A method and apparatus for measuring a property of tear film

TECHNICAL FIELD OF THE INVENTION

The invention relates to tear fluid that is found in or on the eye of a subject, and in particular relates to a method and apparatus for measuring a property of a tear film of the tear fluid.

BACKGROUND TO THE INVENTION

Tear fluid in the eye of a subject (for instance an animal, a mammal, a human) is a result of lacrimation (i.e. the process of tear secretion) that is driven by lacrimal glands, the accessory lacrimal glands and goblet cells of the conjunctiva, coupled with some fluid permeating from corneal and conjunctival tissue. Tear film stability has been proposed as an important early indicator of various conditions. In particular, changes in the tear film dynamics, i.e., variation in the composition of the tear film and its mechanical properties as related to that chemical composition may have diagnostic significance for several diseases and medical conditions, including, among others: dry-eye, corporeal dehydration, diabetes, rheumatoid arthritis, lupus, scleroderma, Sjogren's syndrome, thyroid disorders and vitamin A deficiency.

Tear fluid plays a vital role in protecting the ocular surface from environmental hazards as well as invading pathogens. Tear fluid maintains optimal conditions for ocular health and vision through hydrating and lubricating the ocular surface. Tear fluid is a complex mixture containing soluble and insoluble mucins, proteins and aqueous components covered by a lipid layer.

As shown in Figure 1 which depicts an illustration of the tear film of a subject, tear film 2 is composed of three main layers:

(i) An outer layer 4 called the lipid layer - this layer 4 is typically around 0.1 micro-meter (μιη) thick, and is formed from the secretions of the Meibomian, Zeiss and Moll glands. The outer lipid layer 4 is composed primarily of low polarity lipids (e.g. wax and cholesterol esters) and high polarity lipids (e.g. triglycerides, free fatty acids, phospholipids). Its primary functions are to prevent the overflow of tears and evaporation. (ii) An intermediate aqueous (water) layer 6 - this layer 6 is typically around 7-8 μιη thick, and is formed by secretions from the main and accessory lacrimal glands of Krause and Wolfring. This layer 6 is composed of water, salts, glucose, urea, enzymes, proteins and glycoproteins. Its main functions are to supply oxygen to the corneal epithelium, remove debris and irritants, and to prevent bacterial infections.

(iii) An inner layer 8 called the mucin layer - this layer 8 is typically around 0.2- 0.8 μιη thick, and is formed from secretions from the conjunctival goblet cells, stratified squamous cells of the cornea and conjunctival epithelium. Layer 8 has four principal functions. The mucin layer helps to stabilize the tear film 2, it converts the corneal epithelium from being hydrophobic to hydrophilic, it lubricates the ocular and palpebral surfaces and it creates a slippery coating over foreign bodies, thereby protecting the cornea and conjunctiva from abrasive damage.

The composition of tear film 2 in the eye is regulated in two ways:

(i) Hormonally - Androgens are primarily responsible for regulating lipid production, while oestrogen and progesterone receptors in the conjunctiva and lacrimal gland regulate the normal function of these tissues.

(ii) Neurally - Neural fibers adjacent to the lacrimal gland and goblet cells control aqueous and mucus secretion.

The balance between the three layers 4, 6, 8 of the tear film 2 (e.g., the thickness ratios, the viscosity, the surface energy, the evaporation rate, etc.) has a significant influence of the stability of the tear film 2.

It has been found that analysis of tear film 2 can be used to monitor the body's response to therapeutic drugs (including, but not limited to, drugs applied to the eye) either directly or through their ocular side effects. Among the many therapeutic drugs that can be monitored in this way, one can think of drugs used in the management of various diseases including heart failure and cardiovascular diseases (e.g. diuretics and beta-blockers), psychological disorders such as bi-polar disorder and depression (e.g. tricyclic

antidepressants etc.), inflammation, glaucoma through the detection of therapeutic drugs such as phenobarbital, carbamazepine and Methotrexate, drugs used in chemotherapy, as well as drugs used in the management of respiratory disorders such as emphysema and Chronic Obstructive Pulmonary Disease (COPD) through monitoring a 1 -antitrypsin.

Tear film 2 is also the interface of the eye with the environment; which means that environmental pollutants can have a direct or indirect influence on the tear film stability. It has been found that indoor and ambient air pollutants, such as particulate matter, affect the tear film stability. In particular, it has been found that exposure to dust in an indoor environment can decrease the tear film break up time (TFBUT) compared to exposure to clean air (i.e. the tear film breaks up more quickly when exposed to dust or particulate matter), which implies that dust and particulate matter associated with air pollution causes reduced tear film stability.

Water soluble air pollutants, such as a large variety of gaseous pollutants and water soluble particulate matter (e.g. nitrates, sulphates, sea salt, etc.), directly affect the composition of the tear film 2. For example changing the ionic concentration of the water layer may alter the stability of the lipid layer as a result of the changes in 'wettability'. The water insoluble particles - depending on their dimension and surface properties - can induce mechanical strain along the layers of the tear film 2 and this affects the stability of the tear film 2.

Several methods exist for the assessment of tear film adequacy and stability. These methods include:

1. The Schirmer test - this test is used to determine whether the eye produces enough tear volume to maintain an appropriate moisture level.

2. Tear prism height test - this test is used to measure tear volume.

3. Tear film break-up time (TFBUT) test - this test measures the relative stability of the pre-corneal tear film. The test involves the measurement of the time interval between a subject's last complete blink and the break-up of his or her tear film. Non- invasive tear film break-up time (NITFBUT) methods have been developed that rely on optical techniques. The break-up time of the tear film (quality) can be determined using a non- invasive break-up time (NIBUT) procedure. Changes in the projection of Placido rings on the eye (edge shift of Placido rings) indicate the break-up time of the tear film. This evaluation can be made automatically and the break-up time is represented in color to facilitate subject/patient consultation. Dry patches that break up early can be identified.

4. Tear film evaporation time (TFET) test - this test quantitatively measures tear evaporation from the ocular surface.

5. Vital staining - this test is used to determine the health of the ocular surface. Typically this test is performed using various staining dyes, e.g., fluorescein, rose Bengal, alcian blue, scarlet red, lissamine green, etc., which are administered to the subject's eye in the form of eye drops. The ideal time to measure the presence of staining is approximately 3- 5 minutes after eye drop administration. 6. Tear protein composition test - This test is used to assess the protein content in the tear film to determine if certain components are absent or present. In particular this test focuses on detecting proteins such as lysozyme C, lactoferrin, serotransferrin, serum albumin, and zinc-alpha-2-glycoprotein.

7. Tear osmolarity test - this can be performed via any of three main methods: i) Freezing point depression (a method in which the freezing point of the ocular fluid with high osmolarity is depressed as particle content has increased);

ii) Vapour pressure (a method in which vapour pressure of the ocular fluid with high osmolarity is lower for the same reason that vapour pressure of a solution is lower than the vapour pressure of the pure solvent);

iii) Electrical impedance (Determining the electrical impedance of the ocular fluid leads to a measure of tear osmolarity as decreased water content is reflected in the impedance level).

However, many of the existing methods of tear film adequacy and stability analysis are obtrusive, discontinuous (i.e., require point measurements at certain times), and require in vitro analysis by a highly skilled expert. In addition, many existing methods are limited in their application by the need for larger volumes of tear fluid than are typically found in the eye at any given time.

Methods for the analysis of tears and the physiological condition of the eye (e.g. intra-ocular pressure) using contact lenses have been proposed. For example US

2014/0107445 describes that the electrical properties of the tear fluid can be tracked using a contact lens. The method allows relatively unobtrusive measurements of tear film properties based on electric properties of tear fluid, which can be related to several substances, e.g. glucose.

However, there remains a need for less obtrusive, at least semi-continuous methods of tear fluid analysis which are easy to use in a home or clinical setting, for example in the management of diabetes mellitus and the prediction of diabetic peripheral neuropathy. Many subjects with diabetes show signs of compromised ocular surfaces and recent studies have suggested that detailed ocular surface tests could add significant clinical information which could become an important part of diabetes assessment in the future.

