Characterization and Application of Nanomaterials (2022) Volume 5 Issue 1 doi:10.24294/can.v5i1.1681 66 Review Article Application of nanotechnology in ophthalmology: Where are we? Marcela Gómez-Garzón1, M. Alejandra Martínez-Ceballos1*, Arley Gómez-López1,2, Adriana Rojas-Villarraga1,2 1 División de investigaciones, FUCS, Cl. 10#18-75, Bogotá, Colombia. E-mail: mariamace9@gmail.com 2 Instituto de investigaciones. Fundación universitaria de ciencias de la salud (FUCS), Bogotá, Colombia ABSTRACT Nanotechnology is a subject that studies, processes, and applies various functional materials, equipment, and sys- tems, and controls substances on a nanoscale. Nanomedicine refers to its application in diagnosing, treating, preventing, and monitoring various diseases. Drugs administered through eye drops must travel a long distance to avoid various eye barriers reaching the posterior segment of the eye, to achieve the lowest drug level. This review focuses on nano- technology-based eye disease treatment systems and highlights the obstacles affecting the drug management of eyes and nano-systems for the treatment of eye diseases. This paper summarizes the development prospect of nanotechnology and the challenges it faces in the treatment and diagnosis of ophthalmic diseases, to provide information and new ideas for the implementation of treatment and the development of a refractory eye disease management system. Keywords: Ophthalmology Nanotechnology; Nanomedicine; Nanoparticles ARTICLE INFO Received: 18 January 2022 Accepted: 20 March 2022 Available online: 31 March 2022 COPYRIGHT Copyright © 2022 Marcela Gómez-Garzón, et al. EnPress Publisher LLC. This work is li- censed under the Creative Commons At- tribution-NonCommercial 4.0 International License (CC BY-NC 4.0). https://creativecommons.org/licenses/by-nc/ 4.0/ 1. Introduction The World Health Organization estimates that in 2018, about 1.3 billion people suffered from some form of visual impairment, mainly due to uncorrected ametropia and cataracts. About 36 mil- lion blind people are blind due to cataracts, trachoma, corneal scar, glaucoma, diabetic retinopathy, age-related macular degeneration, and congenital malformations. It is estimated that 80 percent of these cases could have been avoided. The eyes are divided into anterior and posterior segments. The an- terior segment includes the cornea, conjunctiva, anterior chamber, iris, ciliary body, and lens. Eye drops are widely used in the treatment of anterior segment diseases because of their accessibility. However, due to the corneal barrier and the rapid filtration of tears, the bioavailability of topical eye drops is poor. The posterior segment is composed of the choroid, vitreous, and retina. Eye drops must go through a long distance and pass through several eye barriers to reach the posterior pole of the eye, which leads to low bioavailability when the drug reaches its action site[2]. Nanotechnology is a discipline that studies, designs, synthesizes, operates, and applies various functional materials, equipment, and sys- tems, and controls substances at the nanoscale (1–100 nm). According to the National Nanotechnology Initiative, the essence of nanotechnol- ogy is the ability to work atom by atom at the molecular level in order to create a huge structure and a new molecular organization. The aim is to develop these properties by controlling structures and devices at the atomic, molecular, and supramolecular levels, and to learn how to 67 manufacture and use these devices efficiently. It can be used to diagnose, treat, prevent and monitor various diseases. Nanotechnology is widely used in different fields. For example, in the field of molecular biolo- gy, the biological detection method of DNA se- quencing is developed through a nanopore se- quencer[4,5]. In clinical pharmacology, it is used to prepare nano drugs[6]. Recently, the US Food and Drug Administration approved a number of nano drugs, including polymer nano-particles, poly- mer-drug conjugates, and degradable polymer structures classified by material type. Their function is to promote the diffusion of drugs through ana- tomical barriers, improve the bioavailability and half-life of drugs, and promote the controlled re- lease mechanism. It is also used to optimize diag- nostic imaging, using inorganic iron oxide nanopar- ticles as a reagent[7] to enhance image contrast. The application of nanotechnology in the treatment of eye diseases has become the hope of millions of patients with vision diseases. Nano-carriers and nano suspensions react by re- leasing drugs at specific sites, thereby reducing the drug dose and minimizing the risk of side