Real-Time Monitoring Platform for Ocular Drug Delivery.

Real-time measurement is important in modern dissolution testing to aid in parallel drug characterisation and quality control (QC). The development of a real-time monitoring platform (microfluidic system, a novel eye movement platform with temperature sensors and accelerometers and a concentration probe setup) in conjunction with an in vitro model of the human eye (PK-Eye™) is reported. The importance of surface membrane permeability when modelling the PK-Eye™ was determined with a "pursing model" (a simplified setup of the hyaloid membrane). Parallel microfluidic control of PK-Eye™ models from a single source of pressure was performed with a ratio of 1:6 (pressure source:models) demonstrating scalability and reproducibility of pressure-flow data. Pore size and exposed surface area helped obtain a physiological range of intraocular pressure (IOP) within the models, demonstrating the need to reproduce in vitro dimensions as closely as possible to the real eye. Variation of aqueous humour flow rate throughout the day was demonstrated with a developed circadian rhythm program. Capabilities of different eye movements were programmed and achieved with an in-house eye movement platform. A concentration probe recorded the real-time concentration monitoring of injected albumin-conjugated Alexa Fluor 488 (Alexa albumin), which displayed constant release profiles. These results demonstrate the possibility of real-time monitoring of a pharmaceutical model for preclinical testing of ocular formulations.

Optical aberrations following implantation of multifocal intraocular lenses: a systematic review and meta-analysis protocol.

INTRODUCTION: Multifocal intraocular lens (IOLs) are used to restore vision at different focal distances. The technology of multifocal IOLs is continually advancing. Optical aberrations a property of lenses that causes spreading of light over a region resulting in a blurred or distorted image. This study aims to systematically review investigator measured and patient reported optical aberrations following implantation of multifocal IOLs during phacoemulsification surgery to treat presbyopia in adults. METHODS AND ANALYSIS: We will conduct an electronic database search for randomised controlled trials, prospective non-randomised studies, observational studies in Ovid MEDLINE, Ovid EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus and ClinicalTrials.gov in March 2021. Eligibility criteria will include quantitative articles written in English and containing data on optical aberrations. Two independent reviewers will screen titles and abstracts and extract data from full texts, reporting outcomes according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data extraction of key characteristics will be completed using customised forms. Methodological quality will be assessed using Cochrane Handbook 6.2. ETHICS AND DISSEMINATION: Ethics approval is not required for this review, as it will only include published data. Findings will be published in a peer-reviewed journal and disseminated across ophthalmic networks. We anticipate that the findings of this work will be of interest to multiple stakeholders: people who have undergone cataract surgery, eye health professionals, ophthalmic surgeons, device manufacturers and policy-makers. It will also inform researchers to where there are gaps in evidence and identify areas for future research. PROSPERO REGISTRATION NUMBER: CRD42021271050.

Effects of Flow Hydrodynamics and Eye Movements on Intraocular Drug Clearance.

New in vitro prototypes (PK-Eye™) were tested with and without eye movement to understand diffusion and convection effects on intraocular clearance. Port placement in front ((i) ciliary inflow model) and behind the model lens ((ii) posterior inflow model) was used to study bevacizumab (1.25 mg/50 µL) and dexamethasone (0.1 mg/100 µL) in phosphate-buffered saline (PBS, pH 7.4) and simulated vitreal fluid (SVF). Dexamethasone was studied in a (iii) retinal-choroid-sclera (RCS) outflow model (with ciliary inflow and two outflow pathways). Ciliary vs. posterior inflow placement did not affect the half-life for dexamethasone at 2.0 µL/min using PBS (4.7 days vs. 4.8 days) and SVF (4.9 days with ciliary inflow), but it did decrease the half-life for bevacizumab in PBS (20.4 days vs. 2.4 days) and SVF (19.2 days vs. 10.8 days). Eye movement only affected the half-life of dexamethasone in both media. Dexamethasone in the RCS model showed approximately 20% and 75% clearance from the RCS and anterior outflows, respectively. The half-life of the protein was comparable to human data in the posterior inflow model. Shorter half-life values for a protein in a ciliary inflow model can be achieved with other eye movements. The RCS flow model with eye movement was comparable to human half-life data for dexamethasone.

The control of conjunctival fibrosis as a paradigm for the prevention of ocular fibrosis-related blindness. "Fibrosis has many friends".

The processes involved in ocular fibrosis after disease or ocular tissue injury, including surgery play an important part in the development or failure of treatment of most blinding diseases. Ocular fibrosis is one of the biggest areas of unmet need in ophthalmology. Effective anti-scarring therapies could potentially revolutionise the management of many diseases like glaucoma worldwide. The response of a quiescent or activated conjunctiva to glaucoma surgery and aqueous flow with different stimulatory components and the response to different interventions and future therapeutics is a paradigm for scarring prevention in other parts of the eye and orbit. Evolution in our understanding of molecular and cellular mechanisms in ocular fibrosis is leading to the introduction of new and re-purposed therapeutic agents, targeting a wide range of key processes. This review provides current and futures perspectives on different approaches to conjunctival fibrosis following glaucoma surgery and highlights the challenges faced in implementing these therapies with maximal effect and minimal side effects.

