Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma.

PURPOSE: This study aimed to develop a clinically feasible and practical therapy for multi-ocular protection following ocular injury by using a thermosensitive drug delivery system (DDS) for sustained delivery of TNF-α and VEGF inhibitors to the eye. METHODS: A thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock polymer) loaded with 0.7 mg of adalimumab and 1.4 mg of aflibercept was injected subconjunctivally into Dutch-belted pigmented rabbits after corneal alkali injury. Control rabbits received 2 mg of IgG-loaded DDS or 1.4 mg of aflibercept-loaded DDS. Animals were followed for 3 months and assessed for tolerability and prevention of corneal neovascularization (NV), improvement of corneal re-epithelialization, inhibition of retinal ganglion cell (RGC) and optic nerve axon loss, and inhibition of immune cell infiltration into the cornea. Drug-release kinetics was assessed in vivo using an aqueous humor protein analysis. RESULTS: A single subconjunctival administration of dual anti-TNF-α/anti-VEGF DDS achieved a sustained 3-month delivery of antibodies to the anterior chamber, iris, ciliary body, and retina. Administration after corneal alkali burn suppressed CD45+ immune cell infiltration into the cornea, completely inhibited cornea NV for 3 months, accelerated corneal re-epithelialization and wound healing, and prevented RGC and optic nerve axon loss at 3 months. In contrast, anti-VEGF alone or IgG DDS treatment led to persistent corneal epithelial defect (combined: <1%; anti-VEGF: 15%; IgG: 10%, of cornea area), increased infiltration of CD45+ immune cells into the cornea (combined: 28 ± 20; anti-VEGF: 730 ± 178; anti-IgG: 360 ± 186, cells/section), and significant loss of RGCs (combined: 2.7%; anti-VEGF: 63%; IgG: 45%) and optic nerve axons at 3 months. The aqueous humor protein analysis showed first-order release kinetics without adverse effects at the injection site. CONCLUSIONS: Concomitant inhibition of TNF-α and VEGF prevents corneal neovascularization and ameliorates subsequent irreversible damage to the retina and optic nerve after severe ocular injury. A single subconjunctival administration of this therapy, using a biodegradable, slow-release thermosensitive DDS, achieved the sustained elution of therapeutic levels of antibodies to all ocular tissues for 3 months. This therapeutic approach has the potential to dramatically improve the outcomes of severe ocular injuries in patients and improve the therapeutic outcomes in patients with retinal vascular diseases.

Intrinsic Optical Properties of Boston Keratoprosthesis.

Purpose: To benchmark the optical performance of Boston Keratoprosthesis (B-KPro). Methods: Back focal lengths (BFL) of B-KPros for various eye axial lengths were measured using an optical bench, International Organization for Standardization-certified for intraocular lens characterization, and compared against manufacturer's specification. The modulation transfer function (MTF) and the resolution efficiencies were measured. The theoretical geometry-dependent higher-order aberrations (HOA) were calculated. The devices were characterized with optical profilometry for estimating the surface scattering. Aberration correction and subsequent image quality improvement were simulated in CODE-V. Natural scene-imaging was performed in a mock ocular environment. Retrospective analysis of 15 B-KPro recipient eyes were presented to evaluate the possibility of achieving 20/20 best-corrected visual acuity (BCVA). Results: BFL measurements were in excellent agreement with the manufacturer-reported values (r = 0.999). The MTF specification exceeded what is required for achieving 20/20 visual acuity. Astigmatism and field curvature, correctable in simulations, were the primary aberrations limiting imaging performance. Profilometry of the anterior surface revealed nanoscale roughness (root-mean-square amplitude, 30-50 nm), contributing negligibly to optical scattering. Images of natural scenes obtained with a simulated B-KPro eye demonstrated good central vision, with 10/10 visual acuity (equivalent to 20/20). Full restoration of 20/20 BCVA was obtainable for over 9 years in some patients. Conclusions: Theoretical and experimental considerations demonstrate that B-KPro has the optical capacity to restore 20/20 BCVA in patients. Further image quality improvement can be anticipated through correction of HOAs. Translational Relevance: We establish an objective benchmark to characterize the optics of the B-KPro and other keratoprosthesis and propose design changes to allow improved vision in B-KPro patients.

