The tears mainly comprise of water and sodium chloride, sugar,
urea and proteins.
Tears are composed of:1
Water
Electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, and calcium). These are what give tears their salty taste.
Proteins (lysozyme, lactoferrin, lipocalin, and IgA). The tears have only about one-tenth of the protein of the blood plasma.
Lipids (fats)
Mucins (proteins that help with lubrication)
The Composition of Basal Tears and Role in Eye Health
Tears play an important role in keeping us healthy. Tears keep the surface of our eyeballs clean and moist and help protect our eyes from damage. Tears are made of mucus, water, and oil, and each component plays a role in the eye.1
Mucus coats the surface of the eye and helps bind the tear layer to the eye. Without a healthy mucus layer, dry spots may form on the cornea, the clear, dome-like structure on the front of the eye.
The water saline solution contains various vitamins and minerals vital to normal cell function. These nutrients are important for keeping the epithelium (top layer of cells on the surface of the eye) healthy and functioning normally.
The oil of the tear film prevents evaporation of the tears. If the oil component is not normal, the tears evaporate too quickly. Some people don't make enough oil (or sometimes too much oil), resulting in dry eyes.
Carbonic anhydrase inhibitors (CAIs)
These are potent and most commonly used systemic
antiglaucoma drugs. These include acetazolamide
(most frequently used), methazolamide,
dichlorphenamide and ethoxzolamide.
Our tears also contain natural antibiotics called lysozymes. Lysozymes help to keep the surface of the eye healthy by fighting off bacteria and viruses.
Serum electrolyte imbalances may occur with
higher doses of CAIs. These may be in the form of (i)
Bicarbonate depletion leading to metabolic acidosis.
This is associated with ‘malaise symptom complex’,
which includes: malaise, fatigue, depression, loss of
libido, anorexia and weight loss. Treatment with
sodium bicarbonate or sodium acetate may help to
minimize this situation in many patients. (ii) Potassium
depletion. It may occur in some patients, especially
those simultaneously getting corticosteroids, aspirin
or thiazide diuretics. Potassium supplement is
indicated only when significant hypokalemia is
documented. (iii) Serum sodium and chloride may be
transiently reduced; more commonly with
dichlorphenamide.
3.4 Tears
Tear fluid is media that have received interest for diagnostics since the antiquity. It is mainly composed of water and electrolytes and can be treated as an ultrafiltrate of the plasma containing hundreds of proteins, lipids, glycoproteins, hormones and glucose, for which free blood concentration relationships can be derived directly. It is secreted by the lacrimal glands, forming a mechanical and antimicrobial film layer over the ocular surface. The basal secretion rate is in the order of 1 μL per minute which can be increased up to 100-folds via stimulation [124]. The strength of tear in POC analysis is that there is no need for extensive sample preparation; collected media can be analysed as it is. Typically, tear samples are collected minimally-invasively via either Schirmer paper strips or glass/plastic capillary tubes. The disadvantages of using tear is the limited sample volume, not being suitable for self-sampling, inter/intra-individual variations, evaporation and concentration dependency on collection method. Similar to other media, clinical application of tear-based diagnostics requires a fundamental understanding of tear transport mechanisms and chemistry as well as established correlations between tear and blood concentrations.
A paper-based analytical device has been developed as an alternative to enzyme linked immunosorbent assay (ELISA) for the diagnosis of severe dry eye disease via quantification of lactoferrin from tear samples (Fig. 9D) [125]. In the presence of lactoferrin, a concentration-dependent fluorescent line is obtained under UV light through the reaction between lactoferrin in the sample and terbium at the active site of the paper-based device. The length of resulting concentration-dependent fluorescent line is utilized for the distance-based quantification of lactoferrin. The applicability of the sensor was demonstrated by comparing the measured lactoferrin levels with those obtained from ELISA, from which a positive correlation was obtained.
An electrochemical paper-based analytical device (Fig. 9E) has been introduced for the detection of eye trauma and evaluation of anterior surface integrity via measuring ascorbic acid concentration from tear fluid [126]. Ascorbic oxidase immobilized in the sensing area interacts with the ascorbic acid within the sample creating a resistance change, which is quantified by the handheld multi-metre. Preliminary clinical studies demonstrated that proposed device is a promising alternative for the current techniques in early diagnosis of eye injury.