SUMMARY OF THE INVENTION

As noted above, existing methods and techniques for the analysis of tear film or the measurement of properties of tear film, such as properties related to the stability of the tear film, suffer from a number of disadvantages. In particular, there is a general lack of methods for on-demand, semi-continuous or continual tear film stability analysis, a lack of unobtrusive methods of tear film stability analysis which do not require in vitro analysis by a highly skilled expert, a lack of methods that are effective in the presence of tear volumes typically found in the eye, a lack of an objective measurement of the tear film and its properties, and a lack of methods for fast and automated unobtrusive tear film analysis.

The various aspects and embodiments of the invention described herein aim to address one or more (or all) of these disadvantages.

According to a first aspect, there is provided an apparatus for measuring a property of tear film in an eye of a subject, the apparatus comprising a disturbance device configured to cause a disturbance to the tear film in the eye of the subject; and a

measurement device configured to measure the property of the tear film in the eye of the subject following the disturbance to the tear film. By disturbing the tear film using the disturbance device, the measurement of a property of the tear film by the measurement device can be improved.

In some embodiments, the disturbance device is configured to: cause a disturbance to the tear film in the eye to induce blinking by the subject; and/or cause a disturbance to the tear film in the eye to break up the tear film; and/or cause a disturbance to the tear film in the eye to induce tear film secretion.

In some embodiments, the disturbance device is configured to force air or a liquid towards the eye to cause the disturbance to the tear film. In other embodiments, the disturbance device comprises a light source that is configured to illuminate the eye to induce blinking and cause the disturbance to the tear film. In other embodiments, the disturbance device comprises a first contact lens and a light source, wherein the first contact lens is configured to be worn on part of the eye of the subject and to change shape and/or size or wettability in response to light from the light source, and thereby cause the disturbance to the tear film. These embodiments have the advantage that the disturbance can be applied relatively unobtrusively to the subject, and can also be easily applied in a non-clinical setting.

In some embodiments, the measurement device comprises a second contact lens that is configured such that a property of the second contact lens or a change in a property of the second contact lens depends on a property of the tear film or a change in the property of the tear film. In some embodiments, the property of the second contact lens comprises the curvature or rate of change of curvature of the second contact lens, a speed of movement of the second contact lens across the eye, the distortion of a surface of the second contact lens or localized thickness variations. In alternative embodiments, the second contact lens comprises an RF antenna and wherein a property of the RF antenna depends on a property of the tear film, such that a signal transmitted by the RF antenna is variable in dependence on the property of the tear film. In some embodiments, a control unit in the measurement device is configured to receive a signal from the RF antenna in the second contact lens and to determine the property of the tear film from the signal. These

embodiments have the advantage that the tear film property can be measured unobtrusively. It will be appreciated that in embodiments where the disturbance device and the measurement device both comprise a contact lens (the above-mentioned first contact lens and second contact lens respectively), the functions of the first contact lens and the second contact lens can be implemented in a single contact lens (i.e. the first contact lens and the second contact lens are the same contact lens).

In some embodiments, the measurement device comprises an imaging device that is configured to obtain one or more images of the eye following the disturbance and a control unit that is configured to analyze the one or more images to determine the property of the tear film. In some embodiments, the control unit is configured to analyze the one or more images to determine changes in specular reflection from the eye. In some embodiments, the measurement device further comprises a light source for illuminating the eye to enable the imaging device to obtain the one or more images of the eye. These embodiments have the advantage that the tear film property can be measured unobtrusively.

In some embodiments, the property of the tear film comprises any one or more of the stability of the tear film, the tear volume, the thickness of the tear film, a change in the thickness of the tear film, the thickness or relative thickness of one or more layers of the tear film, a change in the thickness or relative thickness of one or more layers of the tear film, the recovery of the tear film following the disturbance, a rheological property of the tear film, the viscosity of the tear film, or the break up of the tear film.

In some embodiments, the apparatus further comprises a processing unit for determining a condition of the subject based on the measured property of the tear film. The condition of the subject can be a health condition, such as a disease or medical condition, including, among others: dry-eye, corporeal dehydration, diabetes, rheumatoid arthritis, lupus, scleroderma, Sjogren's syndrome, thyroid disorders and vitamin A deficiency.

According to a second aspect, there is provided a method for measuring a property of tear film in an eye of a subject, the method comprising causing a disturbance to the tear film in the eye of the subject using a disturbance device; and measuring a property of the tear film in the eye of the subject following the disturbance to the tear film using a measurement device. By disturbing the tear film using the disturbance device, the

measurement of a property of the tear film by the measurement device can be improved.

In some embodiments, the step of causing a disturbance comprises: causing a disturbance to the tear film in the eye to induce blinking by the subject; and/or causing a disturbance to the tear film in the eye to break up the tear film; and/or causing a disturbance to the tear film in the eye to induce tear film secretion.

In some embodiments, the step of causing a disturbance comprises forcing air or a liquid towards the eye to disturb the tear film. In other embodiments, the disturbance device comprises a light source, and the step of causing a disturbance comprises illuminating the eye to induce blinking and cause the disturbance to the tear film. In other embodiments, the disturbance device comprises a contact lens and a light source, wherein the contact lens is worn on part of the eye of the subject and is configured to change shape and/or size or wettability in response to light from the light source, and wherein the step of causing a disturbance comprises illuminating the contact lens with light from the light source to cause the contact lens to change shape and/or size or wettability and cause the disturbance to the tear film. These embodiments have the advantage that the disturbance can be applied relatively unobtrusively to the subject, and can also be easily applied in a non-clinical setting.

In some embodiments, the measurement device comprises a contact lens that is configured such that a property of the contact lens or a change in a property of the contact lens depends on a property of the tear film or a change in the property of the tear film, and wherein the step of measuring the property of the tear film comprises measuring the property of the contact lens or the change in the property of the contact lens. In some embodiments, the property of the contact lens comprises the curvature or rate of change of curvature of the contact lens, a speed of movement of the contact lens across the eye, the distortion of a surface of the contact lens or localized thickness variations. In alternative embodiments, the contact lens comprises an RF antenna and wherein a property of the RF antenna depends on a property of the tear film, such that a signal transmitted by the RF antenna is variable in dependence on the property of the tear film. In some embodiments, the step of measuring the property of the tear film comprises receiving a signal from the RF antenna in the contact lens and determining the property of the tear film from the signal. These embodiments have the advantage that the tear film property can be measured unobtrusively.

In some embodiments, the measurement device comprises an imaging device and the step of measuring comprises obtaining one or more images of the eye following the disturbance using the imaging device, and analyzing the one or more images to determine the property of the tear film. In some embodiments, the step of analyzing comprises analyzing the one or more images to determine changes in specular reflection from the eye. In some embodiments, the measurement device further comprises a light source for illuminating the eye to enable the imaging device to obtain the one or more images of the eye. These embodiments have the advantage that the tear film property can be measured unobtrusively.

In some embodiments, the property of the tear film comprises any one or more of: the stability of the tear film, the tear volume, the thickness of the tear film, a change in the thickness of the tear film, the thickness or relative thickness of one or more layers of the tear film, a change in the thickness or relative thickness of one or more layers of the tear film, the recovery of the tear film following the disturbance, a rheological property of the tear film, the viscosity of the tear film, or the break up of the tear film.

In some embodiments, the method further comprises the step of: determining, by a processing unit, a condition of the subject based on the measured property of the tear film. The condition of the subject can be a health condition, such as a disease or medical condition, including, among others: dry-eye, corporeal dehydration, diabetes, rheumatoid arthritis, lupus, scleroderma, Sjogren's syndrome, thyroid disorders and vitamin A deficiency.

BRIEF DESCRIPTION OF THE DRAWINGS

For a better understanding of the invention, and to show more clearly how it may be carried into effect, reference will now be made, by way of example only, to the accompanying drawings, in which:

Figure 1 is an illustration of the structure of tear film;

Figure 2 is a block diagram of an apparatus according to the invention;

Figure 3 is a flow chart illustrating a method of measuring a tear film property according to the invention;

Figure 4 is a block diagram illustrating a disturbance device according to a first embodiment;

Figure 5 is a block diagram illustrating a disturbance device according to a second embodiment;

Figure 6 is a block diagram illustrating a disturbance device according to a third embodiment;

Figure 7 is an illustration of the use of a contact lens according to Figure 6 to apply force; Figure 8 is an illustration of a specific embodiment of the contact lens of

Figure 6;

Figure 9 is an illustration of another specific embodiment of the contact lens of

Figure 6;

Figure 10 is an illustration of another specific embodiment of the contact lens of Figure 6;

Figure 11 is a block diagram illustrating a measurement device according to a first embodiment;

Figure 12 illustrates the measurement of specular reflection to measure tear film rupture;

Figure 13 is a block diagram illustrating a measurement device according to a second embodiment;

Figure 14 is a top view of a contact lens according to an embodiment;

Figure 15 shows cross-sectional views of a part of a contact lens in first and second states;

Figure 16 is a schematic of a measurement device according to an embodiment;

Figure 17 is a flow chart illustrating a method for determining a tear film property using the contact lens of Figure 14; and

Figure 18 illustrates the mechanism of volume response for hydrogels; and

Figure 19 is a graph illustrating the reflectance change of the eye following cyclic air blasts.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A block diagram of an apparatus 20 for measuring a property of tear film, and in particular embodiments a property related to the stability of the tear film, in an eye of a subject is shown in Figure 2. The apparatus 20 comprises a disturbance device 22 and a measurement device 24.

