Source: https://patents.google.com/patent/JP2015503933A/en
Timestamp: 2020-01-17 15:11:31
Document Index: 78494349

Matched Legal Cases: ['arts 14', 'art 200', 'art 200', 'art 200', 'art 200', 'art 200', 'art 18']

JP2015503933A - Pulse meter / oximeter that can be worn on the body - Google Patents
Pulse meter / oximeter that can be worn on the body Download PDF
JP2015503933A
JP2015503933A JP2014527775A JP2014527775A JP2015503933A JP 2015503933 A JP2015503933 A JP 2015503933A JP 2014527775 A JP2014527775 A JP 2014527775A JP 2014527775 A JP2014527775 A JP 2014527775A JP 2015503933 A JP2015503933 A JP 2015503933A
JP2014527775A
アイゼン，レオン
ファイン，イリア
ゴールディノフ，レオニド
オキシトーン メディカル エルティディ．
2011-08-30 Priority to GB1114881.4 priority Critical
2011-08-30 Priority to GB1114881.4A priority patent/GB2494622A/en
2012-08-26 Application filed by オキシトーン メディカル エルティディ．, オキシトーン メディカル エルティディ． filed Critical オキシトーン メディカル エルティディ．
2012-08-26 Priority to PCT/IB2012/054349 priority patent/WO2013030744A1/en
2015-02-05 Publication of JP2015503933A publication Critical patent/JP2015503933A/en
Provided is a pulse meter / oximeter that is not greatly affected by the blood circulation volume and the flow of non-pulsed blood flowing in the tissue. A pulse meter / oximeter according to the present invention includes (A) a dome-shaped structure (40), (B) a plurality of light sources having different wavelengths, and light detection in response to the different wavelengths. The structure (40) fixes a predetermined region (42) on the distal end of the ulna (38), removes the influence of venous blood flow from the predetermined region, and the photodetector (52) measures light emitted from the light source (50), and the light is trans-illumination light from the tip of the ulna (38) through the predetermined region (42). [Selection] Figure 4
The present invention relates to a measurement system and a measurement method using a pulse meter / oximeter attached to a wrist, and more particularly to a pulse meter / oximeter attached to a wrist.
Various aspects of the invention are disclosed below. The discussion here is to provide background art for understanding the present invention. Therefore, the matters described here are not recognized as prior art.
In the medical field, doctors want to monitor certain physiological characteristics of patients. Accordingly, various devices have been developed to monitor a patient's physiological characteristics. Such a device provides the patient, doctor and even health care professional with the information necessary to ensure optimal health of the patient. As a result, such monitoring devices are indispensable in modern medicine.
Devices that monitor a patient's physiological characteristics typically measure pulse and oxygen levels. The device created on that basis is also referred to as a pulse meter / oximeter. A pulse meter / oximeter measures various blood characteristics (eg, a pulse corresponding to the arterial blood oxygen saturation of hemoglobin (SPO2) or the heart rate of the patient). The pulse actually measured by the pulse meter / oximeter is the amount of time variation of arterial blood in the measured value of each heart cycle. The pulse meter / oximeter used to obtain the above physiological characteristics is referred to as PPG for photoplethysmography.
The pulse meter / oximeter uses a non-invasive optical sensor. This optical sensor detects an optical response amount indicating the amount of light absorbed by the patient's tissue irradiated with light. One of the above physiological characteristics is calculated based on the amount of light absorbed. Specifically, the light passing through the tissue is related to the wavelength of light absorbed by the blood, which corresponds to the amount of hemoglobin component present in the blood. Based on the amount of light absorbed by different wavelengths, parameters related to hemoglobin in arterial blood are predicted using various algorithms. The amount of pulsed fluctuation of arterial blood at the site irradiated during the propagation of the blood pressure waveform changes the intensity of the optical response detected by the photodetector of the optical sensor.
The quality of the pulsometer / oximeter depends in part on the blood reflux characteristics irradiated with light and in part on the pulsed variation of the blood volume in the irradiated tissue. A pulsometer / oximeter usually utilizes a site where blood is sufficiently circulated. For example, a patient's finger, toe, and earlobe, on which sensors are placed.
