Drug Delivery and Medical Devices

Drug Delivery and Medical Devices Publications

Gholizadeh S, Wang Z, Chen X, Dana R, Annabi N. Advanced nanodelivery platforms for topical ophthalmic drug delivery. Drug Discov Today 2021;Abstract
Conventional eye drops have several limitations, including the need for multiple applications per dose, hourly based dosage regiments, and suboptimal ocular bioavailability (<5%). The efficacy of topical ophthalmic medications can be significantly improved by controlling their contact time with the adherent mucin layer and by inducing sustained release properties, thus allowing for a prolonged contact time of the drug with ocular tissues, which eventually will lead to improved drug bioavailability and a significant decrease in the frequency of eyedrop instillation. In this review, we critically highlight recent and innovative nanodrug delivery platforms, with a primary focus on the integration of nanotechnology, biomaterials, and chemistry to facilitate precise spatial and temporal control over sustained drug release to the cornea.
Jacobs DS, Carrasquillo KG, Cottrell PD, Fernández-Velázquez FJ, Gil-Cazorla R, Jalbert I, Pucker AD, Riccobono K, Robertson DM, Szczotka-Flynn L, Speedwell L, Stapleton F. CLEAR - Medical use of contact lenses. Cont Lens Anterior Eye 2021;44(2):289-329.Abstract
The medical use of contact lenses is a solution for many complex ocular conditions, including high refractive error, irregular astigmatism, primary and secondary corneal ectasia, disfiguring disease, and ocular surface disease. The development of highly oxygen permeable soft and rigid materials has extended the suitability of contact lenses for such applications. There is consistent evidence that bandage soft contact lenses, particularly silicone hydrogel lenses, improve epithelial healing and reduce pain in persistent epithelial defects, after trauma or surgery, and in corneal dystrophies. Drug delivery applications of contact lens hold promise for improving topical therapy. Modern scleral lens practice has achieved great success for both visual rehabilitation and therapeutic applications, including those requiring retention of a tear reservoir or protection from an adverse environment. This report offers a practical and relevant summary of the current evidence for the medical use of contact lenses for all eye care professionals including optometrists, ophthalmologists, opticians, and orthoptists. Topics covered include indications for use in both acute and chronic conditions, lens selection, patient selection, wear and care regimens, and recommended aftercare schedules. Prevention, presentation, and management of complications of medical use are reviewed.
Jones L, Hui A, Phan C-M, Read ML, Azar D, Buch J, Ciolino JB, Naroo SA, Pall B, Romond K, Sankaridurg P, Schnider CM, Terry L, Willcox M. CLEAR - Contact lens technologies of the future. Cont Lens Anterior Eye 2021;44(2):398-430.Abstract
Contact lenses in the future will likely have functions other than correction of refractive error. Lenses designed to control the development of myopia are already commercially available. Contact lenses as drug delivery devices and powered through advancements in nanotechnology will open up further opportunities for unique uses of contact lenses. This review examines the use, or potential use, of contact lenses aside from their role to correct refractive error. Contact lenses can be used to detect systemic and ocular surface diseases, treat and manage various ocular conditions and as devices that can correct presbyopia, control the development of myopia or be used for augmented vision. There is also discussion of new developments in contact lens packaging and storage cases. The use of contact lenses as devices to detect systemic disease has mostly focussed on detecting changes to glucose levels in tears for monitoring diabetic control. Glucose can be detected using changes in colour, fluorescence or generation of electric signals by embedded sensors such as boronic acid, concanavalin A or glucose oxidase. Contact lenses that have gained regulatory approval can measure changes in intraocular pressure to monitor glaucoma by measuring small changes in corneal shape. Challenges include integrating sensors into contact lenses and detecting the signals generated. Various techniques are used to optimise uptake and release of the drugs to the ocular surface to treat diseases such as dry eye, glaucoma, infection and allergy. Contact lenses that either mechanically or electronically change their shape are being investigated for the management of presbyopia. Contact lenses that slow the development of myopia are based upon incorporating concentric rings of plus power, peripheral optical zone(s) with add power or non-monotonic variations in power. Various forms of these lenses have shown a reduction in myopia in clinical trials and are available in various markets.