The disturbance device 22 is provided to cause a disturbance to the tear film in the eye of the subject, the effect of which is then measured by measurement device 24. The disturbance device 22 can use any suitable mechanical or optical means to apply a stimulus and cause a disturbance or modulation of the tear film in the eye. The disturbance can be intended to induce the subject to blink (since blinking replenishes or forms the tear film), to induce tear film secretion by the eye (so that the volume of the tear film that is available to be measured by the measurement device 24 is increased following the disturbance), and/or to directly or indirectly cause the tear film in the eye to break up (rupture).

In some embodiments, the disturbance device 22 can be configured to apply a force to the eye of the subject to cause the disturbance of the tear film. In these embodiments, the disturbance device 22 can be placed in contact with the eye in order to apply the force, or it can be a small distance from the eye and apply the force by forcing (blasting) air or liquid (e.g. water or a saline solution) towards and into the eye of the subject. Forcing (blasting) air or liquid towards and into the eye of the subject may directly disturb the tear film (e.g. cause the tear film to move and/or break up) and/or may induce the subject to blink. The air or liquid blast can be a short blast (impulse), or it can be a controlled flow.

In alternative embodiments, the disturbance device 22 can be configured to illuminate the eye to cause the disturbance to the tear film. For example the disturbance device 22 can be configured to flash a light source in order to disturb the tear film (e.g. by inducing the subject to blink). In another example, the disturbance device 22 can be configured to directly disturb the tear film using light, for example using high power light sources, such as a laser, or using infra-red light to induce evaporation of the tear film.

The measurement device 24 is provided to measure a property of the tear film (particularly a property related to the stability of the tear film) in the eye of the subject following the disturbance caused by the disturbance device 22. In some embodiments the measurement device 24 is located a distance from the eye of the subject so that the measurements are obtained unobtrusively. For example the measurement device 24 can be, or include, a camera or other imaging device. In other embodiments, part of the measurement device 24 (for example a contact lens) can be located on the eye of the subject for measuring a property of the tear film, and the measurement device 24 can comprise a control unit or other component that is located a distance from the contact lens that can read the

measurement of the property from the contact lens.

The measurement device 24 can be configured to measure any required property of tear film. In particular, the measurement device 24 can be configured to measure any one or more of the stability of the tear film or a property related to the stability of the tear film, such as the tear volume, the thickness of the tear film (e.g. the thickness of layers 4, 6, 8), a change in the thickness of the tear film, the thickness or relative thickness of one or more particular layers of the tear film (e.g. lipid layer 4, intermediate layer 6 or mucin layer 8), a change in the thickness or relative thickness of one or more particular layers of the tear film, the recovery of the tear film following the disturbance, a rheological property of the tear film, the viscosity of the tear film, or the break-up of the tear film.

Thus, the main elements of the apparatus 20 are the application of a controlled mechanical stimulus (e.g. blast of air, water or a saline solution) or optical stimulus (e.g. a flash or flashes of light) to disturb/modulate the tear film (including indirectly by inducing the subject to blink) and/or induce tear film secretion, and an unobtrusive means to measure a property of the tear film, particularly a property related to the stability of the tear film.

It will be appreciated from the explanation of the invention provided below that the disturbance device 22 and measurement device 24 may be separate standalone devices, units or modules (i.e. they are not interconnected), or the functionality of the disturbance device 22 and measurement device 24 may be implemented in a single device (for example by respective units or modules).

In some embodiments, the apparatus 20 further comprises a processing unit for determining the condition of the subject based on the measured property of the tear film. The condition of the subject can be a health condition, such as a disease or medical condition, including, among others: dry-eye, corporeal dehydration, diabetes, rheumatoid arthritis, lupus, scleroderma, Sjogren's syndrome, thyroid disorders and vitamin A deficiency. Thus, the processing unit can, for example, compare the measured property of the tear film to one or more thresholds or population values for one or more specific conditions to determine whether, and to what extent, the subject has the condition.

In addition or alternatively to determining the condition of the subject as described above, the processing unit can be configured to control the operation of the disturbance device 22 and/or the measurement device 24.

The processing unit may comprise one or more microprocessors that may be programmed using software to perform the required functions. The processing unit may be implemented as a combination of dedicated hardware to perform some functions and a processor (e.g., one or more programmed microprocessors and associated circuitry) to perform other functions. Examples of components that may be employed in various embodiments of the present disclosure include, but are not limited to, conventional microprocessors, application specific integrated circuits (ASICs), and field-programmable gate arrays (FPGAs).

The flow chart in Figure 3 illustrates a method of measuring a property of tear film in the eye of a subject according to the invention. In a first step, step 101, the method comprises causing a disturbance to the tear film in the eye of the subject using a disturbance device 22. Following the disturbance, a property of the tear film in the eye of the subject is measured using a measurement device 24.

Various exemplary embodiments and implementations of the disturbance device 22 and measurement device 24 and use of the disturbance device 22 and measurement device 24 are set out below.

A first exemplary embodiment of the disturbance device 22 is shown in Figure 4. In this embodiment, the disturbance device 22 is for applying a force to the eye of the subject by forcing air or liquid (e.g. water or a saline solution) towards and into the eye. Thus, the disturbance device 22 comprises a pump 30 or other component that can generate a blast or puff of air or liquid. Where the pump 30 or other component is for generating a blast of liquid, the disturbance device 22 can also comprise a reservoir 32 that holds the liquid for use by the pump 30. The disturbance device 22 also includes a disturbance device control unit 34 that is connected to the pump 30 and that controls the operation of the pump 30. The control unit 34 may control the operation of the pump 30 in response to the receipt of a control signal from measurement device 24.

The control unit 34 can be implemented in numerous ways, with software and/or hardware, to perform the required function(s). The control unit 34 may comprise one or more microprocessors that may be programmed using software to perform the required functions. The control unit 34 may be implemented as a combination of dedicated hardware to perform some functions and a processor (e.g., one or more programmed microprocessors and associated circuitry) to perform other functions. Examples of controller components that may be employed in various embodiments of the present disclosure include, but are not limited to, conventional microprocessors, application specific integrated circuits (ASICs), and field-programmable gate arrays (FPGAs).

As noted above, forcing air or liquid towards and into the eye of the subject may directly disturb the tear film (e.g. cause the tear film to move and/or break up) and/or induce the subject to blink. For example, it will be appreciated that forcing air into the eye of the subject can increase the evaporation rate of the tear film, and thus increase the rate of tear film break-up. It will also be appreciated that forcing air or liquid into the eye can also mechanically break up the tear film by pushing the tear film away from a local region in which the air or liquid is concentrated and creating a low volume and/or thin layer of tear fluid. It will be appreciated that an air-blast based disturbance device 22 can be similar to or the same as the device used to generate an air puff in non-contact air puff tonometers that are used for measuring intra-ocular pressure (IOP).

In some embodiments, it can be preferable for the disturbance device 22 to force liquid into the eye of the subject since the potential irritation of the eye caused by reducing the tear film thickness as a result of evaporation. However, the use of liquid disturbances can affect the concentration of chemicals in the tear film and hence in some embodiments (e.g. depending on the tear film property to be measured), it can be preferred for the disturbance to be a blast of air or a flash of light.

It will be appreciated that as the tear film on the eye has a small volume and small thickness (e.g. 4-13 microliter (μΐ) volume and 8-10μ1 thickness), the amount of air or liquid required to disturb the tear film is small (e.g. less than Ιμΐ).

