METHODS THEREOF

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This application claims priority under 35 U.S.C.§ 119 e. to U.S. Provisional Application No. 62/372,624, filed August 9, 2016, the content of which is hereby incorporated by reference in its entirety.

FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to portable devices for monitoring eye diseases by measuring the intraocular pressure ("IOP") of a subject. More specifically, the disclosed devices measure the IOP in a non-contact manner. The disclosure also provides methods for measuring the IOP of an eye.

BACKGROUND

[0003] Glaucoma is one type of eye diseases that often leads to vision loss in a staggering proportion of population. As of 2010, about 60.5 million people worldwide had been suffering from different types of glaucoma. Quigley, et al., Br J Ophthalmol ; 90(3): 262- 267 (2006). Glaucoma has become the second leading cause for blindness in the U.S. and worldwide. Mantravadi, et al., Primary Care 42 (3): 437^19 (2015). Increased eye pressure is the most important risk factor for glaucoma, and may be caused by a number of reasons, e.g., family histories, injuries, migraines, high blood pressure, obesity, and age. If the value for inner eye pressure is above 21mmHg or 2.8 kPa, the optical nerve failure may slowly develop, eventually resulting in blindness if not treated properly in time. Resnikoff, et al., Bull WorldHealth Organ, 82 (11), 844-851 (2004); Foster, et al., Br J Ophthalmol 86. pp. 238-242 (2002).

[0004] One of the notable dangers from glaucoma is the permanent vision loss for which there is no effective cure. Though laser treatment or surgery may be used to treat glaucoma at a very early stage, the only approach to keep the vision for most patients suffering from glaucoma is to take medicine when the IOP becomes abnormally high. [0005] There are three major kinds of devices that are commonly used for IOP

measurement during the hospital visit. The most common method for IOP measurement is Goldmann Applanation Tonometry ("GAT"). GAT was introduced in 1957 and has since been commonly used for the IOP testing. Goldmann, et al., Ophthalmologica, 134 (4), 221- 242 (1957). In GAT, a special probe head is placed against the cornea, and attaches and flattens the corneal surface during testing. Once the specific area (0.12 in diameter) on the corneal surface is flattened, the opposing force of corneal pressure is obtained by a sensor and used to calculate the IOP.

[0006] Dynamic contour tonometry ("DCT") is another routine method for measuring the IOP. Differing from the GAT, the DCT uses a contour match probe that does not provide the corneal deformation. In contrast with GAT, results from DCT are less influenced by corneal thickness and other biomechanics properties. Kaufmann, et al., Investigative Ophthalmology and Visual Science, 45 (9), 31 18-3121 (2004).

[0007] Instead of using a contact probe, the air puff tonometer ejects an air impulse into the cornea, and causes a very short deformation of the cornea. The changes in time course are then collected by an electro-optical detector system to calculate the IOP values. Kling, et al., PLoS One, 9, el 04904 (2014). The IOP values from air puff tonometers are usually higher than those obtained using GAT and DCT. Carbonaro et al., Eye, 24 (7), 1 165-70 (2010).

[0008] Primarily used in a hospital setting, the benefits from those devices are limited for patients with abnormal IOP because the IOP may vary over the course of a day or day-to-day, and it may also be influenced by blood pressure, ocular manipulation, sleep patterns, exercise and many other factors. Moses, et al., Arch Ophthalmol., 101 (2), pp. 249-252 (1983).

Accordingly, when a hospital-based device cannot provide a real-time test for glaucoma patients, portable or home-use self-tonometry is highly needed for people who suffer from glaucoma.

[0009] Therefore, to closely monitor the IOP, glaucoma patients have a compelling need for a home-based daily test method for their disease management. The following are several products in the market. The Ocuton S tonometer was developed for operation by patients without assistance from medical experts. Draeger, et al., Fortschr Ophthalmol 88 (3): 304- 307 (1991). The Ocuton S tonometer is a hand-held, electronic, automatic, tonometer based on the same principles as the GAT. Kothy, et al., Med Sci Monit, 9 (1), 1-4 (2003). To operate, a patient needs to place this device in front of the eye, using a fixation light to help control the position. To measure the IOP, a polymethylmethacrylate probe can automatically contact and flatten the cornea. The contact area has specific diameter that is similar with a GAT probe. This device, however, requires sophisticated anesthesia and sterilization for each use, thereby limiting the practicality of this device. Many patients who lack the ability to self-administer anesthesia are unable to use the Ocuton S tonometer. Even for people properly using the device, they may still hold the risks of infection, corneal abrasion, and ulceration.

[0010] Tono-Pen is another common portable tonometer. However, Tono-Pen is an expensive clinical device, and may also be technically challenging for typical patients to maintain and operate.

[0011] Therefore, the current "home-use" tonometers have limitations that preventthe daily monitoring of IOP for patients in need, e.g., the demand for anesthesia and sterilization, the high cost, and the technical challenges of keeping the machine in position and operating it properly. Therefore, there is a need for affordable, portable, non-contact, easily-operable devices or methods for monitoring eye diseases, and/or measuring the IOP.

SUMMARY OF THE INVENTION

[0012] In the disclosure, an ultrasonic wave generated by a transmitter, either at a constant frequency or variable frequencies, is directed to the corneal and reflected by the corneal to a receiver that is connected to a demodulator and/or a processor. Such a transmitted and subsequently reflected ultrasonic wave is also called a carrier wave or a carrier signal. While, before, or after the ultrasonic wave is directing to the corneal, a vibration generated by a separate generator, at variable frequencies, is directed to an area proximately or directly to the eyes, and affects the carrier waves. Thus, the carrier wave or the carrier signal, which carries the information of the vibrating eyes, is later demodulated or processed to provide the resonant frequency of the eyes (Figure 1). [0013] It was suggested that the inner pressure may have an approximately linear relationship with its resonant frequency in specific ranges. See Baldi et al., IEEE Sensors Journal, 3 (6), pp. 728-733 (2003). The linear relationship has been applied to many technical fields, e.g., engineering and cell biology. One study suggests that the relationship may be applied to the IOP. See Han, et al., Optics in Health Care and Biomedical Optics: Diagnostics and Treatment, 143 (2002) .