Ghaffarieh A, Ciolino JB. Potential of Application of Iron Chelating Agents in Ophthalmic Diseases. Semin Ophthalmol 2021;:1-5.Abstract
The investigations discussed in this review indicate that iron may exacerbate different eye diseases. Therefore, it is plausible that reducing cellular or body iron stores could influence disease pathogenesis, so it is logical to consider the iron chelators' potential protective role in the various ophthalmic diseases in the form of topical eye drops or slow releasing injectable compounds as an adjuvant treatment.
Kalra G, Ichhpujani P, Thakur S, Singh RB, Sharma U, Kumar S. A pilot study for smartphone photography to assess bleb morphology and vasculature post-trabeculectomy. Int Ophthalmol 2021;41(2):483-490.Abstract
PURPOSE: The current grading systems used for bleb morphology assessment in patients post-trabeculectomy are based on standardized slit-lamp photographs and anterior segment imaging devices. The lack of availability of these expensive and non-portable devices in resource-deficient settings is a significant deterrent in their widespread utilization for proper post-operative management. The rapidly evolving utilization of smartphone photography has significantly benefited diagnostics of posterior segment disorders and is now being increasingly utilized for monitoring anterior segment pathologies as well as post-surgical course. In this study, we study a novel use of smartphones for bleb photography for assessing the morphological characteristics as vascularity and microcysts. METHODS: In this pilot, observational study, we compared the trabeculectomy bleb images of five subjects, obtained by iPhone X (dual lens) and iPhone 6S (single lens). We captured two image sets with both smartphones first with a focussed torchlight and then with a built-in flash video light. RESULTS: The images resulting from the newer iPhone X were substantially superior than those from iPhone 6S. For the 12-megapixel dual-camera set-up on the iPhone X, the 1 × lens resulted in better images than the 2 × lens with contrast and overall clarity of the area of interest. While the macro-lens attachment had promising results at 1 × zoom, there is no added advantage of the macro-lens attachment as it resulted in considerable loss of image quality at twice the zoom. Using a 20 D lens helped attain higher magnification and better framing as it reduced the focussing distance needed to get sharp images. The images obtained from both smartphones were of higher quality when illuminated from an external source when compared to the native iPhone flash due to even exposure and fewer autofocus artefacts. CONCLUSION: Analyses of all image sets showed that the current generation in-built camera app on IOS and newer iPhone camera optics resulted in high-quality images of the ocular surface with high magnification without any loss in clarity.
Ting DSJ, Foo VH, Yang LWY, Sia JT, Ang M, Lin H, Chodosh J, Mehta JS, Ting DSW. Artificial intelligence for anterior segment diseases: Emerging applications in ophthalmology. Br J Ophthalmol 2021;105(2):158-168.Abstract
With the advancement of computational power, refinement of learning algorithms and architectures, and availability of big data, artificial intelligence (AI) technology, particularly with machine learning and deep learning, is paving the way for 'intelligent' healthcare systems. AI-related research in ophthalmology previously focused on the screening and diagnosis of posterior segment diseases, particularly diabetic retinopathy, age-related macular degeneration and glaucoma. There is now emerging evidence demonstrating the application of AI to the diagnosis and management of a variety of anterior segment conditions. In this review, we provide an overview of AI applications to the anterior segment addressing keratoconus, infectious keratitis, refractive surgery, corneal transplant, adult and paediatric cataracts, angle-closure glaucoma and iris tumour, and highlight important clinical considerations for adoption of AI technologies, potential integration with telemedicine and future directions.
