Advances in understanding the unique chemical, mechanical, electrical, and magnetic properties of nanoscale (1 dimension of 1-100 nm) materials have directly facilitated the emergence of nanoenabled technological platforms. Fabrication of these nanomaterials has allowed a diversity of applications to open up, especially in the fields of chemistry, biology, materials science, electronics, and photonics, to name a few.1,2 As might be expected, these breakthroughs in classic sciences have started to directly affect medically oriented research activities, whereby through the application of nanomaterials, true nanotechnology can be developed for the express purpose of affecting critical outcomes in patient-centered activities, viz., personalized medicine, reduced healing times, increased therapeutic advantage, and so on. The application of nanotechnology platforms to the field of medicine is far reaching and too vast to cover in a single review article, but suffice it to say that nanotechnology has dramatically affected drug discovery, drug therapeutic efficacy, drug and gene delivery systems, biocompatible implant materials, regenerative medicine, and diagnostic devices.3–5 Herein, a review of some major applications of nanotechnology platforms will be surveyed in the context of treating serious ophthalmologic diseases. Of course, it should be noted that there may be significant overlap in platforms applied to different diseases [ie, nanoparticle (NP)–based treatments are ubiquitous but are a similar technology], and case studies thought to be significant and portraying the essence of the nanotechnological platform are provided, including a discussion on sensor and diagnostic strategies. Finally, these nanotechnology-based strategies are further organized for particular anterior and posterior segment eye diseases.
Numerous ocular disorders have been identified that are static or dynamic that ultimately adversely affect patient vision. Even if these disorders are not immediately sight threatening, reduction in vision acuity can have a direct effect on a patient’s quality of life, where loss of vision may directly lead to loss of employment and entire families being reduced to extreme poverty. In concert with this, classic drug therapies have restricted treatment efficiency due to the presence of numerous barriers that isolate the eye from the external environment, isolate different compartments within the eye, and isolate the eye from the host itself (Fig. 1A). At every level of the eye, significant barriers exist that directly influence drug delivery. For example, the mucoaqueous tear layer decreases drug adhesion at the tissue interface and absorbed amounts by lowering residence time (Fig. 1B).6 Specialized corneal epithelium with tight junctions and desmosomes creates a physical barrier for molecules larger than 500 daltons.7 The iris blood vessels, ciliary epithelium, and retinal vessels restrict the passage of molecules via the blood-aqueous layer and blood-retina barriers, respectively.8
It is hoped that through using nanotechnology platforms some of these clinical issues may be overcome. For example, through incorporating drugs into engineered NP delivery vehicles, some of the barriers to drug delivery might be reduced. Although it is evident that NP delivery is, perhaps, the most common application of nanotechnology in ophthalmology, it is not the only one. For example, the anatomy of the eye necessitates injections for both treatment and diagnosis. Nanotechnology enables the production of microneedles [using microelectromechanical (MEMS) and nanoelectromechanical manufacturing systems (NEMS)] for appropriate administration to these regions of the eye, as well as drainage valves for glaucoma treatment.9,10 Biosensors, diagnostic labeling strategies, and detection monitors are also some of the other areas where nanoenabled technology can play a role in maintaining eye health.
NANOTECHNOLOGY THERAPEUTIC APPROACHES FOR ANTERIOR SEGMENT DISEASES
The anterior segment of the eye is classically defined as that which includes the cornea, iris, ciliary body, and lens. This region is directly exposed to the external environment and, despite the barrier present from the continuous tear film, has a high probability of injury from foreign objects. Moreover, despite natural barriers, microorganisms may still invade the cornea and result in keratitis or conjunctivitis. These serious conditions are only exacerbated through the improper use of contact lens materials, where nonspecific protein adsorption and subsequent microbial colonization break the natural tear film barrier and increase the risks associated with infections. Also, surgeries done for cataract, glaucoma, and cornea replacements further enhance risks associated with infection.11 That said, the following are some important disease states that may affect the eye.
Keratitis, conjunctivitis, and uveitis12 are diseases related to inflammation in the cornea, conjunctiva, and pigmented vascular regions of the eye, respectively. Induction of inflammation within these tissues may occur through several pathways including, but not limited to, an infection due to the presence of bacteria, fungi, and viruses. The most common treatment vehicle for these types of infections is topical antimicrobial eye drops. However, because of the tear film encasing these tissues, residence time at the tissue site is significantly reduced. Relatively recent work has attempted to engineer NPs so as to interact with mucins produced by the epithelia of the eye via hydrogen bonding and electrostatic interactions. Through utilizing this nanotechnology strategy, it was found that ocular residence time increased significantly, reaching upward of ∼300 minutes, hence increasing bioavailability.13 Commonly used cationic mucoadhesive polymers, chitosan and Eudragit, were recently utilized as NP reservoirs for terbinafine hydrochloride and obtained an extended drug release time of ∼8 hours.14 Mucoadhesive agents were also formulated in combination with thermosetting and hydrogel-forming polymers so as to enhance the sustained drug release due to the polymer swelling, erosion, and/or drug diffusion through the gel.15 In early studies, polyethylene oxide (PEO)–Eudragit microspheres (Fig. 2, nanosphere structure) loaded with ofloxacin were found to increase drug bioavailability with a relatively controlled release profile up to ∼300 minutes.15 In a more recent study, poloxamer/chitosan in situ–forming gels, which had shown to prolong retention time 2- to 4-fold,16 was used to treat fungal keratitis in rabbits.17 Kesavan et al18 used the cyclic oligosaccharide, hydroxypropyl-β-cyclodextrin, to increase the solubility of dexamethasone and combined their formulation with the anionic mucoadhesive Carbopol. Their hydroxypropyl-β-cyclodextrin–based, pH-induced mucoadhesive hydrogel resulted in higher bioavailability and a sustained release profile compared with conventional dexamethasone eye drops. Besides charged polymers, polyamidoamine (PAMAM) dendrimers were considered as mucoadhesive because of their strong electrostatic interactions with mucins in the tear film.19 Furthermore, acyclovir-encapsulated thiolated PAMAM dendrimers (Fig. 2, dendrimer structure) showed promising drug loading, bioadhesion, and controlled release pattern.20