[0014] Without being bound by a theory, the resonant frequency of the human cornea can be influenced by IOP. Higher inner pressure can change the vibrating characteristics of the cornea and result in a higher resonant frequency. The relationship between these two parameters may be described in an empirical curve with which one can calculate the inner pressure based on the resonant frequency of the cornea. Without being bound by a theory, the empirical curve for one eyeball may be different from another. Thus, the users may build their own database for the relationship between the resonant frequency and the IOP. The means to build the database or create the empirical curve is known in the art.

[0015] Figure 3 shows the relationship between the inner pressure (unit in mmHg) and resonant frequency of pig eyes. Without being bound by a theory, at a low eye pressure range (lower than 30 mmHg), the resonant frequency and inner pressure have an approximately linear relation; when the eye pressure is above 30 mmHg, the frequency may reach its maximum and stay as a "constant" roughly around 400 Hz. Thus, the linear relationship may be used to determine the exact pressure value based on the resonant frequency. A high frequency may mean an abnormal pressure which necessitates treatment for the eyes.

[0016] Therefore, by measuring the resonant frequency of the eyes, the present invention provides a novel method or a novel apparatus for monitoring the inner pressure or the IOP of the eyes.

[0017] The disclosure provides a method of measuring IOP of an eye of a subject. The method can measure the IOP in a non-contact manner, i.e., without contacting the cornea. In one embodiment, the method comprises vibrating the eye with a vibrator in direct contact with the eyelid, wherein the vibration occurs at a frequency; directing an acoustic wave to a spot on corneal surface of the eye, wherein the acoustic wave is generated by an ultrasonic transmitter; Receiving the reflected signal from eye surface by receiver; and processing the reflected signal via a data processing system, wherein the reflected signal is converted to resonant frequency based on a plurality of parameters stored in the data processing system. In one aspect, the IOP can be measured based on the resonant frequency. The acoustic wave is at a frequency between about 20 kHz and about 80 kHz, about 30 kHz and about 70 kHz, or about 40 kHz and about 60 kHz. In one embodiment, the acoustic wave is at a frequency of about 40 kHz. The acoustic wave may be an ultrasonic wave.

[0018] In a preferred embodiment, the vibrating frequency ranges from about 100 Hz to about 500 Hz. In another embodiment, the vibrating frequency ranges from about 150 Hz to about 400 Hz. In one embodiment, the vibrating frequency ranges from about 150 Hz to about 340 Hz. In one particular embodiment, the vibrating frequency ranges from about 160 Hz to about 240 Hz. In another embodiment,- the vibration can affect the carrier signal or carrier waive. In one embodiment, the vibration is generated continuously, intermittently, or alternatively from the vibrator in direct contact with the eyelid, or through a medium between the vibrator and the eyelid.

[0019] In another aspect, the ultrasonic signal is transmitted by a transmitter connecting the eye and the receiver. In one embodiment, the vibrator comprises a detachable eyelid holder. In another embodiment, the receiver and the transmitted are separated by a specific distance such that the ultrasonic signal reflected by the eye surface can be received by the receiver. In one embodiment, the signal received by the receiver is further processed by an electronic circuit or a program stored in the data processing system. In a further embodiment, fast Fourier transform is used to process the data, wherein a frequency strength or an amplitude as function of frequency is determined. In another embodiment, the resonant frequency is calculated based on the amplitude as function of frequency.

[0020] In one aspect, an empirical curve of a data pair between the resonant frequency and the IOP is stored in the data processing system. In another aspect, the inner pressure is determined as an output based on the resonant frequency as an input in the data pair. In one embodiment, the subject is a mammal.

[0021] Another aspect of the invention is related to a device for measuring IOP of an eye of a subject. The device comprises a vibrator connected to a detachable eyelid holder that is in direct contact with the eyelid, wherein the detachable eyelid holder is pressed against the eyelid to generate a vibration on the eye at a frequency; an ultrasonic transmitter that generates an acoustic wave directed to a spot on the eye surface; a receiver that receives the reflected signal from the eye; and a data processing system that can process the reflected signal and calculate the IOP based on resonant frequency calculated from the reflected signal. In one aspect, the device further comprises a sensor for constant pressure. The receiver of the device, in one aspect, can be separated from the ultrasonic transmitter by a distance such that the signal is received by the ultrasonic receiver. In one embodiment, the vibration frequency ranges from about 100 Hz to about 500 Hz, about 150 Hz to about 400 Hz, or about 160 Hz to about 240 Hz.

[0022] In another aspect of the invention, the acoustic wave is at a frequency between about 20 kHz and about 80 kHz, about 30 kHz and about 70 kHz, or about 40 kHz and about 60 kHz. In one embodiment, the acoustic wave is at a frequency at about 40 kHz. In one embodiment, the acoustic wave is an ultrasonic wave. In another embodiment, the acoustic wave is generated continuously, intermittently, or alternatively with the vibration generated from the vibrator. In a further embodiment, the acoustic wave is driven by a signal generator circuit.

[0023] In another aspect, a light spot is used to fix position of the eye. The source of the light spot includes but is not limited to a LED light, an incandescent light, a fluorescent light, a high-intensity discharge ("HID") light, and/or a combination thereof. In one aspect, the ultrasonic signal is processed by an electronic circuit or a program stored in the data processing system. In another aspect, fast Fourier transform is used to process the data, during which a frequency strength or/and an amplitude as the function of frequency is determined. In yet another embodiment, resonant frequency is calculated based on the amplitude as the function of frequency. [0024] In one embodiment, an empirical curve between the resonant frequency and the IOP is stored in the data processing system. In another embodiment, the ultrasonic signal is processed by an electronic circuit or a program stored in the data processing system. The empirical curve provides a data pair of the resonant frequency and the IOP. In another aspect, the empirical curve or data set stored in the data processing system is based on a reference including, but not limited to, a scientific article, a result from a clinical trial, a test result, or a combination thereof.