effects. For example, brimonidine, cyclosporine, cortico- steroids, intravitreal sustained-release implants, etc. In terms of diagnosis and follow-up, noninvasive intraocular pressure measurement for detecting high intraocular pressure and remote monitoring of nanodevices will contribute to the early diagnosis of progressive optic atrophy and clinical monitoring of patients with glaucomatous optic neuropathy[9,10]. In this review, we focus on the eye disease treatment system based on nanotechnology. Firstly, the anatomical structure of the eye and the obstacles to drug administration were briefly introduced. Subsequently, ophthalmic diseases and nano-systems for the treatment of these diseases are reviewed. Finally, the application prospects and challenges of nanotechnology in the treatment and diagnosis of ophthalmic diseases are summarized. This review will provide information and new ideas for the implementation of treatment and the devel- opment of a common eye disease management sys- tem. 2. Ocular anatomy and ocular bar- rier Figure 1 shows nanotechnology delivers oph- thalmic drugs through the various ocular anatomical structures. Table 1 depicts different eye structures and possible therapeutic targets. Its thickness, func- tion, physiology, and composition are emphatically introduced. These special functions can promote or prevent the effect of topical drugs. It also outlines possible action goals to understand the progress of nanotechnology in ophthalmology. Table 1. Different eye structures and possible therapeutic targets Obstacle Barrier thick- ness Function Physiology Constitution Other compo- nents Tear film 3 μm thick, 3 μl vol- ume[11] Lubrication, debris removal, antibacterial protection, stem cell nutrition, and corneal transplantation maintenance; affect the refractive index of the visual system[12]. Dynamic functional units: three chambers (fornication, lacrimal meniscus, and anterior lacrimal membrane). Surfactant and stabil- ity of tear film Lipid component, water component, and mucus component[12]. Immunoglobulin, lysozyme, lac- toferrin, OC, and β[14]. Corneal 540–600 μm A barrier against in- fection and ocular mechanical injury. Two-thirds of the eye refraction (image perception)[15]. Corneal epithelium: 5–7 layers of non-stratified squamous epithe- lium are connected by desmo- somes and connected through gap junctions, allowing the diffusion of small molecules <1,000 Dalton. It is in direct contact with aqueous humor through the Na+-K+-ATPase pump[16] present in endothelial cells. Avascular lens. Viscoelastic structures are rich in glucosa- mine and proteogly- cans[17]. Sixth floor: Bowman, stroma, Dua layer, Descemet, en- dothelial layer, corne- al epithelium. Collagen 1, III, V and VIII. Proteo- glycans (decorin, lumican, keratin, Mimecan, disac- charide, and fi- bromodulin) and glycopro- teins[15,17]. 68 Table 1. (Continued) Obstacle Barrier thick- ness Function Physiology Constitution Other compo- nents Conjunc- tival 44.9 ± 3.4 μm Through mucus, it helps to diffuse the tear film, maintain the stability of the tear film and prevent the adhesion between infection and mu- cus[19]. Corneal epi- thelial healing[20]. The outermost layer of the eyeball. Bulbar conjunctiva, eyelid, and forceps. Goblet cells produce mucin[21]. Multilayer non kerat- inized columnar epi- thelium (goblet cells) in contact with lamina propria (highly vas- cularized connective tissue)[21]. TFF1 and TFF3 proteins are in- volved in the scarring process of corneal tissue[19]. Scleral 0.53 ± 0.14 mm Viscoelastic properties give eye strength and resistance when in- traocular pressure increases[14]. The matrix is composed of pro- teoglycan, elastin, and large col- lagen fibers. It is indirectly nour- ished by the sclera and irrigated by long and short posterior ciliary vessels and choroids. Venous drainage occurs in the vortex vein[22]. Five-sixths of the eye robe. The innermost layer (Lá Mina fus- ca)[14]. Use Iris and cili- ary bod y: 1–2 mm Iris, light input regu- lator. Ciliary body: regulates, produces (apigenin) and regu- lates (electrochemical gradient) aqueous humor flow and se- cretes hyaluronic acid to the vitreous. Aqueous humor: nu- trition of avascular ocular structure, ho- meostasis of ocular tissue, clearance of metabolites, transport of neurotransmitters, and stability of ocular structure[23]. Ciliary body cornea scleral junc- tion (iris angle): the space where aqueous humor flows from the posterior chamber to the anterior chamber. Aqueous humor contributes to the circulation of inflammatory cells and mediators under pathological conditions and the diffusion of drugs to different tissues[24]. The