According to FIG. 1, a conventional sensor 10 is placed on a patient's finger 12. This sensor 10 has a clip composed of two parts 14 and 16, and the sensor 10 is sandwiched between fingers 12 to measure the pulse / oxygen concentration. The sensor 10 is connected to a cable 18 that connects the sensor 10 to a monitoring system and receives and processes signals from the sensor 10. Therefore, this type of sensor used in continuous monitoring mode requires the patient to be in a certain location, for example in the vicinity of the monitoring system, which limits patient movement. Further, the force applied to the patient's finger 12 by the portions 14, 16 can be uncomfortable over time, and the patient can remove the sensor 10 and discontinue the required monitoring. As a result, this type of sensor is unsuitable as a long-term continuous pulse meter / oximeter.
US Patent Application Publication No. 2010/056934 US Patent Application Publication No. 2009/247785 US Patent Application Publication No. 2010-331709 US Patent Application Publication No. 2002/188210 US Pat. No. 6,210,340 Japanese Patent Application Publication No. 2009-160274 Japanese Patent Application Publication No. 2005-270544 Japanese Patent Application Publication No. 2009-254522 Japanese Patent Application Publication No. 2010-220939 Japanese Patent Application Publication No. 2005-040261 International Publication No. 2010-111127 International Publication No. 2011-013132 Korean Patent Application Publication No. 2011/0006990 Specification British Patent No. 2341233
Often occurring in physiological signal measurement devices, artifacts or other anomalies appear in the measurement data, which degrade the quality of the collected data. It may not be possible for this type of data to be used reliably to indicate a physiological process. In this regard, the pulse meter / oximeter is no exception. Such devices are vulnerable to artifacts caused by the patient's intentional or unintentional movement at random. Therefore, artifacts generated from such an environment distort the obtained data and ultimately adversely affect the measurement quality of the pulse meter / oximeter. The reliability and measurement accuracy of a pulse meter / oximeter are greatly influenced by the blood circulation volume and the flow of non-pulsed blood flowing through the tissue. As a result, artifacts are a major cause for inaccurate readings of the pulse meter / oximeter. Due to the above facts, the measurement method using the pulse meter / oximeter reflection cannot be applied to various parts of the patient's body. This measurement method tends to be weak against artifacts due to a region where blood circulation is weak and a large movement of the patient. Furthermore, the measurement of such a body part is based on a method in which a light emitter and a light receiver are on the opposite side of the body measurement part, light is emitted from the light emitter, propagates through the body, and the light receiver receives the light. It is not suitable for the pulsometer / oximeter to be adopted. In such a configuration, the part of the body for which pulse / oxygen measurement is preferred may be too thick for light to pass through. For this reason, the measured value of the pulse / oxygen concentration is erroneous.
The devices disclosed in these documents use either a reflection mode (0 °) or a propagation (transmission) mode (180 °) in light detection. Our patent document 10 discloses a system and method for measuring blood analysis concentration parameters associated with light absorption methods. This system and method uses a PPG device. The PPG device irradiates a patient with light of at least two wavelengths, determines relative absorption at each wavelength, and performs a PPG measurement. Further, using a dynamic light scattrring (DLS) apparatus, the DLS measurement of the object is executed, and the pulse parameter of the object is measured rheologically. Furthermore, the result of the PPG measurement value and the DLS measurement value is correlated temporally using an electronic circuit. This is done using the time correlation between the PPG measurement and the DLS measurement to evaluate the value of the blood analysis concentration parameter related to light absorption.
According to one embodiment of the present invention, the pulse meter / oximeter of the present invention is responsive to (A) a dome-shaped structure 40, (B) a plurality of light sources 50 of different wavelengths, and the different wavelengths. And a photodetector 52. The structure 40 fixes the predetermined region 42 on the distal end of the ulna 38, removes the influence of venous blood flow from the predetermined region, the photodetector 52 measures the light emitted from the light source 50, The light is trans-illumination light from the distal end of the ulna 38 through the predetermined region 42.