Another smartphone-assisted analytical device has been tested for the quantification of tear fluid electrolytes (Na+, K+, Ca2 +) and pH for the early diagnosis of dry eye disease (Fig. 9F) [127]. Paper-based microfluidic device consists of a capillary tube and a reservoir for sample collection, a leaf-like sensing unit with fluorescent chelating agents for fluorescence detection of electrolytes and a portable black-box for image capture without light interferences. Captured images are then analysed with a custom-made smartphone app for the quantitative measurement. In a similar study, a colorimetric paper-based device has been proposed for the determination of glucose levels in tear fluid [128]. Multilayer modification of the sensing area through the utilization of chitosan enables uniform colour response which decreases the end-user dependent variance in the signal readout. A commercially available image processing software was utilized for the quantitative determination of glucose in tear fluid.
Commercial use of LFAs for tear fluid analysis includes early diagnosis of dry eye disease. FDA approved InflammaDry test (Quidel) measures the concentration of matrix metalloproteinase 9 (MMP-9), which was shown to elevate in the tear fluid during the development of dry eye disease [129]. Nevertheless, it can only provide a qualitative result, by simply answering yes/no question. Tearscan system developed by the Advanced Tear Diagnostics is designed to quantify lactoferrin levels, which can be used as an indicator for dry-eye disease as it reflects tear production rate [130]. The same company has also launched an LFA for the detection of allergic conjunctivitis via detection of immunoglobulin E in tear fluid. Similar to InflammaDry, Tearscan system can only provide qualitative analysis. As a remedy, the company has recently installed TearScanTM 270 MicroAssay System for real-time quantitative analysis of lactoferrin and immunoglobulin E assays.
Tear fluid components such as proteins, lipids and mucin may act as antibacterial agents by trapping and coating micro-organisms (oponization) and allowing them to be flushed away (Dumbleton, 2002). However, they also accumulate on contact lens surfaces which may contribute to contamination, deterioration and mechanical difficulties. Human tears contain approximately 60 different proteins, with lyso2yme encompassing about 30% of the total (Kidane et al, 1998; Keith et al, 2001). According to Moradi et al (2004), lactoferrin and tear-specific prealbumin are the next most abundant components. Garrett and Milthorpe (1996) and Kidane et al (1998) agree that accumulation of protein deposits incur mechanical irritation on the ocular surface. The protein deposition patterns on the anterior lens surface may provide some insight into this irritation. The surface chemistry of the lens material is the primary factor dictating protein adhesion (Keith et al, 2001).
The tear film covers and protects the ocular surface. It contains various molecules including a large variety of proteins. The protein composition of the tear fluid can change with respect to various local and systemic diseases. Prior to the advent of the proteomic era, tear protein analysis was limited to a few analytical techniques, the most common of which was immunoelectrophoresis, an approach dependent on antibody availability. Using proteomics, hundreds of tear proteins could potentially be identified and subsequently studied. Although detection of low-abundance proteins in the complex tear proteome remains a challenge, advances in sample fractionation and mass spectrometry have greatly enhanced our ability to detect these proteins. With increasing proteomic applications, tears show great potential as biomarkers in the development of clinical assays for various human diseases.
In this chapter, we discuss the structure and functions of the tear film and methods for its collection. We also summarize potential tear protein biomarkers identified using proteomic techniques for both ocular and systemic diseases. Finally, modern proteomic techniques for tear biomarker research and future challenges are explored.
An innovative glucose sensor on a contact lens was recently developed by a group of researchers from the University of Washington. A primary drawback of the current enzyme-based finger-pricking method is that it is invasive, inconvenient, and may cause infection. The usage of a contact lens coupled with tear fluid allows both noninvasive and continuous detection of glucose. Tear fluid contains a variety of biomarkers, namely glucose, cholesterol, sodium, and potassium(23). The concentration of glucose in tear fluid is much lower compared to blood and is in the range of 0.1–0.6 mM L−1(24).
The design and fabrication of the contact-lens sensor are illustrated in Figure 4. To mimic an actual contact lens, the sensor was fabricated on a 100-μm-thick film of flexible and transparent polyethylene terephthalate polymer. The electrodes were formed using three layers of metal, namely titanium, palladium, and platinum. Three electrodes were used for the electrochemical sensor, namely the working, counter, and reference electrodes.
Figure 4. (a) Design and (b) fabrication of contact-lens glucose sensor.