The cornea and conjunctiva contain membrane transporters responsible for nutrient transport, making transporter-targeted delivery a promising strategy to enhance absorption of poorly permeating drugs. Amino acid and peptide transporters are the most common targeting regions. Acyclovir (ACV), hydrophilic antiviral nucleoside used for herpes simplex virus 1–induced corneal keratitis, prepared in l-Glu-ACV and l-Asp-ACV prodrug forms, acts as a substrate for corneal B0,+ transporter and leads to increased corneal permeability.21,22 Further to this, dipeptide prodrugs of ACV were encapsulated into poly(lactic-co-glycolic acid) (PLGA) NPs in order to slow down the degradation of prodrugs and therefore improve the therapeutic effect upon topical administration.23 Biotinylated lipid prodrugs of ACV were designed for targeting the sodium-dependent multivitamin transporter in the cornea.24 With an extended strategy, econazole-impregnated PLGA was encapsulated in p-HEMA contact lenses for fungal keratitis treatment, yielding (in vitro) an extended antifungal activity against Candida albicans.25 Recently, a gatifloxacin-loaded p-(HEMA-co-MAA) hydrogel was shown to exhibit sustained release (70% in 25 hours) and favorable healing profiles (in 48 hours) using a rat model with bacterial keratitis.26
Any insult, accidental or intentional, to the cornea may result in a disturbance of the tissue itself. However, unlike other cutaneous tissues where wound healing processes usually yield scar tissue and angiogenesis, the latent properties of the corneal tissue actively inhibit this end result, which would drastically impede vision. When reviewing the literature in this area, it is obvious that the majority of testing has been conducted on animals, but there are major differences between animal models and the human cornea that should be realized when trying to apply results of one to the other. Current clinical practice involves suturing the cornea; however, this practice increases the potential for postoperative complications such as infections, astigmatism, corneal scars (sometimes necessitating further corneal procedures), and postsurgical cataracts. Therefore, adhesives are under development to replace or supplement sutures. An ideal adhesive is considered to adhere to the moist corneal surface, rapidly seal the wound, restore intraocular pressure (IOP), maintain eye structural integrity, have a refractive index close to native cornea, be biocompatible and elastic, maintain a microbial barrier, and be bioabsorbed during tissue regeneration.27 First, polymer glues have been developed such as cyanoacrylate and fibrin.28 However, these glues were not very effective because of inflexibility and the requirement for autologous blood components, although they are used for the conjunctiva. Nanostructured (∼10-nm diameter) dendrimers are highly branched, monodisperse polymers exhibiting a 3-dimensional shape with numerous end groups. The biggest advantage afforded by dendritic systems is the controllable crosslinked networks, coupled with the high density of functional side chains in the nanovolume and macrovolume.29 Dendrimer-based hydrogels were shown to promote rapid wound healing, without scar formation and inflammation, in comparison to sutures for the leghorn chicken model.30 Another hydrogel system composed of PEO functionalized peptide-based dendrimeric crosslinker was effective in closing a 4.1-mm corneal laceration (ex vivo), while withstanding IOP prior to healing.31 Finally, through engineering the crosslinkers, degradation time for this adhesive could be tuned between hours and months. Thus, nanoscale dendrimers may be used to tailor various wound healing properties for extensive recovery periods.
The formation of blood vessels within the avascular corneal tissue is a critical outcome associated with inflammation, infection, and degenerative or traumatic diseases and is referred to as corneal neovascularization.32 Available therapies are corticosteroids, nonsteroidal anti-inflammatory eye drops, photodynamic therapy, photocoagulation, and antibody (bevacizumab) against vascular endothelial growth factor A (VEGF-A). Inhibition of angiogenic factors such as VEGFs, platelet-derived growth factor, basic fibroblast growth factor, metalloproteinases, and interleukins is considered the goal of impeding this process.32–34 Recently, hypoxia due to extended contact lens wear was shown to up-regulate VEGF and hypoxia-inducible factor 1a expressions leading to corneal angiogenesis.35 They also indicated that hypoxia-inducible factor 1a knockdown using shRNA decreased the expression of interleukin 1b and metalloproteinases 2/9 compared with negative control in mice. This study implied gene level control of angiogenesis factors as a promising strategy. Complementary work showed that plasmid-containing shRNA against VEGF-A encapsulated in PLGA tested on BALB/c mice reduced (∼80%) VEGF-A protein expression compared with naked plasmid (20%) and showed a 2-fold decrease in neovascularization area after 4 weeks.36 In another study, micelles composed of copolymer and plasmid DNA expressing soluble VEGF receptor 1 (VEGFR-1) (sFit-1) were used for gene therapy.37 The expressed sFit-1 acted as a sink of VEGF and prevented activation of angiogenesis cascade. Results of the study indicated stable micelle (Fig. 2, micelle structure) nanovector injection leading to prolonged sFit-1 expression and decreased vascularization of the cornea.
NANOTECHNOLOGY THERAPEUTIC APPROACHES FOR POSTERIOR SEGMENT DISEASES
The posterior segment of the eye consists of the vitreous humor, the retina, choroid, and optic nerve. Intraocular liquid circulation, the corneal epithelium limiting molecular diffusion, and the retinal-blood barrier are the primary reasons that the mobility of drugs from the anterior to the posterior segments of the eye is retarded.7,8 In fact, no easy route for administration to the posterior regions of the eye has been developed; current efforts focus on intravitreal injection, subretinal injection, transscleral administration, subconjunctival injection, and topical instillation. However, risk of postadministrative complications may increase, causing retinal toxicity, retinal detachment, or intraocular infections (including potentially devastating endophthalmitis). New treatment strategies should focus on decreasing the frequency of injections as a means of reducing the risk of postadministrative complications; where nanotechnology could be helpful is to develop strategies for increased drug biodistribution, passing retina-blood barrier, as well as controlled and targeted delivery.
