Drug Delivery and Medical Devices

Drug Delivery and Medical Devices Publications

Reyes N, Huang JJ, Choudhury A, Pondelis N, Locatelli EVT, Hollinger R, Felix ER, Pattany PM, Galor A, Moulton EA. FL-41 Tint Reduces Activation of Neural Pathways of Photophobia in Patients with Chronic Ocular Pain. Am J Ophthalmol 2023;Abstract
PURPOSE: To assess the therapeutic effect of tinted lenses (FL-41) on photophobia and light-evoked brain activity using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular surface pain. DESIGN: Prospective case series. METHODS: 25 subjects from the Miami Veterans Affairs (VA) eye clinic were recruited based on the presence of chronic ocular pain, dry eye symptoms, and photophobia. Using a 3T MRI scanner, subjects underwent two fMRI scans using an event-related design based on light stimuli: one scan while wearing FL-41 lenses and one without. Unpleasantness ratings evoked by the light stimuli were collected after each scan. RESULTS: With FL-41 lenses, subjects reported decreased (n=19), maintained (n=2), or increased (n=4) light-evoked unpleasantness ratings. Group analysis at baseline (no lens) revealed significant light evoked responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral insula, bilateral frontal pole, visual, precuneus, paracingulate, and anterior cingulate cortices (ACC) as well as cerebellar vermis, bilateral cerebellar hemispheric lobule VI, and bilateral cerebellar crus I and II. With FL-41 lenses, light-evoked responses were significantly decreased in bilateral S1, bilateral S2, bilateral insular, right temporal pole, precuneus, ACC, and paracingulate cortices as well as bilateral cerebellar hemispheric lobule VI. CONCLUSION: FL-41 lenses modulated photophobia symptoms in some individuals with chronic ocular pain. In conjunction, FL-41 lenses decreased activation in cortical areas involved in processing affective and sensory-discriminative dimensions of pain. Further research into these relationships will advance the ability to provide precision therapy for individuals with ocular pain.
Kamat V, Grumbine MK, Bao K, Mokate K, Khalil G, Cook D, Clearwater B, Hirst R, Harman J, Boeck M, Fu Z, Smith LEH, Goswami M, Wubben TJ, Walker EM, Zhu J, Soleimanpour SA, Scarlett JM, Robbings BM, Hass D, Hurley JB, Sweet IR. A versatile pumpless multi-channel fluidics system for maintenance and real-time functional assessment of tissue and cells. Cell Rep Methods 2023;3(11):100642.Abstract
To address the needs of the life sciences community and the pharmaceutical industry in pre-clinical drug development to both maintain and continuously assess tissue metabolism and function with simple and rapid systems, we improved on the initial BaroFuse to develop it into a fully functional, pumpless, scalable multi-channel fluidics instrument that continuously measures changes in oxygen consumption and other endpoints in response to test compounds. We and several other laboratories assessed it with a wide range of tissue types including retina, pancreatic islets, liver, and hypothalamus with both aqueous and gaseous test compounds. The setup time was less than an hour for all collaborating groups, and there was close agreement between data obtained from the different laboratories. This easy-to-use system reliably generates real-time metabolic and functional data from tissue and cells in response to test compounds that will address a critical need in basic and applied research.