[0025] In another embodiment, the device of this disclosure further comprises a noise reduction circuit to remove noise from environment. In yet another embodiment, the device of this disclosure comprises a data collector that can collect the signal received by the receiver in a time course.

[0026] In another embodiment, the device further comprises a controllable output system, said output system capable of creating constant pressure on the eye. In one aspect, the controllable output system comprises a sensor for monitoring pressure, a spring, a spring plate, or an elastic component.

BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG. 1 shows a basic flowchart of an exemplary device for testing IOP, which includes applying the demodulation method of this disclosure.

[0028] FIG. 2 shows a perspective view of an exemplary apparatus for testing IOP.

[0029] FIG. 3 shows a linear relationship between the resonant frequency and the IOP.

[0030] FIG. 4 shows an exemplary incident carrier wave as a standard sinusoidal signal ¾, where f _c =10, Ac=l .

[0031] FIG. 5 shows an exemplary reflected carrier signal y'(t), where f _c is shifted from medium(fc = 10 Hz) and the deviation is f _s = +1-2 Hz.

[0032] FIG. 6 shows an exemplary differentiation of y'(t) in MATLAB™, the signal is transferred from FM signal to AM signal. [0033] FIG. 7 shows an exemplary signal after envelope detection where the blue curve is the AM signal and the red curve is the envelope signal.

[0034] FIG. 8 shows an exemplary equations for calculating the carrier wave.

[0035] FIG. 9 shows exemplary equipment for measuring the IOP: A) a USB

oscilloscope and a computer; B) an ultrasonic system; C) a signal generator; and D) a vibrator and a model.

[0036] FIG. 10 shows an exemplary frequency modulation of an acoustic wave by a vibrating surface.

[0037] FIG. 11 shows an exemplary wave patterns of the modulated carrier

signal from the oscilloscope view.

[0038] FIG. 12 shows an exemplary carrier signal in the frequency domain.

[0039] FIG. 13 illustrates the carrier signal of FIG. 12 modulated by a vibrational signal in time domain.

[0040] FIG. 14 shows the differentiation of the carrier signal of FIG. 13 and the

envelope of the outcome signal under the Hilbert function by MATLAB™.

[0041] FIG. 15 shows the results of the curve frequency calculated by fast Fourier transform.

[0042] FIG. 16 illustrates the change of resonant frequency at the shift of the vibrational frequency.

[0043] FIG. 17 illustrates one exemplary electric circuit for the envelope detection.

[0044] FIG. 18 shows a block diagram of an exemplary phase lock loop system.

DETAILED DESCRIPTION

[0045] After reading this description, it will become apparent to one skilled in the art how to implement the disclosure in various alternative embodiments and alternative applications. However, not all embodiments of the present disclosure are described herein. It will be understood that the embodiments presented here are presented by way of an example only, and not limitation. As such, this detailed description of various alternative embodiments should not be construed to limit the scope or breadth of the present disclosure as set forth below.

[0046] Before the present disclosure is disclosed and described, it is to be understood that the aspects described below are not limited to specific devices, methods of preparing such devices, or uses thereof, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0047] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference in their entirety into the present disclosure.

Definitions

[0048] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0049] In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:

[0050] The terminology used herein is for the purpose of describing particular

embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0051] All numerical designations, e.g., pH, temperature, time, concentration, amounts, and molecular weight, including ranges, are approximations which are varied (+) or (-) by 10%, 1%, or 0.1%, as appropriate. It is to be understood, although not always explicitly stated, that all numerical designations may be preceded by the term "about." It is also to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0052] The term "about" when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by (+) or (-) 10%, 5%, 1%, or any subrange or subvalue there between. Preferably, the term "about" when used with regard to a dose amount means that the dose may vary by

+/- 10%.

[0053] The term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements but do not exclude others. "Consisting essentially of," when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed disclosure. "Consisting of shall mean excluding more than trace amounts of other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0054] The term "treating" or "treatment" covers the treatment of a disease described herein, in a plant, and includes: (i) inhibiting a disease, i.e., arresting its development;

(ii) relieving a disease; (iii) slowing progression of the disease; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.

[0055] The term "intraocular pressure" or "I OP" refers to the pressure that is maintained within the eye. The anterior chamber of the eye is bounded by the cornea, iris, pupil and lens. It is filled with aqueous humor, a watery fluid responsible for providing the cornea and lens with oxygen and nutrients. The aqueous humor provides the necessary pressure to help maintain the shape of the eye. When normal secretion of the aqueous humor is interrupted, IOP is affected. The average IOP in a normal population is 12-22 millimeters of mercury (mmHg). In a normal population, pressures up to 20 mmHg may be in normal range. Pressures of about 22 mmHg or higher are typically indicative of abnormal IOP.

[0056] The term "vibrator" refers to a machine or device that can transmit vibration. The vibrator may contain a vibration generator, a medium coupled to the generator, or the combination thereof. The vibration generated or transmitted by the vibrator may be controlled at a frequency and a range of frequencies. In one embodiment, the vibrator is used for shaking the eye surface. In another embodiment, the frequency of vibrations generated by the vibrator is adjustable so that when working, the vibrator minimizes or does not cause any discomfort to the eyelid. In another embodiment, the frequency response of the vibrator is linear in its working range. The vibrators of the present invention can be present in different shapes. In one embodiment, the vibrator is a coin- shape. In another embodiment, the vibrator is of any shapes with a flat surface. For the coin-shaped vibrator, the radius is at least 0.001, 0.01mm, 0.05 mm, 0.1 mm, 0.5 mm, lmm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, or 20 mm. In another embodiment, the radius is between 0.001 mm and 20 mm, 0.01 mm and 10 mm, 0.1 mm and 5 mm, or 1 mm and 3 mm. In a specific embodiment, the radius is between 1 mm and 3 mm. The surface area of the vibrator may be larger or smaller than the area of an eyelid. In some embodiments, the surface area is no larger than the area of an eyelid. The surface of the vibrator can be in direct or indirect contact with an eyelid. In one embodiment, the surface of vibrator is in direct contact with an eyelid. A smooth surface of the vibrator can avoid or minimize any discomfort caused by the contact.

