Recent Advances in Ocular Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 27046

Special Issue Editors

Centre for Ophthalmology, University Eye Hospital Tübingen, Tübingen, Germany
Interests: retinal organ culture models; glaucoma; retinal diseases; neuroprotection; ocular drug delivery; nanoparticles; ocular gene delivery; aptamers; AMD; IRD
Special Issues, Collections and Topics in MDPI journals
1. Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Department of Ophthalmology, Reina Sofia University Hospital and University of Cordoba, 14004 Cordoba, Spain
2. Department of Ophthalmology, Massachusetts Eye and Ear and Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA
Interests: ophthalmology; cornea; tissue engineering; regenerative medicine

Special Issue Information

Dear Colleagues,

Eye diseases are either treated with eye drops or, more rarely, systemically with intravitreal injections. However, the treatment efficacy of eye drops is low because only 1–5% of the administered drug remains in the eye long enough to be effective. For retinal diseases, this percentage drops down to less than 1% due to low ocular penetration. Therefore, repeated intravitreal injections are needed to treat retinal diseases, which can result in side effects and systemic spreading. Hence, more robust drug delivery systems need to be developed in order to avoid unwanted side effects and achieve better therapeutic outcomes. Nano- and microparticles offer great opportunities to overcome these challenges.

This Special Issue aims to capture the current state-of-the-art advances in ocular drug delivery. Suggested topics include the following: novel micro- and nanoparticles; improvements in implantable devices and slow release systems; new approaches in targeted ocular drug delivery; and challenges and obstacles of ocular drug delivery (systems).

Dr. Sven Schnichels
Dr. Miguel González-Andrades
Guest Editors

Manuscript Submission Information

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Keywords

  • nanoparticle
  • nanorobots
  • micelles
  • implantable devices
  • slow release system
  • biodegredabale impants
  • targeted drug delivery
  • glaucoma
  • AMD
  • retinitis pigmentosa
  • retina
  • cornea

Published Papers (10 papers)