1 is a perspective view of a conventional pulse meter / oximeter. FIG. 1 is a perspective view of a wrist-mounted pulse meter / oximeter according to one embodiment of the present invention. FIG. The perspective view of the pulse meter / oximeter in the state with which the wrist was mounted | worn. The side view of the pulse meter / oximeter of the present invention. 1 is a perspective view of a pulse meter / oximeter according to the present invention. FIG. FIG. 3 is a side view of a structure used in a pulse meter / oximeter. Sectional drawing of the pulse meter / oximeter of other Examples of this invention. Sectional drawing of the pulse meter / oximeter of other Examples of this invention. The graph showing the data of a pulse / oxygen concentration. 3 is a graph showing pulse / oxygen concentration data according to an embodiment of the present invention. The figure showing the method of acquiring the data of a pulse / oxygen concentration by one Example of this invention. 3 is a graph showing pulse / oxygen concentration data according to an embodiment of the present invention. The figure showing the chart of correlation by one example of the present invention. The figure showing the histogram by one Example of this invention. The figure showing the histogram by the other Example of this invention. The schematic diagram showing the conventional reflection type apparatus (left) and the transmission type apparatus (right). The schematic diagram showing the transmission irradiation type | mold apparatus of this invention. The figure showing the measurement structure / method of the pulse meter / oximeter according to the present invention. The figure showing the measurement structure / method of the pulse meter / oximeter according to the present invention. The figure showing the measurement structure / method of the pulse meter / oximeter according to the present invention. The figure showing the measurement structure / method of the pulse meter / oximeter according to the present invention. The figure showing the measurement structure / method of the pulse meter / oximeter according to the present invention. The perspective view of the state which does not mount | wear the wrist of the apparatus of this invention. The elements on larger scale of FIG. 17A. The flowchart figure showing the measuring method by the pulse meter / oximeter of this invention.
The present invention will be described below with reference to the drawings. This is for the purpose of describing a preferred embodiment of the present invention and to facilitate an understanding of the principles or inventive concepts of the present invention. It is not intended to be unnecessarily detailed for a basic understanding of the invention. The description with the drawings will be apparent to those skilled in the art to practice the invention.
The present invention is not limited to the arrangement and structure of the components shown in the following description and the attached drawings. The invention is also applicable to other variants that can be implemented in various ways. The terms and phrases of the present invention are for understanding the invention and are not intended to limit the scope of the claims of the invention.
The term “trans illumination” is defined as an optical measurement mode. That is, the measured light is light reflected from the surface at 0 ° or more (simple reflection) and less than 180 ° (simple propagation). In general, the reflection angle in the transillumination mode is between 20 ° and 160 °. In the transillumination mode, the measured light is emitted from the light source, hits the reflective surface (which may be curved) at a certain angle, is reflected at a certain angle, and returns to the detector. In practice, trans-illumination light is emitted from a common light source, passes through various optical paths, and includes measurement light at the detector.
One embodiment of the present invention includes a pulse meter / oximeter. This pulse meter / oximeter is mounted on a wrist band, and a dome-shaped structure is used to fix a region above the tip of the ulna. This area is the measurement area. The measurement is performed by a detector placed on the fixed area. This detector is arranged around the fixed area so as to detect light emitted from light sources of various wavelengths. The reflection is therefore measured at an angle between 20 ° and 60 ° from the emitted light, not in either a perfect reflection mode or a perfect propagation mode. With this transformer illumination mode. An excellent s / n ratio can be achieved from the beginning, and a continuous and reliable measurement of the pulse meter / oximeter on the wrist is possible.
The pulse meter / oximeter of the present invention includes (A) a dome-shaped structure 40, (B) a plurality of light sources 50 having different wavelengths, and a photodetector 52 that responds to the different wavelengths, The structure 40 fixes the predetermined region 42 on the distal end of the ulna 38, removes the influence of venous blood flow from the predetermined region, the photodetector 52 measures the light emitted from the light source 50, and The light is trans-illumination light from the distal end of the ulna 38 through the predetermined region 42.
The present invention is far ahead of the prior art due to the features described below. The following features of Patent Document 10 are novel and inventive.