[0057] The vibrator can be made from various materials. In one embodiment, the material is non-allergic and safe. Non-limiting examples of materials for the vibrators include plastics, polymers, silicones, epoxies, hydrogels, rubber, composites, thermoplastic elastomers, copolymers, copolyesters, polyamides, polyolefins, polyurethanes, vulcanizates, polyvinyl chloride, resins, fluropolymers, PTFE, FEP, ETFE, PFA, MFA, polycarbonate, acrylic, polypropylene, nylon, sulfone resins, synthetic materials, natural polymers, cellulose polymers, collagen, glass-reinforced materials, quartz, a silicate, a ceramic, or other materials. In one embodiment, the material comprises medical hard polymer or alloy. [0058] The term "acoustic wave" refers to a type of longitudinal wave that may propagate by means of adiabatic compression and decompression and that has the same direction of vibration as its direction of travel.

[0059] The term "fast Fourier transform" refers to a reversible operation, which includes Forward fast Fourier transform and Inverse fast Fourier transform.

[0060] The term "resonant frequency" refers to a frequency capable of exciting a resonance maximum in a given body or system. The resonant frequency, in this invention, can be used to determine the IOP of an eyeball.

[0061] The disclosure provides devices for measuring the IOP. Figure 1 shows one embodiment of the devices. As shown in Figure 1, the device may comprise two portions, the first one, named the processor, which not only initiates both generators but also receives the mixed signals coming from the demodulator part in order to process the data analysis. The second portion is the demodulator, which includes but is not limited to, several components, e.g., a filter, an envelope detector, a noise reduction filter, a frequency detector, and an amplitude detector. In one embodiment, the reflected wave, which preferably shows the max peaks, is treated before it is transmitted to a CPU. In another embodiment, the reflected wave may be transmitted directly to a CPU. In a further embodiment, the reflected wave may be separated into a frequency section and an amplitude section.

[0062] Figure 2 shows an intuitive view of the device's conformation. In one embodiment, the device could be operated by wearing it at head like an eye goggles. The size of the device will be similar to the eye goggles as well.

[0063] The component 1 plays the role of the vibrator as the low frequency signal is initiated from the apparatus and vibrate the eyelid, while in working mode. In one embodiment, in the non-working mode, the vibrator would be stopped. The frequency of vibrations generated by the vibrator is adjustable so that when working, the vibrator minimizes or does not cause any discomfort to the eyelid. In another embodiment, the frequency response of the vibrator is linear in its working range. [0064] The components 2 and 3 are a receiver and a transmitter, respectively. 4 is a soft material making contact with the skin. 5 is the nose pad and 6 is the elastic head band, which serve the purpose of placing and securing the device at head .7 is the LED screen board, while 8 is the power switch and 9 represents a group of buttons which are used for power switch, adjusting the frequencies, adjusting receiver and transmitter positions as well as other parameters. The advantage of the device according to the present invention and the indication above, is that this device can be used and tested at different body positions compared to conventional device on market today, and the whole device is portable and easily fits in a bag or box without causing any physical damage to the apparatus. As there is a wide range in terms of people's eye sizes, the distance between 2 and 3 is flexible, in one embodiment.

[0065] In one embodiment, the apparatus can be worn as a eye goggles while the buttons can be controlled by hands. In another embodiment, the apparatus is operated by one or more persons.

[0066] If the apparatus does not show the result on the display after a general test, users should first double check the connection between 1 and the core part to confirm the vibrator is operating. Then, by controlling the button on 9, users need to set the distance between 2 and 3 to its maximum or minimum value based on the user's own eye size. The user may wear the apparatus, and decrease or increase the value continuously until a stable result is achieved on the screen board. In another embodiment, the apparatus further comprises a distance sensor that can measure the distance between the apparatus and the corneal. Based on the distance information, one of ordinary skill in the art would know how to adjust the distance between the transmitter and the receiver to achieve the optimal results. The system can adjust the distance between components 2 and 3 automatically to provide the optimal result, which eliminates the errors by the users trying to adjust the values by themselves.

[0067] The device depicted in Figure 2 is intended to reveal the core principle of the device to those who are skilled in the art. More changes and modifications could be made, and the final construction is not limited to the illustration above. [0068] Thus, the disclosure provides a device, which may use the ultrasonic method for the IOP testing so the contact with the eye ball can be avoided. The device, which is intended to be an affordable, household-use device, is easy to operate and comfortable for users. The device can be used for glaucoma patients' daily IOP tests, helping them control their eye condition. It is more affordable and time efficient. With the invention, doctors can monitor patients' eye health conditions and provide guidance to the patients remotely.

Relationship between inner pressure and resonant frequency of the eyeball

[0069] Considering the variety of adverse effects associated with an invasive pressure sensor, non-invasive testing of IOP is preferable, which typically uses wireless measurement. It was suggested that for a thin membrane, the inner pressure applied to the membrane has an approximately linear relationship with its resonant frequency in specific ranges. See Baldi et al., IEEE Sensors Journal, 3 (6), pp. 728-733 (2003). The linear relationship has been applied to many technical fields, e.g., engineering and cell biology. One study suggests that the relationship may be applied to the IOP. See Han, et al., Optics in Health Care and Biomedical Optics: Diagnostics and Treatment, 143 (2002).

[0070] Without being bound by a theory, the resonant frequency of the human cornea can be influenced by IOP. Higher inner pressure can change the vibrating characteristics of the cornea and result in a higher resonant frequency. The relationship between these two parameters may be described in an empirical curve with which one can calculate the inner pressure based on the resonant frequency of the cornea. Without being bound by a theory, the empirical curve for one eyeball may be different from another. Thus, the users may build their own database for the relationship between the resonant frequency and the IOP. The means to build the database or create the empirical curve is known in the art.

[0071 ] Figure 3 shows the relationship between the inner pressure (unit in mmHg) and resonant frequency of pig eyes. Without being bound by a theory, at a low eye pressure range (lower than 30 mmHg), the resonant frequency and inner pressure have an approximately linear relation; when the eye pressure is above 30 mmHg, the frequency may reach its maximum and stays as a "constant" roughly around 400 Hz. Thus, the linear relationship may be used to determine the exact pressure value based on the resonant frequency. A high frequency may mean an abnormal pressure which necessitates treatment for the eyes.