Choroidal neovascularization (CNV) is characterized by the growth of choroidal capillaries under the retinal pigment epithelium. Choroidal neovascularization could lead to hemorrhage, scar formation, and retinal detachment due to exudation. Nanotechnology-based therapies inhibiting angiogenesis are the focus of sustained drug release and targeted gene therapy efforts for this work. To obtain sustained delivery, previous work has demonstrated that dexamethasone acetate was encapsulated in PLGA NPs and tested both in vitro and in a laser-induced rat model.38 The results indicated controlled release for 40 days and dose-dependent inhibitory effect on CNV. Similarly, an antiangiogenic peptide (a serpin-derived peptide SP6001) was self-assembled into NPs with a cationic polymer and then loaded in PLGA microparticles.39 This peptide-NP system succeeded in decreasing neovascularization for 14 weeks prior to single dose administration in a mouse model. In another study, an integrin-antagonist peptide (C16Y) was encapsulated in polylactic acid/polylactic acid-polyethylene oxide (PLA/PLA-PEO) NPs for sustained drug release.40 It was shown that C16Y significantly inhibits CNV in both naked and encapsulated forms. However, in longer periods, NP-peptide form was more effective in tissue healing compared with naked peptide because of the short half-life of peptide in solution. Gene therapy utilizing the plasmid for the proteolytic plasminogen kringle 5 (K5) was loaded to PLGA:chitosan NPs and administrated via intravitreous injection, yielding the inhibition of VEGF expression and a sustained suppression of CNV.41 Further work using siRNA against VEGFR1 encapsulated in PEG-LPH NPs (PEGylated liposome–protamine–hyaluronic acid) has shown successful inhibition of VEGF expression was inhibited using siRNA.42 Gene therapy strategies obviously hold much promise for the molecular-level treatment of disease; however, it is important to acknowledge that general acceptance of genetic delivery and therapy by the general population remains to be tested.
Besides the success of gene delivery to the eye, Singh et al43 went a step forward and developed NPs for targeted delivery. Poly(lactic-co-glycolic acid) NPs, coated with transferrin and an integrin-binding RGD peptide (or combinations thereof), was used for targeted gene delivery via endocytosis.43 Peptide-coated PLGA NPs loaded with anti-VEGF intraceptor plasmid were intravenously administered to Brown Norway rats with CNV, resulting in increased retinal delivery, anti-VEGF expression in retinal vascular endothelial cells, and significantly smaller CNV areas compared with nonfunctionalized NPs. Recently, a very similar NP system was tested in 2 murine age-related macular degeneration models and a primate CNV model in order to identify whether they could regress neovascularization, decrease fibrotic scarring, improve visual acuity, and demonstrate safety profile.44 Results indicated a safe treatment strategy with restored vision by 40% and suppressed subretinal fibrosis.
Retinal neovascularization is thought to be caused by angiogenesis in the retina and is associated with age-related macular degeneration, diabetic retinopathy, and other retinal diseases. Similar to corneal and CNV, growth factor antagonists and gene therapy are the treatment options.45 Besides these strategies, NPs such as cerium oxide, gold, and silicate were shown to suppress angiogenesis by different routes.46–48 Oxidative stress is one of the factors promoting retinal neovascularization. Cerium oxide NPs (nanoceria) are thought to mimic the activity of superoxide dismutase and clear out reactive oxygen species. Intravitreal injection of nanoceria inhibited reactive oxygen species, VEGF overproduction, and neovascular lesion formation.48 On the other hand, Au NPs were found to suppress VEGFR-2 signaling pathway by blocking ERK1/2 activation. Intravitreally injected Au NPs effectively inhibited VEGF-induced neovascularization in a mouse model.47 Similar to Au NPs, silicate NPs were also found to inhibit ERK1/2 activation and suppress in vitro VEGF-induced neovascularization. Intravitreal injection of silicate NPs was shown to reduce retinal neovascularization in mice model with oxygen-induced retinopathy.46
Retinoblastoma (RB) is a prolific retinal cancer presenting in 1 in 15,000 to 20,000 live births.49 Current treatment options include enucleation, radiation therapy, and chemotherapy with carboplatin, etoposide phosphate, or vincristine sulfate with local laser therapy. The local delivery of chemotherapeutic agents to the eye significantly reduces the systemic adverse effects, where it is hoped that nanotechnology may enable targeted chemotherapeutic50,51 and gene delivery52 systems for RB treatment.
Previous efforts have shown that the administration of carboplatin-encapsulated PAMAM dendrimers reduced RB tumor growth after 1-dose injection in LHβ-Tag mouse model more effectively than free drug.53 In another study, PLGA-PEG-folate micelles were utilized for folate receptor–targeted delivery and sustained release of doxorubicin for up to 14 days.54 Even if doxorubicin uptake is inhibited because of its efflux through MDR1 pumps, PLGA-PEG-folate nanosystem was not affected because it enters the cell via folate receptors.55 Hence, the Y-79 RB cell line overexpressing folate receptors showed 4 times higher uptake of micelle-doxorubicin, compared with doxorubicin alone. Recently, Gary-Bobo et al56 developed a bitherapy strategy where chemotherapy was combined with phototherapy in a single NP system, which also exhibits targeted delivery. The mesoporous silica NPs encapsulating a photosensitizer (for phototherapy) and camptothecin (for chemotherapy) were functionalized with mannose or galactose for receptor targeting on Y-79 cells. Their results indicated that bitherapy has a higher therapeutic effect than phototherapy alone.