In some embodiments, it is preferable for the disturbance device 22 to concentrate the air or water blast at a particular part of the eye (i.e. not at the whole exposed part of the eye) in order to create a local disturbance to the tear film.

In the case of an air blast, it is preferable for the air to have a constant relative humidity.

In the case of a water blast, it is preferable for the water to have a salt concentration that is similar to or the same as tears.

A second exemplary embodiment of the disturbance device 22 is shown in

Figure 5. In this embodiment, the disturbance device 22 is for shining or flashing a light source in order to disturb the tear film (e.g. by inducing the subject to blink). Thus, the disturbance device 22 comprises a light source 36 that can generate or emit light. The light source 36 may be a light emitting diode (LED), a laser light source or any other suitable source of light. The disturbance device 22 also includes a disturbance device control unit 38 that is connected to the light source 36 and that controls the operation of the light source 36. The control unit 38 may control the operation of the light source 36 in response to the receipt of a control signal from measurement device 24.

The control unit 38 can be implemented in numerous ways, with software and/or hardware, to perform the required function(s). The control unit 38 may comprise one or more microprocessors that may be programmed using software to perform the required functions. The control unit 38 may be implemented as a combination of dedicated hardware to perform some functions and a processor (e.g., one or more programmed microprocessors and associated circuitry) to perform other functions. Examples of controller components that may be employed in various embodiments of the present disclosure include, but are not limited to, conventional microprocessors, application specific integrated circuits (ASICs), and field-programmable gate arrays (FPGAs).

The control unit 38 may be configured to flash or pulse the light source to cause the subject to blink and thereby disturb the tear film, or to continuously illuminate the eye to cause the subject to blink, or to use the light source to directly disturb the tear film.

The light source 36 may be configured to generate light at one or more specific wavelengths, and in some embodiments the wavelength of the generated light can be changed or controlled by the control unit 38. The wavelength or wavelengths of light can be in the visible spectrum for inducing blinking, or in the infra-red spectrum for causing evaporation of the tear film. In some embodiments, the one or more specific wavelengths can be selected so that the light is absorbed by the tear film or one or more of the layers 4, 6, 8 of the tear film (also referred to as wavelength selective absorption).

In some embodiments, as described in more detail below, the measurement device 24 requires the eye to be illuminated with artificial light (e.g. if ambient light is not sufficient or desired for the measurements of the tear film property), the light source 36 can be used to provide this artificial light. Thus, in some embodiments, after the light source 36 is used to cause the disturbance to the tear film, the light source 36 can be used to illuminate the eye to enable the measurement device 24 to make or obtain the measurement of the tear film property. In these embodiments, the light source 36 may be controlled to emit light for use by the measurement device 24 at the same or a different wavelength to the light used to cause the disturbance. Depending on the way in which the measurement device 24 is to obtain the measurement (i.e. depending on the measurement technique being used), the light source 36 may be controlled to generate light at one or more specific wavelengths (e.g. in the visible and/or near infra-red spectrum) under control of the control unit 38, and/or the control unit 38 can control the light source 36 to generate light that has been amplitude and/or frequency modulated. Frequency modulation can be used to enable post-processing of the measured signal in the Fourier domain, and more generally modulation of the emitted light can enhance the accuracy and/or selectivity of the tear film property measurement. In particular, when the tear film is disturbed ripples will be created on the surface, and these ripples have a certain frequency which can be measured using Fourier analysis. In some embodiments, the light source 36 can be arranged with respect to the eye such that the light is incident to the eye at a non-zero angle that leads to reflections of the light from the different tear film layers, which can enable separate analysis of the tear film layers. A third exemplary embodiment of the disturbance device 22 is described with reference to Figures 6-10. In this embodiment, the disturbance device 22 is in the form of a contact lens that can apply a force to the eye in response to light incident on the contact lens. As is known, a contact lens (or a pair of contact lenses) can generally be worn relatively unobtrusively by a subject for a significant length of time (e.g. for several hours or even days), and the contact lens according to this embodiment is configured so that a force can be selectively applied by the contact lens when a tear film property measurement is to be made. Since the force required to disturb the tear film is relatively small, the tear film property measurement can be made almost or completely unobtrusively for the subject.

Figure 6 illustrates a contact lens 40 according to a general embodiment of the invention. Figure 6(a) shows a front view of the contact lens 40 and Figure 6(b) shows a side view of the contact lens 40. The term "contact lens" should be understood to refer to any device that is suitable for wearing in or on the eye for an extended period of time. It should be appreciated that contact lenses according to embodiments of the invention are preferably, but need not be, transparent. The contact lens 40 is generally circular with a concave curvature configured to contact a corneal surface of an eye.

In accordance with the invention, to enable the contact lens 40 to be used to apply a force to the eye, the contact lens 40 comprises a material 41 that is responsive to light. In particular, the material 41, which is also referred to herein as a 'first' material, is responsive to light in the sense that a property of the material 41 changes when light is incident on the contact lens 40. The property of the material 41 that changes should be a property that can lead to a force or strain being generated by the contact lens 40. In some embodiments, the first material 41 can be responsive to a particular wavelength or wavelengths of light (so the property of the material 41 only changes when light of a particular wavelength or wavelengths illuminates the material 41).

In some embodiments, the material 41 is responsive to light with a wavelength between 400-475 nano-meters (nm), e.g. in the blue/violet part of the visible spectrum. In other embodiments, the material 41 is responsive to light with a wavelength corresponding to the green and/or red (or infra-red) parts of the spectrum. It will be appreciated that the wavelength or wavelengths of light that the material 41 is responsive to can depend on the specific nature/type and/or configuration of the material 41.

In some embodiments, the property of the material 41 that changes in response to incident light can be the shape and/or size of the material 41. Therefore, illuminating the contact lens 40 (and in particular the first material 41 in the contact lens 40) with light (or light of a particular wavelength or wavelengths) can cause the shape and/or size of the material 41 to change in response to light, which can apply a force to the eye of the subject. In some embodiments, depending on the type and/or configuration of the first material 41, the change in the size and/or shape of the material 41 can be any of an increase in the size/length of the material 41 when light is incident on the first material 41, a decrease in the size/length of the material 41 when light is incident on the first material 41, an increase in the volume of the material 41 when light is incident on the first material 41, or a decrease in the volume of the material 41 when light is incident on the first material 41.

Figure 7 is an illustration of the use of a contact lens 40 according to the invention to apply force. In Figure 7(a) the contact lens 40 is in a 'relaxed' state, i.e. the contact lens 40, when worn by a subject, does not apply any force, or any appreciable force, to the eye of the subject. In this state, light of the particular wavelength or wavelengths is not incident on the contact lens 40 (or light at the particular wavelength or wavelengths is incident on the contact lens 40 but below an intensity level required to actuate the first material 41). As shown in Figure 7(b), when light 42 at the particular wavelength or wavelengths is incident on the contact lens 40 (or light at the particular wavelength or wavelengths is incident on the contact lens 40 with an intensity above a minimum threshold), the shape and/or size of the first material 41 changes so that the shape of the contact lens 40 moves into a 'force' state in which the contact lens 40 applies a force F to the eye. In the embodiment shown in Figure 7(b) the change in the shape and/or size of the first material 41 results in a contraction in the diameter of the contact lens 40 and the eye being squeezed by the contact lens 40. However, it will be appreciated that the effect of the change in size and/or shape of the first material 41 on the shape of the contact lens 40 can depend on the arrangement or configuration of the first material 41 in the contact lens and the nature of the change in size and/or shape of the first material 41 in response to the incident light.

The change in size and/or shape from the state shown in Figure 7(a) to the state shown in Figure 7(b) can be relatively instantaneous, or take up to a few seconds, depending on the nature/type and/or configuration of the first material 41.

In some embodiments, the first material 41 can be a light-responsive polymer, i.e. a polymer that is responsive to light. For example, the light-responsive polymer can be a nano-composite film, a liquid-crystalline elastomer, another form of polymer with liquid crystals, an azobenzene- or spiropyran- or Triphenylmethane-based system,

salicylideneaniline, or a polypeptide-based system, or any combination thereof. In some alternative embodiments, the property of the material 41 that changes in response to incident light is the wettability of the material 41. Therefore, illuminating the contact lens 40 (and in particular the first material 41 in the contact lens 40) with light (or light of a particular wavelength or wavelengths) can cause the wettability of the material 41 to change in response to light, which can apply a force to the eye of the subject. Good wettability is important for force transfer between the contact lens 40 and the eye. In particular, the material 41 can be such that the incident light changes the surface of the contact lens 40 such that it switches between hydrophilic and hydrophobic states, and the switching between these two states will enable a stable, reproducible contact between the eye and the contact lens 40.

