seeded on fibers promoted faster epithelialization and less scarring. Corneas were fixed and stained for alpha smooth muscle actin (α-SMA), and then analyzed by confocal microscopy. Immunostaining showed that expression of α-SMA was lower in corneas treated with MSCs seeded on fibers, suggesting suppression of myofibroblastic transformation. MSCs cultured on electrospun fibers facilitate wound healing in CFCs and on explanted corneas through differential secretome profiles compared to MSCs cultured on 2D substrates. Future work is merited to further understand the nature and basis of these differences and their effects in animal models. STATEMENT OF SIGNIFICANCE: Previous studies have shown that the secretome of bone marrow-derived mesenchymal stem cells (MSC) is promotes corneal wound healing by facilitating improved wound closure rates and reduction of scarring and neovascularization. The present research is significant because it provides evidence for the modulation of the secretome as a function of the MSC culture environment. This leads to differential expression of therapeutic factors secreted, which can impact corneal epithelial and stromal healing after severe injury. In addition, this article shows that co-continuous delivery of the MSC secretome improves cell migration and proliferation over aliquoted delivery, and that MSCs grown on three-dimensional electrospun fiber constructs may provide a favorable microenvironment for cultured MSCs and as a carrier to deliver their secreted factors to the ocular surface.

Evaluating New Ophthalmic Digital Devices for Safety and Effectiveness in the Context of Rapid Technological Development.

IMPORTANCE: The US Food and Drug Administration's medical device regulatory pathway was initially conceived with hardware devices in mind. The emerging market for ophthalmic digital devices necessitates an evolution of this paradigm. OBJECTIVES: To facilitate innovation in ophthalmic digital health with attention to safety and effectiveness. EVIDENCE REVIEW: This article presents a summary of the presentations, discussions, and literature review that occurred during a joint Ophthalmic Digital Health workshop of the American Academy of Ophthalmology, the American Academy of Pediatrics, the American Association for Pediatric Ophthalmology and Strabismus, the American Society of Cataract and Refractive Surgery, the American Society of Retina Specialists, the Byers Eye Institute at Stanford and the US Food and Drug Administration. FINDINGS: Criterion standards and expert graders are critically important in the evaluation of automated systems and telemedicine platforms. Training at all levels is important for the safe and effective operation of digital health devices. The risks associated with automation are substantially increased in rapidly progressive diseases. Cybersecurity and patient privacy warrant meticulous attention. CONCLUSIONS AND RELEVANCE: With appropriate attention to safety and effectiveness, digital health technology could improve screening and treatment of ophthalmic diseases and improve access to care.

Corneal Wound Healing Effects of Mesenchymal Stem Cell Secretome Delivered Within a Viscoelastic Gel Carrier.

Severe corneal injuries often result in permanent vision loss and remain a clinical challenge. Human bone marrow-derived mesenchymal stem cells (MSCs) and their secreted factors (secretome) have been studied for their antiscarring, anti-inflammatory, and antiangiogeneic properties. We aimed to deliver lyophilized MSC secretome (MSC-S) within a viscoelastic gel composed of hyaluronic acid (HA) and chondroitin sulfate (CS) as a way to enhance corneal re-epithelialization and reduce complications after mechanical and chemical injuries of the cornea. We hypothesized that delivering MSC-S within HA/CS would have improved wound healing effects compared the with either MSC-S or HA/CS alone. The results showed that a once-daily application of MSC-S in HA/CS enhances epithelial cell proliferation and wound healing after injury to the cornea. It also reduced scar formation, neovascularization, and hemorrhage after alkaline corneal burns. We found that combining MSC-S and HA/CS increased the expression of CD44 receptors colocalized with HA, suggesting that the observed therapeutic effects between the MSC-S and HA/CS are in part mediated by CD44 receptor upregulation and activation by HA. The results from this study demonstrate a reproducible and efficient approach for delivering the MSC-S to the ocular surface for treatment of severe corneal injuries. Stem Cells Translational Medicine 2019;8:478-489.

Pupil size and LASIK: a review.

PURPOSE: To provide a literature review on the evidence both for and against pupil size as an independent predictor of adverse visual outcomes after LASIK. METHODS: Peer-reviewed publications on the effect of pupil size on LASIK outcomes since 2002 are reviewed. Particular attention was paid to the following attributes of each publication: type of study, number of patients or eyes, mean age, mean level of myopia, mean pupil size, testing conditions, ablation zone diameter, presence or absence of blend zones, and mean follow-up period. RESULTS: Among the 19 studies examined, none correlates a persistent relationship between pupil size and night vision complaints (NVCs) beyond 3 months when LASIK was performed with a 6.0-mm optical zone or larger ablation. The studies that did explicitly determine a correlation either included some or all patients with ablation zones smaller than 6.0 mm or did not specify ablation diameter at all. Among the studies that had drawn more mixed conclusions, the studies either covered short follow-up intervals (1 to 3 months) or showed a progressive improvement in NVCs over time in a relatively small patient cohort. CONCLUSIONS: As keratorefractive technology continues to evolve, the role of pupil size warrants further investigation; however, based on the literature reviewed herein, modern LASIK has negated the role of the low light pupil in predicting adverse visual outcomes after LASIK outside of the early postoperative period.

Biocompatibility of poly(ethylene glycol)/poly(acrylic acid) interpenetrating polymer network hydrogel particles in RAW 264.7 macrophage and MG-63 osteoblast cell lines.

Hydrogel polymers comprise a novel category of synthetic materials being investigated for use in cartilage replacement. One candidate compound, a poly(ethylene glycol)/poly(acrylic acid) (PEG/PAA) interpenetrating polymer network (IPN), was developed for use in corneal prostheses and was recently engineered for potential orthopedic use. The current study examined the effects of particles of this compound on two cell lines (MG-63 osteoblast-like cells and RAW 264.7 macrophages) over a 48-h time course. To mimic the effects of wear debris, particles of the compound were generated and introduced to the cells. In the MG-63 cell line, the particles had no significant effect on cell viability measured by PicoGreen assay and trypan blue exclusion. In contrast, a significant decrease in cell viability was detected in the Raw 264.7 macrophage cells at the final timepoint with the highest concentration of hydrogel (3.0% v:v). A concentration- and time-dependent increase in TNF-alpha release characteristic of other known biocompatible materials was also detected in RAW 264.7 cells, but nitric oxide and interleukin (IL)-1beta showed no response. In addition, the MG-63 cell line demonstrated no IL-6 response. Particles of the PEG/PAA IPN thus seem to stimulate biological responses similar to those in other biocompatible materials.