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Research

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14 pages, 6708 KiB  
Article
Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma
by Chengxin Zhou, Fengyang Lei, Jyoti Sharma, Pui-Chuen Hui, Natalie Wolkow, Claes H. Dohlman, Demetrios G. Vavvas, James Chodosh and Eleftherios I. Paschalis
Pharmaceutics 2023, 15(8), 2059; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15082059 - 31 Jul 2023
Cited by 2 | Viewed by 1094
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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18 pages, 4638 KiB  
Article
Lipid-DNA Nanoparticles as Drug-Delivery Vehicles for the Treatment of Retinal Diseases
by Sven Schnichels, David Simmang, Marina Löscher, Andreas Herrmann, Jan Willem de Vries, Martin S. Spitzer and José Hurst
Pharmaceutics 2023, 15(2), 532; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15020532 - 04 Feb 2023
Cited by 1 | Viewed by 1550
Abstract
Retinal eye diseases are the leading cause of blindness in the Western world. Up to date, the only efficient treatment for many retinal diseases consists of invasive intravitreal injections of highly concentrated drugs. Despite the fact that these injections are unpleasant for the [...] Read more.
Retinal eye diseases are the leading cause of blindness in the Western world. Up to date, the only efficient treatment for many retinal diseases consists of invasive intravitreal injections of highly concentrated drugs. Despite the fact that these injections are unpleasant for the patients, they potentially cause serious side effects, e.g., infections, bleeding within the eye or retinal detachment, especially when performed on a monthly basis, thus decreasing the injection frequency and lowering the desired drug dose. Therefore, a sustained released at the region of interest with a sustained release is desired. Recently, novel lipid-DNA nanoparticles (NPs) were shown to be an efficient drug delivery platform to the anterior segment of the eye. In this study, we investigated the distribution and tropism of the NPs when applied intravitreally, as a potential medication carrier to the posterior part of the eye. This technology is perfectly suited for the delivery of low molecular weight drugs to the back of the eye, which so far is greatly hindered by fast diffusion rates of the free drugs in the vitreous body and their intrinsically low retainability in ocular tissue. Excellent biodistribution, adherence and presence for up to five days was found for the different tested nanoparticles ex vivo and in vivo. In conclusion, our lipid-DNA based nanocarrier system was able to reach the retina within minutes and penetrate the retina providing potentially safe and long-term carrier systems for small molecules or nucleotide-based therapies. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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11 pages, 1154 KiB  
Article
Intravitreal Application: Physicochemical Properties of Drugs Dissolved in Silicone Oils of Different Density in Comparison to the Porcine Vitreous Body
by Maximilian Hammer, Sonja K. Schickhardt, Patrick R. Merz, Ramin Khoramnia, Alexander F. Scheuerle, Walter Mier, Philipp Uhl and Gerd U. Auffarth
Pharmaceutics 2022, 14(7), 1364; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14071364 - 28 Jun 2022
Cited by 2 | Viewed by 1666
Abstract
Silicone oil endotamponades provide a reservoir for drugs in the eye. Following vitrectomy surgery to treat retinal detachments, extensive diabetic retinopathy or endophthalmitis, they can be used as long-term lipophilic depots. This study aimed to investigate the physicochemical properties of intravitreally applied drugs [...] Read more.
Silicone oil endotamponades provide a reservoir for drugs in the eye. Following vitrectomy surgery to treat retinal detachments, extensive diabetic retinopathy or endophthalmitis, they can be used as long-term lipophilic depots. This study aimed to investigate the physicochemical properties of intravitreally applied drugs of different lipophilicity, namely vancomycin, ceftazidime and voriconazole. For this purpose, an in vitro model of the silicone-oil-filled eye compared to porcine vitreous bodies (PVBs) was used. In a glass container, either light or heavy silicone oil or PVB was set into equilibrium with an aqueous fluid. Vancomycin, voriconazole and ceftazidime were added in concentrations commonly applied in clinical practice. The time course of the concentration of the drugs was determined in the hydrophilic phase for up to 24 h. With silicone oil present, the concentrations of vancomycin, voriconazole and ceftazidime were elevated in the aqueous humor when compared to the vitreous body (p < 0.001 for all drugs). With increasing lipophilicity, higher concentrations of the drug dissolved in silicone oil after 24 h (52.7%, 49.1% and 34.3% for vancomycin, ceftazidime and voriconazole, respectively). While no difference between lighter- and heavier-than-water silicone oil was apparent for vancomycin and ceftazidime (p = 0.17 and p = 0.72), voriconazole dissolved significantly better in the heavier-than-water silicone oil (p = 0.002). A higher-than-expected percentage of the glycopeptide vancomycin dissolved in the porcine vitreous body, possibly due to protein binding. In conclusion, silicone oils influence the drug concentration and distribution of intravitreally applied drugs depending on their lipophilicity. The addition of F6H8 used to create heavy silicone oils attenuates these effects for lipophilic drugs. Knowledge of the distribution of these intravitreally applied drugs is crucial to ensure the desired anti-infectious effect. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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20 pages, 3008 KiB  