middle part of the eyeball is composed of the iris, cili- ary, body, and choroid. Iris (three layers): posterior iris (pigment epithelium), anterior iris muscle (round or contractile, radial or dilator of the pupil), and matrix (vascular- ized connective tis- sue). The ciliary body (flat part and fold part)[24]. Aqueous humor consists of organic and inorganic ions, carbohy- drates, glutathi- one, urea, amino acids, proteins (collagenase, im- munoglobulin), oxygen, carbon dioxide, and wa- ter[23]. Crystal- line 3.5–5 mm Reflex power (20% of the total eyeball). An image focused on the outside of the retina. Enzyme-mediated oxidant defense mechanisms (gluta- thione reductase and catalase)[25]. It is nourished by aqueous humor. Metabolic activity is involved in ion exchange through sodium, potassium, calcium, and chloride channels, as well as glucose, amino acids, and antioxidants (glutathione) [26]. No vascular structure, transparent. It is divided into the capsule, crystalline epithelium, cortex, and nucleus. 60% protein (crystal- line α, β, γ). It is surrounded by collagen capsules (mainly type IV and XVIII) and laminin, entactin, proteoglycan (heparan sulfate), pearl, and fibronectin. In the banded region, the main components are fibrin and elas- tin[25,26]. Membrane pro- teins (different cell connections of lens epithelial cells): Cadherin, calmodulin, type II neural adhesion molecule, endog- enous major pro- tein (hydropho- bic), and apigenin 0 enzyme (glycer- aldehyde 3 phos- phate dehydro- genase). The cytoskeleton in- cludes actin, α-actin, anquirina, trompomudulina, myosin, and spec- tria[25,26]. 69 Table 1. (Continued) Obstacle Barrier thick- ness Obstacle Barrier thickness Obstacle Barrier thickness Choroid 220–350 μm Flush the retina and replenish oxygen and nutrition. Absorb light, regu- late body temperature, and adjust intraocular pressure by control- ling blood flow[27]. Drainage of aqueous humor from the anterior chamber through the uveoscleral pathway (accounting for 35% of its drainage vol- ume)[27]. Blood vessels, mela- nocytes, fibroblasts, immunocompetent cells, and supporting structures (collagen and elastic connective tissue). Four layers: chorion, chorionic column, two layers of blood vessels, and suprachoroidal[27]. Vitreous humor 4 cc Its transparency al- lows light to pass through the retina and gives the eye struc- ture. Due to its physico- chemical properties and ionic charge, it poses obstacles and challenges to drugs working at the poste- rior pole level[28]. The viscoelastic gel is located between the lens and retina. It contains water (98%), collagen fibers (II, V, IX, and XI), polyure- alic acid, electrolyte (sodium, potassium, calcium, and chlo- rine), prealbumin, and transfer protein. Equivalent to 80% (4 cc) of eye vol- ume[29.30]. More than 1,205 proteins[30]. Retinal pigment epithe- lium 0.4–1 mm[31] The light energy gathered at the macula is absorbed through the ocular refraction system (cornea and lens) to improve the visual quality. The cell’s own DNA repair mechanism includes the defense mechanism against reactive oxy- gen species[33]. High infusion of chorionic gonadotropin (1400 cc/min/100 g tissue)[34]. Antioxidants: superoxide dis- mutase and cata- lase. Retinal pigment epithe- lium 0.4–1 mm[31] Through the melanin in EPR melanosomes, carotenoids (lutein and zeaxanthin), and ascorbic acid in light receptors, photooxi- dation, and oxidative damage are prevented through the light ab- sorption mecha- nism[32]. It transports ions and water from subretinal space to chorionic ca- pillaries through the Na+-K+-ATPase pump and K+/Cl- transporter and maintains intraoc- ular pressure to a certain ex- tent[33,35] The maintenance of intracellular pH is mediated by the chloride bicar- bonate exchanger on the basement lateral membrane of EPR[33]. Retinal nerve sensation Light transduction of external images[36]. It is perfused by the central retinal artery and receives metabolic input through the choroid[31]. The self-regulation of retinal pressure is mainly mediated by the increase in retinal vascular resistance[37]. The outer membrane (photoreceptor and Muller cell), outer nuclear layer (photo- receptor nucleus), outer plexiform layer (photoreceptor axon), inner nuclear layer (bipolar cell), inner plexiform layer (bi- polar cell and ama- crine cell), ganglion cell layer, nerve fiber layer, inner limiting membrane (basement membrane formed by Muller cell exten- sion)[31,36]. 70 Figure 1. Nanotechnology delivers ophthalmic drugs through different ocular anatomical structures. NP: nanoparticles. 