DESCRI PTI ON

A CONTACT LENS DESI GN SENSI NG TEAR GLUCOSE LEVEL Technical Field

The invention is intended for patients with diabetes, and relates to a type of contact lens by means of which tear glucose level is monitored thanks to a biosensor disposed thereon.

Prior Art

Diabetes mellitus is a metabolic disorder which takes place due to genetic and environmental factors combined, and results in an excessive increase in blood glucose levels (i.e. hyperglycemia). If not under control, Diabetes mellitus is one of the major causes of morbidity/mortality. It is essential that blood glucose levels are followed up closely in order to prevent diabetes-related complications. To that end, it is suggested for diabetic patients to monitor blood glucose levels by drawing blood from the finger tip (i.e. finger-stick procedure) about five times a day. A patient performing blood glucose level monitoring by finger-sticking technique five times a day has to pierce his/her finger tip 1800 times annually. This obligation, in turn, causes fears in the patients, at the same time bearing a risk of disorders and possible infections. The inconveniences and risks of said method resulting from blood drawing lead to a decrease in patient compliance with the treatment and inability to achieve continuous patient monitoring. Moreover, this method means an annual cost of about 1300 Turkish Liras in average for a patient in Turkey. As a result of these, it becomes difficult to monitor blood glucose levels of the patients and patient compliance decreases at a percent up to 67% (1). More than 1.1 million undertreated Diabetes mellitus- related death incidents have been reported in 2005 and said figure is expected to double by 2030 (2).

The glucose level in tear rises in direct proportion to blood glucose level. Contact lens application is intended for estimating blood glucose level by tear glucose level determination and such contact lens designs exist in the state of the art. The existing contact lenses capable of determining glucose level comprise electrochemical, crystalline colloidal array, holographic, or fluorescence emitting biosensors applied on the contact lens (3). In all of the previously developed contact lens designs, the patient tries to perform instant determination of reaction on 1-2 sensors on the lens by means of a separate device in order to be able to measure said value. All of these methods require a secondary external device for tear glucose level determination, and thus blood glucose level estimation. Said secondary device may be an electrical circuit, a smartphone camera, or a handheld fluorophotometer. Although these methods provide noninvasive blood glucose level monitoring without requiring blood collection, they fail to provide continuous patient monitoring since an external device is needed for performing measurement.

In the state of the art, there exist no contact lens sensing designs in which boronic acid fluorophores and azobenzene derivatives and/or metal-induced fluorescence / luminescence enhancement methods are used in combination and a homogeneous distribution on the contact lens is provided. The metal-induced fluorescence / luminescence enhancement technique with metal particles has been recently used particularly in laboratory imaging in healthcare field, due to upgradeability thereof to detectable levels without an intermediate device, and to the fact that weak and infrared wavelength fluorescence can be transformed into visible light wavelength (4).

Summary of the I nvention

The contact lens design according to the invention performs blood glucose level monitoring, thereby allowing a non-invasive blood glucose level monitoring. Hence, there is no longer any need to perform measurement by finger-sticking in order to be able to understand whether blood glucose level has increased or not. In addition, unlike the existing contact lens designs, the present invention is capable of giving signal itself once the tear glucose level exceeds a certain threshold value, without requiring the use of a separate external device for measurement. As said signal is given in the form of a visible wavelength color, continuous blood glucose level monitoring is achieved by a change in the color with which the patient sees the world and / or a change in the color of the pupils of the patients is visible from outside.

The aim of the contact lens design according to the invention is not to estimate and monitor blood glucose level by way of exact tear glucose level determination, but to produce the contact lens in a way to give a signal of hyperglycemia, and thus the patient draws blood sample only when necessary (in case of hyperglycemia when the contact lens "signals") and perform exact glucose level determination, and to plan precise treatment accordingly.

Although the present contact lens does not totally eliminate the need for blood glucose level determination by finger-sticking procedure, it reduces the necessity of blood drawing, as well as decreasing the number of finger prickling procedure performed. It is particularly useful for the patients, whose compliance with the treatment is reduced due to the inconvenience of drawing blood repetitively during the day, thereby increasing patient compliance. Moreover, it makes non- invasive and continuous blood sugar monitoring of diabetic patients possible. This will have two important effects economically. First of all, the need for blood drawing and blood glucose level measurement systems, which are costly, will be decreased. Only when the patients receive a signal regarding a possible increase in blood glucose level from the contact lens that they are wearing, will they apply blood glucose level determination for therapeutic purposes. Second of all, it will be ensured that long-term multi-system diabetes complications in the body (e.g. neuropathy, nephropathy, retinopathy etc) resulting from undetectable increases in blood glucose level is prevented, and thus morbidity and mortality associated therewith is reduced or eliminated, at the same time reducing labor losses experienced by the patients and their caregivers. Additionally, eye-glasses numbers of the patients, either shortsighted or farsighted, will be adjusted thanks to the present product.