Gomes PJ, Ciolino JB, Arranz P, Gonzalo A, Fernández N, Hernández G. Bilastine 0.6% preservative-free eye drops, an effective once-daily treatment to reduce signs and symptoms of allergic conjunctivitis: A pooled analysis of two randomized clinical trials. J Investig Allergol Clin Immunol 2023;Abstract
BACKGROUND AND OBJECTIVE: Allergic conjunctivitis is the most common type of ocular allergy. The objective of this study was to evaluate the efficacy of a new once-daily, preservative-free, bilastine 0.6% eye drop formulation for the treatment of allergic conjunctivitis. METHODS: Two double-masked, vehicle controlled, clinical studies (a Phase 2 Dose Ranging Study and a Phase 3 Efficacy Study) were conducted to assess the efficacy of bilastine ophthalmic solution for the treatment of signs and symptoms of allergic conjunctivitis. Both studies used the Ora-CAC® Conjunctival Allergen Challenge (CAC) Model to allow observations of allergic responses under controlled conditions. Each study was analyzed separately and then combined to create an integrated dataset. RESULTS: Efficacy was achieved for the primary efficacy endpoint of ocular itching for three bilastine concentrations (0.2%, 0.4%, and 0.6%) at 15 minutes and 8 hours post-instillation and bilastine 0.6% ophthalmic solution was also efficacious at 16 hours post-instillation. Bilastine 0.6% ophthalmic solution demonstrated non-inferiority to ketotifen 0.025% at the onset of action. From the integrated data set, differences between vehicle and bilastine 0.6% were significant at all time points both at onset (15 minutes) and at a prolonged duration (16 hours) after instillation. CONCLUSION: This multi-trial assessment suggests that bilastine 0.6% ophthalmic solution is efficacious for the treatment of the signs and symptoms of allergic conjunctivitis, with a rapid and prolonged duration of action, and has a favorable safety profile. The added convenience of a once-a-day dosing regimen may contribute to patient adherence and improve their quality of life.
Madrolu VSK, Male SR, Bhardwaj R, Theagarayan B. Influence of prismatic effect due to decentration of optical center in ophthalmic lens. Health Sci Rep 2023;6(8):e1472.Abstract
BACKGROUND AND AIMS: Induced prismatic effects due to poor fitting spectacle frames is a common problem, seen in most of the spectacle wearers and this improper fitting is often due to optical center demarcation on lenses and this error causes asthenopic symptoms and diplopia. However, these errors are most common in developing countries due to lack of awareness, hence a standardized regulation is required. The current study aimed to estimate the amount of prismatic effect that is induced due to the decentration of an optical center in ophthalmic lens. METHODS: A quantitative cross-sectional study was conducted in single vision spectacle wearers (N = 120) with a mean age of 25 ± 5 years. The pupillometric evaluation was performed to mark the pupil center on the spectacle lens. A lensometry evaluation was done to mark the optic center of the spectacle lens. A comparison was made to note whether the optic center is aligned with pupillary center. Objective assessment was performed through Prentice's rule (P = cF) and subjective symptoms were assessed through a validated visual comfort questionnaire. RESULTS: In this sample, around 57% of the individual with single vision glasses were not looking through the optic center and experiencing induced prismatic effect of -0.7 to 0.6 prism diopter, with mean decentration of 3.5 mm. Forty percent of the individuals with misaligned optic center showed asthenopic symptoms and visual discomfort. CONCLUSION: Optometrist should check quality of dispensing and visual performance before handing over the newly dispensed glasses to the patients.
Gaddie IB, Donnenfeld ED, Karpecki P, Vollmer P, Berdy GJ, Peterson JD, Simmons B, Edell ARP, Whitson WE, Ciolino JB, Baba SN, Holdbrook M, Trevejo J, Meyer J, Yeu E, Yeu E. Lotilaner Ophthalmic Solution 0.25% for Demodex Blepharitis: Randomized, Vehicle-Controlled, Multicenter, Phase 3 Trial (Saturn-2). Ophthalmology 2023;130(10):1015-1023.Abstract
PURPOSE: To evaluate the safety and efficacy of lotilaner ophthalmic solution 0.25% compared with vehicle for the treatment of Demodex blepharitis. DESIGN: Prospective, randomized, double-masked, vehicle-controlled, multicenter, phase 3 clinical trial. PARTICIPANTS: Four hundred twelve patients with Demodex blepharitis were assigned randomly in a 1:1 ratio to receive either lotilaner ophthalmic solution 0.25% (study group) or vehicle without lotilaner (control group). METHODS: Patients with Demodex blepharitis treated at 21 United States clinical sites were assigned either to the study group (n = 203) to receive lotilaner ophthalmic solution 0.25% or to the control group (n = 209) to receive vehicle without lotilaner bilaterally twice daily for 6 weeks. Collarettes and erythema were graded for each eyelid at screening and at all visits after baseline. At screening and on days 15, 22, and 43, 4 or more eyelashes were epilated from each eye, and the number of Demodex mites present on the lashes was counted with a microscope. Mite density was calculated as the number of mites per lash. MAIN OUTCOME MEASURES: Outcome measures included