In these alternative embodiments, the first material 41 can be a light- responsive polymer, for example a polymer comprising or containing spiropyran moieties grafted onto membrane surfaces, which exhibit reversible wettability- switching and protein adhesion.

It will be appreciated that the first material 41 can have a known response to incident light, and therefore the force applied by the contact lens 40 to the eye can be controlled through the selective illumination of the contact lens 40 with light.

A contact lens 40 according to the invention shown in Figures 6 and 7 can be used to apply a force of the order of 5-200 milliNewtons (mN) to the eye. This amount of force is sufficient to disturb the tear film.

It will also be appreciated that the first material 41 may be such that on removal of the incident light, the property of the first material 41 reverts to an original value or state (e.g. an original size and/or shape or wettability). Alternatively, the first material 41 may be such that the property of the first material 41 reverts to an original value or state (e.g. an original size and/or shape or wettability) on application of light of a different wavelength, or white light.

In some embodiments, the contact lens 40 can be formed entirely from the first material 41, but in other embodiments the contact lens 40 can be formed partly from the first material 41, and partly from one or more other materials. These other materials can be materials that are conventionally used to construct and form contact lenses. For example the other materials can include a silicone hydrogel. Where the contact lens 40 is partly formed from the first material 41, the contact lens 40 can comprise one or more regions of first material 41, and/or the contact lens 40 can comprise one or more layers of first material 41 within the structure of the contact lens 40. Figure 8 illustrates a contact lens 40 according to a first specific embodiment of the invention. In this embodiment, the contact lens 40 comprises a plurality of regions 43 made from the first material 41. The rest of the contact lens 40 is formed from a second material (e.g. a conventional material used in contact lenses). In the illustrated embodiment, the contact lens 40 comprises eight regions 43 of the first material 41 spaced generally evenly around the contact lens 40. In this embodiment, when light is incident on the first material 41, the first material 41 reduces in size and results in the diameter of the contact lens 40 being reduced, as indicated by arrows 44. This reduction in size squeezes the eye

behind/underneath the contact lens 40 (i.e. applies a force to the eye). Those skilled in the art will appreciate that the arrangement shown in Figure 8 is merely exemplary, and other arrangements and configurations of the first material 41 can be used.

In some embodiments, to improve the application of the force from the contact lens 40 to the eye, the contact lens 40 can comprise one or more regions of a hydrophilic material. The one or more regions of hydrophilic material can be located at least on the side of the contact lens 40 that is in contact with the eye during use. As the surface of the eye is covered with a liquid (the tear film), the hydrophilic material will therefore grip the liquid and thus the eye more than a hydrophobic material (which would repel the liquid). It will be appreciated that the hydrophilic material and the first material 41 can be located in different parts of the contact lens 40 or in different layers of the contact lens 40. In some

embodiments, the first material 41 can be a hydrophilic material.

An exemplary embodiment of a contact lens 40 comprising a hydrophilic material is shown in Figure 9. In this embodiment, the contact lens 40 comprises a first material 41 as described above, and a region 45 of hydrophilic material arranged around the periphery of the contact lens 40. Region 45 is shown as an annulus in Figure 9, but it will be appreciated that region 45 can take other shapes, and/or multiple regions 45 can be provided. Thus, in this embodiment, when the first material 41 is illuminated with light and the first material 41 causes the contact lens 40 to contract to apply a force, the annulus 45 of hydrophilic material improves the grip of the contact lens 40 to the eye, and thereby improves the application of the force to the eye.

In some embodiments, the contact lens 40 can also include one or more regions 46 of hydrophobic material in addition to the one or more regions 46 of hydrophilic material. In the embodiment shown in Figure 9, the region 46 is located in the center of the contact lens 40, but it will be appreciated that the region 46 can take different shapes and/or locations as desired. Another exemplary embodiment of a contact lens 40 comprising a hydrophilic material is shown in Figure 10. In this embodiment, the contact lens 40 comprises a plurality of regions 47 of hydrophilic material that are interspersed with a plurality of regions 48 of hydrophobic material.

Returning now to the measurement of the tear film property, the types of tear film property that can be measured can depend on the type of disturbance applied to the eye, and thus the type of disturbance used can depend on what tear film property is to be measured. For example, directly during and after blinking, tear film is formed on the eye. Thus after induced blinking the measurement device 24 can be used to measure the stability of the tear film over time. The tear film stability is related to the composition of the tear film, and thus the composition of the tear film can also be determined or estimated. For some of the other tear film properties that can be measured, the disturbance should directly affect the tear film, for example disturbing (moving) the tear film on a part of the eye and/or increasing the evaporation rate and thus the break up of the tear film.

In another exemplary embodiment, the disturbance device 22 can make use of electrical stimulation to induce the subject to blink. Suitable methods of electrical stimulation include transcutaneous electrical nerve stimulation (TENS).

A first exemplary embodiment of a measurement device 24 is shown in Figure 11. In this embodiment the measurement device 24 is located a distance from the eye of the subject so that the measurements are obtained unobtrusively. In particular, the measurement device 24 comprises an imaging device 50, for example a camera, that can obtain one or more still images of the eye (or part of the eye), or a sequence of images (i.e. a video sequence) of the eye (or part of the eye) and a measurement device control unit 52 that is connected to the imaging device 50 and that analyses the image or images obtained by the imaging device 50 to determine the tear film property. The imaging device 50 can obtain images or a video sequence of the eye before, during and/or after the disturbance is applied.

The control unit 52 can be implemented in numerous ways, with software and/or hardware, to perform the required function(s). The control unit 52 may comprise one or more microprocessors that may be programmed using software to perform the required functions. The control unit 52 may be implemented as a combination of dedicated hardware to perform some functions and a processor (e.g., one or more programmed microprocessors and associated circuitry) to perform other functions. Examples of controller components that may be employed in various embodiments of the present disclosure include, but are not limited to, conventional microprocessors, application specific integrated circuits (ASICs), and field-programmable gate arrays (FPGAs).

In some embodiments, the imaging device 50 captures images of the eye in ambient light and the control unit 52 analyses those images to determine the tear film property. However, in other embodiments, in order to measure the property of the tear film, the measurement device 24 may require the eye to be illuminated with artificial light.

Artificial light may be desirable for measurements that have a requirement for high time resolution (e.g. for measuring severe dry eye symptoms). Therefore, the measurement device 24 can comprise a light source 54, for example an LED or a laser light source. The light source 54 can be configured to emit or generate light at any wavelength or intensity required to measure the tear film property. In some embodiments, the light source 54 can emit near infrared and/or shortwave infrared light rather than visible light in order to minimize visual disturbances for the subject that would otherwise be caused by light in the visible range of the light spectrum.

As noted above, the measurement device 24 can be configured to measure any required property of tear film, particularly a property related to the stability of the tear film. In particular, the control unit 52 can be configured to implement any desired technique for measuring any one or more of the stability of the tear film or a property related to the stability of the tear film, such as the tear volume, the thickness of the tear film (e.g. the thickness of layers 4, 6, 8), a change in the thickness of the tear film, the thickness or relative thickness of one or more particular layers of the tear film (e.g. lipid layer 4, intermediate layer 6 or mucin layer 8), a change in the thickness or relative thickness of one or more particular layers of the tear film, the recovery of the tear film following the disturbance, a rheo logical property of the tear film, the viscosity of the tear film, or the break-up of the tear film.

In some embodiments, the imaging device 50 can be used to observe a wave pattern (e.g. a capillary wave pattern) created in the tear film by the applied disturbance. The control unit 52 can be configured to analyze the pattern in the obtained images to determine information about surface tension, viscosity, thickness and/or distribution of the lipid layer 4 and intermediate aqueous layer 6. Those skilled in the art will be aware of various techniques for analyzing the dispersion of the wave pattern to determine one or more of these parameters.

The thickness or change in thickness of the tear film following a stimulus (disturbance), can be measured remotely by using various imaging techniques, which are known to the skilled in the art. For example, in a preferred embodiment the thickness of the total tear film stack (i.e. the total thickness of layers 4, 6, 8), as well as the thicknesses of individual layers of the tear film (i.e. lipid 4, water 6 and mucin 8) can be monitored by analyzing interference patterns that are acquired by illuminating the tear film with broadband light from light source 54.