In the PPG measurement, the tip of the ulna is used as a convex reflector to measure in the trans-illumination mode (propagation at a 20-160 ° angle between the detection light and the radiation light),
Use the area above the tip of the ulna as the measurement area,
Fixing the device of the invention on the distal region of the ulna with a dome-shaped structure;
It is the integration of the pulse measurement device and the oxygen concentration measurement device and the integration of their characteristics.
FIG. 2 is a perspective view of the pulse meter / oximeter 30 of the present invention. As shown in FIG. 3, the pulse meter / oxygen meter 30 is a wrist-mounted pulse meter / oxygen meter that is attached to the wrist 31 of a patient. The pulse meter / oximeter 30 obtains data including pulse data and oxygen saturation (SPO2) from the patient's wrist 31. The user can wear the pulse meter / oximeter 30 in the same way as wearing a wristwatch. Thus, the user wearing the pulse meter / oximeter 30 can perform measurement while walking, running, or riding a bicycle while living in daily life. According to one embodiment of the present invention, the pulse meter / oximeter 30 can be worn anytime and anywhere by a person seeking to obtain pulsed oxygen concentration and pulse data, without attaching a monitoring device. You don't have to be in the monitor area. Thus, the pulse meter / oximeter 30 is a self-preserving or self-active device, and can obtain and analyze various photoelectromagnetic signals and finally obtain pulse / oxygen concentration data. . The pulse meter / oximeter 30 further has a wired or wireless interface, and can exchange data signals with an external device or a remote device. The pulsometer / oximeter 30 obtains pulse / oxygen data and provides it to users at remote locations, hospitals, clinics, or those who need data from such a pulsometer / oximeter. Can send.
As shown in FIGS. 2 and 3, the pulsometer / oximeter 30 includes a wristband 32 connected to a casing 34. The wristband 32 is made of a flexible or stretchable material such as rubber, silicon, soft plastic material, cloth or polished metal, or a combination thereof, and provides comfort to the user when wearing the pulse meter / oximeter 30. It can be provided. The casing 34 is made of a strong and durable material. That is, metal, hard plastic material, and the like. All functional parts in the pulse meter / oximeter 30 are housed and protected from external forces. Although not shown, the functional components housed in the pulse meter / oximeter 30 include electrical devices, mechanical devices, optical devices, such as batteries, processors, integrated circuits, light emitting diodes, shunts or others Other parts that contribute to the function or integrity of your pulse meter / oximeter.
A display unit 36 is disposed on the casing 34. This display 36 gives the user a visual display of pulse / oxygen concentration data or other data. The display unit 36 is, for example, an LCD or another type of display device. Next to the display unit 36 is a button 37. This button 37 provides further other functions and features that the user can access. Alternatively, the parameter provided by the pulse meter / oximeter 30 can be set or viewed. The button 37 is an alphanumeric button, and the user can input a combination of alphanumeric characters. The combination of alphanumeric characters required while using the pulse meter / oximeter can be entered. The button 37 is arranged on the side surface of the casing 34 or in another area so that the user can easily access it.
FIG. 4 is a cross-sectional view of a pulse meter / oximeter according to an embodiment of the present invention. This pulse meter / oximeter is similar to the pulse meter / oximeter 30 and incorporates the above functions. FIG. 5 is a perspective view of the pulse meter / oximeter 30. Both FIGS. 4 and 5 represent the systems and structures that make up the pulse meter / oximeter 30.
The pulse meter / oximeter 30 of FIG. 4 is attached to the user's wrist 31. Accordingly, the pulsometer / oximeter 30 has a structure 40 inside thereof. As a result, the structure 40 fits over the ulna 38 of the wrist 31. The structure 40 has a dome-like structure and fits into the ulna 38. As a result, the pulsometer / oximeter 30 is firmly fixed around the wrist 31.