3. Nanotechnology concept Nanotechnology is a discipline that studies, designs, synthesizes, operates, and applies func- tional materials, equipment, and systems by con- trolling nanomaterials (1–100 nm). The application of nanotechnology in the di- agnosis, treatment, and control of various diseases is being implemented rapidly. This new branch of science is called nanomedicine. With the advance- ment of nanotechnology in medicine and surgery, its application in ophthalmology has made progress. Therefore, new eye nano-systems with different shapes and characteristics to optimize the bioavail- ability of drugs, prolong the contact time and re- duce the eye removal process had been designed[39]. There are many nano-systems that have been applied in the treatment of different eye diseases. Nanoparticle-filled contact lenses with acetazola- mide for the treatment of glaucoma[40], biodegrada- ble subconjunctival implants for the treatment of xerophthalmia [41,42], the development of diclofenac eye release nano colloid system based on hydro- gel[43,44], polymer nano colloid system for inflam- matory diseases[45,46], and nanostructured lipid transporters for controlling drug delivery in ocular infections[47,48]. 3.1 Liposome Liposomes are lipid vesicles comprising one or more phospholipid double chains that surround an aqueous core. According to the size of liposomes and the number of phospholipid double chains, lip- osomes can be divided into small monolayer vesi- cles (10 and 100 nm), and large monolayer vesicles (100 and 300 nm) and multi membrane vesicles[49] containing more than one phospholipid double chain. Liposomes are ideal because they encapsu- late both hydrophilic and hydrophobic drugs and show good compatibility with eye tissues[50,51]. Examples of applications of such nanoparticles in- clude intravitreal nanoliposome suspensions of prednisolone and infliximab[52,53]. 3.2 Polymer nanoparticles Polymer micelles are self-assembled nano- scopic core-shell structures formed by amphiphilic copolymer inside water. The core/shell structure allows the hydrophobic drug to be encapsulated in its hydrophobic core. Because the core is protect- ed by the hydrophilic crown, the bioavailability of the drug in the local administration of ocular tissue is significantly prolonged[54,55]. An experimental study conducted by Mittal et al. in rabbits showed that timolol maleate was biocompatible with the 71 cornea, and the intraocular pressure (IOP) de- creased for a longer time.[56]. 3.3 Nano suspension Nano suspensions are colloidal dispersions in which the hydrophobic phase is uniformly dispersed in the aqueous medium with the help of surfactant[9]. For example, prednisone, dexamethasone, hydro- cortisone, and other corticosteroids have been ad- ministered through nanosuspensions to treat anteri- or inflammation without the expected side effects of high-dose application, such as cataract and glauco- matous optic neuropathy. 3.4 Dendrimer Dendrimers are monodisperse mac- ro-molecules. Several reaction end groups form an inner cavity around a small molecule. Its tree branch structure presents various repeated ter- minal groups. In particular, low-generation den- drimers can encapsulate hydrophobic drug mole- cules in their inner cavities. Due to this unique structure, dendrimers allow the dissolution of drugs with poor water solubility. In addition, dendrimers can be considered real simulations of globular pro- teins. They are called “artificial proteins” because of their systematicness, electrophoresis, size scale, and other bionic properties[57,58]. Drugs developed using this technology include intravitreal injection of fluocinolone acetoacetate for retinitis pigmentosa and subconjunctival car- boplatin for retinoblastoma[59,60]. 3.5 Nano micelles Nano micelles are drug delivery systems composed of hydrophobic nuclei and hydrophilic caps, which allow the dissolution of hydrophobic drugs and produce transparent aqueous preparations when they are ready to be administered to the ante- rior segment of the eyeball. One of the drugs used in this nanotechnology is cyclosporine. A phase III clinical trial has proved that it is effective, safe, and rapid in the treatment of keratoconjunctivitis sic- ca[61]. 3.6 Niosome Niosomes are two-layer non-ionic surfactant vesicles that can capture hydrophilic and lipophilic drugs. Niosomes are chemically stable, and their non-ionic properties make them less toxic. Due to its hydrophilic surface, niosomes can easily interact and cross the tear film barrier, so they can reach the cornea/conjunctival tissue[63]. Niosomes have been evaluated as anticholinergic and antibiological agents[62,64,65]. The most important characteristics of the drug delivery carrier for the eye are: (i) the size of the gallbladder is large enough to resist the drainage caused by reflex tear and blinking; (ii) the presence of an irregular shape so that it can be cor- rectly installed at the bottom of the eye bag and ac- commodated on the surface of the eye; (iii) it is preferable to be heat sensitive and release the drug content in a controlled manner, but at the same time, before removal with blinking and nasolacri- mal duct drainage[66,67]. 