Three-dimensional Neuroretinal Rim Thickness and Visual Fields in Glaucoma: A Broken-stick Model.

PRECIS: In open-angle glaucoma, when neuroretinal rim tissue measured by volumetric optical coherence tomography (OCT) scans is below a third of the normal value, visual field (VF) damage becomes detectable. PURPOSE: To determine the amount of neuroretinal rim tissue thickness below which VF damage becomes detectable. METHODS: In a retrospective cross-sectional study, 1 eye per subject (of 57 healthy and 100 open-angle glaucoma patients) at an academic institution had eye examinations, VF testing, spectral-domain OCT retinal nerve fiber layer (RNFL) thickness measurements, and optic nerve volumetric scans. Using custom algorithms, the minimum distance band (MDB) neuroretinal rim thickness was calculated from optic nerve scans. "Broken-stick" regression was performed for estimating both the MDB and RNFL thickness tipping-point thresholds, below which were associated with initial VF defects in the decibel scale. The slopes for the structure-function relationship above and below the thresholds were computed. Smoothing curves of the MDB and RNFL thickness covariates were evaluated to examine the consistency of the independently identified tipping-point pairs. RESULTS: Plots of VF total deviation against MDB thickness revealed plateaus of VF total deviation unrelated to MDB thickness. Below the thresholds, VF total deviation decreased with MDB thickness, with the associated slopes significantly greater than those above the thresholds (P<0.014). Below 31% of global MDB thickness, and 36.8% and 43.6% of superior and inferior MDB thickness, VF damage becomes detectable. The MDB and RNFL tipping points were in good accordance with the correlation of the MDB and RNFL thickness covariates. CONCLUSIONS: When neuroretinal rim tissue, characterized by MDB thickness in OCT, is below a third of the normal value, VF damage in the decibel scale becomes detectable.

Implantable self-aligning fiber-optic optomechanical devices for in vivo intraocular pressure-sensing in artificial cornea.

Artificial cornea is an effective treatment of corneal blindness. Yet, intraocular pressure (IOP) measurements for glaucoma monitoring remain an urgent unmet need. Here, we present the integration of a fiber-optic Fabry-Perot pressure sensor with an FDA-approved keratoprosthesis for real-time IOP measurements using a novel strategy based on optical-path self-alignment with micromagnets. Additionally, an alternative noncontact sensor-interrogation approach is demonstrated using a bench-top optical coherence tomography system. We show stable pressure readings with low baseline drift (<2.8 mm Hg) for >4.5 years in vitro and efficacy in IOP interrogation in vivo using fiber-optic self-alignment, with good initial agreement with the actual IOP. Subsequently, IOP drift in vivo was due to retroprosthetic membrane (RPM) formation on the sensor secondary to surgical inflammation (more severe in the current pro-fibrotic rabbit model). This study paves the way for clinical adaptation of optical pressure sensors with ocular implants, highlighting the importance of controlling RPM in clinical adaptation.

Single-shot depth profiling by spatio-temporal encoding with a multimode fiber.

Computational imaging with random encoding patterns obtained by scattering of light in complex media has enabled simple imaging systems with compelling performance. Here, we extend this concept to axial reflectivity profiling using spatio-temporal coupling of broadband light in a multimode fiber (MMF) to generate the encoding functions. Interference of light transmitted through the MMF with a sample beam results in path-length-specific patterns that enable computational reconstruction of the axial sample reflectivity profile from a single camera snapshot. Leveraging the versatile nature of MMFs, we demonstrate depth profiling with bandwidth-limited axial resolution of 13.4 µm over a scalable sensing range reaching well beyond one centimeter.

Effects of gamma radiation sterilization on the structural and biological properties of decellularized corneal xenografts.