collarette cure (collarette grade 0), clinically meaningful collarette reduction to 10 collarettes or fewer (grade 0 or 1), mite eradication (0 mites/lash), erythema cure (grade 0), composite cure (grade 0 for collarettes as well as erythema), compliance with the drop regimen, drop comfort, and adverse events. RESULTS: At day 43, the study group achieved a statistically significant (P < 0.0001) higher proportion of patients with collarette cure (56.0% vs. 12.5%), clinically meaningful collarette reduction to 10 collarettes or fewer (89.1% vs. 33.0%), mite eradication (51.8% vs. 14.6%), erythema cure (31.1% vs. 9.0%), and composite cure (19.2% vs. 4.0%) than the control group. High compliance with the drop regimen (mean ± standard deviation, 98.7 ± 5.3%) in the study group was observed, and 90.7% of patients found the drops to be neutral to very comfortable. CONCLUSIONS: Twice-daily treatment with lotilaner ophthalmic solution 0.25% for 6 weeks generally was safe and well tolerated and met the primary end point and all secondary end points for the treatment of Demodex blepharitis compared with vehicle control. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Jones L, Efron N, Bandamwar K, Barnett M, Jacobs DS, Jalbert I, Pult H, Rhee MK, Sheardown H, Shovlin JP, Stahl U, Stanila A, Tan J, Tavazzi S, Ucakhan OO, Willcox MDP, Downie LE. TFOS lifestyle: Impact of contact lenses on the ocular surface. Ocul Surf 2023;Abstract
Several lifestyle choices made by contact lens wearers can have adverse consequences on ocular health. These include being non-adherent to contact lens care, sleeping in lenses, ill-advised purchasing options, not seeing an eyecare professional for regular aftercare visits, wearing lenses when feeling unwell, wearing lenses too soon after various forms of ophthalmic surgery, and wearing lenses when engaged in risky behaviours (e.g., using tobacco, alcohol or recreational drugs). Those with a pre-existing compromised ocular surface may find that contact lens wear exacerbates ocular disease morbidity. Conversely, contact lenses may have various therapeutic benefits. The coronavirus disease-2019 (COVID-19) pandemic has impinged upon the lifestyle of contact lens wearers, introducing challenges such as mask-associated dry eye, contact lens discomfort with increased use of digital devices, inadvertent exposure to hand sanitizers, and reduced use of lenses. Wearing contact lenses in challenging environments, such as in the presence of dust and noxious chemicals, or where there is the possibility of ocular trauma (e.g., sport or working with tools) can be problematic, although in some instances lenses can be protective. Contact lenses can be worn for sport, theatre, at high altitude, driving at night, in the military and in space, and special considerations are required when prescribing in such situations to ensure successful outcomes. A systematic review and meta-analysis, incorporated within the review, identified that the influence of lifestyle factors on soft contact lens dropout remains poorly understood, and is an area in need of further research. Overall, this report investigated lifestyle-related choices made by clinicians and contact lens wearers and discovered that when appropriate lifestyle choices are made, contact lens wear can enhance the quality of life of wearers.
Patel H, Pavlichenko I, Grinthal A, Zhang CT, Alvarenga J, Kreder MJ, Weaver JC, Ji Q, Ling CWF, Choy J, Li Z, Black NL, Bispo PJM, Lewis JA, Kozin ED, Aizenberg J, Remenschneider AK. Design of medical tympanostomy conduits with selective fluid transport properties. Sci Transl Med 2023;15(690):eadd9779.Abstract
Implantable tubes, shunts, and other medical conduits are crucial for treating a wide range of conditions from ears and eyes to brain and liver but often impose serious risks of device infection, obstruction, migration, unreliable function, and tissue damage. Efforts to alleviate these complications remain at an impasse because of fundamentally conflicting design requirements: Millimeter-scale size is required to minimize invasiveness but exacerbates occlusion and malfunction. Here, we present a rational design strategy that reconciles these trade-offs in an implantable tube that is even smaller than the current standard of care. Using tympanostomy tubes (ear tubes) as an exemplary case, we developed an iterative screening algorithm and show how unique curved lumen geometries of the liquid-infused conduit can be designed to co-optimize drug delivery, effusion drainage, water resistance, and biocontamination/ingrowth prevention in a single subcapillary-length-scale device. Through extensive in vitro studies, we demonstrate that the engineered tubes enabled selective uni- and bidirectional fluid transport; nearly eliminated adhesion and growth of common pathogenic bacteria, blood, and cells; and prevented tissue ingrowth. The engineered tubes also enabled complete eardrum healing and hearing preservation and exhibited more efficient and rapid antibiotic delivery to the middle ear in healthy chinchillas compared with current tympanostomy tubes, without resulting in ototoxicity at up to 24 weeks. The design principle and optimization algorithm presented here may enable tubes to be customized for a wide range of patient needs.