In another preferred embodiment, the tear film rupture (the areas where the continuity of the tear film is disrupted) can be monitored by comparing changes in the specular reflection of the tear film following a disturbance. Changes in the specular reflection can be monitored by measuring the total intensity of light reflected from the tear film, and tear film rupture can be detected by, for example, observing a decrease in specular reflection intensity, which is a result of the creation of open areas of the tear film through rupturing, and also the subsequent recovery of the tear film which results in the filling in of the open areas in the tear film. Figure 12(a) illustrates the measurement of specular reflection from intact (i.e. unruptured) tear film and Figure 12(b) illustrates the measurement of specular reflection from ruptured tear film, where a plurality of ruptures or holes 55 in the lipid layer 4 are shown. It can be seen that the measured light intensity will be affected by the open areas 55 of the tear film. Tracking the specular light intensity changes can be done by an imaging device 50 (e.g. a dimensionless detector) with a field of view that is sufficient for capturing or observing the specular light intensity over a representative area of the tear film (e.g. from a few mm ² to the complete eye surface).

Changes in the specular reflection intensity can also be tracked by calculating the total light intensity over the obtained images, and/or by tracking the size, shape and the number of dry spots of the tear film in the obtained image(s) using image analysis techniques, for example using edge detection techniques. Those skilled in the art will be aware of image analysis techniques that can be used for this purpose, and no further details are provided herein.

A second exemplary embodiment of the measurement device 24 is shown in Figure 13. In this embodiment a contact lens 56 is provided that is to be worn on the eye of the subject and that is used in the measurement of the property of the tear film. In some embodiments, which are described in more detail below, the contact lens 56 can be configured such that a measurable property of the contact lens (for example a physical property of the contact lens, such as the curvature, rate of change of curvature, shape, thickness, a speed of movement of the contact lens across the eye, the distortion of a surface of the contact lens or localized thickness variations, etc.) depends on a property of the tear film. Thus, measuring the property of the contact lens can enable the measurement of the tear film property to be determined. In alternative embodiments, the contact lens 56 can comprise one or more sensing elements, which for example can be arranged in a matrix, array or ring, that can sense or measure deformation of the contact lens 56 caused by changes in the tear film.

The contact lens 56 can be any type of device that can be worn on the eye of the subject. The contact lens 56 may be configured so that it provides a correction to the vision of the subject, or configured such that it does not affect or alter the vision of the subject. The contact lens 56 can be made of any suitable rigid or flexible material.

The measurement device 24 also comprises a measurement device control unit 57 that is configured to measure or obtain a measurement of the property of the contact lens 56, and determine the tear film property from the measurement of the property of the contact lens 56. The measurement device control unit 57 is configured to be used remotely from the contact lens (i.e. not in contact with the contact lens 56) so that measurements of the tear film property can be obtained unobtrusively.

In some embodiments, the control unit 57 comprises an imaging device (e.g. a camera) that can be used to obtain an image or images or a video sequence of the contact lens 56 in the eye of the subject before, during and/or after the disturbance is applied. The control unit 57 can be configured to analyze the output from the imaging device to determine the property of the contact lens 56 and thus the tear film property.

In alternative embodiments, which are described in more detail below, the contact lens 56 can comprise a radio frequency (RF) antenna that is used to transmit a signal representing the property of the contact lens 56, and the control unit 57 can comprise a receiver that can receive the signal from the RF antenna and the control unit 57 can determine the property of the contact lens 56 from the signal and thus the tear film property. In some embodiments, the contact lens 56 is configured such that the configuration of the RF antenna depends on the tear film property, and thus the signal transmitted by the RF antenna depends on the tear film property. In some embodiments, the control unit 57 can also comprise a transmitter for transmitting an interrogation signal to the contact lens 56 to cause the contact lens 56 to transmit a signal using the RF antenna.

In addition to the imaging device or transmitter/receiver components mentioned above, the control unit 57 can be implemented in numerous ways, with software and/or hardware, to perform the required function(s). The control unit 57 may comprise one or more microprocessors that may be programmed using software to perform the required functions. The control unit 57 may be implemented as a combination of dedicated hardware to perform some functions and a processor (e.g., one or more programmed microprocessors and associated circuitry) to perform other functions. Examples of controller components that may be employed in various embodiments of the present disclosure include, but are not limited to, conventional microprocessors, application specific integrated circuits (ASICs), and field-programmable gate arrays (FPGAs).

As noted above, in some embodiments a property of the contact lens 56 can depend on a tear film property. Some examples are provided below:

(i) The curvature of the contact lens 56 can be used to measure tear volume and tear film thickness. A more curved lens surface indicates a larger tear volume and thicker tear film, while a less curved surface indicates a smaller tear volume and thinner tear film.

(ii) The rate of change of the curvature of the lens 56 can be used to measure tear film evaporation rate, i.e., TFET. A faster change in lens curvature indicates a higher TFET, while a slower change in lens curvature indicates a lower TFET.

(iii) The speed of motion of the contact lens 56 over the eye, which can be measured by tracking movement of the contact lens 56 or a part of the contact lens 56 over time relative to a fixed point (e.g. the pupil of the eye), can be used to measure tear film viscosity, viscoelasticity and/or surface tension. Faster movement of the contact lens 56 indicates low tear film viscosity, while slower movement implies higher tear film viscosity.

(iv) The distortion of the surface of the contact lens 56 or local changes in the curvature of the contact lens can be used to estimate TFBUT and tear film stability, since a more distorted (i.e., uneven) lens shape indicates local areas of tear film rupture and therefore low tear film stability.

(v) The localized variations/differences in thickness of the contact lens 56 can be used to estimate the thickness of the tear film.

An exemplary embodiment of a contact lens 56 that comprises an RF antenna, the configuration of which depends on a tear film property, is described below with reference to Figures 14-17.

In Figure 14 the contact lens 56 comprises a round lens part 60 with a concave curvature configured to mount to a corneal surface of an eye. The lens part 60 comprises an indicator material, the volume of which is variable in dependence on a property of tear film. In some embodiments the entire lens part 60 is formed from the indicator material. In some embodiments the lens part 60 is partially formed from the indicator material and partially formed from another material, e.g. a conventional contact lens material. The indicator material can be a hydrogel or a molecularly imprinted polymer. The contact lens 56 further comprises an RF antenna 62 disposed on the lens part 60. The RF antenna 62 can be in the form of a wire embedded in or fixedly mounted on the indicator material. In such embodiments a volume change of the indicator material causes an alteration of the strain experienced by the antenna wire (i.e. the strain increases as the indicator material expands/swells, and decreases as the indicator material shrinks/deswells). In some alternative embodiments the RF antenna 62 comprises a slotted patch antenna embedded in or fixedly mounted on the indicator material. In such embodiments both the strain in the antenna material and the size of the slot are altered by a volume change of the indicator material.

Figures 15(a) and 15(b) show a partial cross section of a contact lens 56 according to a specific embodiment. A first section 72 of the lens part 70 of the contact lens 56 comprises an indicator material and a second section 74 of the lens part 70 comprises a conventional contact lens material. An antenna wire 76 is disposed on the lens part 70 such that it passes over the first section 72. Figure 15(a) shows the situation where the indicator material is not experiencing any volume increase compared to a baseline state. Figure 15(b) shows the situation where the indicator material has swelled by a measurable amount compared to the baseline state. It can be seen from Figure 15(b) that the antenna wire 76 is caused to stretch by the swelling of the indicator material.

Due to the piezoresistive effect, the resistance of a conductor (such as an antenna wire) varies in dependence on the strain experienced by that conductor. The strain depends on the degree of stretching being experienced by the conductor. Therefore, the resistance of the antenna wire varies in dependence on the volume of the indicator material. Changing the resistance of an antenna wire causes changes in the antenna transfer functions (e.g. the resonance frequency of the antenna, the quality factor (QF), etc.). This effect can be amplified by utilizing an antenna configuration which experiences a relatively high amount of stretching in response to a given volume increase of the indicator material.

Changes to the antenna transfer functions can be detected by a transceiver (in control unit 57) coupled to the antenna, without requiring contact between the transceiver and the antenna. Advantageously, this means that the sensor output of the contact lens of Figure 14 can be read remotely, causing little or no discomfort or inconvenience for the subject.

