Patent Description:
Noninvasive blood test measurements are performed by attaching a measurement device to the patient's skin. These devices are usually operated by sending electromagnetic signals (e.g., visual light, IR radiation, RF radiation, etc.) via the patient skin targeting a blood vessel and reading reflection received from the blood vessel. Different humans' skin has different characteristics, such as, different thicknesses of different skin layers, different amount of hair, different amount of pigment etc., and therefore may absorb differently the electromagnetic signals sent from the noninvasive measurements device. Accordingly, there is a need for a noninvasive blood measurement deceive that may be calibrated specifically to each user so to measure accurately, concentrations of various materials in the blood for patients with different skin characteristics and different anatomy.

<CIT> provides a method of calibrating an optical analysis system that makes use of multivariate optical signal analysis allowing to realize cost-efficient and robust implementation of a spectral analysis of an optical signal. The calibration method makes use of determining a parameter of a reference sample by means of the optical analysis system and comparing the actually determined parameter with a reference parameter that represents a precise and real property of the reference sample. Based on this comparison a calibration value can be determined that is applicable to perform a calibration of the optical analysis system with respect to at least one compound or analyte of the reference sample. Parameters and reference parameters of a reference sample may refer to a concentration of an analyte dissolved in the sample, or to spectroscopic background signals that have to be taken into account when performing a spectral analysis based on optical signals obtained from the reference sample. Various different reference samples providing a reference with respect to different acquisition conditions and different analyte or compound concentrations can be universally used. Analyte-specific reference data is preferably stored in a calibration unit of the optical analysis system and allows a high degree of automation of the calibration process.

Some aspects of the invention are directed to a system for calibrating a device for measuring materials concentration in the blood. The system includes at least two sets of calibrating elements, each set comprising a plurality of calibrating elements. Each of the calibrating elements includes, a first layer simulating a specific human skin characteristics; a second layer comprising a specific concentration of one or more materials in the blood; and a third layer for simulating illumination reflection from a blood vessel in a skin tissue. The specific human skin characteristics comprise at least one of: skin thickness, skin color, skin hair density, skin tone, skin temperature, skin optical properties and skin hair color. All calibrating elements in a set the first layer may be the same first layer simulating the same specific human skin characteristics such that each set of calibrating elements simulate different specific human skin characteristics. Each calibrating element in a set of calibrating elements includes a different second layer comprising a different concentration of the one or more material. The third layer isolates the calibrating element from noise and reflections not related to the measured one or more materials in the second layer. The system further includes a controller that is configured to: receive illumination intensities from the device for measuring materials concentration when the device is attached to each calibrating element of the system; associate the received illumination intensities with the specific human skin characteristics and the specific concentration of the calibrating element to which the device is attached; and save the illumination intensities associated with the specific human skin characteristics and the specific concentration in lookup tables in a memory of the device for measuring materials concentration.

In some embodiments, the received illumination intensities may include illumination intensities at various wavelengths and the saved lookup tables include lookup tables for illumination intensities of a specific wavelength associated with the specific human skin characteristics, the one or more materials and the specific concentration. In some embodiments, the system may further include a third layer for simulating illumination reflection from a blood vessel in a skin tissue.

An additional aspect of the present invention is related to a method of calibrating a device for measuring materials concentration in the blood. The method includes: attaching the device for measuring materials concentration to each calibrating element included in one of two or more sets of calibrating elements. Each of the calibrating elements includes: a first layer simulating specific human skin characteristics; a second layer comprising a specific concentration of one or more materials in the blood; and a third layer for simulating illumination reflection from a blood vessel in a skin tissue. The specific human skin characteristics comprise at least one of: skin thickness, skin color, skin hair density, skin tone, skin temperature, skin optical properties and skin hair color. In all calibrating elements in a set, the first layer is the same first layer simulating the same specific human skin characteristic and each set of calibrating elements simulates different specific human skin characteristics, each calibrating element in a set of calibrating elements includes a different second layer comprising a different concentration of the one or more materials, and the third layer isolates the calibrating element from noise and reflections not related to the measured one or more materials in the second layer. The method further includes: receiving, by a controller of a calibrating system, illumination intensities from the device for measuring materials concentration when the device is attached to each calibrating element; associating, by the controller, the received illumination intensities with the specific human skin characteristics and the specific concentration of the one or more materials in the second layer of the calibrating element to which the device is attached; and recording, by the controller, the illumination intensities associated with the specific human skin characteristics and the specific concentrations in a memory of the device for measuring materials concentration.