Gomes PJ, Ciolino JB, Arranz P, Hernández G, Fernández N. Bilastine 0.6% preservative-free eye drops, a once-daily treatment for allergic conjunctivitis. J Investig Allergol Clin Immunol 2023;Abstract
BACKGROUND: Bilastine is a second-generation antihistamine approved for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. This trial evaluated the efficacy and safety of a new bilastine 0.6% preservative-free eye-drops formulation for the symptomatic treatment of allergic conjunctivitis. METHODS: This phase 3, multicenter, double-masked, randomized study evaluated the efficacy, safety and tolerability of bilastine 0.6% ophthalmic solution compared to ketotifen 0.025% and vehicle. The primary efficacy endpoint was ocular itching reduction. The Ora-CAC® Allergen Challenge Model was used to assess ocular and nasal symptoms at 15 minutes (onset of action) and 16 hours post-treatment. RESULTS: Subjects (N=228) were 59.6% male, and the mean (SD) age was 44.1 (13.4) years. Bilastine demonstrated efficacy in reducing ocular itching compared to vehicle at both onset of action and 16 hours post-treatment (P <0.001). Ketotifen showed improvement compared to vehicle 15 minutes post-treatment (P <0.001). Bilastine demonstrated statistical non-inferiority to ketotifen for all 3 post-CAC timepoints at 15 minutes post-instillation, based on an inferiority margin of 0.4. Bilastine demonstrated improvement over vehicle (P <0.05) for conjunctival redness, ciliary redness, episcleral redness, chemosis, eyelid swelling, tearing, rhinorrhea, ear and palate pruritus and nasal congestion at 15 minutes post-treatment. Ophthalmic bilastine was safe and well tolerated. Mean drop comfort scores were significantly better (P <0.05) for bilastine compared with ketotifen immediately upon instillation, and similar compared with vehicle. CONCLUSIONS: Ophthalmic bilastine effectively reduced ocular itching for 16 hours post-treatment, suggesting that it could be used as a once-daily treatment for the signs and symptoms of allergic conjunctivitis. ClinicalTrials.gov identifier: NCT03479307.
Gholizadeh S, Chen X, Yung A, Naderi A, Ghovvati M, Liu Y, Farzad A, Mostafavi A, Dana R, Annabi N. Development and optimization of an ocular hydrogel adhesive patch using definitive screening design (DSD). Biomater Sci 2023;11(4):1318-1334.Abstract
Adhesive hydrogels based on chemically modified photocrosslinkable polymers with specific physicochemical properties are frequently utilized for sealing wounds or incisions. These adhesive hydrogels offer tunable characteristics such as tailorable tissue adhesion, mechanical properties, swelling ratios, and enzymatic degradability. In this study, we developed and optimized a photocrosslinkable adhesive patch, GelPatch, with high burst pressure, minimal swelling, and specific mechanical properties for application as an ocular (sclera and subconjunctival) tissue adhesive. To achieve this, we formulated a series of hydrogel patches composed of different polymers with various levels of methacrylation, molecular weights, and hydrophobic/hydrophilic properties. A computerized multifactorial definitive screening design (DSD) analysis was performed to identify the most prominent components impacting critical response parameters such as adhesion, swelling ratio, elastic modulus, and second order interactions between applied components. These parameters were mathematically processed to generate a predictive model that identifies the linear and non-linear correlations between these factors. In conclusion, an optimized formulation of GelPatch was selected based on two modified polymers: gelatin methacryloyl (GelMA) and glycidyl methacrylated hyaluronic acid (HAGM). The ex vivo results confirmed adhesion and retention of the optimized hydrogel subconjunctivally and on the sclera for up to 4 days. The developed formulation has potential to be used as an ocular sealant for quick repair of laceration type ocular injuries.