Article
Polyaphron Formulations Stabilised with Different Water-Soluble Polymers for Ocular Drug Delivery
by Roman V. Moiseev, Fraser Steele and Vitaliy V. Khutoryanskiy
Pharmaceutics 2022, 14(5), 926; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14050926 - 24 Apr 2022
Cited by 9 | Viewed by 2740
Abstract
As drug delivery to the eye has evolved over the last decades, researchers have explored more effective treatments for ocular diseases. Despite this, delivering drugs to the cornea remains one of the most problematic issues in ophthalmology due to the poor permeability of [...] Read more.
As drug delivery to the eye has evolved over the last decades, researchers have explored more effective treatments for ocular diseases. Despite this, delivering drugs to the cornea remains one of the most problematic issues in ophthalmology due to the poor permeability of the cornea and tear clearance mechanisms. In this study, four different types of polyaphron formulations are prepared with 10% poloxamer 188 (P188), 10% poly(2-ethyl-2-oxazoline), 1% polyquaternium 10, and 3% sodium carboxymethylcellulose solutions mixed with 1% Brij® L4 in a caprylic/capric triglycerides solution. Their physicochemical characteristics, rheological properties, and stability are assessed. Additionally, a polyaphron with 3% polyquaternium 10 was prepared for the assessment of ex vivo corneal retention along with four other polyaphrons. The best retention on the ex vivo cornea was displayed by the 3% polyquaternium 10-based formulation. The 10% poloxamer 188 along with 1% polyquaternium 10-based polyaphrons appeared to be the most stable among the four prepared formulations. A toxicological evaluation of these formulations was performed using a slug mucosal irritation test and bovine corneal opacity and permeability assay, with all four polyaphrons proving good biocompatibility with ocular tissues. The developed drug delivery systems demonstrated an excellent potential for ocular drug delivery. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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13 pages, 3102 KiB  
Article
Biomarkers to Predict the Success of Treatment with the Intravitreal 0.19 mg Fluocinolone Acetonide Implant in Uveitic Macular Edema
by Lucy Joanne Kessler, Grzegorz Łabuz, Gerd U. Auffarth and Ramin Khoramnia
Pharmaceutics 2022, 14(4), 688; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14040688 - 22 Mar 2022
Cited by 3 | Viewed by 1654
Abstract
To predict the need for additional local corticosteroids after receiving the 0.19 mg fluocinolone acetonide (FAc) implant in patients with macular edema secondary to non-infectious uveitis previously treated with local peribulbar corticosteroids. The number of corticosteroids required prior FAc, visual acuity, central retinal [...] Read more.
To predict the need for additional local corticosteroids after receiving the 0.19 mg fluocinolone acetonide (FAc) implant in patients with macular edema secondary to non-infectious uveitis previously treated with local peribulbar corticosteroids. The number of corticosteroids required prior FAc, visual acuity, central retinal thickness, ellipsoid zone reflectivity ratio (EZR), and choroidal vascularity index (CVI) were compared between patients who did and did not require additional corticosteroids after FAc implantation. Pearson’s correlation coefficient (R) between putative predictors and the number of adjunctive corticosteroids after FAc implantation were measured; significant candidates were included in a generalized regression model. Patients who required additional corticosteroids after FAc had higher CVI and central retinal thickness as well as worse EZR at subsequent visits (p < 0.05). The number of corticosteroids required prior to FAc implantation (R: 0.49), CVI change from baseline to 6 months (R: −0.41), and central retinal thickness at baseline (R: −0.36) correlated to the number of additional corticosteroids (all p < 0.05). A higher number of corticosteroids per year before FAc implantation was predictive for an increase in corticosteroids required after FAc (odds ratio = 2.65), while a decrease in CVI from baseline to 6 months was inversely correlated (odds ratio = 0.82). Our results suggest that the more corticosteroids prior to FAc and the greater the short-term CVI reducing effect, the less is the chance to get additional corticosteroids after FAc. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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22 pages, 1841 KiB  
Article
Optimization of the Micellar-Based In Situ Gelling Systems Posaconazole with Quality by Design (QbD) Approach and Characterization by In Vitro Studies
by Meltem Ezgi Durgun, Burcu Mesut, Mayram Hacıoğlu, Sevgi Güngör and Yıldız Özsoy
Pharmaceutics 2022, 14(3), 526; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14030526 - 27 Feb 2022
Cited by 8 | Viewed by 2899
Abstract
Background: Fungal ocular infections can cause serious consequences, despite their low incidence. It has been reported that Posaconazole (PSC) is used in the treatment of fungal infections in different ocular tissues by diluting the oral suspension, and successful results were obtained despite low [...] Read more.