Reproduced from Liao, Y. T.; Yao, H.; Parviz, B.; Otis, B. A 3uW Wirelessly Powered CMOS Glucose Sensor for an Active Contact Lens. IEEE J. Solid-State Circuits2012, 47 (1), 38–40.
A constant voltage of 0.4 V was applied to the working and reference electrodes, while current measurements were taken via the working electrode. The counter electrode acts as a current drain and was connected to the auxiliary lead of the potentiostat(25). Similar to other electrochemical glucose sensors, the measured current is proportional to the concentration of glucose in the fluid. The sensor was tested using a polydimethlylsiloxane (PDMS) eye model to mimic a real eye. To mimic tears, glucose was dispensed via a syringe pump on top of the contact lens while another syringe pump aspirated the fluid via the tear ducts. Experimental measurements indicate that the sensor has good sensitivity and is able to detect very low concentrations of glucose of 0.01 mM, which is below the normal level of glucose in human tears of 0.1–0.6 mM. The contact-lens sensor also has very good response rates and produces measurements that reach 90% of the maximum value in fewer than 20 s.
The first sensors for bioanalyte detection in tears used flexible electronics inserted into the lachrymal glands in the eye. These sensors were uncomfortable and had problems relating to tear evaporation and bioanalyte degradation. More recently, strip-based sensors have been commercially available, for example, Schirmer's strip. These strips are placed into the space behind the lower eyelid and can detect bioanalytes in the available fluid tear film. While these sensor strips are effective, in practice they typically irritate the eye causing both discomfort to the patient as well as potential changes in tear production and bioanalyte concentration. To overcome this irritation, sensor electronics have been integrated into soft contact lenses. This work was pioneered by Babak A. Parviz and his lab at the University of Washington in 2007 [74]. The contact lens sensors have the electrodes, sensing mechanisms, power, and wireless data transfer all integrated into the soft polymer. The integrated contact lens sensor has revolutionized the way that tear fluid is sensed, and research into this platform has grown exponentially as the contact lens can be used continuously without any interference from or interaction with the wearer. While challenges for the contact lens platform are numerous, particularly the issue of power, the promise of contact lens-based tear sensors has widely been recognized leading to not only a great volume of academic literature and research on the subject but new business ventures including the Google Contact Lens (as seen in Figure 4), which was announced in 2014 and put on hold in 2018 [76, 77].
Figure 4. The glucose sensing contact lens developed by Google and Novartis.
Reproduced with permission from [77].
Tear fluid-based wearable sensors most commonly use either electrochemical or optical means of bioanalyte sensing. Electrochemical sensing is usually done through the binding of the bioanalyte of interest to an enzyme bound to gold electrodes. The function of the enzyme, usually an oxidation or reduction, produces current that is proportional to the concentration of the bioanalyte and subsequently detected by the electrodes. Common enzyme/bioanalyte pairs are glucose/glucose oxidase, glucose/cellobiose dehydrogenase/bilirubin oxidase, ascorbate/tetrathiafulvalene-tetracyanoquinodimethane (TTF/TCNQ) complex/bilirubin oxidase, and lactate/lactose oxidase. They are ideal for electrochemical sensing as the high selectivity of the enzymes can produce desired reactions even at low concentrations.
Optical sensing, most commonly used for glucose, uses responsive materials to generate a signal that can be measured optically. The responsive material used is often a boronic acid derivative, which is a fluorophore for monosaccharides, and polymer crystalline colloidal arrays. These materials change their interaction with light when bound to glucose. Unfortunately, these changes must generally be measured by exciting the material with light, meaning that a laser source must be directed into the sensor while on the eye to quantify the bioanalyte present. One way that optical sensors have tried to circumnavigate this difficulty has been by using readout methods that can be processed externally. For example, contact lenses with holographic fluids/arrays have been manufactured that change color depending on the glucose concentration in the tears (as seen in Figure 5). Another method that has shown promise is based on a contact lens printed with a photonic repeating pattern. The contact lens swells (using a hydrogel functionalized with phenylboronic acid) in the presence of glucose. By taking a picture of the printed photonic pattern using a smartphone the glucose concentration can be calculated.
