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ANNUAL REVIEW
Nanotechnology-Based Approaches for Ophthalmology
Applications: Therapeutic and Diagnostic Strategies
Mehdi Ghaffari Sharaf, MSc,*Þ Sibel Cetinel, PhD,*Þ Lisa Heckler, MD,þ Karim Damji, MD,þ
Larry Unsworth, PhD, PEng,*Þ§ and Carlo Montemagno, PhD*Þ§
Purpose: The purpose of this article was to review recent advances in
applications of nanotechnology in ophthalmology.
Design: Literature review.
Methods: Research articles about nanotechnology-based treatments for
particular eye diseases and diagnostic technologies were searched through
Web of Science, and the most recent advances were reported.
Results: Nanotechnology enabled to improve drug and gene delivery
systems, medicine solubility and short half-life in biological systems, controlled release, targeted delivery, bioavailability, diffusion limitations, and
biocompatibility so far. These promising achievements are the assurance of
next-generation treatment technologies. As well as treatment, nanofabrications
systems such as microelectromechanical manufacturing systems removed
the limitations of nanodevice generations and led the development of diagnostic tools such as intraocular pressure monitors and biosensors.
Conclusions: 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; herein, we attempt to show
unmodified nanoparticles as well as interesting and representative biomimetic strategies can be used for specific diseases. Finally, through combining microelectromechanical and nanoelectromechanical manufacturing
system strategies, interesting manufacturing and sensor development
can be accomplished for early detection and, in some cases, treatment
of ocular diseases.
Key Words: nanotechnology, keratitis, neovascularization, glaucoma,
corneal wounds
(Asia-Pac J Ophthalmol 2014;3: 172Y180)
A
dvances 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
From the *Chemical & Materials Engineering, †Ingenuity Lab, and ‡Ophthalmology
and Visual Sciences, University of Alberta; and §National Institute of Nanotechnology, National Research Council, Edmonton, Alberta, Canada.
Received for publication March 18, 2014; accepted May 8, 2014.
The authors have no funding or conflicts of interest to declare. Mehdi Ghaffari
Sharaf and Sibel Cetinel contributed equally to this article.
Reprints: Larry D. Unsworth, PhD, PEng, ECERF W7-070D, University of
Alberta, Edmonton, AB, Canada T6G 2V4.
E-mail: [email protected]; or Carlo Montemagno, PhD,
Ingenuity Lab, 1-070C, 11421 Saskatchewan Dr, Edmonton, Alberta,
Canada T6G 2M9. E-mail: [email protected].
Copyright * 2014 by Asia Pacific Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.1097/APO.0000000000000059
172
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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.3Y5 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)Ybased 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
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Nanotechnology in Ophthalmology Applications
FIGURE 1. Schematic presentation of the ocular structure (A) and the mucoadhesive tear film (B).
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.
Inflammation-Induced Diseases
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)YEudragit microspheres (Fig. 2,
* 2014 Asia Pacific Academy of Ophthalmology
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
situYforming 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-A-cyclodextrin,
to increase the solubility of dexamethasone and combined their
formulation with the anionic mucoadhesive Carbopol. Their
hydroxypropyl-A-cyclodextrinYbased, 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 transportertargeted 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 1Yinduced
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, econazoleimpregnated 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
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Sharaf et al
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FIGURE 2. Schematic representation of some NP structures used in nanotechnology. Linear polymers could be attached to molecules
by covalent conjugation. Nanospheres could be loaded with drug and ensure sustained release. Dendrimers are branched polymers,
which could encapsulate or covalently conjugate drug molecules. Nanocapsules could encapsulate relatively large amount of molecules.
Micelles are self-assembled amphiphilic particles that can encapsulate both lipophilic and lipophobic molecules. Liposomes are
vesicles formed by lipid bilayers.
exhibit sustained release (70% in 25 hours) and favorable healing
profiles (in 48 hours) using a rat model with bacterial keratitis.26
Corneal Wounds
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
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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.
Corneal Neovascularization
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.32Y34
* 2014 Asia Pacific Academy of Ophthalmology
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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 retinablood barrier, as well as controlled and targeted delivery.