3.7 Cube The structure of the cube consists of a contin- uous, highly distorted lipid double chain with two disjoint and consistent waterways. Compared with the simple liposome structure, the cube has in- creased surface area and the ability to encapsulate various hydrophilic, hydrophobic, and amphiphilic molecules. Due to the strong electric repulsion and the high proportion of liposomes[68–70], cuboids have higher physicochemical stability than liposomes. The use of dexamethasone in eye drops is associat- ed with this nanoparticle, indicating a higher avail- ability of the drug in aqueous humor[71]. 3.8 Hydrogel Hydrogels are a network composed of multi- functional monomers and relays, which react to form a flexible underwater structure. Because the porosity of the hydrogel matrix can be adjusted by changing the crosslinking density, the hydrogel network has been widely studied as a controlled and continuous drug delivery system. The ability to change with the surrounding environment is of great significance for the formation of hydrogels in situ. Hydrogels will be crosslinked when the tem- perature rises from room temperature to body tem- perature, and their phase-controlled release is af- fected by pH value or light stimulation[72,73]. 72 Controlled release silicone and hydrogel contact lenses containing timolol are a new technology de- veloped in recent years[74]and have good application prospects. 3.9 Polymer nanofibers Nanofibers are made of solid fiber materials with a diameter of less than microns. They have a porous structure and a very high surface area. Nanofibers are nonwoven fiber structures sim- ilar to the extracellular matrix. They are composed of highly organized polymer fibers and aqueous compounds comprised of protein polysaccharides to support tissue formation. Therefore, tissue engi- neering is one of its main applications. The device developed and studied is regenerative therapy. This is to protect the biocompatibility, physiology, and transparency of the cornea[75,76[. In addition, because the diameter of nanofibers is very small and the surface area is very large, higher drug content can be loaded in a very small part of[77,78] packages. 3.10 Nano preparation for treating eye dis- eases Most ophthalmic products on the market are topical preparations for anterior administration. The biggest disadvantage is that only 5% of the in- jected dose reaches the anterior chamber. Also, the dose penetrating the posterior chamber is small due to multiple and complex anatomical barriers of the eyeball. Nano-sized ophthalmic drugs (Figure 1) have the advantages of good solubility, large disso- lution area, fast dissolution speed, strong biological adhesion, and strong corneal penetration. It is sug- gested that the particle size should be less than 10 μm to minimize the irritation to the eye structure and reduce the tear and bleeding of the drip dose, so as to improve the effectiveness of eye treatment. 3.11 Nano suspension Nano suspension is a submicron colloidal dis- persion of pure drug particles in the external liquid phase. An important feature of nanosuspension is to increase the saturated solubility, so as to improve the dissolution rate of compounds. In this system, the drug is bound or dissolved in the structure, en- capsulated or captured in the structure by binding to the matrix, and a general drug delivery system is generated, including microemulsion, liposome, ni- osomes, dendrimer, and cyclodextrin[79,80]. Advantages of using nanoparticles include im- proved local delivery of macromolecules and low water-soluble molecules, such as glucocorticoids or cyclosporine, for the treatment of immune diseases affecting vision[81]. Other unstable macromolecules, such as nucleic acids, are administered through na- noparticles, providing promising results for gene transfer in the treatment of retinopathy[82,83]. Nano- particle-mediated drug delivery increases the con- tact time between the administered drug and the target tissue, such as brimonidine, one of the tradi- tional glaucoma treatment methods, or corticoster- oids for the treatment of autoimmune uveitis[78,84]. Some nano-formulations allow the nonsteroidal an- ti-inflammatory drug indomethacin to reach the posterior internal structure of the eye through a transmucosal pathway[85]. New applications include the use of gold nanoparticles to make the possibility of targeted drug delivery reach specific types of cancer, such as choroidal melanoma, and keep nor- mal cells intact[86]. 