5.2 Ocular Applications of Nanoparticulate Drug Delivery System
Topical ophthalmic drugs exhibit poor absorption in the eye due to the cornea's low permeability to drugs, rapid tear turnover and nasolacrimal drainage, and systemic absorption. One of the major drawbacks in ocular delivery is maintaining an adequate concentration of the drug in the precorneal area. Topical drop administration of ophthalmic formulations in aqueous solutions leads to extensive drug loss due to tear fluid and eyelid dynamics [30]. This limitation invites the need for use of prodrugs and viscosity agents that may prolong the drug residence time, and colloidal systems.
Drug nanosuspension for ocular drug delivery system has been developed by Pignatello et al. The codispersion of cloricromenehydrochloride (AD6) in Eudragit RS or RL polymers resulted in nanosuspensions displaying good mean sizes for ophthalmic applications and a positive surface charge. The suspensions allowed for improved corneal adhesion, thereby lending higher drug levels at desired site of action and also stability upon storage, particularly at low temperatures. According to preliminary biological evaluation of the nanosuspensions that showed a higher drug availability in the rabbit aqueous humor after the drug's administration in Eudragit RL nanosuspensions, AD6-loaded Eudragit Retard nanosuspensions offer a potential means of increasing the shelf life and bioavailability of this drug after ophthalmic application [31].
Polymeric NPs are attractive colloidal systems because they demonstrate increased stability, are biocompatible and biodegradable, and also have a longer elimination half-life in tear fluid (up to 20 min) than do conventional drugs applied topically to the eye, which have half-lives of just 1–3 min.
NPDDS as an ophthalmic delivery system also has been investigated by Kassem et al. The effect of particle size (in the micro and nano size range) as well as that of viscosity of the nanosuspensions on the ocular bioavailability was studied by measuring the intraocular pressure of normotensive albino rabbits using a tonometer. The experimental study reveals that nanosuspensions always enhance the rate, extent, and intensity of ophthalmic drug absorption as compared to solution and microcrystalline suspensions. The data related to the effect on bioavailability suggests that the differences are statistically highly to very highly significant as compared to the microcrystalline suspensions [31].
NPDDSs have shown potential in the treatment of external eye diseases. Specific targeting to retinal pigment epithelial cells in the eye is possible [32,33].
Aptamers have been reported for various targets and are used as inhibitors as well. An aptamer-based therapeutic is available known as pegaptanib or Macugen [34] for the treatment of age-related macular degeneration. Liposomal verteporfin (Visudyne) is also reported for wet macular degeneration[35,3].
NPDDS (polymeric NPs, nanogels, liposomes, micelles, dendrimers, chitosan and protein NPs) are so far used in several ophthalmic diseases like diabetic retinopathy, retinoblastoma, and retinitis pigmentosa. Nanodiamond with drug (timolol maleate) embedded in contact lenses has been used to treat glaucoma [5].
Qaddoumi et al. suggested that PLGA-based NPDDSs could be used for enhancing drug absorption in the eye and the controlled release of proteins and drugs. Few ocular applications have proved to be very novel approaches involving periocular routes for retinal drug delivery of Celecoxib and Aldose reductose inhibitors [36].
Salgueiro et al. showed ophthalmic application of cyclophosphamide-loaded polybutylcyanoacrylate (PBCA) nanosphere as an immunosuppressive agent. The average particle size and polydisparity index indicates that they are fit for ophthalmic application without induced corneal or conjunctival irritation [37].
A contact lens is an optical device, usually intended for vision correction, positioned over the cornea in such a way that it remains on the surface of the eye during blinking; and can be exploited as potential drug delivery device[82]. It consists of curved plastic discs, which stick to corneal tear film owing to their surface tension. These can be classified into two categories: soft contact lenses consisting of polymers of hydroxyethyl methacrylate (pHEMA) and rigid contact lenses mainly consisting of poly (methyl methacrylate) (PMMA). According to FDA, contact lenses are classified as hydrophilic and hydrophobic. Due to their ability to hold water, hydrophilic contact lenses can be used for a longer time (up to 6 nights and 7 days). It is necessary to increase their gaseous permeability for their continuous use during closed eye. This can be achieved by stemmed silicone contact lenses, allowing their continued use for 30 days without risk of ocular hypoxia[83].