Neovascularization-Related Diseases
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 integrinantagonist 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 halflife 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
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Nanotechnology in Ophthalmology Applications
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 liposomeY
protamineYhyaluronic 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.46Y48 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 oxygeninduced retinopathy.46
Retinoblastoma
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 LHA-Tag mouse model more
effectively than free drug.53 In another study, PLGA-PEG-folate
micelles were utilized for folate receptorYtargeted 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
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TABLE 1. Summary of Articles Reviewed for Nanotechnology Diagnostic Approaches
Authors
Piffaretti et al
73
Kang et al74
Chen et al75
Ghaed et al76
Chitnis et al77
Ha et al
Xue et al78
Kim et al79
Todani et al80
Laukhin et al81
Sanchez et al82
Goto et al83
Leonardi et al84
Title
Year
Major Contribution
Rollable and implantable IOP sensor for the continuous
adaptive management of glaucoma
A Wireless Intraocular Pressure Sensor With Variable
Inductance Using a Ferrite Material
Capacitive Contact Lens Sensor for Continuous Noninvasive
IOP Monitoring
Circuits for a Cubic-Millimeter EnergyVAutonomous
Wireless Intraocular Pressure Monitor
A Minimally Invasive Implantable Wireless Pressure Sensor
for Continuous IOP Monitoring
2013
Rollable and implantable piezo-resistive
IOP contact lens
Wireless IOP pressure sensor (with
ferrite material)
Wireless capacitive contact lens sensor
for IOP
Nanowatt power levels for IOP monitoring
microsystem
Implantable IOP capacitive pressure sensor,
with a hypodermic needle to directly
access the vitreous
Flexible polymer-based capacitive pressure
sensor for IOP
Implantable SU-8Ybased wireless
pressure sensor
Portable tonometer using a micro
reflected air pressure sensor for IOP
2013
2013
2013
Polymer-Based Miniature Flexible Capacitive Pressure
Sensor for IOP Monitoring Inside a Mouse Eye
A SU-8YBased Microfabricated Implantable Inductively
Coupled Passive RF Wireless Intraocular Pressure Sensor
A Noncontact IOP Measurement Device Using a Micro
Reflected Air Pressure Sensor for the Prediagnosis
of Glaucoma
Intraocular pressure measurement by radio wave telemetry
2012
Non-invasive Intraocular Pressure Monitoring With a Contact
Lens Engineered With a Nanostructured Polymeric
Sensing Film
Prototype of a Nanostructured Sensing Contact Lens for
Noninvasive Intraocular Pressure Monitoring
Direct Electrochemical Detection of DNA Methylation
for Retinoblastoma and CpG Fragments Using A
Nanocarbon Film
Wireless contact lens sensor for intraocular pressure
monitoring: assessment on enucleated pig eyes
2011
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
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
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2013
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2012
2012
2011
2011
2010
2009
WIT (Implandata GmbH)
implantable sensor
Piezo-resistiveYbased IOP contact
lens sensor
Piezo-resistiveYbased IOP contact
lens sensor
Sensor for direct electrochemical
detection of DNA methylation for RB
Issues around SENSIMED Triggerfish
sensor for IOP
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 lineYderived neurotrophic factor resulted in
neuroprotective effects on retinal ganglion cells in animal glaucoma models.66,67 Similar to glial cell lineYderived 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
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FIGURE 3. Schematic presentation of (A) the capacitive pressure sensor. An increase in the pressure of the environment of the
sensor will affect the flexible thin membrane that will result in change in distance and therefore capacitance between 2 electrodes,
(B) implantable IOP sensor with hypodermic needle, (C) capacitive contact lens sensor, (D) implantable ring-shaped WIT with
an ASIC chip and a circular microcoil antenna.
and identify constituent proteins, showing that lysyl oxidaseYlike 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 NEMSY
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
* 2014 Asia Pacific Academy of Ophthalmology
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.88Y90
Thus, active research is ongoing in order to develop IOP
monitoring systems using different methods such as capacitive
pressure sensors, micromachined pressure sensor, and piezoresistive IOP sensors.3 An ultrathin, flexible, polymer-based capacitive MEMS pressure sensor (500 500 100 Km3) 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
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Sharaf et al
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 A-(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-parallelgold plate (metal-insulator-metal) capacitor, and a pressuresensitive 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 (cytosinephosphoguanosine) 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.
CONCLUSIONS
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.
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