As shown in FIG. 5, the structure 40 has an inner portion 42. The inner portion 42 is adapted to receive (accept) the ulna 38 when the user wears the pulse meter / oximeter 30 around the wrist 31. The shape of the structure 40 therefore conforms to the general shape of the ulna 38, so that when the pulsometer / oximeter 30 is wrapped around the wrist 31, it is between the pulsometer / oximeter 30 and the wrist 31. Achieve good contact. Such good contact between the user's wrist and the pulse meter / oximeter constitutes a good interface between the sensing function element of the pulse meter / oximeter 30 and the user's skin tissue. Thus, an appropriate data collection interface between the user and the pulse meter / oximeter 30 can be achieved. In other embodiments, the sensor component can also be embedded in padding or other protective material (rubber), which can cause the sensor component to experience external vibration shocks or while the user is wearing the sensor. Protect from power to do. Such materials attenuate external forces and further reduce motion artifacts that appear in the pulse / oxygen data, allowing for better data collection.
The dome structure 40 is made of a flexible material. For example, silicon, plastic, soft material, or a combination thereof. This allows the structure 40 to be easily deformed and adapted to the shape of the bone, ie the shape of the ulna 38 to which the pulse meter / oximeter 30 is coupled. Accordingly, the structure 40 of the present invention can be adjusted to fit comfortably to users having ulna of various sizes and shapes. In addition to housing the ulna 38 when the pulsometer / oximeter 30 is mounted on the wrist 31, the structure 40 can be used by the user and various electro-optic elements (part of the pulsometer / oximeter 30). It functions as an intermediate structure disposed between. This emits and detects the electron-magnetism-wavelength used to obtain a pulse / oxygen concentration measurement. Another function of the structure 40 is to protect the photodetector from the incidence of external light.
The pulsometer / oximeter 30 includes an optical device having a plurality of light sources 50 arranged in the vicinity of the structure 40 and an optical detector 52 arranged in a part of the structure 40. As shown in FIG. 5, the portion 42 has an opening 44. Light emitted from the light source 50 through the opening 44 propagates in the wrist 31. Similarly, portion 42 has an aperture 46 through which light is received by optical detector 52.
As shown in FIG. 4, the light source 50 and the optical detector 52 are arranged such that light from the light source 50 propagates through the wrist tissue and is collected by the optical detector 52. Accordingly, the ulna 38 of the wrist 31 is disposed between the light source 50 and the optical detector 52. Thereby, the light emitted from the light source 50 is scattered by the ulna 38 and reaches the optical detector 52. In the embodiment shown here, the light emitting device / photodetector is arranged around the wrist 31. In particular, the configuration is shown arranged around the ulna 38, but other configurations are possible. The light source 50 and the optical detector 52 can be arranged in the vicinity of the ulna 38 to obtain highly reliable pulse / oxygen concentration data. Such a trans-illumination sensor configuration measures multiple scattered components of the light transmitted to the detector, but does not detect specific components of the light and transmitted forward components.
In one embodiment, the light source 50 emits visible light having a wavelength of 660 nm, but is not limited thereto, and may emit infrared light having a wavelength of, for example, 940 nm. The light emitted by both LEDs is detected by the optical detector 52. Light that diffuses through the tissue and reaches the optical detector 52 is absorbed by blood and soft tissue, depending on the concentration of hemoglobin in the blood. The amount of light absorbed at each wavelength depends on the degree of oxygenation of hemoglobin in the blood. The light emitted by the light source 50 is scattered at various parts of the ulna 38 and finally reaches the optical detector 52.
The amount of light scattered by the ulna 38 increases the amount of light absorbed by blood present in the tissue and the amount of light absorbed by other structures that allow blood to flow through various internal regions through which light is transmitted / propagated. The increase in optical path length obtained by the pulsometer / oximeter 30 configuration increases the interaction between the propagating light and the surrounding tissue, which can ultimately provide a robust signal from which Pulse / oxygen concentration data can be obtained.
More specifically, the technique for detecting the oxygen saturation amount of hemoglobin by the spectrophotometer, which is performed by the pulse meter / oximeter 30, is based on the Beer-Lambert law. This law relates the solute concentration to the intensity of light transmitted through the solution. In combination with the pulsed blood measurement technique, this technique is also referred to as PPG (photoplethysmography). In order to measure the concentration of a light-absorbing substance in a transparent solution from the intensity of light transmitted through the solution, the intensity and wavelength of incident light, the path length through which the light propagates, It is necessary to know the extinction coefficient of the medium through which light propagates.