Therapeutic contact lenses consist of soft lenses formed of pHEMA polymeric matrices with or without silicone, incorporated with drugs using various techniques: immersing in a drug solution, colloidal particle-laden, molecular imprinting, ion ligands, or microemulsion-loaded gels [84]. The mechanism of action of these systems includes drug diffusion (owing to a concentration gradient) into tear film followed by dispersion in tear fluid (post lens) and subsequent absorption by the cornea. Due to constant drug absorption through the cornea, concentration in postlens tear fluid remains lower than the concentration in the contact lens. This is called the sink effect. This results in enhanced drug retention, about 30min, on the corneal surface and bioavailability increases. It offers several advantages such as a reduction of drug-level fluctuations and in the dose administered. Moreover, it reduces demand for the addition of permeation/penetration enhancers and preservatives commonly used in multidose eye drops (which usually elicit ocular irritation). Key parameters in their design are lens thickness, central posterior curve, polymer type, lens diameter, and water content [82]. Oxygen permeability is an important factor while designing contact lenses. The oxygen permeability of the contact lens polymer can be determined by Dk [(cm2/s) {mL O2/(mL mm Hg)}] value, which is the product of D (the oxygen diffusion coefficient, cm2/s) and k (the oxygen solubility of the lens, mL O2/(mL mm Hg). There is a proportional relationship between Dk value and oxygen permeability [85]. Dk values greater than 20 under open-eye conditions or greater than 75 during periods of prolonged eyelid closure are considered adequate to avert corneal hypoxia or edema. The initial studies were based on the “soak and release” method, which consists of dipping lenses in eye drop solutions followed by drug uptake and its subsequent release into the postlens tear film. But this method has several drawbacks such as low affinity for most ocular drugs. If the affinity is too high, the drug will not release and if the affinity is too low, the drug will quickly release from contact lenses, attaining peak concentration in the eye followed by a sharp decline; ultimately therapeutic levels are not achieved. The affinity of contact lenses for a drug depends on the molecular weight of the drug, which for values between 300 and 500 Da is released in order of minutes to hours [86,87].
Molecular imprinting is a recent and promising preparation method. It involves the utilization of template drug and functional monomers during the polymerization process which leads to the generation of macromolecular memory sites with suitable size and chemical groups to stably accommodate drugs [88]. The molecularly imprinted pockets imitate drug's receptors and its structurally similar analogs, therefore augmenting drug loading capacity meanwhile assuring an adequate release rate. Drug affinity greatly depends on the kind of functional monomers used and their ratio in the polymeric matrix. Drug release patterns can be altered by monitoring monomer composition as well as diversity and the number of interactions at the recognition site. Lower crosslinker concentrations are preferred for the preparation of contact lenses. Degree of crosslinking directly affects the stability of the imprinted cavity, hydrogel transparency, and optical performance, as well as flexibility and water content. Translucence/reduced transparency and lack of flexibility are not at all desirable as it hinders vision and causes discomfort. Similarly, diminished water content results in insufficient oxygen dissolution and diffusion on the corneal surface [89].
Medicated contact lenses with nanoparticles incorporated into it during the production stage increase drug loading capacity. Lipid-based nanoformulations such as microemulsions and liposomes can be incorporated into a contact lens matrix which gives them thermodynamic stability and high drug loading capacity. Both hydrophilic and hydrophobic drugs can be incorporated into it. On the other hand, it is necessary to control the amount of nanoformulation enclosed in contact lens matrix such that it retains higher loading capacity keeping transparency uncompromised [87].
Contact lenses have to present controllable zero-order release profiles with no burst drug release, and drug concentration has to be sustained at maximum safe concentration and at minimum effective concentration in tear fluid. The shape is also important considering that these can retain transparency and stability during the release of drugs and can maintain an acceptable oxygen and carbon dioxide permeability regarding their thickness [90].
Early and fast diagnosis and evaluation of diseases is gaining momentum in the general public as it is important for maintaining a healthy lifestyle and also helps the patient to check on their diseases. Till now, we have already encountered many biosensors which were either dependent on urine, saliva, blood, skin, fluid discharge, etc. Tear fluid is not only helpful in ocular diseases, but also for checking for diabetes and cancers. It is only because of its noninvasiveness and least complexity. Ocular-based biosensors function by observing the alterations in the analytes in tear discharge, which in turn helps to determine the progress of the disease. Tear discharge is highly enriched with proteins similar to blood [58]. Because of this similarity between tear discharge and blood, biosensors are developed which specifically target analytes only within the tear. Contact lenses are not only meant to embellish the eyes with different beautiful colors but also give an open platform for addressing to ocular issues and for their diagnosis. They have been successfully affiliated with the management and maintenance of diseases such as diabetes and glaucoma [59]. The popularity of lacrimal contact lens biosensors is so high that big companies, Google and Novartis, started a new line of contact lens biosensors for diabetes regulation [60]. Apart from eyes, there are many biosensor systems which have been exclusively developed for skin-related problems.