Resonant frequency measurement

[0072] In one embodiment, the vibration may lead to the resonant frequency of the cornea. After a vibration is applied to the cornea, an ultrasonic wave emits into the vibrating corneal surface and is reflected to an ultrasound receiver. The vibrational characteristic of the cornea is carried by the reflected ultrasonic wave. The reflected wave, after received by a receiver, is processed by a main processor to derive the IOP value of the eyeball based on the relationship between the resonant frequency and IOP.

[0073] In one embodiment, the relationship between the resonant frequency and IOP is linear. In another embodiment, the linear relationship is positive.

Vibrating system

[0074] A contact vibrating system is used for vibrating the cornea. The vibrating system can provide a continuous, intermittent, or alternative vibration to the eyelid and the cornea. The vibrating frequency may change from about 100 Hz to about 500 Hz, about 150 Hz to about 400 Hz, about 150 Hz to about 340 Hz, or about 160 Hz to about 240Hz. The range of frequencies may refer to the testing range of eyeball pressure. Han, et al., Proc. SPIE 4916, Optics in Health Care and Biomedical Optics: Diagnostics and Treatment, 143, doi: 10.1117/12.482946 (September 11, 2002). That means when the vibrating system starts working, it may provide continuously, intermittently, or alternatively changing frequencies to the cornea. The maximum vibrating frequency in these ranges can be obtained by an ultrasonic system which indicates the resonant frequency of cornea.

[0075] The vibration can come from different sources. In one embodiment, the vibration is generated by a low frequency piezo transducer. The transducer has a working frequency range from 10 Hz to 10,000Hz, 50 Hz to 1,000 Hz, or from 100 Hz to 500 Hz. The frequency response of the vibrator is linear. Without being bound by a theory, the linear response may mean for each driven frequency in the working range, the vibrator keeps its displacement at a constant value to show such a linear change pattern. The displacement of the vibrator can be set by factory. In some embodiments, the constantly displacement is at least 0.01 mm, 0.05mm, 0.1mm, 0.2mm, 0.5 mm, 1 mm, or 10 mm.

[0076] In some embodiments, the operation driver of piezo transducer is a signal generator circuit, which generates a sine wave DC signal to drive the vibration. The rated voltage is at least 0.1 V, 1 V, 3 V, or 10 V. In another embodiment, the voltage is between 3V and 5V.

[0077] The disclosed device further comprises a noise-reducing means. The means to reduce noise is well known in the art. In some embodiments, the noise is reduced with a layer of foam. The working noise of the vibrator can be reduced to no more than 100 dB, 50 dB, 10 dB, or 1 dB. In another embodiment, the working noise is no more than 50 dB.

[0078] In one embodiment, the vibration system comprises a vibration generator and a vibration output system. The vibration output system can deliver the vibration generated by the vibration generator to the intended locations or the intended body parts. In another embodiment, the vibration output system may deliver the vibration at the frequency of the original vibration generator, manipulate, reduce the frequency of, or magnify the frequency of the vibration. In another embodiment, the vibration output system may also alter the orientation of the vibration. In one aspect of the invention, the controllable output system may further comprise a sensor in combination with a spring, a spring plate, or an elastic component. The controllable output system may be used to create the constant pressure or to control the frequency changing pattern or the frequency and/or orientation of the vibration. In another aspect of the invention, the vibration from the vibrating system is not an ultrasonic signal.

Ultrasonic sensor/transducer

[0079] In one embodiment, an ultrasonic transducer is used to emit ultrasound beam to the eye surface and receive the reflected wave from the eye. As long as fiting the disclosed device, the size of ultrasonic transducer can vary. In one embodiment, A reasonable size example of the transducer is 2mm x 2mm x 1mm.

[0080] The central frequency or operating frequency of the transducer is at least 1 kHz, 10 kHz, 20 kHz, 40 kHz, or 100 kHz. In one embodiment, the frequency is around 40 kHz. A variation from the central frequency is permitted for this application. The variation, in one example, is around 1 kHz. For a higher resolution operation, the operating frequency of the transducer can be increased to at least 50 kHz, 80 kHz, 130 kHz, 300 kHz, or 1,000 kHz.

[0081] In a preferred embodiment, the ultrasonic transducer, or the ultrasound beam is focused. That is to say, the beam does not spread out to the extent that would undermine the function or results of the invention. A focusing beam can increase the accuracy and resolution of the result, and can also decrease the noise. There are several technologies to focusing beam. One example is using beam guider. Another example is using an acoustic lens to create a focused ultrasound beam.

Frequency modulation of the shaking surface

[0082] The vibrational characteristics of the shaking surface can be obtained and carried by a high frequency acoustic wave. An ultrasonic beam with specific frequency is used as a carrier wave to measure the shaking frequency of the eyeball surface, or the surface of the cornea. When an acoustic sinusoidal wave (or a carrier wave) is emitted into a shaking surface, the wave pattern of the carrier wave can be influenced by the surface, resulting in a frequency shift of the carrier wave. When the carrier wave has a specific frequency f _c , the shaking surface has its own vibrational frequency f _s - The carrier wave can be explained by the following Equation 1 :

[0083] y(t)=Ac cos(2 m fc t) Eq. 1

[0084] Where y is the carrier wave, A _c is the amplitude of carrier wave, and f _c is the frequency of carrier wave. In one embodiment, the carrier wave pattern shows as a standard sinusoidal wave (Fig 4), when y(t) is plotted in the time domain and the frequency of the carrier wave equals 10 and the amplitude of the carrier wave equals 1 , i.e., f _c = 10 and Ac = 1. [0085] The incidence wave is emitted into the shaking cornea and is reflected by the surface. The reflected wave is then modulated and may carry information from the surface (or cornea). The reflected wave can be calculated based on the following equation:

[0086] y'(t)=Ac cos(2 π fct + fdeita cos(2 π f _s t)/f _s ) Eq. 2

[0087] In the equation, y' is the reflected wave, f _s is the vibrational frequency of surface (or cornea), and fdeita is the frequency deviation of the carrier signal (frequency change of f _c ). Thomas, et al., Communication Theory, ISBN 0-07-059091-5, pp. 136 (2015). In one embodiment, the result is shown in Fig. 5, when y'(t) is plotted in time domain, the

frequency of carrier wave equals 10, and the amplitude of carrier wave equals 1 with the frequency deviation of the carrier signal about 2, i.e., f _c = 10, Ac = 1, and fdeita = 2. At this condition, the reflected wave has a shifting f _c and the deviation is ±2.