In some embodiments, receiving illumination intensities may include receiving illumination intensities at various wavelengths and recording the illumination intensities may include creating lookup tables for illumination intensities of a specific wavelength associated with the specific human skin characteristic and the specific concentration.

The subject matter regarded as the invention is defined by the claims.

However, it will be understood by those skilled in the art that the invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components modules, units and/or circuits have not been described in detail so as not to obscure the invention. Some features or elements described with respect to one embodiment may be combined with features or elements described with respect to other embodiments. For the sake of clarity, discussion of same or similar features or elements may not be repeated.

Although embodiments of the invention are not limited in this regard, discussions utilizing terms such as, for example, "processing," "computing," "calculating," "determining," "establishing", "analyzing", "checking", or the like, may refer to operation(s) and/or process(es) of a computer, a computing platform, a computing system, or other electronic computing device, that manipulates and/or transforms data represented as physical (e.g., electronic) quantities within the computer's registers and/or memories into other data similarly represented as physical quantities within the computer's registers and/or memories or other information non-transitory storage medium that may store instructions to perform operations and/or processes. Although embodiments of the invention are not limited in this regard, the terms "plurality" and "a plurality" as used herein may include, for example, "multiple" or "two or more". The terms "plurality" or "a plurality" may be used throughout the specification to describe two or more components, devices, elements, units, parameters, or the like. The term set when used herein may include one or more items. Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Additionally, some of the described method embodiments or elements thereof can occur or be performed simultaneously, at the same point in time, or concurrently.

Reference is now made to <FIG> which is a diagrammatic representation of a system for calibrating a device for measuring materials concentration in the blood according to some embodiments of the invention. System <NUM> includes at least two sets <NUM> and <NUM> of calibrating elements 105a-105d and 106a-106d. In some embodiments, system <NUM> may include additional sets, for example, set <NUM>, of calibrating elements 107a-107d. A detailed description of a calibrating element is given with respect to <FIG>. System <NUM> further includes a controller <NUM>, and may include a storage unit <NUM> a user interface <NUM> and a communication unit <NUM>. Communication unit <NUM> may be configured to send and receive information from a device <NUM> for measuring materials concentration in the blood.

In some embodiments, controller <NUM> may include a processor <NUM> that may be, for example, a central processing unit (CPU), a chip or any suitable computing or computational device, an operating system <NUM> and a memory <NUM>. System <NUM> may include a desktop computer, laptop commuter, a tablet, a mainframe computer or the like. Processor <NUM> may be configured to carry out methods according to embodiments of the present invention by for example executing instructions stored in a memory such as memory <NUM>.

Operating system <NUM> may be or may include any code segment designed and/or configured to perform tasks involving coordination, scheduling, arbitration, supervising, controlling or otherwise managing operation of controller <NUM>, for example, scheduling execution of programs. Operating system <NUM> may be a commercial operating system. Memory <NUM> may be or may include, for example, a Random Access Memory (RAM), a read only memory (ROM), a Dynamic RAM (DRAM), a Synchronous DRAM (SD-RAM), a double data rate (DDR) memory chip, a Flash memory, a volatile memory, a non-volatile memory, a cache memory, a buffer, a short term memory unit, a long term memory unit, or other suitable memory units or storage units. Memory <NUM> may be or may include a plurality of, possibly different memory units.