TV commercials often advertise that one must leave the house by first applying a thick layer of sunblock or sunscreen, or there are also advertisements for dry skin which usually is experienced in the winters. No matter what the season, one must always take good care of their skin. There is an adage which goes like Beauty is Skin deep!, where the literal meaning refers to the fact that external beauty is not worthy enough when compared to one’s inner beauty and serenity. A good healthy skin shows ones good and healthy lifestyle. UV radiations from the sun can harshly damage our skin leading to some very serious problems such as carcinomas, melanomas, skin patch and patterns, hyperpigmentation, etc. In order to prevent such skin problems, many researchers have amalgamated immunological analyses with artificial neural networking (ANN), deep convulsional neural networking (DCNN), and various other machine learning approaches. Schmidt and Zillikens [61] postulated a skin diseases detection system based on the study of autoantibodies and mucous membranes by the employing immunofluorescence (IF) microscopy. Esteva et al. [62] gave a deep learning approach in order to classify skin lesions, while, on the other hand, Codella et al. [63] proposed a method for skin cancer detection which was also based on deep learning strategy. A latest smart biosensor system has been developed by Połap et al. [64] which includes a homely-based smart camera which captures images of the skin and hunts for any severely damaged skin alterations using a key point search strategy. Once the image gets clustered as per their locations, the chosen clusters are forwarded to the neural network model which then analyses them for skin features. This biosensor system is simple and dynamic in nature. It can give the slightest skin changes as outputs on the connected device the user chooses. The outputs of this model have accuracy rates of around 80%–82.4%.
Conventional hydrogel materials were not thought to need any surface modification, due to their inherent hydrophilicity. However, it was found that specific bulk lens material side chain moieties could impart enhanced surface properties (see Box 4). This finding encouraged the industry to develop materials with surface active side groups, surface modifying endcaps or interpenetrating networks, which not only increase surface hydrophilicity, but also attempt to direct the tear fluid/lens surface interactions for increased biocompatibility and decreased biofouling (Portoles et al., 1993). Omafilcon A (Proclear) lenses contain a hydrophilic methacrylate monomer with a zwitterion side group modeled after the phosphatidyl choline head-group (Figure A.4). This charged side group preferentially holds water to the lens surface, and was the first material to be approved by the FDA for use in patients with dry eyes.
Box 4
Effect of contact lens surface structure on biocompatibility
In the mid-1980s, Vistakon developed Etafilcon A (a PHEMA-based lens polymer with 3% methacrylic acid) as a daily wear lens. Initial in vivo wear showed a high percentage of protein adsorbing to the lens surface; however, the lenses also had a significantly decreased rate of infections compared to other lenses on the market. Investigation into the situation revealed that the pendant carboxyl groups of the methacrylic acid monomers imparted a negative charge to the lens surface. This charged surface preferentially adsorbed lysozyme, a small, positively-charged protein in the tear film with antibacterial properties (Boles et al., 1992). The coating of adsorbed lysozyme induced antibacterial properties to the surface and ultimately increased the lens biocompatibility and usefulness.
The first silicone hydrogel materials to market in 1998 were surface treated with high energy gases or plasma treatments with gas mixtures (see Chapter I.2.12) to modify the surfaces without affecting the bulk material properties. Balafilcon A (Pure Vision), for example, is plasma oxidized, which causes glassy, silicate islands to form on the surface. These islands create bridges crossing over the hydrophobic balafilcon regions. The balafilcon regions that are left exposed may also be modified and have lower hydrophobicity. Furthermore, these islands are separated from each other to a degree that allows the lens material to maintain its flexibility. Lotrifilcon A & B (Night ’n Day & O2 Optix), on the other hand, use a plasma coating (deposition) to combat the hydrophobicity. This treatment uniformly coats the lens surface with a 25 nm thick hydrophilic polymer produced by using glass plasma (Sweeney, 2004). Both resultant balafilcon and lotrafilcon lens surfaces have low molecular mobility, which minimizes the migration of hydrophobic silcone moieties to the surface. However, the lack of chain mobility also increases the lens modulus, creating “stiffer”materials.