Description of the Drawings

Fig. 1 : Schematic view of the newly designed contact lens. Boronic acid- containing fluorophore / azobenzene dye, positioned around metal particles or in the close vicinity thereof (<10 nm) if needed, is applied to the entire inner (or outer) surface of the lens as a film layer or will be embedded into the polymer matrix of the contact lens material. Main difference from previous contact lens designs of the same purpose is that the sensor is almost homogeneously present all over the lens and the lens reacts as a whole, instantly and spontaneously that the reaction is evident for the patient / from outside as a color change. The biosensor may not be applied in the centre of the pupil, the visual axis, in a ~3 mm diameter area, or said biosensor may be less frequently applied in this region, in order that the density of metal particles will not affect the sight of the patient.

Detailed Description of the I nvention

I ntroduction

The invention relates to a contact lens design intended for patients with diabetes. In the present invention, thanks to the biosensors disposed on the lens, the changes in glucose level can be monitored continuously and without any outside intervention.

It is known that boronic acid-containing fluorophores react with glucose and other carbohydrates of saccharide group, exhibiting high affinity, and that they emit fluorescence. However, the fluorescence emitted is not at a visible wavelength or level, and so the emitted fluorescence needs to be increased by stimulating with an external fluorophotometer to be able to detect it. It is also known that boronic acid-containing azobenzene derivative dyes, when combined with the glucose, also exhibit color changes at visible wavelength spectrum, and yet the concentration of glucose must reach levels as high as 100 mM in order for said fluorescence to be revealed (5). Metal-induced fluorescence enhancement (MIFE) technique is based on the principle that metal particles that will increase fluorescence are positioned in the close vicinity of fluorophore (<10 nm). To that end, metals such as gold (Au) and silver (Ag), which do not damage the eye, and even have some antiseptic properties, are used. By means of this technique, the fluorescence or color change emitted by boronic acid-containing fluorophores or azobenzene derivatives upon reacting with glucose can be increased (6). When applied to the contact lens, this method leads to a change in the color of the contact lens in the presence of high concentration glucose; thus, the patients themselves or their relatives are given a warning signal with a change in the color with which the patient visions the world or a change in the color of the pupils of the patients visible from the outside.

Detailed Technological Description

Boronic acid derivatives, reversible glucose affinity of which is high in aqueous (liquid) medium, serve as a glucose biosensor on the contact lens (7,8). Boronic acid derivatives are free of the disadvantages of toxicity or in vivo instability.

By using boronic acid-containing molecules as glucose sensor, the changes in the fluorescence emitted by the boronic acid-containing fluorophores, or in the color (colorimetry) in the presence of glucose using azobenzene dyes matched with boronic acid can be detected, as a result of glucose-boronic acid reaction. The common problem regarding these two approaches is that the emitted fluorescence/colorimetry is not so intense to be observed from the outside, or that they require much higher glucose concentrations than already present in tear for a detectable fluorescence / colorimetry. The resulting fluorescence / colorimetry is required to be made intense enough to be self-detectable in visible light wavelength with a view to overcome the aforementioned problem. To that end, at least three methods can be developed making use of metal particles.

It is possible, thanks to the metal particles positioned in the close vicinity of the boronic acid-containing sensor molecule (<10 nm), to increase the fluorescence provided by fluorophores by means of metal induced florescence enhancement (MIFE) technique, or to increase the colorimetry provided by colorimetric sensors. MIFE phenomenon occurs when fluorescence properties are changed [a dramatic increase in fluorescence intensity (quantum gain), the half-life of fluorescence becoming shorter, and thus achieving an increase in photo- resistance] by non-radiation-related matching of fluorophore dipole with electron cloud of metal (surface plasmons) (9-15). Only when positioned at a wavelength distance (5 - 50 nm, typically <10 nm) where metal is released with fluorophore, can MIFE be exposed; in contrast, the metal particles positioned at a further distance have no effect on fluorescence properties of fluorophore. MIFE can be achieved by metals such as gold, silver, copper, nickel, and tin (10, 11). Compared to gold (Au) particles, silver (Ag) particles have a higher efficiency of scattering fluorescence upon facing with a stimulant with the same wavelength (16); therefore, silver island films (SIFs) on glass or plastic surface are frequently preferred, the methodologies regarding the preparation thereof are available in literature in detail (11). MIFE works not only on glass- or silica-based surfaces, but also on modified plastic (i.e. treated polycarbonate) surfaces with a thickness of «50 μιτι. It is assumed that it will also work when applied on (silicone) hydrogel-based soft contact lenses.