Elhusseiny AM, VanderVeen DK. Outcomes of Glaucoma Drainage Devices in Childhood Glaucoma. Semin Ophthalmol 2020;:1-11.Abstract
PURPOSE: Angle surgery is the gold standard for the management of many types of childhood glaucoma, yet glaucoma drainage devices (GDD) are effective tools for refractory advanced cases or secondary childhood glaucomas. The purpose of this article is to review recently published literature focused on the use of GDDs for pediatric glaucoma, including GDD general principles and surgical outcomes. METHODS: Literature review of various electronic databases was performed. RESULTS: 71 papers were reviewed for outcomes of GDD in childhood glaucomas. Success rates were usually defined by intraocular pressure (IOP) of 5-22 mmHg, with or without medications. Success rates were typically higher for non-valved GDDs but varied by length of follow-up. Non-valved GDDs afford lower and longer-lasting IOP control in pediatric eyes than valved GDD, however, no randomized controlled trials exist in childhood glaucoma. CONCLUSION: Various designs of GDDs are available for management of childhood glaucoma with good short-term success rates; individual patient factors should be taken into consideration when selecting a specific device.
Inomata T, Nakamura M, Iwagami M, Midorikawa-Inomata A, Sung J, Fujimoto K, Okumura Y, Eguchi A, Iwata N, Miura M, Fujio K, Nagino K, Hori S, Tsubota K, Dana R, Murakami A. Stratification of Individual Symptoms of Contact Lens-Associated Dry Eye Using the iPhone App DryEyeRhythm: Crowdsourced Cross-Sectional Study. J Med Internet Res 2020;22(6):e18996.Abstract
BACKGROUND: Discontinuation of contact lens use is mainly caused by contact lens-associated dry eye. It is crucial to delineate contact lens-associated dry eye's multifaceted nature to tailor treatment to each patient's individual needs for future personalized medicine. OBJECTIVE: This paper aims to quantify and stratify individual subjective symptoms of contact lens-associated dry eye and clarify its risk factors for future personalized medicine using the smartphone app DryEyeRhythm (Juntendo University). METHODS: This cross-sectional study included iPhone (Apple Inc) users in Japan who downloaded DryEyeRhythm. DryEyeRhythm was used to collect medical big data related to contact lens-associated dry eye between November 2016 and January 2018. The main outcome measure was the incidence of contact lens-associated dry eye. Univariate and multivariate adjusted odds ratios of risk factors for contact lens-associated dry eye were determined by logistic regression analyses. The t-distributed Stochastic Neighbor Embedding algorithm was used to depict the stratification of subjective symptoms of contact lens-associated dry eye. RESULTS: The records of 4454 individuals (median age 27.9 years, SD 12.6), including 2972 female participants (66.73%), who completed all surveys were included in this study. Among the included participants, 1844 (41.40%) were using contact lenses, and among those who used contact lenses, 1447 (78.47%) had contact lens-associated dry eye. Multivariate adjusted odds ratios of risk factors for contact lens-associated dry eye were as follows: younger age, 0.98 (95% CI 0.96-0.99); female sex, 1.53 (95% CI 1.05-2.24); hay fever, 1.38 (95% CI 1.10-1.74); mental illness other than depression or schizophrenia, 2.51 (95% CI 1.13-5.57); past diagnosis of dry eye, 2.21 (95% CI 1.63-2.99); extended screen exposure time >8 hours, 1.61 (95% CI 1.13-2.28); and smoking, 2.07 (95% CI 1.49-2.88). The t-distributed Stochastic Neighbor Embedding analysis visualized and stratified 14 groups based on the subjective symptoms of contact lens-associated dry eye. CONCLUSIONS: This study identified and stratified individuals with contact lens-associated dry eye and its risk factors. Data on subjective symptoms of contact lens-associated dry eye could be used for prospective prevention of contact lens-associated dry eye progression.