Background: Fungal ocular infections can cause serious consequences, despite their low incidence. It has been reported that Posaconazole (PSC) is used in the treatment of fungal infections in different ocular tissues by diluting the oral suspension, and successful results were obtained despite low ocular permeation. Therefore, we optimized PSC-loaded ocular micelles and demonstrated that the permeation/penetration of PSC in ocular tissues was enhanced. Methods: The micellar-based in situ gels based on the QbD approach to increase the ocular bioavailability of PSC were developed. Different ratios of Poloxamer 407 and Poloxamer 188 were chosen as CMAs. Tsol/gel, gelling capacity and rheological behavior were chosen as CQA parameters. The data were evaluated by Minitab 18, and the formulations were optimized with the QbD approach. The in vitro release study, ocular toxicity, and anti-fungal activity of the optimized formulation were performed. Results: Optimized in situ gel shows viscoelastic property and becomes gel form at physiological temperatures even when diluted with the tear film. In addition, it has been shown that the formulation had high anti-fungal activity and did not have any ocular toxicity. Conclusions: In our previous studies, PSC-loaded ocular micelles were developed and optimized for the first time in the literature. With this study, the in situ gels of PSC for ocular application were developed and optimized for the first time. The optimized micellar-based in situ gel is a promising drug delivery system that may increase the ocular permeation and bioavailability of PSC. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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18 pages, 2502 KiB  
Article
Compartmental and COMSOL Multiphysics 3D Modeling of Drug Diffusion to the Vitreous Following the Administration of a Sustained-Release Drug Delivery System
by Emily Dosmar, Gabrielle Vuotto, Xingqi Su, Emily Roberts, Abigail Lannoy, Garet J. Bailey, William F. Mieler and Jennifer J. Kang-Mieler
Pharmaceutics 2021, 13(11), 1862; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111862 - 04 Nov 2021
Cited by 10 | Viewed by 4252
Abstract
The purpose of this study was to examine antibiotic drug transport from a hydrogel drug delivery system (DDS) using a computational model and a 3D model of the eye. Hydrogel DDSs loaded with vancomycin (VAN) were synthesized and release behavior was characterized in [...] Read more.
The purpose of this study was to examine antibiotic drug transport from a hydrogel drug delivery system (DDS) using a computational model and a 3D model of the eye. Hydrogel DDSs loaded with vancomycin (VAN) were synthesized and release behavior was characterized in vitro. Four different compartmental and four COMSOL models of the eye were developed to describe transport into the vitreous originating from a DDS placed topically, in the subconjunctiva, subretinally, and intravitreally. The concentration of the simulated DDS was assumed to be the initial concentration of the hydrogel DDS. The simulation was executed over 1500 and 100 h for the compartmental and COMSOL models, respectively. Based on the MATLAB model, topical, subconjunctival, subretinal and vitreous administration took most (~500 h to least (0 h) amount of time to reach peak concentrations in the vitreous, respectively. All routes successfully achieved therapeutic levels of drug (0.007 mg/mL) in the vitreous. These models predict the relative build-up of drug in the vitreous following DDS administration in four different points of origin in the eye. Our model may eventually be used to explore the minimum loading dose of drug required in our DDS leading to reduced drug use and waste. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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17 pages, 2083 KiB  
Article
DABCO-Customized Nanoemulsions: Characterization, Cell Viability and Genotoxicity in Retinal Pigmented Epithelium and Microglia Cells
by Ana R. Fernandes, Tiago dos Santos, Pedro L. Granja, Elena Sanchez-Lopez, Antonello Santini, Maria L. Garcia, Amelia M. Silva and Eliana B. Souto
Pharmaceutics 2021, 13(10), 1652; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13101652 - 10 Oct 2021
Cited by 11 | Viewed by 1916
Abstract
Quaternary derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO) and of quinuclidine surfactants were used to develop oil-in-water nanoemulsions with the purpose of selecting the best long-term stable nanoemulsion for the ocular administration of triamcinolone acetonide (TA). The combination of the best physicochemical properties (i.e., mean droplet [...] Read more.
Quaternary derivatives of 1,4-diazabicyclo[2.2.2]octane (DABCO) and of quinuclidine surfactants were used to develop oil-in-water nanoemulsions with the purpose of selecting the best long-term stable nanoemulsion for the ocular administration of triamcinolone acetonide (TA). The combination of the best physicochemical properties (i.e., mean droplet size, polydispersity index, zeta potential, osmolality, viscoelastic properties, surface tension) was considered, together with the cell viability assays in ARPE-19 and HMC3 cell lines. Surfactants with cationic properties have been used to tailor the nanoemulsions’ surface for site-specific delivery of drugs to the ocular structure for the delivery of TA. They are tailored for the eye because they have cationic properties that interact with the anionic surface of the eye. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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Review