Memory <NUM> may store any executable code, e.g., an application, a program, a process, task or script. The executable code may include codes for calibrating a device for measuring materials concentration in the blood or any other codes or instruction for executing methods according to embodiments of the present invention. The executable code may be executed by processor <NUM> possibly under control of operating system <NUM>.

Storage <NUM> may be or may include, for example, a hard disk drive, a floppy disk drive, a Compact Disk (CD) drive, a CD-Recordable (CD-R) drive, a universal serial bus (USB) device or other suitable removable and/or fixed storage unit. Content may be stored in storage <NUM> and may be loaded from storage <NUM> into memory <NUM> where it may be processed by processor <NUM>. For example, storage <NUM> may include reference data related to measuring materials concentration in the blood, such as amplitude of reflected IR light in different wave lengths , representing: glucose blood levels, LDL (low density lipoproteins) levels in the blood , HDL (high density lipoprotein )levels in the blood ,cholesterol levels in the blood , TG( Tri Glycerides) levels in the blood , Albumin levels in the blood Hemoglobin levels in the blood cardiac pulse frequency , cardiac pulse signal intensity, skin temp rate, body movement or lack of movement, body acceleration in different directions horizontal positioning , skin thickness, skin pigmentation,.

User interface <NUM> may be or may include a screen, a pointing device and an audio device or any other device that may allow a user to send instructions and/or information to controller <NUM> and receive information from controller <NUM>. For example, user interface <NUM> may include, a mouse, a touch screen or a pad, a keyboard, a microphone, speakers and the like.

In some embodiments, system <NUM> may further include a communication unit <NUM> for communication with at least one device <NUM> for measuring materials concentration in the blood. Communication unit <NUM> may include any applicable input/output (I/O) devices to connected controller <NUM> and device <NUM>, for example, a wired or wireless network interface card (NIC), a modem, a universal serial bus (USB) device or external hard drive and the like.

Embodiments of the invention may include an article such as a computer or processor non-transitory readable medium, or a computer or processor non-transitory storage medium, such as for example a memory, a disk drive, or a USB flash memory, encoding, including or storing instructions, e.g., computer-executable instructions, which, when executed by a processor or controller, carry out methods disclosed herein.

The storage medium may include, but is not limited to, any type of disk including floppy disks, optical disks, compact disk read-only memories (CD-ROMs), rewritable compact disk (CD-RWs), and magneto-optical disks, semiconductor devices such as read-only memories (ROMs), random access memories (RAMs), such as a dynamic RAM (DRAM), erasable programmable read-only memories (EPROMs), flash memories, electrically erasable programmable read-only memories (EEPROMs), magnetic or optical cards, or any type of media suitable for storing electronic instructions, including programmable storage unit.

A system according to embodiments of the invention may include components such as, but not limited to, a plurality of central processing units (CPU) or any other suitable multi-purpose or specific processors or controllers, a plurality of input units, a plurality of output units, a plurality of memory units, and a plurality of storage units. A system may additionally include other suitable hardware components and/or software components. In some embodiments, a system may include or may be, for example, a personal computer, a desktop computer, a mobile computer, a laptop computer, a notebook computer, a terminal, a workstation, a server computer, a tablet computer, a network device, or any other suitable computing device. Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Additionally, some of the described method embodiments or elements thereof can occur or be performed at the same point in time.

Reference is now made to <FIG> which is an illustration of a device for measuring materials concentration in the blood according to some embodiments of the invention. Device <NUM> may be a wearable monitoring device configured to measure concentration of materials such as, glucose, albumin, insulin and the like, in a user's blood. Device <NUM> may include a measuring unit <NUM>, a processor <NUM>, a communication unit <NUM> and a memory <NUM>. Measuring unit <NUM> may include at least one sensor <NUM> and at least one light emitting source <NUM>. In some embodiments, measuring unit <NUM> may be adjacent to and in contact with the skin of a subject so as to reduce noise from the environment. It should be noted that with light emitted from the at least one light emitting source <NUM>, device <NUM> may perform optical measurements that are noninvasive in contrast to commercially available invasive and minimal invasive solutions.