Veronese C, Maiolo C, Armstrong GW, Primavera L, Torrazza C, Della Mora L, Ciardella AP. New surgical approach for sutureless scleral fixation. Eur J Ophthalmol 2020;30(3):612-615.Abstract
PURPOSE: The aim of this article is to describe a novel surgical technique for sutureless scleral fixation of an intraocular lens using the newly developed FIL SSF Carlevale IOL (Soleko, Italy). METHODS: Four eyes of four patients with poor capsular support were recruited to our study, three resulting from intraocular lens subluxation and one case resulting from traumatic cataract. A novel sutureless sclera-fixated intraocular lens was implanted into the posterior chamber of each eye with sclerocorneal plugs fixating the lens to the wall of the eye. RESULTS: Mean age of patients was 52 ± 16 years, ranging from 35 to 70 years. Mean follow-up was 6.50 ± 1.29 months (range: 5-7 months). Mean preoperative best-corrected visual acuity was 0.50 ± 0.33 logMAR (range: 1-0.3 logMAR). Postoperative best-corrected visual acuity improved to 0.08 ± 0.08 logMAR (range: 0.2-0 logMAR). There was no significant change in the mean intraocular pressure and there were no postoperative complications, such as iatrogenic distortion or breakage of the intraocular lens haptic, intraocular lens decentration, endophthalmitis, or retinal detachment. DISCUSSION: To the best of our knowledge, this is the first report of outcomes using the novel sutureless sclera-fixated FIL SSF Carlevale IOL. This new surgical technique offers a simplified and effective approach for sutureless scleral intraocular lens fixation with good refractive outcomes.
Jumelle C, Gholizadeh S, Annabi N, Dana R. Advances and limitations of drug delivery systems formulated as eye drops. J Control Release 2020;321:1-22.Abstract
Topical instillation of eye drops remains the most common and easiest route of ocular drug administration, representing the treatment of choice for many ocular diseases. Nevertheless, low ocular bioavailability of topically applied drug molecules can considerably limit their efficacy. Over the last several decades, numerous drug delivery systems (DDS) have been developed in order to improve drug bioavailability on the ocular surfaces. This review systematically covers the most recent advances of DDS applicable by topical instillation, that have shown better performance in in vivo models compared to standard eye drop formulations. These delivery systems are based on in situ forming gels, nanoparticles and combinations of both. Most of the DDS have been developed using natural or synthetic polymers. Polymers offer many advantageous properties for designing advanced DDS including biocompatibility, gelation properties and/or mucoadhesiveness. However, despite the high number of studies published over the last decade, there are several limitations for clinical translation of DDS. This review article focuses on the recent advances for the development of ocular drug delivery systems. In addtion, the potential challenges for commercialization of new DDS are presented.
Ross AE, Bengani LC, Tulsan R, Maidana DE, Salvador-Culla B, Kobashi H, Kolovou PE, Zhai H, Taghizadeh K, Kuang L, Mehta M, Vavvas DG, Kohane DS, Ciolino JB. Topical sustained drug delivery to the retina with a drug-eluting contact lens. Biomaterials 2019;217:119285.Abstract
Intravitreal injections and implants are used to deliver drugs to the retina because therapeutic levels of these medications cannot be provided by topical administration (i.e. eye drops). In order to reach the retina, a topically applied drug encounters tear dilution, reflex blinking, and rapid fluid drainage that collectively reduce the drug's residence time on the ocular surface. Residing under the tears, the cornea is the primary gateway into the eye for many topical ophthalmic drugs. We hypothesized that a drug-eluting contact lens that rests on the cornea would therefore be well-suited for delivering drugs to the eye including the retina. We developed a contact lens based dexamethasone delivery system (Dex-DS) that achieved sustained drug delivery to the retina at therapeutic levels. Dex-DS consists of a dexamethasone-polymer film encapsulated inside a contact lens. Rabbits wearing Dex-DS achieved retinal drug concentrations that were 200 times greater than those from intensive (hourly) dexamethasone drops. Conversely, Dex-DS demonstrated lower systemic (blood serum) dexamethasone concentrations. In an efficacy study in rabbits, Dex-DS successfully inhibited retinal vascular leakage induced by intravitreal injection of vascular endothelial growth factor (VEGF). Dex-DS was found to be safe in a four-week repeated dose biocompatibility study in healthy rabbits.