Translating Minimally Invasive Glaucoma Surgery Devices.

Glaucoma is the leading cause of irreversible blindness with over 70 million people affected worldwide. The surgical management of glaucoma aims to lower intraocular pressure by increasing aqueous outflow facility. The latest manufacturing techniques have allowed for the development of a number of novel implantable devices to improve safety and outcomes of glaucoma surgery. These are collectively referred to as minimally invasive glaucoma surgery (MIGS) devices and are among the smallest devices implanted in the human body. This review discusses the design criterion and constraints as well as the user requirements for MIGS devices. We review how recent devices have attempted to meet these challenges and give our opinion as to the necessary characteristics for the development of future devices.

Novel approaches to model effects of subconjunctival blebs on flow pressure to improve clinical grading systems after glaucoma drainage surgery.

Clinical grading systems following glaucoma filtration surgery do not include any effects of the bleb on the intra-ocular pressure and are relatively subjective, therefore carrying the risk of inter and/or intra-observer variability. The main objective of the study is to quantify and model the effect of subconjunctival bleb on flow pressure for assessment of clinical grading following glaucoma surgery. Subconjunctival bleb was created by inserting a tube into ex vivo rabbit eyes via an ab externo approach through the anterior chamber and exiting into the subconjunctival space. Sterile dyed water was injected through the tube into the developing bleb. For the in vitro approach a silicone bleb was created by clamping a circular silicone sheet, injecting dyed water through a fixed resistance outlet tube. Photographic measurements of the bleb height, planform area and pressure were taken as a function of time. Clinical blebs were also collected over a few months. Mathematical algorithm software was used to build the bleb model. Bleb height and volume increase as pressure in the bleb increases. The bleb planform area tended to a constant determined by the section of conjunctiva prior to shunt insertion. These increases were in accordance with the bleb model developed in the Appendix. They show that the pressure in the bleb is related to the resistance of the outflow. The linearity of clinical grading systems is reviewed and a new grading approach is proposed. The pressure in the bleb has a strong dependence on bleb extent, height and a weak dependence on conjunctival thickness. The pressure in a bleb can be estimated from bleb height, radius, and flow rate inlet in agreement with the bleb flow model. These results provide support for an improved bleb categorization system.

Hydrodynamics of Intravitreal Injections into Liquid Vitreous Substitutes.

Intravitreal injections have become the cornerstone of retinal care and one of the most commonly performed procedures across all medical specialties. The impact of hydrodynamic forces of intravitreal solutions when injected into vitreous or vitreous substitutes has not been well described. While computational models do exist, they tend to underestimate the starting surface area of an injected bolus of a drug. Here, we report the dispersion profile of a dye bolus (50 µL) injected into different vitreous substitutes of varying viscosities, surface tensions, and volumetric densities. A novel 3D printed in vitro model of the vitreous cavity of the eye was designed to visualize the dispersion profile of solutions when injected into the following vitreous substitutes-balanced salt solution (BSS), sodium hyaluronate (HA), and silicone oils (SO)-using a 30G needle with a Reynolds number (Re) for injection ranging from approximately 189 to 677. Larger bolus surface areas were associated with faster injection speeds, lower viscosity of vitreous substitutes, and smaller difference in interfacial surface tensions. Boluses exhibited buoyancy when injected into standard S1000. The hydrodynamic properties of liquid vitreous substitutes influence the initial injected bolus dispersion profile and should be taken into account when simulating drug dispersion following intravitreal injection at a preclinical stage of development, to better inform formulations and performance.

The Implications of an Ab Interno Versus Ab Externo Surgical Approach on Outflow Resistance of a Subconjunctival Drainage Device for Intraocular Pressure Control.

PURPOSE: Minimally invasive glaucoma surgery (MIGS) devices that drain into the subconjunctival space can be inserted via an ab externo or ab interno approach. Limited experimental data exists as to the impact of either technique on intraocular pressure (IOP) control. We performed microfluidic studies by using ex vivo rabbit eyes to assess the effect of each approach on outflow resistance of a subconjunctival drainage device for IOP control. METHODS: A microfluidic experiment system was designed, consisting of a controlled reservoir of water connected to a pressure pump/flow sensor. The flow rate of water was fixed at 2 µl/min to simulate aqueous humor production. The pressure readings for each approach were recorded at a frequency of 1 Hz. A baseline reading was made before tube insertion into the eye (PEEK tube length set to aim for an initial outflow resistance of 5 to 10 mm Hg/µL/min) followed by measurements for a cumulative 2-ml volume entering the subconjunctival space. Results were adjusted for water viscosity at 37°C and reported as outflow resistance (mm Hg/µL/min ± standard error of mean). RESULTS: Outflow resistance via the ab interno approach was 90.4% higher than with the ab externo approach being measured at 0.80 ± 0.11 mm Hg/µL/min and 0.42 ± 0.05 mm Hg/µL/min, respectively. Bleb formation was observed to be less predictable with the ab interno approach. CONCLUSIONS: The ab interno approach demonstrated greater outflow resistance and less predictable bleb formation than the ab externo approach. These results have implications for long-term IOP control and success depending on the approach to device insertion and could be an important consideration for future MIGS devices. TRANSLATIONAL RELEVANCE: The effect of the ab interno versus ab externo approach of a MIGS device inserted into the subconjunctival space was assessed. The ab interno approach demonstrated greater outflow resistance and less predictable bleb formation that may have implications for the development of future MIGS devices.