[0088] The equations for the calculation are summarized in Figure 8.

[0089] Thus, by emitting a carrier signal into a vibrating surface, the frequency of the signal is modulated. The modulated signal has a time-course frequency deviation, which may indicate the strength of shaking, and the deviation circle is dominated by the shaking surface. Further processing can extract the information and derive the strength and frequency of the shaking surface.

[0090] In one aspect of the invention, the carrier signal may be ultrasonic waves in the range of 20 k Hz to about 200 k Hz. In another aspect, 40 kHz ultrasonic waves are used as the carrier signal. 40 kHz ultrasonic waves are widely used in communication and measurement, such as parking radar and distance detectors. The advantages of using 40 kHz ultrasonic waves include, but are not limited to, good penetrability through air and low scattering. At 40 kHz, the ultrasonic wave struggles to penetrate across the corneal-air interface, and thus using the wave at such frequency may lower the risk of burning the eye tissue and is perfect for the surface testing. One aspect of the invention is to provide an affordable device. Since the 40 kHz transducers are relatively inexpensive compared to those for different frequencies, their utilization helps provide an affordable device. Envelope detection method for frequency extract

[0091] Several methods may be used for modulating the frequency. In one aspect of the invention, the envelope detecting is used to modulate the frequency, which is a mathematic way to envelop a high-frequency carrier signal and to extract the low frequency information. Although it has been commonly used in demodulation of AM and FM radio, the disclosure provides that this method can be used to derive the resonant frequency of the cornea.

[0092] As explained above, without being bound by a theory, the modulated signal carries the information of the shaking frequency and the strength of the cornea. The carrier signal can be received by a receiver transmitter. Then the data of the acoustic wave can be transformed to an electrical signal. To reduce noise, the signal may first pass through a noise reduction module before being sent to a data processor.

[0093] The first step of data processing is to differentiate the reflected waves, or to transform the FM signal to AM signal, which allows use of the envelope detection method. A simple way to transform the FM signal to the AM signal is to differentiate the signals. The slope of FM signal is viewed as the amplitude of AM signal. After differentiation, the higher frequency deviation part indicates larger amplitude, but the deviation time circle remains the same. The signal differentiation can be determined by a differentiator circuit, or a program. In one embodiment, the result of differentiation of the reflected waves is shown in Figure 6.

[0094] The second step is envelope detection, or to use a lower frequency wave to cover the envelope of the signal. After the FM-AM transformation, the signal is enveloped to derive the envelope signal. The envelope detection can be conducted by an electronic circuit called an envelope detector or a programming process. An envelope detector or an envelope program can be used to derive the envelope signal. In one embodiment, the signal after envelope detection is shown in Figure 7.

[0095] The third step is to calculate the frequency of envelope signal. The amplitude of the enveloped signal is proportional to the derived frequency, as mentioned before, and the frequency of enveloped signal is the shaking frequency of surface (f _s ). Thus, a fast Fourier transform can be applied based on the relationship between the amplitude and the frequency. In one embodiment, a fast Fourier transform is applied to the red curve and the result shows the frequency of envelope signal is 2, which is equal to f _s = 2 that is set. After these three steps, the frequency of shaking corneal f _s can be successfully extracted from the carrier signal y'(t).

[0096] All the data process steps can be done by a program, depending on the design needed for the product. This method has high resolution and accuracy, which can be applied in data set with 40 kHz carrier wave.

Phase lock loop method for demodulation

[0097] In another aspect of the invention, the resonant frequency of corneal can be extracted by designed electrical circuit. There are several methods to demodulate high frequency signal. In one embodiment, the phase lock loop is used in this invention to process the signal received by system.

[0098] Phase lock loop(or PLL) is the most popular electrical method used in signal- processing systems, frequency modulation (FM) demodulation, frequency shift keying (FSK) demodulation, tone decoding, frequency multiplication, signal conditioning, clock synchronization, and frequency synthesis are some of the many applications of a PLL. PLL is a non-linear feedback loop. Figure. 18 shows the block diagram of a basic PLL system. The system comprises three parts: phase comparator, low-pass filter (LPF), and voltage-controlled oscillator (VCO). All parts are connected to form a closed-loop frequency-feedback system.

[0099] The input signal Vs with an input frequency fs will first pass through the phase comparator. The comparator basically works as a detector which compares the input frequency fs with the feedback frequency fo. The comparator provides a DC error voltage Ve, which is proportional to the phase and frequency difference of the input signal and the VCO. The DC voltage signal Ve then passes through a LPF to be filtered, and is applied to the control input of the VCO as signal Vd. Vd varies in a direction that reduces the frequency difference between the VCO and signal-input frequency. When the input frequency is sufficiently close to the VCO frequency, the closed-loop nature of the PLL forces the VCO to lock in frequency with the signal input Vs.

[0100] However, if the carrier Vs deviates (fluctuates) in frequency, the loop keeps itself locked. For this to happen the VCO frequency follows the incoming signal, and in turn for this to occur the voltage Vo must vary.

[0101] In FM demodulation applications, the variations in output voltage Vo correspond to the modulation applied to the signal. By amplifying the variation in Vo, it generates the demodulated signal.

Determination of the IOP value

[0102] As mentioned above, the disclosure provides methods of determining the reflected carrier signal, the shaking strength, and the frequency of the corneal surface. The shaking frequency of the cornea is set to shift in a specific range. Continuously applying the process would determine the shaking strength of each frequency point in this range. The strongest shaking frequency, without being bound by a theory, may be the resonant frequency of the cornea. Thus, this disclosure provides methods of obtain the resonant frequency of the cornea. Under the methods, the value of the resonant frequency can be transferred to the processor and compared to the empirical curve or a database to derive the IOP value of the measured eye.