In general, pulsatile expansion of the vascular bed increases the path length of light propagation. This increases the amount of light absorption. The detected optical response is composed of a time-dependent AC signal and a non-pulsed background DC signal. Accordingly, an AC component of the light absorption amount at each wavelength is first determined using an algorithm for processing a specific signal, and this AC component is divided by a DC component corresponding to each wavelength. Using these two visible and infrared (IR) wavelengths, this is generated by two different light sources 50, but in the form of pulses using the ratio of the light absorbed by each component at these two frequencies. The ratio (R) of the added “absorption amount” can be obtained. This is a γ parameter in the literature. It is as follows:
R = (AC 660 / DC 660 ) / (AC 940 / DC 940 )
A measurement of pulse / oxygen concentration is obtained, in which the difference in measured light absorption occurring at different times corresponding to different arterial blood volumes is called volumetric measurements, which is different It represents the differential volume of blood present at a measurement site in the patient's arterial vessel over time.
According to another embodiment of the present invention, the data collection, data analysis, and data processing described above is performed at that location, i.e., by processing elements located within the pulse meter / oximeter 30. FIG. 4 shows a component 56 disposed within the casing 34 of the pulse meter / oximeter 30. This component 56 includes various electronic components that electrically support various operations performed by the pulse meter / oximeter 30. This component includes a microprocessor, battery, integrated circuit, memory device, wireless / wired communication device. Component 56 stores various software platforms and algorithms and performs various operations accordingly to support various signal processing operations performed by pulse meter / oximeter 30. For example, such signal processing utilizes a fast Fourier transform (FFT) algorithm and various pattern recognition routines that analyze the collected physiological data. The component 56 is further coupled to an input / output (I / O) device to connect the pulse meter / oximeter 30 to an external device, and the pulse meter / oximeter 30 downloads and uploads various data. It is possible. These data are, for example, user data, physiological parameters or other data, which are useful for monitoring for health care or for the user, including patient physiological parameters or other parameters.
FIG. 6 shows a structure 40 that houses the ulna 38 of the wrist 31. The structure 40 has a dome shape or a cone shape, and is shaped so as to cover the ulna 38 and accommodate the ulna 38. Accordingly, the structure 40 is composed of a portion 42 which is an inner surface. Its dimensions and features are adapted to the external surface of the surrounding tissue with the ulna 38 of the wrist 31. Thus, the structure 40 has a structure capable of accommodating the ulna 38 and surrounding tissue. The structure 40 is generally circular and consequently contains the ulna 38, similar to the shape of a cap placed over the round structure. The ulna 38 has a circular outer surface.
FIG. 7A shows a pulse meter / oximeter 70 according to another embodiment of the present invention. The pulse meter / oximeter 70 is similar to the pulse meter / oximeter 30 of FIGS. 1-6. Pulse meter / oximeter 70 includes components similar to those of pulse meter / oximeter 30. As a result, the pulsometer / oximeter 70 performs the heart rate and oxygen concentration measurements performed by the pulsometer / oximeter 30.
The pulse meter / oximeter 70 has a CLS device 72 which is a coherent light scattering device. The CLS device 72 can detect a pulse that can supplement or enhance the measured value of the pulse / oxygen concentration obtained from the CLS device 72. Accordingly, the pulse meter / oximeter 70 can detect artifacts (usually caused by the movement of the user) included in the pulse / oxygen data. The pulse meter / oximeter 70 has a coherent light source (for example, a diode laser) and emits coherent light. In addition, the pulse meter / oximeter 70 has a light detector that can detect this coherent light scattering response. Thus, the pulse meter / oximeter 70 continuously measures the scattering response of the coherent light from within the tissue of the wrist 31, and generates data indicating a Doppler signal or a dynamic speckle signal.
Patent Document 11 discloses a method for detecting a pulse / oxygen concentration measurement value in the presence of motion artifacts using a DLS (dynamic light scattering) method.