Using a measured change in an antenna transfer function, such as QF, it is possible to calculate (using known techniques) the resistance change which caused the observed change in the antenna transfer function. The resistance change will be related to the underlying volume change of the indicator material by a correlation function, the exact form of which will depend on specific factors such as the form of the antenna wire, the form of the indicator material, and the relative arrangement of the antenna wire and the indicator material. In some embodiments a calibration graph or look-up table relating antenna wire resistance to indicator material volume is created in respect of each particular design of the contact lens 56, to enable the volume change of the indicator material to be determined from a calculated resistance change. In some embodiments the control unit 57 is arranged to determine a correlation function relating resistance change to volume change, and to apply this to the calculated resistance values.

Similarly, the volume of the indicator material will be related to the underlying change of the tear film property by a correlation function, the exact form of which will depend on specific factors such as the nature of the indicator material, the arrangement of the indicator material, and the nature of the property. In some embodiments the control unit 57 is arranged to determine a correlation function relating indicator material volume to tear film property value, and to apply this to the calculated volume values.

In some alternative embodiments, the contact lens 56 comprises a strain gauge and a separate RF antenna. It will be appreciated that in some embodiments the output of the contact lens 56 can be based on the detection of a property other than strain. For instance, in some embodiments conductive plates are disposed on the indicator material such that the distance between the plates is altered by a change in volume of the indicator material. The dielectric constant of the indicator material between the plates will also be altered by a change in volume of the indicator material. The plates thus form a variable capacitor, the capacitance of which depends on the volume of the indicator material. In some embodiments the contact lens 56 comprises particles of a conductive material (e.g. graphite, gold spheres, etc.) suspended in the indicator material, which in such embodiments is selected to have low or no conductivity. In such embodiments changes in the volume of the indicator material alter the distances between the conductive particles, which in turn alters the conductance indicator material. Various ways of detecting changes in electrical properties such as conductance and/or capacitance suitable for implementing in a contact lens will be known to the skilled person. In some embodiments, the contact lens 56 can comprise a sensor that directly measures a tear film property and provides the measurement signal to the RF antenna.

Figure 16 shows the measurement device 24 of Figure 13 in more detail. The contact lens 56 is as described above with reference to Figures 14 and 15 and comprises RF antenna 62 and an indicator material arranged to change volume in response to a change in a property of tear film, such that the strain experienced by the RF antenna 62 depends on the volume of the indicator material. In Figure 16 the RF antenna 62 is shown extending outwardly from the lens part for clarity, but it will be appreciated that this will not be the case in most embodiments. The RF antenna 62 is part of a passive antenna circuit. In some embodiments the RF antenna 62 is tuned to a predefined frequency for a given strain state (i.e. a given volume of the indicator material). In some embodiments the RF antenna 62 and associated circuitry is formed from a transparent conductive material, e.g. indium tin oxide (ITO), so as not to impair the sight of the subject. In some embodiments the RF antenna 62 and associated circuitry is arranged around the perimeter of the contact lens 56 so as not to impair the sight of the subject.

The control unit 57 comprises an RF transceiver for transmitting RF energy to and receiving RF energy from the contact lens 56. The RF transceiver comprises an RF signal generator, an antenna 93 and a tuning circuit. In preferred embodiments the transceiver is arranged to transmit RF energy in a frequency including frequencies up to a few tens of MHz. Preferably the transceiver is arranged to transmit RF energy in a range away from commonly used communication bands, and also below the energy absorption range of tissue. Preferably the transceiver is able to be tuned to receive a wide range of RF frequencies (e.g. because the resonance frequency of the contact lens antenna 62 may change in accordance with changes in the tear film property.

In some embodiments, the control unit 57 is arranged to determine a value of the property of the tear film based on RF energy received from the contact lens 56. In some such embodiments the control unit 57 is arranged to measure a transfer function of the antenna 62 at a first time and at a second, later, time. The measured transfer function can comprise any of: a quality factor (QF), a resonance frequency, harmonics of a resonance frequency, time constants of an RLC circuit of the RF antenna 62.

In some embodiments the control unit 57 is a hand-held device. In some embodiments the control unit 57 is incorporated into a portable electronic device such as a smartphone or tablet computer. In some embodiments the control unit 57 is configured to be worn on a body part of the user, e.g. on a wrist or around the neck, etc. In some embodiments the control unit 57 is configured to be mounted to a pair of spectacles. In some embodiments the control unit 57 is integrated into a pair of spectacles.

In some embodiments the control unit 57 is arranged to determine a resistance of the RF antenna 62 based on the measured transfer function. In some embodiments the control unit 57 is arranged to determine a volume of the indicator material in the contact lens 56 based on a determined resistance of the contact lens RF antenna 62, e.g. by comparing a determined resistance value to a calibration graph or look-up table relating antenna wire resistance to indicator material volume. In some embodiments the control unit 57 is arranged to determine a value of a tear film property based on a determined volume of the indicator material, e.g. by comparing a determined indicator material volume to a calibration graph or look-up table relating indicator material volume to tear film property value.

The operation of the measurement device 24 of Figure 13 will be further described with reference to Figure 17, which illustrates a method for determining a tear film property.

In a first block 501 of the method the control unit 57, using the transceiver module, measures an antenna transfer function at a first time, to determine an initial value for that antenna transfer function. During the performance of block 501 the control unit 57 is positioned such that the distance between the control unit 57 and the contact lens 56 is less than a maximum read range of the control unit 57. The measuring comprises the control unit 57 transmitting (using the antenna 93) RF energy in the direction of the contact lens 56. In some embodiments the frequency of the transmitted RF energy is in the range 13-14 mega Hertz (MHz). In some embodiments the transmitted RF energy comprises a pulse having a duration and a variable frequency over the duration. In some embodiments the transmitted RF energy is varied between at least two different frequencies. In some embodiments the transmitted RF energy is varied between three different frequencies. In some embodiments the transmitted RF energy is varied over a continuous range of frequencies. The measuring further comprises the RF antenna 62 of the contact lens 56 receiving the RF energy transmitted by the control unit 57.

The RF energy received by the contact lens RF antenna 62 induces an RF voltage in the contact lens RF antenna 62, which causes the RF antenna 62 to emit RF energy. The RF energy emitted by the RF antenna 62 is then received by control unit antenna 93. The RF voltage in the RF antenna 62 is linked to the RF voltage in the control unit antenna 93, such that the two antennas are coupled in a manner similar to weakly coupled transformer coils. A characteristic relating to the RF signal received by the control unit antenna 93 is detected and recorded by the control unit 57. In some embodiments the characteristic comprises the amplitude of the received RF signal. In some embodiments the characteristic comprises the voltage in the control unit antenna 93. In some embodiments the characteristic is continuously detected and recorded for at least the duration over which the RF energy was transmitted by the control unit 57. In some embodiments the control unit 57 generates a time-series of values of the characteristic. The measuring further comprises calculating a value of the transfer function based on the characteristic relating to the received RF signal. In some embodiments the calculating is performed by a processing unit of the control unit 57.

In a particular example in which the transfer function comprises a QF and the characteristic comprises the amplitude of the received RF signal, the calculating is performed as follows. The QF describes the width of the frequency spectrum of an antenna at 3dB below the peak. To calculate a QF it is therefore necessary to measure the spectrum of the received RF energy at at least two frequencies. A suitable calculation process comprises determining the maximum amplitude of the received signal and a corresponding frequency, fo, of the transmitted signal; determining a first frequency, fi , of the transmitted signal corresponding to an amplitude 3 decibels (dB) less than the maximum amplitude;

determining a second frequency, ft, of the transmitted signal corresponding to an amplitude 3dB less than the maximum amplitude; and calculating a QF value using:

QF = . (Equation 1)

However; it is often the case that the shape of the antenna band-pass characteristic (in particular the fact that it is symmetric) is known. In such cases f ₂ -fo = fo-fi , meaning that it is only necessary to determine the peak frequency fo, and one of the -3dB frequencies (either ft or ft).

In examples in which the characteristic comprises the voltage in the control unit antenna 93, the calculating process is slightly different. In such examples the maximum voltage is determined and this value is multiplied by 0.707 in order to obtain the equivalent - 3dB value. The frequencies corresponding to the maximum voltage and the -3dB equivalent voltage are then determined and input into equation 1.