Glaucoma is characterized by high IOP and the death of retinal ganglion cells. Recently, it has been postulated that the activation of subclinical inflammation (chronic) may lead to exfoliation glaucoma, as well as defects in microfibrils themselves may contribute to glaucoma by altering the biomechanical properties of surrounding tissue as well as affecting signaling.57,58
Increased IOP is thought to be mainly caused by resistance to outflow through the trabecular meshwork, and elevated pressure is believed to ultimately induce neuronal cell damage and vision loss.59 Thus, the main treatment strategy is based on decreasing the IOP either through suppressing the production or increasing the outflow of aqueous humor. Timolol and brimonidine are 2 commonly used IOP-lowering agents. Nanotechnology approaches are under development to obtain therapeutics with increased bioavailability, prolonged retention time, and sustained drug delivery. One such work showed that timolol-encapsulated chitosan NPs were shown to be more effective on lowering IOP compared with drug solution, in vivo, in rabbits.60 In another study, brimonidine-loaded Eudragit polymers increased the residence time and drug release from 6 to 72 hours.61 Similarly, subconjunctival administration of timolol-encapsulated microspheres exhibited sustained drug release for up to 3 months in an in vitro study.62 For controlled and extended drug release, contact lenses with disperse PGT (propoxylated glyceryl triacylate) NPs containing timolol were developed.63 When the lens was loaded with 5% timolol-PGT, therapeutic dose continued to be released for up to 1 month under in vitro conditions. Also, reduction in IOP was observed in preliminary animal studies in beagle dogs.
A nanodevice fabricated by MEMS techniques offers an alternative for IOP medication and glaucoma drainage implants.64 This nanodrainage prototype could be implanted in the sclera and creates a bypass for aqueous humor outflow.65 Together with controlling the IOP levels, regeneration of damaged neuronal cells or even neuroprotection should be also considered as treatment strategies. Administration of microparticles encapsulated with glial cell line–derived neurotrophic factor resulted in neuroprotective effects on retinal ganglion cells in animal glaucoma models.66,67 Similar to glial cell line–derived neurotrophic factor, heat shock proteins could also be utilized for inducing ocular neuroprotection. Jeun et al68 developed superparamagnetic NP agents (EMZF-SPNPAs) to induce heat shock proteins by local magnetic hyperthermia. They have tested both silica-coated and uncoated EMZF-SPNPAs for their toxicity and diffusion rate to retina. In this study, 5.5-nm NPs have been injected into vitreous instead of intravenous. Both coated and uncoated particles diffused to retina and did not show any toxic effect to the cell. Finally, several articles are now investigating exfoliation glaucoma using atomic force microscopy (AFM) techniques. Antibody-modified AFM tips have recently been used to define the protein aggregation and identify constituent proteins, showing that lysyl oxidase–like 1 protein is colocalized with the fibrous protein aggregates.69
Another interesting use of AFM involves looking at stiffness of tissues for understanding biomechanical implications of exfoliation, where optic nerve heads were shown to have a decreased stiffness for cases of exfoliation that may reflect tissue weakness.70
NANOTECHNOLOGY DIAGNOSTIC APPROACHES
Nanotechnology has the profound potential for the development of platform technologies that may make it possible to monitor and, thus, treat ocular diseases; even at the molecular level. Microelectromechanical manufacturing system and NEMS–based engineering for developing submicron-size mechanical tools is opening the opportunities for implantable monitoring biosensors that are proving to be extremely valuable in treating chronic diseases such as glaucoma, diabetic retinopathy, and age-related macular degeneration.71 With this increased ability to detect initial disease states, it is to be hoped that the efficacy of therapeutic intervention will dramatically increase while severely reducing patient costs.72
Monitoring IOP is considered an important diagnostic tool for the onset of glaucoma; IOP is considered a critical factor in glaucoma progression (Table 1).85 Intraocular pressure is dynamic and exhibits a diurnal variation, where continuous IOP characterization at night (ie, outside the hospital setting) may have the most benefit for the management of glaucoma.71,86 Hence, minimally invasive IOP monitoring devices are actively being sought. The SENSIMED Triggerfish system (SENDIMED AG, Switzerland) is the most studied IOP monitor, utilizing a wireless Pt-Ti strain gauge that measures the changes in the area of the cornea-scleral junction, all embedded within a silicone contact lens.3,71,84,87 That said, some have concluded that this sensor cannot be used clinically for sensing an IOP decrease induced by topical glaucoma medication.88–90
Thus, active research is ongoing in order to develop IOP monitoring systems using different methods such as capacitive pressure sensors, micromachined pressure sensor, and piezo-resistive IOP sensors.3 An ultrathin, flexible, polymer-based capacitive MEMS pressure sensor (500 × 500 × 100 μm3) for IOP monitoring has been developed (Fig. 3A) and shown to have advantageous properties such as high sensitivity to pressure changes, low temperature sensitivity, and low consumed power, making it more suitable for implantation.91 Noninvasive sensor using a wireless capacitive contact lens (Fig. 3C) for continuously monitoring IOP was shown to have the capability to track pressure variation profiles with minimal lag. A minimally invasive implantable IOP sensor for continuous wireless monitoring has also been developed, using a hypodermic needle (30-gauge) to access the vitreous, a micromachined capacitive pressure sensor, and a polyimide coil, to form a parallel LC circuit whose resonant frequency is a function of IOP (in real time) (Fig. 