Chen L, Kuang L, Ross AE, Farhat W, Boychev N, Sharfi S, Kanu LN, Liu L, Kohane DS, Ciolino JB. Topical Sustained Delivery of Miltefosine Via Drug-Eluting Contact Lenses to Treat Acanthamoeba Keratitis. Pharmaceutics 2022;14(12)Abstract
This study aimed to develop a miltefosine-eluting contact lens (MLF-CL) device that would allow sustained and localized miltefosine release for the treatment of Acanthamoeba keratitis. MLF-CLs were produced in three different miltefosine doses by solvent-casting a thin miltefosine-polymer film around the periphery of a methafilcon hydrogel, which was then lathed into a contact lens. During seven days of in vitro testing, all three formulations demonstrated sustained release from the lens at theoretically therapeutic levels. Based on the physicochemical characterization of MLF-CLs, MLF-CL's physical properties are not significantly different from commercial contact lenses in terms of light transmittance, water content and wettability. MLF-CLs possessed a slight reduction in compression modulus that was attributed to the inclusion of polymer-drug films but still remain within the optimal range of soft contact lenses. In cytotoxicity studies, MLF-CL indicated up to 91% viability, which decreased proportionally as miltefosine loading increased. A three-day biocompatibility test on New Zealand White rabbits revealed no impact of MLF-CLs on the corneal tissue. The MLF-CLs provided sustained in vitro release of miltefosine for a week while maintaining comparable physical features to a commercial contact lens. MLF-CL has a promising potential to be used as a successful treatment method for Acanthamoeba keratitis.
Rhee MK, Jacobs DS, Dhaliwal DK, Szczotka-Flynn L, Prescott CR, Jhanji V, Steinemann TL, Koffler BH, Jeng BH. Contact Lens Safety for the Correction of Refractive Error in Healthy Eyes. Eye Contact Lens 2022;48(11):449-454.Abstract
Contact lenses are a safe and effective method for correction of refractive error and worn by an estimated 45 million Americans. Because of the widespread availability and commercial popularity of contact lenses, it is not well appreciated by the public that contact lenses are U.S. Food and Drug Administration (FDA)-regulated medical devices. Contact lenses are marketed in numerous hard and soft materials that have been improved over decades, worn in daily or extended wear, and replaced in range of schedules from daily to yearly or longer. Lens materials and wear and care regimens have impact on the risks of contact lens-related corneal inflammatory events and microbial keratitis. This article reviews contact lens safety, with specific focus on the correction of refractive error in healthy eyes.
Wang Y, Jacobs DS. Role of therapeutic contact lenses in management of corneal disease. Curr Opin Ophthalmol 2022;33(4):306-310.Abstract
PURPOSE OF REVIEW: The current review highlights areas of innovation and research in the use of contact lenses in the treatment of corneal ectasia and ocular surface disease. RECENT FINDINGS: A series of academic reports were published by a committee of experts reviewing evidence-based practice patterns of contact lens use. There continues to be active research in the use of contact lenses in the management of keratoconus, including mini-scleral lenses, custom impression-based scleral lenses and wavefront-guided scleral lenses. Recent reports on contact lenses for ocular surface disease were primarily reviews, retrospective case reports or case series, with publications on contact lens use in corneal epithelial defects, graft-vs.-host disease, limbal stem cell deficiency and neurotrophic keratitis. There are recent publications on advances in drug-eluting contact lenses. SUMMARY: Corneal specialists should be aware of current advances in the field of contact lens expanding their use in corneal ectasia and ocular surface disease.