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16 pages, 1714 KiB  
Review
Novel Treatments for Age-Related Macular Degeneration: A Review of Clinical Advances in Sustained Drug Delivery Systems
by Yolanda Jiménez-Gómez, David Alba-Molina, Mario Blanco-Blanco, Lorena Pérez-Fajardo, Felisa Reyes-Ortega, Laura Ortega-Llamas, Marta Villalba-González, Ignacio Fernández-Choquet de Isla, Francisco Pugliese, Indira Stoikow and Miguel González-Andrades
Pharmaceutics 2022, 14(7), 1473; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14071473 - 15 Jul 2022
Cited by 3 | Viewed by 2325
Abstract
In recent years, the number of patients with ocular diseases is increasing as a consequence of population aging. Among them, one of the most common is the age-related macular degeneration (AMD), a condition that leads to vision loss if it is not treated. [...] Read more.
In recent years, the number of patients with ocular diseases is increasing as a consequence of population aging. Among them, one of the most common is the age-related macular degeneration (AMD), a condition that leads to vision loss if it is not treated. AMD is a multifactorial disorder with two advanced forms, dry and neovascular AMD. Currently, although there is no approved therapy that significantly impacts dry AMD progression, several pharmacologic therapies exist for neovascular AMD. Notwithstanding, evidence suggests a suboptimal result in a high number of patients receiving these therapeutic options. Consequently, finding effective strategies is not only a still unmet medical need in dry AMD but also in neovascular AMD. This underlines the need for new drug delivery technologies that can improve the pharmacological action and drug concentration at the target sites. In this regard, sustained drug delivery systems are presented as the most promising therapeutic options in AMD patients. This review summarized the pathogenesis and the current treatment options for AMD, focusing on the emerging ocular sustained drug delivery approaches undergoing clinical trials. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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21 pages, 1220 KiB  
Review
Topical Drug Delivery to the Posterior Segment of the Eye
by Marina Löscher, Chiara Seiz, José Hurst and Sven Schnichels
Pharmaceutics 2022, 14(1), 134; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14010134 - 06 Jan 2022
Cited by 26 | Viewed by 5522
Abstract
Topical drug delivery to the posterior segment of the eye is a very complex challenge. However, topical delivery is highly desired, to achieve an easy-to-use treatment option for retinal diseases. In this review, we focus on the drug characteristics that are relevant to [...] Read more.
Topical drug delivery to the posterior segment of the eye is a very complex challenge. However, topical delivery is highly desired, to achieve an easy-to-use treatment option for retinal diseases. In this review, we focus on the drug characteristics that are relevant to succeed in this challenge. An overview on the ocular barriers that need to be overcome and some relevant animal models to study ocular pharmacokinetics are given. Furthermore, a summary of substances that were able to reach the posterior segment after eye drop application is provided, as well as an outline of investigated delivery systems to improve ocular drug delivery. Some promising results of substances delivered to the retina suggest that topical treatment of retinal diseases might be possible in the future, which warrants further research. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery)
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