3B).75,77 Radiowave telemetry is also used in the wireless IOP transducer (WIT) (Implandata GmbH, Hannover, Germany) that is an implantable microstructured device consisting of 2 parts, an ASIC chip and a microcoil antenna, with a pressure, temperature, an identification encoder, an analog-to-digital converter, and telemetry into a single implantable microchip (Fig. 3D). This telemetric IOP allows patients without a healthy cornea or who have received an implanted artificial cornea (keratoprosthesis) to be monitored.80 Rollable and implantable IOP measurement devices based on a piezo-resistive pressure sensor have been used to develop an IOP contact lens sensor.73 This sensor uses a flexible highly piezo-resistive bilayer film based on a polycarbonate [poly-(bisphenol-A-carbonate)] matrix containing a conducting top layer of nanocrystals of the organic molecular metal β-(ET)2I3. Changes in cornea curvature are measured and provide IOP determination.81,82 Microelectromechanical manufacturing system technology has also facilitated the development of a portable tonometer using a microreflected air pressure sensor, where a wireless IOP sensor is reported that uses variable inductance according to the external pressure.74,79 Moreover, microfabricated sensors containing a planar spiral gold coil inductor, 2-parallel-gold plate (metal-insulator-metal) capacitor, and a pressure-sensitive diaphragm were developed and showed high pressure sensitivities.78 Nanowatt power levels for IOP monitoring microsystem were also recently developed, which provided accuracy in measured IOP of 0.5 mm Hg.76
Other important sensors are being developed that allow for direct, molecular-level identification for therapeutic purposes. An excellent example of this has been worked on for directly detecting RB. Retinoblastoma has been linked to the inactivation of the RB gene (Rb), which is a tumor suppressor gene.49 The promoter region of the Rb gene is methylated in a significant number of primary RB tumors.83,92 A direct electrochemical detection of DNA methylation for RB has been devised using a 40-nm-thick nanocarbon film electrode that has a nanocrystalline sp2 and sp3 hybrid structure, providing a wide potential window, low background current, little surface fouling, and high electrode activity compared with boron-doped diamond and glassy carbon electrodes. Through these unique properties of nanocarbon, it is possible to detect biomolecules with slower electron transfer rates, such as nicotinamide adenine dinucleotide phosphate and pyrimidine bases, allowing direct detection of single-nucleotide polymorphisms and, consequently, the oxidization of all DNA bases individually, enabling the identification of DNA bases and their derivatives (cytosine and its derivative 5-methylcytosine, for example).93,94 These nanocarbon films have been used to characterize DNA methylation directly from a 6mer oligonucleotide without any treatment,93 and 24mer oligomers containing methylation sites for RB (RB1) gene fragments and the CpG (cytosine-phosphoguanosine) repeat sequences (60mers) could be detected using nanocarbon film electrodes.83 Moreover, electrochemical experiments using the nanocarbon film electrode provided quantitative detection of DNA methylation ratios solely by measuring methylated 5′-CpG repetition oligonucleotides (60mers) with different methylation ratios.
The pursuit of personalized medicine approaches for combating ocular diseases may be possible only through the development of nanotechnology platforms that include molecular-level engineering. Nanoparticle engineering is a common thread for numerous drug delivery and imaging paradigms; covered herein we attempt not only to show that unmodified NPs are like ceramic and Au used for direct disease therapy and imaging, but also to detail interesting and representative biomimetic strategies that are also used for specific diseases. Finally, through combining MEMS and NEMS strategies, interesting manufacturing and sensor development can be accomplished for early detection and, in some cases, treatment of ocular diseases.
1. Daniel MC, Astruc D . Gold nanoparticles: assembly, supramolecular chemistry, quantum-size–related properties, and applications toward biology, catalysis, and nanotechnology. Chem Rev. 2004; 104: 293–346.
2. Ferrari M . Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer. 2005; 5: 161–171.
3. Zarbin MA, Montemagno C, Leary JF, et al. Nanotechnology in ophthalmology. Can J Ophthalmol. 2010; 45: 457–476.
4. Zarbin MA, Montemagno C, Leary JF, et al. Nanomedicine in ophthalmology: the new frontier. Am J Ophthalmol. 2010; 150: 144–162.
5. Lo R, Li P-Y, Saati S, et al. A passive MEMs drug delivery pump for treatment of ocular diseases. Biomed Microdevices. 2009; 11: 959–970.
6. Kaur IP, Kanwar M . Ocular preparations: the formulation approach. Drug Dev Ind Pharm. 2002; 28: 473–493.
7. Hamalainen KM, Kananen K, Auriola S, et al. Characterization of paracellular and aqueous penetration routes in cornea, conjunctiva, and sclera. Invest Ophthalmol Vis Sci. 1997; 38: 627–634.
8. Bill A . Blood-circulation and fluid-dynamics in eye. Physiol Rev. 1975; 55: 383–417.
9. Patel SR, Berezovsky DE, McCarey BE, et al. Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye. Invest Ophthalmol Vis Sci. 2012; 53: 4433–4441.
10. Patel SR, Lin ASP, Edelhauser HF, et al. Suprachoroidal drug delivery to the back of the eye using hollow microneedles. Pharm Res. 2011; 28: 166–176.
11. Willcox MDP . Pseudomonas aeruginosa infection and inflammation during contact lens wear: a review. Optom Vis Sci. 2007; 84: 273–278.
12. Durrani OM, Meads CA, Murray PI . Uveitis: a potentially blinding disease. Ophthalmologica. 2004; 218: 223–236.
13. Khutoryanskiy VV . Advances in mucoadhesion and mucoadhesive polymers. Macromol Biosci. 2011; 11: 748–764.
14. Tayel SA, El-Nabarawi MA, Tadros MI, et al. Positively charged polymeric nanoparticle reservoirs of terbinafine hydrochloride: preclinical implications for controlled drug delivery in the aqueous humor of rabbits. Aaps Pharmscitech. 2013; 14: 782–793.