When an initial value for the antenna transfer function has been determined, the method moves to block 502 in which the tear film property changes. It will be appreciated that block 502 occurs in the eye, and is not a step in the operation of the measurement device 24. Block 502 can correspond to the application of the disturbance to the eye by disturbance device 22. The change can comprise either an increase or a decrease in the property, and can lead to a change in the volume of the indicator material, and thus a change in the

strain/resistance of the RF antenna wire. In block 507 the control unit 57 measures the antenna transfer function at a second time, to determine a final value for that antenna transfer function (the term "final" is used merely to distinguish this value from the initial value, and is not intended imply that no further values of the antenna transfer function are determined). The determination of the final antenna transfer function value is performed in the same manner as the determination of the initial antenna transfer function value. In some embodiments the second time is immediately after the first time, i.e. such that the control unit 57 is continuously determining an updated antenna transfer function value, i.e. before, during and after the application of a disturbance to the eye.

In block 508 the control unit 57 determines a change in the tear film property between the first time and the second time using the initial antenna transfer function value and the final antenna transfer function value. In some embodiments the determining comprises calculating a resistance change which caused the observed change in the antenna transfer function; calculating a change in the strain experienced by the contact lens antenna 62 based on the initial and final antenna transfer function values; or determining a volume change of the indicator material, e.g. using a calibration graph or look-up table relating antenna wire resistance to indicator material volume, or relating antenna wire strain to indicator material volume.

It will be appreciated that the initial antenna transfer function and the final antenna transfer function used in step 508 do not have to be consecutive measurements of the antenna transfer function value.

In embodiments of the above approach, the indicator material can be a material that gives a specific response to tear chemistry (e.g. changes in tear lipid, mucin, or water content) and generates strain. For example the material can be a hydrogel. Figure 18 illustrates the mechanism of volume response for hydrogels through changes in the COO and COOH bonds, and the resulting volume response as a function of changes in pH. Changes in pH can correspond to changes in water content. Thus, the use of such a hydrogel allows contact lens 56 to be used to measure tear film composition, or changes in the tear film composition. It is important to note that the swelling/shrinking response of a hydrogel is related to the balance between the polymer-water Gibbs energy, which is associated with the elastic nature of the hydrogel polymer network.

In some embodiments, where a localized air or water blast is used to locally disrupt or disturb the tear film, the measurement device 24 can monitor the dynamics of the tear film to determine and measure the return to equilibrium (i.e. the recovery) of the tear film. The dynamics of the tear film in returning to equilibrium are an indicator of the tear film rheo logical properties and hence its composition.

The local tear thickness (which is, as mentioned, disturbed and next returns to equilibrium) is preferably be measured or monitored by a reflection method, such as specular refiection (since the thickness of the tear film, as part of a layer of optical materials, is expected to impact the reflectivity), although other techniques can be used if desired. As noted above, a reflection measurement could be done remotely, e.g. using an imaging device 50 and optionally a light source 54, or a contact lens, optionally in combination with an imaging device 50.

Monitoring the tear film over time after a local thinning of the tear film layer using the disturbance device 22 would provide a curve of reflectivity over time, and the slope (and/or other properties) of the curve are an indicator of the rheo logical (viscosity) properties of the tear film.

There are three ways in which these measurements could be obtained. The first is to apply a single disturbance (e.g. a pulse of air or liquid) and measure the recovery of the tear film to equilibrium. This approach is as described above.

The second is to apply multiple disturbances (e.g. multiple pulses of air and/or liquid), with each disturbance being applied after the tear film has returned to equilibrium from the previous disturbance.

Figure 19 is a graph that illustrates the modelled change in the measured refiectance value of the tear film over time following the application of several disturbances in the form of an air puff or pulse. Three disturbances are shown in Figure 19, each indicated by a vertical dashed line 95. The reflectance of the eye surface, indicated by the solid line 97, is measured at the location where the disturbance is applied (e.g. where the air puff hits the eye). The slope of the refiectance is related to the viscosity of the tear film. It can be seen that the disturbance 95 pushes the tear film away, which provides a sharp drop in the reflectance, indicated by arrow 98. The refiectance value then troughs (i.e. reaches a minimum) shortly after the disturbance, and then recovers back close to the value of the reflectance before the disturbance (which corresponds to the tear film flowing back into the region of the eye in which the disturbance was applied), as indicated by arrow 99.

In some embodiments, the initial drop in reflectance after the disturbance can be used to set a base setting for the power of the air or liquid puff. The disturbance of the tear film should be such that the tear film is not disturbed to such an extent that the tear film will not reform, and/or a blinking reflex is induced. By modifying the power of the air or liquid puff the disturbance can be adjusted to allow the tear film to flow back and reach an equilibrium. The level of recovery of the reflectance (e.g. the peak value of the reflectance after the disturbance) can be used to check possible negative effects of the test (e.g. unwanted drying of the tear film, damage, etc.). For example, if the amount of drying from the air puff is too severe then it may not be possible to measure the recovery of the tear film (i.e. the reflectance will not recover to the pre-disturbance level). In this case the power of the air puff can be reduced until the reflectance after the air puff recovers to the pre-disturbance level.

In the third approach, a variation of the frequency of application of the disturbances can be used to measure rheological/fluidic properties of the tear fluid. The output signal can be plotted as a function of the frequency of the disturbance and from this frequency domain properties of the fluid can be deduced.

In this third approach, it is not the frequency that is monitored, but the frequency is used as an input parameter for the tear film property measurement. A first method is to only use a single event (e.g. a single blast of air or liquid) and measure the recovery of the tear film to 'normal' as indicated by the time until the reflectance value gets back to the initial value before the disturbance was applied. Short term and longer term changes of tear film can be deduced from the time to stable recovery and also the difference between the recovery reflectance and the value before the first disturbance.

A second option is to continuously measure the reflectance during the disturbances and to vary the frequency of the pulses/disturbances. If the frequency is too high for a certain rheology (composition) or thickness of the tear film, then the tear film will not have a sufficient time to recover to normal by the time the next disturbance occurs. So the frequency at which recovery to normal is still acceptable can be an indicator of the tear film properties.

The invention can be applied in several different ways and for several different purposes. For example, fields of application for this invention include:

- Continuous/semi-continuous monitoring of tear film stability for sensitive groups like the elderly, diabetics and people living in air polluted areas;

- Fertility testing (as a supportive information) by means of tracking the salt concentration in tear film, and its effect on evaporation rate;

- Monitoring and management of therapeutic treatment as well as assessment of subject compliance and adherence in treatments of medical conditions, for example hypertension and cardiovascular diseases (e.g. heart failure); - Monitoring and management of therapeutic treatment as well as assessment of subject compliance and adherence in treatment of psychological disorders (e.g. bi-polar disorder, depression), dehydration, inflammation, chemotherapy, glaucoma through detection of therapeutic drugs such as, phenobarbital, carbamazepine, Methotrexate as well as such respiratory disorders as emphysema and COPD through monitoring a 1 -antitrypsin;

- Monitoring and management of ocular side effects of therapeutic drugs, such as the 'dry eye' condition;

-Monitoring and management of indoor air pollution; and

-Monitoring and management of industrial air pollution, e.g., safety in mines, chemical factories etc.

As noted above, the measurement of the tear film stability and/or other tear film properties is useful for various clinical and non-clinical purposes. For example, consider a subject with heart failure that is on beta blockers, e.g., propranolol, atenolol, etc., or on diuretics, e.g., hydrochlorothiazide, metolazone, spironolactone, etc. A physician managing the therapy of the subject with heart failure may use the measurements of the changes in tear film stability to assess the subject's response to the medication and to titrate the medication dose in order to ensure maximum efficacy while minimizing side effects. If the

measurements indicate that the tear film stability is very low, then this may indicate that the medication dose is too high, and indicate that a lower drug dose could be administered. Conversely, if the measurement indicates a high value for tear film stability, then this may indicate a lack of drug efficacy due to low dosage and prompt the physician to prescribe a higher, more therapeutically effective beta blocker or diuretic dose.

There is therefore provided an improved method and apparatus for measuring a property of a tear film of the tear fluid.

Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfil the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. A computer program may be stored/distributed on a suitable medium, such as an optical storage medium or a solid-state medium supplied together with or as part of other hardware, but may also be distributed in other forms, such as via the Internet or other wired or wireless telecommunication systems. Any reference signs in the claims should not be construed as limiting the scope.