First Method

( Boronic acid-containing fluorophore + Ml FE)

A boronic acid-containing fluorophore absorbs radiation at a certain wavelength, followed by releasing a photon with a lower energy (with longer wavelength). Since the stimulation and release photon wavelengths of the fluorescence is dependent on the chemical composition thereof, fluorescence is a molecule- specific sensing mode (17). Boronic acid-containing fluorophores have high glucose affinity and specificity.

Fluorescence dyes give signal via various mechanisms (for example, photo- induced electron transfer (PET), internal charge transfer (ICT), Forster resonance energy transfer (FRET)) (18). With the most frequently used FRET technique, the energy is distributed from the transmitting fluorophore to the receiving fluorophore in a distance-dependent manner (19). Contact lenses with glucose sensing property based on the fluorescence emitted by fluorophores have been dependent on fluorophore stimulation and fluorescence measurement performed by means of a handheld separate instrument so far (3). MIFE technique can be employed so that the fluorescence emitted upon the contact of boronic acid- containing fluorophores with glucose can be visible without requiring the use of a separate device like a fluorophotometer. For this, when metal particles are applied on the contact lens as a film layer in the close vicinity of fluorophore (5- 50 nm), a reaction visible from the outside may occur in case of contact with the tear and emission of fluorescence with high glucose concentration. A self- inducible boronic acid-containing fluorophore which emits fluorescence at a wavelength and density visible from the outside can serve as a biosensor on the contact lens.

In case the emitted fluorescence does not have a visible light wavelength spectrum, up-converting phosphors (UCPs) can also be utilized in order to bring the wavelength to a visible light range. These phosphors transfers low-energy infrared (IR) radiation to high-energy visible light (3). This is achieved thereby due to a higher energy, shorter wavelength energy release, with the absorption of a number of photons, and then dopant-dependent phosphorescence (20). The most efficient known up-converting substances are NaYF4/Er3Yb and NaYF4/Tm3Yb, which release red and green light upon stimulation at 980 nm (21). Among these phosphors, the non-risky ones in terms of nanotoxicology can be used for bringing the wavelength of the fluorescence to a visible light range.

Second Method

(Azobenzene Dyes that contain boronic acid + metal particles)

It has been shown that said dyes significantly change color due to the sensitivity of these dyes to glucose, wherein said dyes are obtained by the addition of boronic acid to the oposition of the azo group (5, 22-24). The B-N point connection between the azo groups and the boronic acid belonging to a colorimetric sensor carries out a significant shift to red during maximum absorption, and following the addition of glucose to the medium this connection is broken and a significant color change occurs. It is possible to apply these obtained dyes, onto solid surfaces also, such as multi layer films by means of their electrostatic interactions due to their electrical loads (5). However this significant color change on said sensors have been indicated on high sugar concentrations up to ΙΟΟηΜ and it seems that an additional reaction is required to obtain a significant color change in tear glucose levels. Therefore it is possible to increase the luminescence provided by colorimetric sensors comprising azo benzene matched with boronic acid by means of metal particles placed in close vicinity and to increase the luminescence to a visible level even under low glucose concentrations found in tears. It can be enabled for boronic acid part to be bound to a glucose molecule by applying a supra molecular chemical strategy in order to increase the sensitivity of the sensor against glucose and to increase specificity and to reduce the sensor's affinity against sugar groups such as fructose.

Third Method

( Boronic acid derivative + metal particles)

Boronic acid derivatives are directly matched with inorganic nanoparticles (Without using a fluorophore or azo benzene dye) (25). Especially metal nano- particles, allow the fabrication of bio-sensors which show adjustable color/shade changes in changing concentrations of glucose having size/shape dependent spectroscopic characteristics (26-28). For example, phenyl boronic acid modified silver nanoparticles can function as continuous glucose sensors. A response dose in glucose concentrations between 0-20 nM concentration at 7.4 (physiological pH) can be adjusted for the silver nanoparticles coated with a molecule (i.e., 4- ((2-borono-4-phluorophenyl)amino)-3-mercapto-4-oxobutanoic acid) which is a phenylboronic acid group having high glucose determination ability and a thiol group having high silver binding ability, and said nanoparticles may function as a sensitive (having a threshold value of 89.0 μΜ) and specific colorimetric sensor (6). The synthesis of fluorophenyl boronic acid modified silver nano-particles, has been described in detail in the literature (6, 29).

Other optical saccharide sensors have also been developed which provide the absorption range to shift to shorter wavelengths and for the dye to change color due to the steric effects created when boronic acids and glucose come together. These polymers comprising amino acids such as poli(L- and D-lysine) besides boronic acid can also be used as colorimetric sensors (30-32). In the case that the obtained colorimetric change is at a level which can be detected on its own in tear glucose concentrations, these compounds also can be used as colorimetric sensors on the contact lens.