15. Di Colo G, Burgalassi S, Chetoni P, et al. Gel-forming erodible inserts for ocular controlled delivery of ofloxacin. Int J Pharm. 2001; 215: 101–111.
16. Gratieri T, Gelfuso GM, Rocha EM, et al. A poloxamer/chitosan in situ forming gel with prolonged retention time for ocular delivery. Eur J Pharm Biopharm. 2010; 75: 186–193.
17. Gratieri T, Gelfuso GM, de Freitas O, et al. Enhancing and sustaining the topical ocular delivery of fluconazole using chitosan solution and poloxamer/chitosan in situ forming gel. Eur J Pharm Biopharm. 2011; 79: 320–327.
18. Kesavan K, Kant S, Singh PN, et al. Effect of Hydroxypropyl-beta-cyclodextrin on the ocular bioavailability of dexamethasone from a ph-induced mucoadhesive hydrogel. Curr Eye Res. 2011; 36: 918–929.
19. Bravo-Osuna I, Noiray M, Briand E, et al. Interfacial Interaction between transmembrane ocular mucins and adhesive polymers and dendrimers analyzed by surface plasmon resonance. Pharm Res. 2012; 29: 2329–2340.
20. Yandrapu SK, Kanujia P, Chalasani KB, et al. Development and optimization of thiolated dendrimer as a viable mucoadhesive excipient for the controlled drug delivery: an acyclovir model formulation. Nanomed Nanotechnol Biol Med. 2013; 9: 514–522.
21. Majumdar S, Hingorani T, Srirangam R, et al. Transcorneal permeation of l- and d-aspartate ester prodrugs of acyclovir: delineation of passive diffusion versus transporter involvement. Pharm Res. 2009; 26: 1261–1269.
22. Anand BS, Katragadda S, Nashed YE, et al. Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: interactions with the neutral and cationic amino acid transporter on the corneal epithelium. Curr Eye Res. 2004; 29: 153–166.
23. Jwala J, Boddu SHS, Shah S, et al. Ocular sustained release nanoparticles containing stereoisomeric dipeptide prodrugs of acyclovir. J Ocul Pharmacol Ther. 2011; 27: 163–172.
24. Vadlapudi AD, Vadlapatla RK, Earla R, et al. Novel biotinylated lipid prodrugs of acyclovir for the treatment of herpetic keratitis (HK): transporter recognition, tissue stability and antiviral activity. Pharm Res. 2013; 30: 2063–2076.
25. Ciolino JB, Hudson SP, Mobbs AN, et al. A prototype antifungal contact lens. Invest Ophthalmol Vis Sci. 2011; 52: 6286–6291.
26. Shi Y, Lv H, Fu Y, et al. Preparation and characterization of a hydrogel carrier to deliver gatifloxacin and its application as a therapeutic contact lens for bacterial keratitis therapy. Biomed Mater. 2013; 8:055007.
27. Grinstaff MW . Designing hydrogel adhesives for corneal wound repair. Biomaterials. 2007; 28: 5205–5214.
28. Miki D, Dastgheib K, Kim T, et al. A photopolymerized sealant for corneal lacerations. Cornea. 2002; 21: 393–399.
29. Grinstaff MW . Dendritic macromers for hydrogel formation: tailored materials for ophthalmic, orthopedic, and biotech applications. J Polymer Sci A Polymer Chem. 2008; 46: 383–400.
30. Berdahl JP, Johnson CS, Proia AD, et al. Comparison of sutures and dendritic polymer adhesives for corneal laceration repair in an in vivo chicken model. Arch Ophthalmol. 2009; 127: 442–447.
31. Oelker AM, Berlin JA, Wathier M, et al. Synthesis and characterization of dendron cross-linked PEG hydrogels as corneal adhesives. Biomacromolecules. 2011; 12: 1658–1665.
32. Chang JH, Gabison EE, Kato T, et al. Corneal neovascularization. Curr Opin Ophthalmol. 2001; 12: 242–249.
33. Gonzalez L, Loza RJ, Han K-Y, et al. Nanotechnology in corneal neovascularization therapy—a review. J Ocul Pharmacol Ther. 2013; 29: 124–134.
34. Chang J-H, Garg NK, Lunde E, et al. Corneal neovascularization: an anti-VEGF therapy review. Surv Ophthalmol. 2012; 57: 415–429.
35. Chen P, Yin H, Wang Y, et al. Inhibition of VEGF expression and corneal neovascularization by shRNA targeting HIF-1 alpha in a mouse model of closed eye contact lens wear. Mol Vis. 2012; 18: 864–873.
36. Qazi Y, Stagg B, Singh N, et al. Nanoparticle-mediated delivery of shRNA.VEGF-A plasmids regresses corneal neovascularization. Invest Ophthalmol Vis Sci. 2012; 53: 2837–2844.
37. Iriyama A, Usui T, Yanagi Y, et al. Gene transfer using micellar nanovectors inhibits corneal neovascularization in vivo. Cornea. 2011; 30: 1423–1427.
38. Xu J, Wang Y, Li Y, et al. Inhibitory efficacy of intravitreal dexamethasone acetate-loaded PLGA nanoparticles on choroidal neovascularization in a laser-induced rat model. J Ocul Pharmacol Ther. 2007; 23: 527–539.
39. Shmueli RB, Ohnaka M, Miki A, et al. Long-term suppression of ocular neovascularization by intraocular injection of biodegradable polymeric particles containing a serpin-derived peptide. Biomaterials. 2013; 34: 7544–7551.
40. Kim H, Csaky KG . Nanoparticle-integrin antagonist C16Y peptide treatment of choroidal neovascularization in rats. J Control Release. 2010; 142: 286–293.
41. Jin J, Zhou KK, Park K, et al. Anti-inflammatory and antiangiogenic effects of nanoparticle-mediated delivery of a natural angiogenic inhibitor. Invest Ophthalmol Vis Sci. 2011; 52: 6230–6237.