Vistakon skirted the plasma treatment issues by developing silicone hydrogel materials with internal wetting agents. Galyfilcon A (Acuvue Advance) and senofilcon A (Acuvue Oasys) both use poly(N-vinyl pyrrolidone)(PVP) as an internal wetting agent which is preferentially associated with the material surface. Galyfilcon A was released as the precursor to an extended wear version, senofilcon A. Both materials are based on copolymerization of a hydrophilic variant of TRIS, HEMA, DMA, and a siloxy macromer. The incorporation of PVP into the lens produces a wettable, lubricious surface without subsequent surface treatment. Galyfilcon A lenses also have PVP in their packing solution. For senofilcon A, the PVP is incorporated as polymeric end-caps that preferentially migrate to the lens surface (McCabe et al., 2004). The results of these formulations are materials with increased surface hydrophilicity and markedly lower modulus (Table A.1).
Comfilcon A, Bioinfinity, is one of the highest water content silicone hydrogel materials (EWC = 48%), and has no surface treatment or internal wetting agent. The first marketed material produced without the use of the TRIS monomer or its variants, comfilcon is produced by polymerization of two siloxy macromers of different sizes, one of which has only one vinyl polymerization site, as well as vinyl amides such as n-methyl-n-vinyl acetamide. Comfilcon A’s unexpectedly high Dk, considering its water content, is attributed to its longer siloxane chains.
In situ forming gels can be also influenced by ionic strength, because polymers undergo their phase transitions as a result of different concentration of salts (e.g., ionic strength). For example, gellan gum is one of the most promising in situ gelling polymers in the human body and applicable for biomedicine technology, such as drug delivery vehicles and protein immobilization media [41]. Gellan gum is an anionic, exocellular, deacetylated bacterial polysaccharide secreted by Sphingomonas paucimobilis (formerly known as Pseudomonas elodea) with a tetrasaccharide repeating unit of 1β-l-rhamnose, 1β-d-glucuronic acid, and 2β-d-glucose. The mechanism of gelation involves the formation of double-helical junction zones followed by aggregation of the double-helical segments to form a three-dimensional (3D) network by complexation with cations and hydrogen bonding with water. This mechanism depends on the nature of cations. Divalent cations promote the gelation much more effectively than the monovalent ones. When gellan gum is dispersed in aqueous solutions it undergoes a liquid-gel transition under the influence of an increase in ionic strength [41, 42]. This behavior was exploited by Salunke and Patil, who developed mucoadhesive in situ gels of salbutamol sulfate using gellan gum and hydroxypropyl methyl cellulose for nasal administration. They evaluated the gelation in a simulated nasal fluid and observed that all the gellan gum formulations showed immediate gelation (low viscosity polymeric dispersions undergoes rapid sol-gel transition) within a period of 10–15 s, depending on the concentration of gellan gum used [42]. Cao et al. prepared a novel in situ gel system for nasal delivery of mometasone furoate and studying its efficacy on allergic rhinitis model. Gellan gum was used as ion-activated in situ gel carrier. They observed that the formulation showed adequate viscosity for easy spray as a liquid, which then undergoes a rapid sol-gel transition due to ionic interaction with artificial nasal fluid. The animal experiment suggested that mometasone furoate in situ gel could be more effective than the nasal suspension in the treatment of allergic rhinitis [41].
This polysaccharide has also been used for ophthalmic purposes. For example, Sun and Zhou developed a sustained ocular delivery of brinzolamide based on gellan gum. The prepared liquid formulation was converted into a flowing gel after the addition of simulated tear fluid and in vitro release profiles showed that the release of brinzolamide from the in situ gel exhibited sustained characteristics [43]. Adeyeye’s group developed and characterized an ion-activated in situ gel-forming estradiol solution eye drops intended for the prevention of age-related cataracts. Gellan gum was used as ion-activated gel-forming polymer. The solution eye drops resulted in an in situ phase change to gel state when mixed with simulated tear fluid, and the gel structure formation was confirmed by viscoelastic measurements. The estradiol release from the gel was controlled and followed non-Fickian mechanism [44]. Li’s group studied an ion-activated ketotifen ophthalmic delivery system developed by using deacetylase gellan gum. The formulation showed an optimum viscosity that would allow easy drop as a liquid, which then underwent a rapid sol-gel transition due to ionic interaction with artificial tears. The in vitro release profiles indicated that the release of ketotifen from in situ gels exhibited a sustained feature and scintigraphic studies indicated that deacetylase gellan gum could increase the residence time of the formulation. At the same dose, in situ gels demonstrated a typical sustained and prolonged drug-effect behavior compared with the conventional drops [45].