According to some embodiments, the EM radiation emitted from the at least one light emitting source <NUM>, may be reflected from a subcutaneous tissue of the subject, and then detected by the at least one sensor <NUM> that may be, according to some embodiments, in the Infra-Red or near Infra-Red (IR) spectrum. For example, Short Wave IR (SWIR) imaging is utilized for measuring physiological signals from the blood of a subject. The SWIR waveband runs from the lower edge of the near IR region at <NUM> up to <NUM>, and may be utilized for inspection of blood vessels in the body of the subject. It should be noted that if required, the range of the SWIR waveband may be increased.

It should be noted that device <NUM> may include measuring unit <NUM> in various configurations, and in some embodiments a single sensor <NUM> is surrounded by a plurality of light emitting sources <NUM> (as for example illustrated in <FIG>). Other configuration may also employ a plurality of sensors <NUM> and light emitting sources.

In some embodiment, each light emitting source <NUM>, or sub-sets (e.g. pairs, triplets etc.) of light emitting sources <NUM> may emit light in a different predetermined wavelength.

In some embodiment, each light emitting source <NUM>, or sub-set of light emitting sources <NUM>, may emit light in a different time and/or in a different frequency, such that not all light emitting sources <NUM> emit light simultaneously. This may provide additional information on the reflected tissue when the time intervals between the emissions of light beams are known.

According to some embodiments, the frequency of sampling by each light emitting source <NUM>, or by each sub-set of light emitting sources <NUM>, may be equal to or higher than Nyquist rate of the measured physiological signal.

In some non-limiting embodiments, polarized optical means may be utilized in order to increase the accuracy in the optical measurements. Specifically, emitting light beams with a predetermined polarization and receiving these beams with a substantially different polarization, for instance with dedicated filters, may improve the signal to noise ratio in the measurements. Furthermore, such polarizing may also provide improved indication on the penetration of the light beam into the tissue as noises from the external skin layer may be reduced while only signals from the beam reflected of the blood vessels is measured.

In some non-limiting embodiments, other sensors may also be utilized. For example acoustic ultrasound sensors, as well as terahertz sensors, RF sensors, microwave sensors and corresponding energy sources.

Reference is now made to <FIG> which is an illustration of a calibrating element according to some embodiments of the invention. A calibrating element <NUM> includes a first layer <NUM> simulating a specific human skin characteristics and a second layer <NUM> consisting a specific concentration of one or more materials in the blood, for example, glucose, albumin and insulin or a combination thereof. In some embodiments, the specific concentration may include specific concentrations of more than one material, for example, albumin and insulin. Skin characteristic according to embodiments of the invention include at least one of: skin thickness, skin temperature skin color, skin hair density, skin optical properties, and skin hair color. In some embodiments, the skin optical properties may include the ability of the skin to absorb, reflect and/or scattered EM radiation, for example, short wave infrared. The skin optical properties may include the scattering parameter (S-parameters) matrix.

According to the invention, calibrating element <NUM> further includes a third layer <NUM> for simulating illumination reflection from a blood vessel in a skin tissue and for isolating the element from noise and reflections not related to the measured one or more materials in the second layer. Calibrating element <NUM> may include substantially the same types of layers as calibrating elements 105a-105d, 106a-106d and 107a-107b illustrated in <FIG>. In some embodiments, calibrating element <NUM>, 105a-105d, 106a-106d and 107a-107b may be configured to allow device <NUM> to be attached to the calibrating element in such a way that external light radiation does not interfere with the sent EM radiation and read EM reflections from the calibrating element. For example, calibrating element <NUM>, 105a-105d, 106a-106d and 107a-107b may have a cylindrical shape to emulate the form of a human wrist or arm. Other shapes may be used.