42. Liu H-a, Liu Y-l, Ma Z-z, et al. A lipid nanoparticle system improves sirna efficacy in RPE cells and a laser-induced murine CNV model. Invest Ophthalmol Vis Sci. 2011; 52: 4789–4794.
43. Singh SR, Grossniklaus HE, Kang SJ, et al. Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV. Gene Ther. 2009; 16: 645–659.
44. Luo L, Zhang X, Hirano Y, et al. Targeted intraceptor nanoparticle therapy reduces angiogenesis and fibrosis in primate and murine macular degeneration. Acs Nano. 2013; 7: 3264–3275.
45. Park K, Chen Y, Hu Y, et al. Nanoparticle-mediated expression of an angiogenic inhibitor ameliorates ischemia-induced retinal neovascularization and diabetes-induced retinal vascular leakage. Diabetes. 2009; 58: 1902–1913.
46. Jo DH, Kim JH, Yu YS, et al. Antiangiogenic effect of silicate nanoparticle on retinal neovascularization induced by vascular endothelial growth factor. Nanomed Nanotechnol Biol Med. 2012; 8: 784–791.
47. Kim JH, Kim MH, Jo DH, et al. The inhibition of retinal neovascularization by gold nanoparticles via suppression of VEGFR-2 activation. Biomaterials. 2011; 32: 1865–1871.
48. Zhou X, Wong LL, Karakoti AS, et al. Nanoceria inhibit the development and promote the regression of pathologic retinal neovascularization in the Vldlr knockout mouse. PLoS One. 2011; 6
49. Theriault BL, Dimaras H, Gallie BL, et al. The genomic landscape of retinoblastoma: a review. Clin Exp Ophthalmol. 2014; 42: 33–52.
50. Das M, Sahoo SK . Folate decorated dual drug loaded nanoparticle: role of curcumin in enhancing therapeutic potential of nutlin-3a by reversing multidrug resistance. PLoS One. 2012; 7:.
51. Parveen S, Sahoo SK . Long circulating chitosan/PEG blended PLGA nanoparticle for tumor drug delivery. Eur J Pharmacol. 2011; 670: 372–383.
52. Mitra M, Kandalam M, Rangasamy J, et al. Novel epithelial cell adhesion molecule antibody conjugated polyethyleneimine-capped gold nanoparticles for enhanced and targeted small interfering RNA delivery to retinoblastoma cells. Mol Vis. 2013; 19: 1029–1038.
53. Kang SJ, Durairaj C, Kompella UB, et al. Subconjunctival nanoparticle carboplatin in the treatment of murine retinoblastoma. Arch Ophthalmol. 2009; 127: 1043–1047.
54. Boddu SHS, Jwala J, Chowdhury MR, et al. In vitro evaluation of a targeted and sustained release system for retinoblastoma cells using doxorubicin as a model drug. J Ocul Pharmacol Ther. 2010; 26: 459–468.
55. Kartner N, Everndenporelle D, Bradley G, et al. Detection of p-glycoprotein in multidrug-resistant cell-lines by monoclonal-antibodies. Nature. 1985; 316: 820–823.
56. Gary-Bobo M, Mir Y, Rouxel C, et al. Multifunctionalized mesoporous silica nanoparticles for the in vitro treatment of retinoblastoma: drug delivery, one and two-photon photodynamic therapy. Int J Pharm. 2012; 432: 99–104.
57. Ghiso J, Doudevski I, Ritch R, et al. Complement activation in exfoliation glaucoma. Society for Neuroscience Abstract Viewer and Itinerary Planner. 2012; 42:.
58. Kuchtey J, Kuchtey RW . The microfibril hypothesis of glaucoma: implications for treatment of elevated intraocular pressure. J Ocul Pharmacol Ther. 2014; 30: 170–180.
59. Chang EE, Goldberg JL . Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology. 2012; 119: 979–986.
60. Wadhwa S, Paliwal R, Paliwal SR, et al. Hyaluronic acid modified chitosan nanoparticles for effective management of glaucoma: development, characterization, and evaluation. J Drug Target. 2010; 18: 292–302.
61. Bhagav P, Upadhyay H, Chandran S . Brimonidine tartrate–Eudragit long-acting nanoparticles: formulation, optimization, in vitro and in vivo evaluation. Aaps Pharmscitech. 2011; 12: 1087–1101.
62. Bertram JP, Saluja SS, McKain J, et al. Sustained delivery of timolol maleate from poly(lactic-co-glycolic acid)/poly(lactic acid) microspheres for over 3 months. Journal of Microencapsulation. 2009; 26: 18–26.
63. Jung HJ, Abou-Jaoude M, Carbia BE, et al. Glaucoma therapy by extended release of timolol from nanoparticle loaded silicone-hydrogel contact lenses. J Control Release. 2013; 165: 82–89.
64. Schwartz KS, Lee RK, Gedde SJ . Glaucoma drainage implants: a critical comparison of types. Curr Opin Ophthalmol. 2006; 17: 181–189.
65. Pan T, Brown JD, Ziaie B . An artificial nano-drainage implant (ANDI) for glaucoma treatment. In: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society IEEE Engineering in Medicine and Biology Society Conference. New York, NY: IEEE. 2006; 1: 3174–3177.
66. Jiang C, Moore MJ, Zhang X, et al. Intravitreal injections of GDNF-loaded biodegradable microspheres are neuroprotective in a rat model of glaucoma. Mol Vis. 2007; 13: 1783–1792.
67. Checa-Casalengua P, Jiang C, Bravo-Osuna I, et al. Retinal ganglion cells survival in a glaucoma model by GDNF/Vit E PLGA microspheres prepared according to a novel microencapsulation procedure. J Control Release. 2011; 156: 92–100.