A Case Report of Complete Blockage of a Baerveldt Glaucoma Implant Following Insertion of a 3-0 Supramid Suture.

PURPOSE: The aim of this study was to present a case of a Baerveldt glaucoma implant lumen being completely occluded with a 3-0 Supramid stent suture. PATIENT AND METHODS: The patient underwent Baerveldt glaucoma implant surgery with placement of an intraluminal 3-0 Supramid stent suture that acts to restrict flow across the device and reduce the risk of postoperative hypotony. Following suturing of the implant to the sclera, the device was flow tested. No flow was observed through the device tube and a significant ballooning of the tube diameter occurred with increased pressure on the device. The device was explanted from the eye and replaced with a different implant without further postoperative complication. The explanted device was assessed using custom microfluidic equipment in an in vitro environment. RESULTS: This phenomenon occurred despite using several different batches of the 3-0 Supramid stent suture and the device had to be removed and replaced with another device without complication. In vitro microfluidic assessment of the device demonstrated no flow across the device tube despite over 150 mm Hg of pressure being exerted on the device. CONCLUSIONS: We hypothesize that the blockage occurred at the junction between the device tube and plate and that the ballooning phenomenon observed was due to a defect in the tube wall. This case highlights the importance of flow testing all glaucoma drainage devices before insertion given the variation in manufacturing conditions to avoid the risk of intraoperative complications.

Genotype-Phenotype Associations of IL6 and PRG4 With Conjunctival Fibrosis After Glaucoma Surgery.

Importance: Postsurgical fibrosis is a critical determinant of the long-term success of glaucoma surgery, but no reliable biomarkers are currently available to stratify the risk of scarring. Objective: To compare the clinical phenotype of patients with conjunctival fibrosis after glaucoma surgery with candidate gene expression tissue biomarkers of fibrosis. Design, Setting, and Participants: In this cross-sectional study, 42 patients were recruited at the time of glaucoma surgery at the Moorfields Eye Hospital from September 1, 2014, to September 1, 2016. The participants were divided into those with fibrosis and those without fibrosis. Main Outcomes and Measures: Genotype-phenotype correlations of the IL6 or PRG4 gene and detailed clinical phenotype. The IL6 and PRG4 protein expression in conjunctival tissues was also assessed using in situ immunohistochemical analysis. Central bleb area, maximal bleb area, and bleb height were graded on a scale of 1 to 5 (1 indicating 0%; 2, 25%; 3, 50%; 4, 75%; and 5, 100%). Bleb vascularity was graded on a scale of 1 to 5 (1 indicating avascularity; 2, normal; 3, mild; 4, moderate; and 5, severe hyperemia). Results: A total of 42 patients were recruited during the study period; 28 participants (67%) had previously undergone glaucoma surgery (fibrotic group) (mean [SD] age, 43.8 [3.6 years]; 16 [57%] female; 22 [79%] white), and 14 participants (33%) had not previously undergone glaucoma surgery (nonfibrotic group) (mean [SD] age, 47.7 [6.9] years; 4 [29%] female; 9 [64%] white). The fibrotic group had marked bleb scarring and vascularization and worse logMAR visual acuity. The mean (SD) grades were 1.4 (0.1) for central bleb area, 1.4 (0.1) for bleb height, and 3.4 (0.2) for bleb vascularity. The IL6 gene was upregulated in fibrotic cell lines (mean, 0.040) compared with nonfibrotic cell lines (mean, 0.011) (difference, 0.029; 95% CI, 0.015-0.043; P = .003). The PRG4 gene was also downregulated in fibrotic cell lines (0.002) compared with nonfibrotic cell lines (mean, 0.109; difference, 0.107; 95% CI, 0.104-0.110; P = .03). The study found a strong correlation between the IL6 gene and the number of glaucoma operations (r = 0.94, P < .001) and logMAR visual acuity (r = 0.64, P = .03). A moderate correlation was found between the PRG4 gene and the number of glaucoma operations (r = -0.72, P = .005) and logMAR visual acuity (r = -0.62, P = .03). Conclusions and Relevance: IL6 and PRG4 represent potential novel tissue biomarkers of disease severity and prognosis in conjunctival fibrosis after glaucoma surgery. Future longitudinal studies with multiple postoperative measures are needed to validate the effect of these potential biomarkers of fibrosis.