To address the shortcomings associated with corneal transplants, substantial efforts have been focused on developing new modalities such as xenotransplantion. Xenogeneic corneas are anatomically and biomechanically similar to the human cornea, yet their applications require prior decellularization to remove the antigenic components to avoid rejection. In the context of bringing decellularized corneas into clinical use, sterilization is a crucial step that determines the success of the transplantation. Well-standardized sterilization methods, such as gamma irradiation (GI), have been applied to decellularized porcine corneas (DPC) to avoid graft-associated infections in human recipients. However, little is known about the effect of GI on decellularized corneal xenografts. Here, we evaluated the radiation effect on the ultrastructure, optical, mechanical and biological properties of DPC. Transmission electron microscopy revealed that gamma irradiated decellularized porcine cornea (G-DPC) preserved its structural integrity. Moreover, the radiation did not reduce the optical properties of the tissue. Neither DPC nor G-DPC led to further activation of complement system compared to native porcine cornea when exposed to plasma. Although, DPC were mechanically comparable to the native tissue, GI increased the mechanical strength, tissue hydrophobicity and resistance to enzymatic degradation. Despite these changes, human corneal epithelial, stromal, endothelial and hybrid neuroblastoma cells grew and differentiated on DPC and G-DPC. Thus, GI may achieve effective tissue sterilization without affecting critical properties that are essential for corneal transplant survival.

Microglia Regulate Neuroglia Remodeling in Various Ocular and Retinal Injuries.

Reactive microglia and infiltrating peripheral monocytes have been implicated in many neurodegenerative diseases of the retina and CNS. However, their specific contribution in retinal degeneration remains unclear. We recently showed that peripheral monocytes that infiltrate the retina after ocular injury in mice become permanently engrafted into the tissue, establishing a proinflammatory phenotype that promotes neurodegeneration. In this study, we show that microglia regulate the process of neuroglia remodeling during ocular injury, and their depletion results in marked upregulation of inflammatory markers, such as Il17f, Tnfsf11, Ccl4, Il1a, Ccr2, Il4, Il5, and Csf2 in the retina, and abnormal engraftment of peripheral CCR2+ CX3CR1+ monocytes into the retina, which is associated with increased retinal ganglion cell loss, retinal nerve fiber layer thinning, and pigmentation onto the retinal surface. Furthermore, we show that other types of ocular injuries, such as penetrating corneal trauma and ocular hypertension also cause similar changes. However, optic nerve crush injury-mediated retinal ganglion cell loss evokes neither peripheral monocyte response in the retina nor pigmentation, although peripheral CX3CR1+ and CCR2+ monocytes infiltrate the optic nerve injury site and remain present for months. Our study suggests that microglia are key regulators of peripheral monocyte infiltration and retinal pigment epithelium migration, and their depletion results in abnormal neuroglia remodeling that exacerbates neuroretinal tissue damage. This mechanism of retinal damage through neuroglia remodeling may be clinically important for the treatment of patients with ocular injuries, including surgical traumas.

Optomechanical and photothermal interactions in suspended photonic crystal membranes.

We present here an optomechanical system fabricated with novel stress management techniques that allow us to suspend an ultrathin defect-free silicon photonic-crystal membrane above a Silicon-on-Insulator (SOI) substrate with a gap that is tunable to below 200 nm. Our devices are able to generate strong attractive and repulsive optical forces over a large surface area with simple in- and out- coupling and feature the strongest repulsive optomechanical coupling in any geometry to date (gOM/2π ≈65 GHz/nm). The interplay between the optomechanical and photo-thermal-mechanical dynamics is explored, and the latter is used to achieve cooling and amplification of the mechanical mode, demonstrating that our platform is well-suited for potential applications in low-power mass, force, and refractive-index sensing as well as optomechanical accelerometry.

Bonding, antibonding and tunable optical forces in asymmetric membranes.

We demonstrate that tunable attractive (bonding) and repulsive (anti-bonding) forces can arise in highly asymmetric structures coupled to external radiation, a consequence of the bonding/anti-bonding level repulsion of guided-wave resonances that was first predicted in symmetric systems. Our focus is a geometry consisting of a photonic-crystal (holey) membrane suspended above an unpatterned layered substrate, supporting planar waveguide modes that can couple via the periodic modulation of the holey membrane. Asymmetric geometries have a clear advantage in ease of fabrication and experimental characterization compared to symmetric double-membrane structures. We show that the asymmetry can also lead to unusual behavior in the force magnitudes of a bonding/antibonding pair as the membrane separation changes, including nonmonotonic dependences on the separation. We propose a computational method that obtains the entire force spectrum via a single time-domain simulation, by Fourier-transforming the response to a short pulse and thereby obtaining the frequency-dependent stress tensor. We point out that by operating with two, instead of a single frequency, these evanescent forces can be exploited to tune the spring constant of the membrane without changing its equilibrium separation.