3.12 Contact lenses Contact lenses are hard or soft polymer devic- es designed to directly adapt to the cornea to correct refractive abnormalities. In 1965, Wichterle et al.[87] patented the idea of using hydrogel contact lenses as drug delivery devices. The patent refers to the inclusion of drugs in the lens hydration process to provide higher drug availability in use. Wrapping drug-loaded nanoparticles in the polymer matrix of contact lenses is an effective strategy to prolong drug delivery. The incorporation of drugs is achieved by printing, simple immersion, and colloidal nanoparticles[88–90]. The diameter of nanoparticles must be very small and used in con- tact lenses to prevent particles from hindering users’ vision. Therefore, it is necessary to delay the release of drugs in other ways. This can be achieved by combining the drug with the particles or dispersing the particles through separable chemical bonds so that the affinity of the drug to the particles is greater 73 than that to the surrounding lens material[89]. This method allows the sustainable release of drugs, which can be adjusted from hours to weeks accord- ing to the needs of patients, and allows the treat- ment of anterior segment lesions. Different nanoparticles, lead liposomes and microemulsions have been patented, which contain pharmaceutical products and then loaded into con- tact lenses. Liposomes are used in various drug de- livery applications due to their high biocompatibil- ity, transparent permanent lens, and several days of drug release. The initial release is due to the un- packaged drug in the lens. Contact lenses loaded with releasing microemulsion will be administered for 4–8 days, and the initial peak is attributed to the unpackaged drug[89]. In 2013, Jung et al. dispersed timolol nanopar- ticles in silica gel contact lenses for 30 days. Pre- liminary studies in beagle dogs have shown prom- ising results in treating glaucoma. The incorporation of nanoparticles into silicon hydrogels leads to the decrease of ion and oxygen permeability and the increase of modulus. The impact on each precursor is directly proportional to the charge of particles[74]. In 2018, Maulvi et al. added gold nanoparticles into contact lenses to improve the absorption of timolol from drug solvent solution, and obtained satisfac- tory release kinetics in vivo, while maintaining the characteristics of contact lenses[91]. The device studied has excellent mechanical properties, and the researchers believe that this material is suitable for administration from daily reusable contact lenses. 3.13 Intraocular implant Ocular implants are a new treatment method for the controlled release of drugs by reducing the dose and increasing the drug load. In addition, the systemic side effects are lesser and closer to the target site, namely the posterior segment of the eye. Biodegradable or non-biodegradable polymers can be used in eye implant systems. Although bio- degradable implants do not need to be removed af- ter implantation into the eye, non-biodegradable implants require additional intervention to remove or fill the implant, which brings additional costs and intraoperative or postoperative surgical risks. The latest development of a biodegradable implant sys- tem is the ENV705™ implant Envisia therapeutic agent and Zordera[92] nanoporous membrane device. The invention discloses a nanoporous mem- brane skunk device, which comprises two layers of biodegradable waterproof films There are na- nopores with the same diameter as the active mate- rial on one side, and only one drug molecule is al- lowed to flow out of the reservoir of each pore at a time. When injecting the device into the vitre- ous body, it is very thin, only 40 μ m in diameter, and the drug release order is close to 0. When most drugs are released, the polymer layer then degrades, eliminating the need to remove the device. This im- plant controls the release rate by adjusting the size of the hole and has been shown to last for 4 months. Therefore, it may become the best biodegradable implant for the treatment of chronic retinal diseas- es[93]. A similar situation occurred when sirolimus was released to the posterior pole[94] through the same device. 