68. Jeun M, Jeoung JW, Moon S, et al. Engineered superparamagnetic Mn0.5Zn0.5Fe2O4 nanoparticles as a heat shock protein induction agent for ocular neuroprotection in glaucoma. Biomaterials. 2011; 32: 387–394.
69. Creasey R, Sharma S, Gibson CT, et al. Atomic force microscopy–based antibody recognition imaging of proteins in the pathological deposits in pseudoexfoliation syndrome. Ultramicroscopy. 2011; 111: 1055–1061.
70. Braunsmann C, Hammer CM, Rheinlaender J, et al. Evaluation of lamina cribrosa and peripapillary sclera stiffness in pseudoexfoliation and normal eyes by atomic force microscopy. Invest Ophthalmol Vis Sci. 2012; 53: 2960–2967.
71. Zarbin MA, Montemagno C, Leary JF, et al. Nanomedicine for the treatment of retinal and optic nerve diseases. Curr Opin Pharmacol. 2013; 13: 134–148.
72. Caldorera-Moore M, Peppas NA . Micro- and nanotechnologies for intelligent and responsive biomaterial-based medical systems. Adv Drug Deliv Rev. 2009; 61: 1391–1401.
73. Piffaretti F, Barrettino D, Orsatti P, et al. Rollable and implantable intraocular pressure sensor for the continuous adaptive management of glaucoma. In: Conference Proceedings : Annual International Conference of the IEEE Engineering in Medicine and Biology Society IEEE Engineering in Medicine and Biology Society Conference. Osaka, Japan: IEEE. 2013; 2013: 3198–3201.
74. Kang B, Hwang H, Lee SH, et al. A wireless intraocular pressure sensor with variable inductance using a ferrite material. J Semiconduct Technol Sci. 2013; 13: 355–360.
75. Chen GZ, Chan IS, Lam DCC . Capacitive contact lens sensor for continuous non-invasive intraocular pressure monitoring. Sensors Actuators A Phys. 2013; 203: 112–118.
76. Ghaed MH, Chen G, Razi-ul H, et al. Circuits for a cubic-millimeter energy—autonomous wireless intraocular pressure monitor. IEEE Trans Circuits Syst I Regul Pap. 2013; 60: 3152–3162.
77. Chitnis G, Maleki T, Samuels B, et al. A Minimally Invasive Implantable Wireless Pressure Sensor for Continuous IOP Monitoring. IEEE Trans Biomed Eng. 2013; 60: 250–256.
78. Xue N, Chang SP, Lee JB . A SU-8–based microfabricated implantable inductively coupled passive RF wireless intraocular pressure sensor. J Microelectromech Syst. 2012; 21: 1338–1346.
79. Kim KH, Kim BH, Seo YH . A noncontact intraocular pressure measurement device using a micro reflected air pressure sensor for the prediagnosis of glaucoma. J Micromech Microeng. 2012; 22: 10
80. Todani A, Behlau I, Fava MA, et al. Intraocular pressure measurement by radio wave telemetry. Invest Ophthalmol Vis Sci. 2011; 52: 9573–9580.
81. Laukhin V, Sanchez I, Moya A, et al. Non-invasive intraocular pressure monitoring with a contact lens engineered with a nanostructured polymeric sensing film. Sensors Actuators A Phys. 2011; 170: 36–43.
82. Sanchez I, Laukhin V, Moya A, et al. Prototype of a nanostructured sensing contact lens for noninvasive intraocular pressure monitoring. Invest Ophthalmol Vis Sci. 2011; 52: 8310–8315.
83. Goto K, Kato D, Sekioka N, et al. Direct electrochemical detection of DNA methylation for retinoblastoma and CpG fragments using a nanocarbon film. Anal Biochem. 2010; 405: 59–66.
84. Leonardi M, Pitchon EM, Bertsch A, et al. Wireless contact lens sensor for intraocular pressure monitoring: assessment on enucleated pig eyes. Acta Ophthalmol. 2009; 87: 433–437.
85. Singh K, Sit AJ . Intraocular pressure variability and glaucoma risk complex and controversial. Arch Ophthalmol. 2011; 129: 1080–1081.
86. Graham SL, Drance SM . Nocturnal hypotension: role in glaucoma progression. Surv Ophthalmol. 1999; 43: S10–S16.
87. Zarbin MA, Arlow T, Ritch R . Regenerative nanomedicine for vision restoration. Mayo Clin Proc. 2013; 88: 1480–1490.
88. Hollo G, Kothy P, Vargha P . Evaluation of continuous 24-hour intraocular pressure monitoring for assessment of prostaglandin-induced pressure reduction in glaucoma. J Glaucoma. 2014; 23: E6–E12.
89. Faschinger C, Mossbock G . Validity of the results of a contact lens sensor? JAMA Ophthalmol. 2013; 131: 696–697.
90. Mottet B, Aptel F, Romanet JP, et al. 24-Hour intraocular pressure rhythm in young healthy subjects evaluated with continuous monitoring using a contact lens sensor. JAMA Ophthalmol. 2013; 131: 1507–1516.
91. Ha D, de Vries WN, John SWM, et al. Polymer-based miniature flexible capacitive pressure sensor for intraocular pressure (IOP) monitoring inside a mouse eye. Biomed Microdevices. 2012; 14: 207–215.
92. Stirzaker C, Millar DS, Paul CL, et al. Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res. 1997; 57: 2229–2237.
93. Kato D, Sekioka N, Ueda A, et al. A nanocarbon film electrode as a platform for exploring DNA methylation. J Am Chem Soc. 2008; 130: 3716–+.
94. Kato D, Sekioka N, Ueda A, et al. Nanohybrid carbon film for electrochemical detection of SNPs without hybridization or labeling. Angewandte Chemie (International Ed in English). 2008; 47: 6681–6684.