Data transfer

[0103] The resultant data may be transmitted wirelessly to a data center, a doctor, a tester, or other person authorized to receive the data. In one embodiment, the data center may include a server that serves up the data in a format that is accessible to authorized users, including but not limited to a web page or mobile device app. In another embodiment, the data may be transferred via a network, including but not limited to the Internet,, an intranet, a local area network ("LAN"), or a wide area network ("WAN"). In one aspect, a cloud- based server on the network may be used to provide data directly or indirectly to users via the network. In another aspect, the data can be provided over a restricted- or unrestricted- access Wi-Fi or Bluetooth connection so that authorized users can access the data from any location within the vicinity of the data center. In a further embodiment, software can be run either locally at the data center or on a cloud-based server to perform various features, such as monitoring data trends and providing comparisons of IOP between different users and/or different times for one or more users.

Working Examples

Example I. The operation of a non-contact intraocular pressure tonometer

[0104] In one example, to test IOP, a user puts the probe in front of the eye. A vibrator is attached surrounding the eyelid to apply small vibrations and fix the probe's position. An ultrasonic system then collects the data and processes a reference IOP value for this test. The test takes less than 15 seconds and the user will receive the result in a minute. During the test, the user needs to look into the probe and not blink. The user may feel a small vibration from the vibrator but not to the point of discomfort.

[0105] After starting the pressure tonometer, the test and data process are automated, and, therefore, there is no need for complex setting adjustments. Without training, a patient can operate the machine independently and receive the result quickly. All the results are collected by the processor and sent to a smart phone or other devices. The user can review and track their IOP histories at any time. Automated medication advice is provided after each test. A sound alarm can remind patients if the IOP is in the abnormal range or if too much time has elapsed since the patient was last tested.

Example II. The measurement and demodulation of resonant frequency

[0106] Anon-contact, household tonometer for glaucoma patients' daily use may include an ultrasonic transducer probe with a main body. The main body contains all functional circuits to operate the system. Figure 9 shows the exemplary devices for measuring the IOP, which includes a USB Oscilloscope, an ultrasonic system, a signal generator, a vibrator, and a model. A computer, or a CPU, with compatible systems or necessary software may also be included as part of the devices.

[0107] A main controller is used to control this device. A 40kHz oscillating circuit provides 40kHz sinusoidal signal that is sent to an ultrasonic transmitter for generating a carrier wave which can be measured by an oscilloscope (Fig. 1 1). As shown in Fig. 12, the main 40kHz peak indicates the central frequency of the carrier signal, and the small sub peaks on both sides of the 40kHz peak illustrates the frequency shifts away from the central. The carrier signal may also be modulated by the vibrational signal. Fig 13 shows the carrier signal modulated by 200Hz vibrational signal in the time domain. The sample rate is 240kHz, lasting 0 to 1 second.

[0108] The carrier wave is then emitted into the measured eye and is reflected by the corneal surface. The frequency of an acoustic wave can be modulated by the vibrating surface (Fig 10). When an ultrasound wave is transmitted to a shaking surface, the reflection wave is modulated by the vibration, the signal of which is then carried by ultrasound back to the receiver.

[0109] The receiver can transform the received wave to an electrical signal. Subsequently, the demodulation process is used to extract the vibrational characters, including the frequency and the power (Fig. 14). In Fig. 14, the blue curve represents the differentiated signal and the orange curve is the envelope of the signal. The envelope curve may filter the high-frequency signals and keep the low- frequency variations.

[0110] The optimal resonant frequency for differentiation is influenced by the initial vibrational frequency. As shown in Figure 15, the shift of the vibrational frequency results in the changed heights of peaks, among which the highest peak indicates the resonant frequency.

[0111] In one embodiment, the frequency of the curve may result from processing the envelope curve by the fast Fourier transform. Fig. 15 shows the envelope curve in frequency domain, in which the small peak represents the frequency of envelope curve at about 200Hz, which is equal to the vibrational frequency. The y axis stands for the strength or power of that specific vibration.

[0112] In one embodiment, the signals can be processed by various devices, including a serial circuit (include noise reducer, differentiator and envelope detector) or an electric circuit. Fig. 17 shows the design of one electric circuit that can be used to process the signal from the resonant frequency. Finally, the outcome data from the processed signals is sent to a controller to derive the IOP value.

[0113] While the exemplary devices described hereinabove use a technique of FM demodulation based on an intermediate conversion to an AM envelope, any suitable FM demodulation technique, such as, for example, any suitable FM discriminator can be used.

[0114] While the exemplary devices described hereinabove use a separate transmit and receive ultrasonic transducers, there can be at least a commonly packaged sensor or transducer package which includes both an ultrasonic transmitter and an ultrasonic receiver. It can also be possible to use a single or common ultrasonic transducer for near simultaneous transmission and reception of the ultrasonic signals using a techniques, such as, for example, a time-multiplexing and/or signal splitting technique. For example, the transducer can emit ultrasound pulses in relatively quick succession, and receive one or more reflected waves between each emitting, thus allowing the device to use a single transducer to record data over time.

[0115] While the exemplary devices described hereinabove use hardware components, such as for example a PLL integrated circuit, any of the functions described hereinabove, such as, for example, including modulation or de-modulation, filtering, signal processing, peak detection, etc. can be done either in hardware or in software or by any suitable combination of hardware and software. Solutions to function blocks in hardware can also include blocks which emulate a hardware function by programming or firmware. For example, a particular function performed in part or whole by a field programmable logic array (FPGA). Functions can also be performed by any suitable processor, such as, for example, a processor of one or more microcomputers, micro-processors, or processors on any suitable computer ranging from a microprocessor or microcomputer board to any suitable personal computing device of any suitable type, including smart phones, tablets, pads, netbooks, notebooks, desktop computers, etc.