3.14 Clinical application In order to clearly understand the anatomy, histology, and physiology of different eye barriers, as well as the main nanoparticles developed in the research field, Table 2 lists the most common eye diseases treated with nanotechnology at different action sites of eye tissue and the most influential eye diseases on vision. 4. Expectation Nanotechnology and nanomedicine are widely used in the field of ophthalmology. In many ways, the use of these devices and nano agents contributes to the bioavailability of drugs, allows diffusion through anatomical barriers which may reduce the side effects of the traditional use of topical oph- thalmic drugs, and is likely to reduce invasive in- tervention to the posterior pole to some extent as well as reducing complications after using some drugs that need surgical treatment. Finally, the ben- efits of drugs have been optimized and the negative effects have been reduced, opening a huge window within the scope of so-called personalized drugs, which likely require further research on people with 74 Table 2. Common eye diseases and treatment application Pathology Drugs/Devices Therapeutic target Associated nanoparti- cles Mechanism of NP ac- tion Keratitis Ofloxacino, colirios, Aciclovir[95] Fluoroquinolone. Inhi- bition of topoisomerase II and IV. Herpes polymerase DNA inhibitor Polyethylene glycol oxide and Eudragit® in the form of micro- spheres Acyclovir drug encap- sulated by polylactic acid microspheres Improve the bioavaila- bility and controlled release of antibiotics. Delay the degradation of acyclovir prodrug Conjunctivitis Tobramicina, colirios[96] Inhibit the synthesis and binding of polypep- tides in ribosomes. Solid lipid NP They increase the bioa- vailability of the corneal surface and help retain it in the conjunctival sac Dry kerato- conjunctivitis Ciclosporina A, colirios[97] Immune modulators that prevent T lymphocyte activation. Chitosan Sustained release carrier Uveitis Nano suspension of predni- sone[52] Subconjunctival prednisolone injection[52] Intravitreal injection of inflixi- mab[53] Prostaglandin and leu- kopenia monoclonal antibody synthesis in- hibitors that inhibit TNF-α activity. Submicron colloidal carrier of hydrophobic drugs in surfactant sta- bilized medium Sustained release and controlled release of drugs, as well as high- er bioavailability and lower toxicity Cataract Lithium with metabolic activi- ty[98] Inhibit ROS activity and regulate the level of H2O2 and lipid peroxi- dation in the surround- ing environment. Deposition of platinum nanoparticles by mag- netron sputtering Inorganic catalytic anti- oxidant Glaucoma Nano transporters: pilocarpine, timolol, carbonic anhydrase in- hibitor, acetazolamida, dor- zolamida, brinazolamida and brimonidina[99] Silicone and hydrogel contact lenses hydrogel contact lenses containing thymolol[74] Thymolol-containing contact lenses[91] Wireless sensors[95] Traditional treatment of non-selective β-blockers to reduce aqueous hu- mor. Continuous intraocular pressure monitoring. Dendrimers, liposomes, nanocapsules, nano- spheres, hydrogels PGT (triglyceride) NP gold Drug sustained release increases the loading and absorption of the thymus Wet DMRE Hyaluronic acid implant: Bevacizumab[100] Nanopore devices: ranibi- zumab biodegradable[92] Humanized monoclonal antibody against vascu- lar endothelial growth factor. Chitosan NA Sustained release vehicle Drug release through nanopores Diabetic ret- inopathy Reservoir stimulation response device: nintedanib[101] Vascular kinase inhibi- tor, blocking VEGF receptor, plate- let-derived growth fac- tor receptor, fibroblast growth factor receptor Polylactic acid glycolic acid microspheres and nitrobenzene monomer UV stimulates drug re- lease Retinitis pigmentosa Vitreous fluorooctane sulfonate Microglia activity at- tenuation. Polyamide dendritic molecule Drug sustained release Retinoblas- toma Subconjunctival carboplatin[60] Photodynamic therapy and ver- tepofina[102] Alkylating agent, inhib- iting DNA replication, RNA transcription, Dano protein synthesis, selective neovascular endothelial cells, in- ducing apoptosis and autophagy. NP dendritic polyami- doamine non-thermal laser activated liposome vertebral body. Sustained release and controlled release of drugs Reactive oxygen species production and cell death in tumor cells. 75 Table 2. (Continued) Pathology Drugs/Devices Therapeutic target Associated nanoparti- cles Mechanism of NP action Optic neuro- myelitis Biosensor[104] NA Carbon nano-tubes AQP4 antibody detec- tion. Endophthal- mitis Damycin, cholinesterase[105] Anti-gram positive natural lipopeptide antibiotics, including SAMR. Chitosan Promote the penetration of antibiotics by open- ing the connec- tion between corneal cells. 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