Zhu Z, Ellwein LB, Wang SK, Zhao J, He M. Meeting the need for corrective spectacles in visually impaired Chinese school children: the potential of ready-made spectacles. Br J Ophthalmol 2019;103(8):1106-1111.Abstract
PURPOSE: To assess the potential of ready-made (spherical) spectacles (RMS) in meeting the need for refractive correction in visually impaired children in China. METHODS: Eligible children aged 5-17 years were identified from the three study sites in China. Distance visual acuity was measured with a retroilluminated logarithm of the minimum angle of resolution chart with tumbling E optotypes. Cycloplegic autorefraction was performed on all children using a handheld autorefractor. If uncorrected visual acuity (UCVA) was ≤20/40 in either eye, best corrected visual acuity was measured with subjective refractive error. RESULTS : A total of 13 702 children were enumerated from the three studies, with 12 334 (90.0%) having both reliable visual acuity measurements and successful cycloplegia. Among the 12 334 study children, the prevalence of UCVA ≤20/40 in the better seeing eye was 16.4% (95% CI 15.0% to 17.8%), with 91.1% (1843) of these improving by ≥3 lines of visual acuity with refractive correction. Prevalence was 12.7% (95% CI 11.5% to 13.9%) for UCVA 20/50 with 97.4% (1521) improving by ≥3 lines, and 9.38% (95% CI 8.39% to 19.4%) for UCVA ≤20/63 with 98.4% (1138) improving by ≥3 lines. Depending on the severity of visual impairment, 62.8%-64.0% of children could be accommodated with RMS if not correcting for astigmatism of ≤0.75 dioptres and anisometropia of ≤0.50 spherical equivalent dioptres. Approximately 87% of children could be accommodated with RMS if astigmatism and anisometropia limits were increased to ≤1.25 and ≤1.50 dioptres, respectively. CONCLUSIONS: RMS could substantially alleviate visual morbidity in two-thirds or more of visually impaired schoolchildren in China. This cost-effective approach to refractive correction might also be useful in low/middle-income countries with poor access to optometric services.
Chitnis GD, Verma MKS, Lamazouade J, Gonzalez-Andrades M, Yang K, Dergham A, Jones PA, Mead BE, Cruzat A, Tong Z, Martyn K, Solanki A, Landon-Brace N, Karp JM. A resistance-sensing mechanical injector for the precise delivery of liquids to target tissue. Nat Biomed Eng 2019;3(8):621-631.Abstract
The precision of the delivery of therapeutics to the desired injection site by syringes and hollow needles typically depends on the operator. Here, we introduce a highly sensitive, completely mechanical and cost-effective injector for targeting tissue reliably and precisely. As the operator pushes the syringe plunger, the injector senses the loss-of-resistance on encountering a softer tissue or a cavity, stops advancing the needle and delivers the payload. We demonstrate that the injector can reliably deliver liquids to the suprachoroidal space-a challenging injection site that provides access to the back of the eye-for a wide range of eye sizes, scleral thicknesses and intraocular pressures, and target sites relevant for epidural injections, subcutaneous injections and intraperitoneal access. The design of this simple and effective injector can be adapted for a broad variety of clinical applications.
Ianchulev T, Chayet A, Kahook M, Packer M, Pasquale L, Weinreb RN. Pharmacodynamic profile of mydriatic agents delivered by ocular piezo-ejection microdosing compared with conventional eyedropper. Ther Deliv 2016;Abstract

AIM: Eyedroppers deliver medication volumes exceeding conjunctival absorptive capacity, causing spillage and risking ocular/systemic complications. We evaluated piezoelectric microdosing. Results/methodology: Subjects (n = 102) received precision microdroplet delivery of phenylephrine (2.5%) and tropicamide (1.0%): 1 × 1.5 μl, 1 × 6 μl or 2 × 3 μl of each (randomized 1:1:1), into one eye. Contralateral eyes received eyedropper doses of both drugs. Outcomes were pupil dilation (0-60 min) and patient satisfaction. Six-microliter microdosing achieved comparable, and 2 × 3 μl met/exceeded dilation speed and magnitude versus eyedropper. Separately, participants preferred piezoelectric saline self-delivery to eyedroppers, reporting better head-positioning comfort, reduced tearing/overflow and increased likelihood of adhering to ocular medication regimens. CONCLUSION: Piezoelectric microdosing achieves comparable effects as eyedroppers delivering 4-17-fold larger doses. Microdosing may enhance patient adherence to ocular medication regimens while minimizing side effects.

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