On the other hand, carrageenan is other type of polymers with similar features to gellan gum regarding their gelling properties. Carrageenan is the generic name for a family of high molecular weight sulfated linear polysaccharides of d-galactose and 3, 6-anhydro-d-galactose obtained by the extraction of certain red seaweeds of the different species of Rhodophyta, such as Chondrus, Eucheuma, Gigartina, and Hypnea. These polysaccharides can be traditionally split into six basic forms: Kappa (κ)-, Iota (τ)-, Lambda (λ)-, Mu (μ)-, Nu (ν)-, and Theta (θ)-carrageenan. Based on their physicochemical properties, κ- and τ-carrageenan can form gel easily, especially in the presence of monovalent and divalent ions [46]. Attwood’s group prepared carrageenan gels loaded with acetaminophen. They observed that τ-carrageenan showed suitable rheological and sustained release characteristics for potential use as vehicles for oral delivery of drugs to dysphagic patients and children [47]. In addition, incorporation of magnetic nanoparticles into polysaccharide hydrogels has also been explored to provide novel functions valuable for specific biomedical applications. As an example, using in situ gelling method, silver and magnetite nanofillers were synthesized in modified κ-carrageenan hydrogels and demonstrated that the drug release in intestine was improved by metallic nanocomposites hydrogels, with limited drug release in stomach [48].
Moreover, gels based on the combination of carrageenan and other polymers have been increasingly evaluated for several routes of administration, particularly in topical drug delivery. For instance, Aguiar’s group comparatively evaluated the rat corneal residence time of a topical ophthalmic formulation containing gellan gum and κ-carrageenan labeled with a radiotracer with respect to an aqueous solution. They observed that ophthalmic hydrogel developed with κ-carrageenan and gellan gum remains for long periods of time on the corneal surface [49].
Alginate is a biomaterial that has found numerous applications in biomedical science and engineering due to its favorable properties, including biocompatibility and ease of gelation [50]. Alginate is a naturally occurring anionic polymer typically extracted from brown algae (Phaeophyceae), including Laminaria hyperborea, Laminaria digitata, Laminaria japonica, Ascophyllum nodosum, and Macrocystis pyrifera[51]. Alginate is a particularly attractive naturally derived ion-responsive polysaccharide, which has been studied widely for its biocompatibility, biodegradability, and reversible aqueous gelation chemistry with di- or trivalent cation. Zhou et al. prepared covalently cross-linked methacrylate-modified alginate hydrogels using high internal phase emulsions to produce highly interconnected porous materials. The highly porous and biocompatible hydrogels showed controllable ion-responsive feature and well-controlled pore morphology, exhibiting promising properties as scaffolds for soft tissue engineering [52].
Combinations of alginate with other molecules have also been studied. Mittal and Kaur evaluated brimonidine tartrate-loaded formulations based on pectin alone or in combination with sodium alginate or a pectin derivative (thiolated pectin) alone or in combination with sodium alginate for in situ gelling eye drops. They observed that thiolation of pectin produced an increase in the gelling behavior, viscosity, and bioadhesive strength of developed formulations. All formulations demonstrated good in vitro release characteristics and those containing pectin displayed a significant decrease in the intraocular pressure compared to the marketed formulation upon instillation in rabbit eye [53].
Ionic strength can also affect the rate of drug release from hydroxypropyl methylcellulose (HPMC) matrices. Asare-Addo et al. studied the effects of ionic strength on theophylline release from HPMC matrix tablets. The ionic concentration strength of the media was varied over a range of 0–0.4 M to simulate the gastrointestinal fed and fasted states and various physiological pH conditions. The results indicated ionic concentration had a significant effect on the release pattern of K100LV matrices. They observed that as the ionic strength increased, the amount of theophylline released also increased (from 28% in water to 48% in the medium with ionic strength of 0.49 M) [54]. This research group also studied HPMC tablets loaded with hydrochlorothiazide or diltiazem HCl. In a similar way, the results showed that the ionic strength had a profound effect on the drug release from the diltiazem HCl K100LV matrices. However, the release of hydrochlorothiazide from tablet matrices showed similarity to all the ionic strength tested [55].
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