Peng C, Kuang L, Zhao J, Ross AE, Wang Z, Ciolino JB. Bibliometric and visualized analysis of ocular drug delivery from 2001 to 2020. J Control Release 2022;345:625-645.Abstract
OBJECTIVE: To perform a bibliometric analysis in the field of ocular drug delivery research to characterize the current international trends and to present visual representations of the past and emerging trends on ocular drug delivery research over the past decade. METHOD: In this cross-sectional study, a bibliometric analysis of data retrieved and extracted from the Web of Science Core Collection (WoSCC) database was performed to analyze evolution and theme trends on ocular drug delivery research from January 1, 2001, to December 31, 2020. A total of 4334 articles on ocular drug delivery were evaluated for specific characteristics, such as publication year, journals, authors, institutions, countries/regions, references, and keywords. Co-authorship analysis, co-occurrence analysis, co-citation analysis, and network visualization were constructed by VOSviewer. Some important subtopics identified by bibliometric characterization were further discussed and reviewed. RESULTS: From 2001 to 2020, the annual global publications increased by 746.15%, from 52 to 440. International Journal of Pharmaceutics published the most manuscripts (250 publications) and produced the highest citations (9509 citations), followed by Investigative Ophthalmology & Visual Science (202 publications) and Journal of Ocular Pharmacology and Therapeutics (136 publications). The United States (1289 publications, 31,512 citations), the University of Florida (82 publications, 2986 citations), and Chauhan, Anuj (52 publications, 2354 citations) were the most productive and impactful institution, country, and author respectively. The co-occurrence cluster analysis of the top 100 keywords form five clusters: (1) micro/nano ocular drug delivery systems; (2) the treatment of inflammation and posterior diseases; (3) macroscopic ocular drug delivery systems/devices; (4) the characteristics of drug delivery systems; (5) and the ocular drug delivery for glaucoma treatment. Diabetic macular edema, anti-VEGF, ranibizumab, bevacizumab, micelles and latanoprost, were the latest high-frequency keywords, indicating the emerging frontiers of ocular drug delivery. Further discussions into the subtopics were provided to assist researchers to determine the range of research topics and plan research direction. CONCLUSIONS: Over the last two decades there has been a progressive increase in the number of publications and citations on research related to ocular drug delivery across many countries, institutions, and authors. The present study sheds light on current trends, global collaboration patterns, basic knowledge, research hotspots, and emerging frontiers of ocular drug delivery. Novel solutions for ocular drug delivery and the treatment of inflammation and posterior diseases were the major themes over the last 20 years.
Jumelle C, Yung A, Shirzaei Sani E, Taketani Y, Gantin F, Bourel L, Wang S, Yüksel E, Seneca S, Annabi N, Dana R. Development and characterization of a hydrogel-based adhesive patch for sealing open-globe injuries. Acta Biomater 2022;137:53-63.Abstract
Full-thickness wounds to the eye can lead to serious vision impairment. Current standards of care (from suturing to tissue transplantation) usually require highly skilled surgeons and use of an operating theater. In this study, we report the synthesis, optimization, and in vitro and ex vivo testing of photocrosslinkable hydrogel-based adhesive patches that can easily be applied to globe injuries or corneal incisions. According to the type and concentration of polymers used in the adhesive formulations, we were able to finely tune the physical properties of the bioadhesive including viscosity, elastic modulus, extensibility, ultimate tensile strength, adhesion, transparency, water content, degradation time, and swellability. Our in vitro studies showed no sign of cytotoxicity of the hydrogels. Moreover, the hydrogel patches showed higher adhesion on freshly explanted pig eyeballs compared to a marketed ocular sealant. Finally, ex vivo feasibility studies showed that the hydrogel patches could seal complex open-globe injuries such as large incision, cruciform injury, and injury associated with tissue loss. These results suggest that our photocrosslinkable hydrogel patch could represent a promising solution for the sealing of open-globe injuries or surgical incisions. STATEMENT OF SIGNIFICANCE: Current management of severe ocular injuries require advanced surgical skills and access to an operating theater. To address the need for emergent management of wounds that cannot be handled in the operating room, surgical adhesives have gained popularity, but none of the currently available adhesives have optimal bioavailability, adhesive or mechanical properties. This study describes the development, optimization and testing of a light-sensitive adhesive patch that can easily be applied to the eye. After solidification using visible light, the patch shows no toxicity and is more adherent to the tissue than a marketed sealant. Thus this technology could represent a promising solution to stabilize ocular injuries in emergency settings before definitive surgical repair.

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