Several studies have been carried out in literature regarding all of the methods that have been mentioned until now in this text as an optical glucose biosensor (1-32). However none of these techniques describe a method regarding the application of a colorimetric contact lens as a biosensor which changes color and which provides a signal without the requirement of another measurement device.

Contact lens production

The designed contact lens has a silicone hydrogel (balafilcon, lortafilcon, sifilcon, comfilcon, galyfilcon, senofilcon etc.) structure and its oxygen transmission is planned to be high (min/t>70) and its water content to be between 25-50%. The biosensor film layer applied on the surface of a lens or embedded in the polymer material, can somewhat effect the oxygen transmissivity of a product, however the transmissivity will not be reduced to the level of hydrogel contact lenses without silicone (min/t «25).

Our contact lens can be produced using turning (Lathe-Cutting), casting (Spin- casting) or molding (Cast-molding) techniques having a plurality of basic curve and diameter parameters and our biosensor shall be preferably embedded into the hydrogel matrix (substance) of the contact lens or applied to the "entire" front / back surface. In the turning (Lathe-Cutting) technique, a polymerized soft contact lens material which has been dehydrated is turned on a cylindrical disk at a speed of 10000 RPM and the desired amount of material is removed from the disc and following this the material is polished (EP 2643152 ΑΪ). This production technique is difficult and expensive. In the casting (Spin-casting) process, a concave mould and the front surface of the lens is established. According to this technique three basic steps are used: i) heating the mould and applying a monomer mixture onto the mould, ii) the lens is spun at a speed higher than 600RPM and the back surface is formed by centric forces and the lens is dried with UV rays or heat, iii) the lens is dipped into an aqueous solution and it expands and is separated from the mould (WO 031400 A2). According to this method, lenses with comfortable edges can be produced, however these lenses carry decentralization risks. In the molding (Cast-molding) technique, the front and rear surfaces of lenses are provided by means of concave and convex moulds. A monomer solution is placed between these two mould and the moulds are dried with UV rays or a thermal process (EP 2643152 ΑΪ). This method provides feasible production and lower costs.

The bio-sensor which is our design can be embedded directly to the polymeric material of the contact lens, or applied on the surface by techniques such as the layer-layer sequenced adsorption (5) of polyelectrolytes by means of electrostatic interaction on the silicone hydrogel contact lens which is produced by means of one of the three techniques or polyvinyl alcohol multi layered films and phenyl boronic acid derivatives. The final contact lens containing the biosensor might produce reversible or irreversible reaction and signaling with the glucose. That is to say, the color change of the contact lens upon reacting with glucose might be reversible preferably (i.e., when blood and tear glucose levels decrease, the color fades away and the contact lens is almost colorless and transparent again); or irreversibly (i.e., patient has to replace the contact lens when it changes color as a result of increased tear glucose concentration). Moreover, as this product will be produced using one of the standard contact lens production techniques, it can also correct the refraction deficiency (diopter value) which the patients may be in need of correction. The basic characteristics of this contact lens have been listed below:

• When the tear glucose level is approximately >6,25-7.0 mg/dl, (blood glucose level > 125-140 mg/dl), a signal is provided with a color change between 380 - 720 nm which can be perceived on its own, and a color change occurs preferably at a linear scale proportional with the glucose concentration.

· This reaction is carried out without the need to be stimulated with another external device, and said reaction can be determined without the need to carry out a measurement with a separate device.

• The change in color in the lens created by the increase in the tear glucose level is at such that the daily life of the patient shall not be disrupted acutely (the color scale can be titrated), and the patient can both track the color change with his/her own eye and the change can be observed from the outside as the change of color in the pupil. • These biosensors are 90% repeatable at each glucose concentration, 85% precise, 90% sensitive, have 85% specificity even in the presence of other saccharides such as fructose, and their response time is short (<30 sec).

• The biosensors do not affect the chemical structure of the contact lens material, oxygen permeability, modulus, water content and optical force (to be tested in the lens production facility).

• This reaction on the contact lens is preferably recyclable (reversible); in other words when the tear glucose concentration returns back to normal or when the lens is cleaned with lens disinfection systems it returns to its original color. If it cannot be recyclable, then disposable lenses (single use) will be produced.

• The biosensor is not dissolved in the tear significantly that might lead absorption of the biosensor elements by the ocular surface or the lymphatics.

• It does not cause eye irritation, and the glucose concentration does not change due to tear release based on reflexes.

· It does not have a toxic effect to the eye surface (cornea and conjunctiva) and nano-toxicology tests are negative.

• Its shelf life is long and it is resistant to heat changes and it is sterile.

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