First layer <NUM> may include any material that may simulate the EM absorption properties of the human skin. For example, first layer <NUM> may include materials that simulate melanin chromophores, skin proteins (collagen, elastin), water, blood lipids, hemoglobin or other blood components, that may simulate the reaction of a human skin to EM radiation emitted from one or more emitting sources <NUM>. Some of calibration elements <NUM> may have (when not falling under the scope of the claims) different first layers simulating different skin characteristics. In some embodiments, sets <NUM>, <NUM> and <NUM> may vary in the simulated thickness for example, elements 105a-105d may all have the same first layer simulating a skin thickness of <NUM>; elements 106a-106d may all have the same first layer simulating a skin thickness of <NUM> and elements 107a-107d may all have the same first layer simulated a skin thickness of <NUM>. In some embodiments, system <NUM> of <FIG> may include sets having skin thicknesses of <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. <NUM> and <NUM>.

In some embodiments, at least some of the sets of calibrating elements may simulate different skin color& tone in addition to different skin thickness. For example, set <NUM> and set <NUM> may both simulate a skin thickness of <NUM> but with different amount of color pigment such as melanin chromophores, hemoglobin, other blood components, skin proteins (Elastin, collagen) etc..

Second layer <NUM> may include a liquid or solid solution comprising a specific concentration of one or more materials to be measured in the blood. For example, second layer <NUM> may include a specific concentration of albumin and/or glucose. In some embodiments, each calibrating element in a set of calibrating elements may include a different second layer having a different concentration of the one or more materials. For example, calibrating element 105a may include <NUM>/dL of albumin, element 105b may include <NUM>/dL of albumin, element 105c may include <NUM>/dL of albumin and element 105d may include <NUM>/dL of albumin. Similar or different albumin concentrations may be included in elements 106a-106d and 107a-107d. In yet another example, elements 106a-106d and 107a-107d may include different concentrations of albumin and glucose. It should be appreciated that while the example illustrated in <FIG> each set of elements <NUM>, <NUM>, <NUM> includes <NUM> calibration elements, any number of calibrating elements may be used in each set. Furthermore, it should be appreciated that according to some embodiments, different sets may have different number of calibrating elements.

Third layer <NUM> may include any material that will isolate and absorb the electromagnetic radiation emitted from one or more emitting source <NUM> the way a human organ/skin will do. For example, third layer <NUM> may include wood aluminum, metal, ,SWIR (short-wavelength infrared) opaque polymers and water.

Reference is now made to <FIG> which is a flowchart of a method of calibrating a device for measuring materials concentration in the blood according to some embodiments of the invention. The method of <FIG> may be performed using a system such as system <NUM>. In operation <NUM>, embodiments may include attaching the device for measuring materials concentration to each calibrating element included in two or more sets of calibrating elements. Device <NUM> may be attached, manually or automatically (e.g., by a robotic system) to at least some of the calibrating elements of system <NUM>. For example, device <NUM> may be attached first to each of calibrating elements 105a-105d of set <NUM> and then be attached to each of calibrating elements 106a-106d of set <NUM>, and so on.

In some embodiments, each time device <NUM> is being attached to a calibrating element, one or more light emitting sources <NUM> may emit EM radiation (e.g., light) into the calibrating element and one or more sensors <NUM> may read EM radiation reflected back from the calibrating element. Processor <NUM> may record in memory <NUM> the intensity (e.g., an optical value) at which the reflected EM radiation was sensed by one or more sensors <NUM>. In some embodiments, one or more light emitting sources <NUM> may emit light at several wavelengths, for example, at <NUM> and <NUM> and sensor <NUM> may sense two different intensities (e.g., different optical values) for each wavelength. In some embodiments, processor <NUM> may be configured to send via communication unit <NUM> the recorded intensities to controller <NUM>.