[0116] Computer code for a device as described hereinabove, such as, for example, including firmware, software, and/or device programming code, etc., can be supplied on a computer readable media. A computer readable non-transitory storage medium as non-transitory data storage includes any data stored on any suitable media in a non-fleeting manner. Such data storage includes any suitable computer readable non-transitory storage medium, including, but not limited to programmable semiconductor devices, hard drives, non-volatile RAM, SSD devices, CDs, DVDs, etc.

[0117] It will be appreciated that variants of the above-disclosed and other features and functions, or alternatives thereof, may be combined into many other different systems or applications. Various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.

[0118] In summary, according to one aspect A method of measuring intraocular pressure of an eye of a subject, includes vibrating the eye by a vibrator in direct contact with an eyelid, wherein the vibration occurs at a frequency; directing an acoustic wave to a spot on corneal surface of the eye, wherein the acoustic wave is generated by an ultrasonic transmitter; receiving a reflected signal from the eye surface by a receiver; and processing the reflected signal via a data processing system, wherein the reflected signal is converted to resonant frequency based on a plurality of parameters stored in the data processing system; wherein the intraocular pressure is measured based on the resonant frequency of step (d). In one embodiment, the frequency of step (a) ranges from about 100 Hz to about 500 Hz. The method of claim 1 or 2, wherein the frequency of step (a) ranges from about 150 Hz to 400 Hz. In another embodiment, the frequency of step (a) ranges from about 150 Hz to about 340 Hz. In yet another embodiment, the frequency of step (a) ranges from about 160 Hz to about 240 Hz. In yet another embodiment, the acoustic wave is at a frequency between about 20 kHz and about 80 kHz, about 30 kHz and about 70 kHz, or about 40 kHz and about 60 kHz. In yet another embodiment, the acoustic wave is at a frequency of 40 kHz. In yet another embodiment, the acoustic wave is an ultrasonic wave. In yet another embodiment, the acoustic wave is generated continuously, intermittently, or alternatively with the vibration from the vibrator in direct contact with the eyelid. In yet another embodiment, the ultrasonic signal is transmitted by a transmitter connecting the eye and the receiver. In yet another embodiment, the vibrator includes a detachable eyelid holder. In yet another embodiment, the receiver and the transmitter are separated by a specific distance such that the ultrasonic signal reflected by the eye surface can be received by the receiver. In yet another embodiment, the specific distance is controlled by a controllable output system, the controllable output system including a sensor, a spring, a spring plate, or an elastic component. In yet another embodiment, the controllable output system is capable of creating a constant pressure or variable pressures on the eye. In yet another embodiment, the ultrasonic signal is processed by an electronic circuit or a program stored in the data processing system. In yet another embodiment, a fast Fourier transform is used to process the data, wherein a frequency strength or an amplitude as a function of frequency is determined. In yet another embodiment, the resonant frequency is calculated based on the amplitude as the function of frequency. In yet another embodiment, an empirical curve of a data pair between the resonant frequency and the intraocular pressure is stored in the data processing system. In yet another embodiment, the inner pressure is determined as an output based on the resonant frequency as an input in the data pair. In yet another embodiment, the subject is a mammal.

[0119] According to another aspect, a device for measuring intraocular pressure of an eye of a subject, the device includes a vibrator, the vibrator is connected to a detachable eyelid holder that is in direct contact with eyelid. The detachable eyelid holder is pressured against the eyelid to generate a vibration on the eye at a frequency. An ultrasonic transmitter generates an acoustic wave directed to a spot on the eye surface. An ultrasonic receiver receives an ultrasonic signal reflected from the eye. The ultrasonic receiver is separated from the ultrasonic transmitter by a distance such that the ultrasonic signal is received by the ultrasonic receiver. A data processing system processes the ultrasonic signal and calculates the intraocular pressure based on resonant frequency calculated from the ultrasonic signal. In one embodiment, the vibration frequency ranges from about 100 Hz to about 500 Hz. In another embodiment, the vibration frequency ranges from about 150 Hz to about 400 Hz. In yet another embodiment, the vibration frequency ranges from about 150 Hz to about 340 Hz. In yet another embodiment, the vibration frequency ranges from about 160 Hz to about 240 Hz. In yet another embodiment, acoustic wave is at a frequency between about 20 kHz and about 80 kHz, about 30 kHz and about 70 kHz, or about 40 kHz and about 60 kHz. In yet another embodiment, the acoustic wave is at a frequency of about 40 kHz. In yet another embodiment, the acoustic wave is an ultrasonic wave. In yet another embodiment, the acoustic wave is generated continuously, intermittently, or alternatively with the vibration generated from the vibrator. In yet another embodiment, the acoustic wave is driven by a signal generator circuit. In yet another embodiment, a light spot is used to fix position of the eye. In yet another embodiment, the light spot comes from a source selected from a group consisting of a LED light, an incandescent light, a fluorescent light, a high-intensity discharge ("HID") light, and/or a combination thereof. In yet another embodiment, the ultrasonic signal is processed by an electronic circuit or a program stored in the data processing system. In yet another embodiment, a fast Fourier transform is used to process the data, wherein a frequency strength or an amplitude as the function of frequency is determined. In yet another embodiment, the resonant frequency is calculated based on the amplitude as the function of frequency. In yet another embodiment, an empirical curve between the resonant frequency and the intraocular pressure is stored in the data processing system. In yet another embodiment, the ultrasonic signal is processed by an electronic circuit or a program stored in the data processing system, the empirical curve having a data pair of the resonant frequency and the intraocular pressure. In yet another embodiment, the empirical curve or data set stored in the data processing system is based on a reference, the reference including a scientific article, a result from a clinical trial, a test result, or a combination thereof. In yet another embodiment, the device further includes a noise reduction circuit to remove noise from environment. In yet another embodiment, the device further includes a data collector, the collector collecting the signal received by the receiver in a time course. In yet another embodiment, the device further includes a controllable output system can create constant pressure on the eye. In yet another embodiment, the controllable output system includes a sensor for monitoring pressure, a spring, a spring plate, or an elastic component. In yet another embodiment, the device further includes a distance sensor capable of measuring the distance between the transmitter and the receiver.