In operation <NUM>, embodiments may include receiving illumination intensities from the device for measuring materials concentration when the device is attached to each calibrating element. In some embodiments, the illumination intensities may be affected by the optical characteristics of at least first layer <NUM> and second layer <NUM>. The EM radiation reflected from second layer <NUM> may be affected by the ability of the material or materials in layer <NUM> (e.g., albumin and/or glucose) to absorb the EM radiation and the scattering, absorbing and reflecting properties of first layer <NUM>. Processor <NUM> may receive from device <NUM>, via communication unit <NUM> the sensed illumination intensities, sensed by sensor <NUM> for each calibrating element separately. Processor <NUM> may further receive information regarding form which calibrating element the illumination intensities was received and at which wavelength. In some embodiments, each calibrating element may be marked with a machine readable tag such as an RFID tag, a barcode or the like. In some embodiments, system <NUM> may further include a tag reader in communication with controller <NUM> that are configured to read an identification code included in the machine readable tag.

Accordingly, processor <NUM> may associate the received illumination intensities with the specific skin characteristics and the specific concentration of the calibrating element to which the device is attached, in operation <NUM>.

An example for intensities (optical values) recorded for various calibrating elements at two wavelengths is given in table <NUM>. The calibrating elements of table <NUM> includes at least two layers, a first layer simulating the skin thickness (<NUM> for set <NUM> and <NUM> for set <NUM>) and a second layer comprising albumin at concentrations of <NUM>-<NUM>/dL.

Processor <NUM> may form lookup tables, such as for example, table <NUM> and save the illumination intensities associated with the specific skin characteristics and the specific concentration in a memory (e.g., memory <NUM>) of the device (e.g., device <NUM>) for measuring materials concentration, in operation <NUM>.

In some embodiments, some of the sets from the at least two sets of calibrating elements may include simulating a human skin with a first amount of color pigments and some of the sets from the at least two sets of calibrating elements includes simulating a human skin with a second amount of color pigments. In some embodiments, the received illumination intensities may include illumination intensities received from calibrating elements simulating a human skin with the first and second amount of color pigments. Accordingly, the lookup tables may further include illumination intensities associated with specific skin thickness having specific color (e.g., amount of pigment in the skin).

Accordingly, when device <NUM> is attached to a human's skin (e.g., human hand) with known skin thickness a reading from sensor <NUM> following illumination at a known wavelength may be accurately associated to a concentration of one or more materials (e.g., albumin and glucose) in the blood using the lookup tables stored in memory <NUM>.

Claim 1:
A system (<NUM>) for calibrating a device for measuring materials concentration in the blood, comprising:
at least two sets (<NUM>),(<NUM>),(<NUM>) of calibrating elements (105a-105d) (106a-106d), (107a-107d) (<NUM>), each set comprising a plurality of calibrating elements,
wherein each of the calibrating elements comprises:
a first layer (<NUM>) simulating specific human skin characteristics;
a second layer (<NUM>) comprising a specific concentration of one or more materials in the blood;
wherein the specific human skin characteristics comprise at least one of: skin thickness, skin color, skin hair density, skin tone, skin temperature, skin optical properties and skin hair color,
wherein in all calibrating elements in a set the first layer is the same first layer simulating the same specific human skin characteristics and each set of calibrating elements simulate different specific human skin characteristics,
wherein each calibrating element in a set of calibrating elements comprises a different second layer comprising a different concentration of the one or more materials; and
a controller (<NUM>) configured to:
receive illumination intensities from the device for measuring materials concentration when the device is attached to each calibrating element of the system;
associate the received illumination intensities with the specific human skin characteristics and the specific concentration of the calibrating element to which the device is attached; and
save the illumination intensities associated with the specific human skin characteristics and the specific concentration in lookup tables in memory of the device for measuring materials concentration,
characterized in that
each of the calibrating elements further comprises a third layer (<NUM>) for simulating illumination reflection from a blood vessel in a skin tissue, wherein the third layer isolates the calibrating element from noise and reflections not related to the measured one or more materials in the second layer.