In FIG. 7B, the CLS device 72 is disposed in the vicinity of the light source 50 and measures the pulse in that region. A part of the light scattered by the CLS device 72 is used as one of the light sources 50 to measure oxygen concentration data. Although the coherency of the CLS device 72 is lost in the scattered light, this coherency is only important for measuring the pulse and not for measuring the oxygen concentration. Scattered light can also be used for measuring the oxygen concentration if the light source is selected to match the appropriate frequency.
As part of the description covering DLS theory related to physiological settings, in good blood pulsation situations where motion artifacts are not important, time derivatives corresponding to DLS time-varying and PPG signals A good correlation can be seen between
FIG. 8 shows a graph 100 representing pulse / oxygen concentration data according to one embodiment of the present invention. Plot set 100 shows PPG and CLS measurements made in the presence of motion artifacts. This set of graphs includes graphs 102, 104 and 106. The vertical axis 108 of the graphs 102-106 represents the signal amplitude and the horizontal axis 110 represents time.
The plot 102 is a measured value of PPG obtained using, for example, a red LED (light source 50) having a wavelength of 660 nm.
The plot 104 represents the measured PPG value obtained by, for example, an IR (infrared) LED of 940 nm.
Plot 106 represents pulse and pulse wavelength measurements obtained using the CLS device 72, particularly using a coherent light scattering technique (CLS).
Each graph 102-106 in the presence of motion artifacts includes transition points where the resulting pulses are distorted by the occurrence and onset of motion artifacts. For example, in plot 102 the occurrence of this motion artifact is indicated by point 112, in plot 104 this occurrence of motion artifact is indicated by point 114, and in plot 106 this occurrence of motion artifact is indicated by point 116. Indicated. Such motion artifacts are the result of motion applied by a user wearing a pulse meter / oximeter 30/70. For example, this occurs when the user voluntarily or involuntarily moves the wrist 31 to which the pulse meter / oximeter is attached.
FIG. 9 is a graph 150 showing pulse / oxygen concentration data according to one embodiment of the present invention. The graph 150 includes a plot of PPG data and CLS data similar to that shown in FIG. Plot 150 (including plots 152, 154, and 156) shows the PPG and CLS measurements in the absence of motion artifacts.
Plot 152 shows a plot 152 of PPG measurements taken with a 660 nm wavelength LED.
Plot 154 shows a plot 154 of PPG measurements taken with a 940 nm wavelength LED.
Plot 156 represents pulse and pulse waveform data taken with the CLS sensor disclosed in the reference.
As shown by plot 150, in the absence of motion artifacts, the PPG signal exhibits different characteristics and shapes than those represented by plot 100 of FIG. In the absence of motion artifacts, pulse / oxygen measurements are more reliable and deterministic than when this motion artifact was present. The CLS device can be used with standard PPG methods to generate filtered pulse / oxygen data. By using such a filter, the wearable pulse meter / oximeter 70 can provide reliable pulse / oxygen data to the user, thereby providing heart rate and oxygen saturation. A measurement of concentration (SPO2) is given.
FIG. 10 is a flowchart 200 illustrating a process for obtaining pulse / oxygen concentration data. The flowchart 200 illustrates a process by which, for example, a pulse meter / oximeter 30 or 70 obtains pulse / oxygen data in the presence of motion artifacts using a PPG and CLS correlation method. In addition, the process 200 works by correlating the resulting CLS data with the PPG data to minimize or eliminate data indicative of artifacts. As a result, reliable pulse / oxygen concentration data (measured values) representing the user's SPO2 level is generated.
The flowchart 200 of the present invention begins at step 202. In this step, pulse / oxygen concentration data is obtained from the wrist of the user wearing the pulse meter / oximeter 70 using the DLS / CLS apparatus and DLS / CLS measurement method together with the PPG and spectrophotometer. Collection of PPG data is performed using a light source (LED) 50 and an optical detector 52. In particular, PPG data is obtained by the use and detection of two electromagnetic signals emitted from two LEDs that generate signals of two wavelengths 660 nm and 940 nm. These two measurements are further used in conjunction with a third optical measurement or DLS / CLS device 72 located in the pulse meter / oximeter 70.
In step 204, the three light measurements including CLS data and PPG data are further processed.
In step 204, a fast Fourier transform is performed on the CLS time-dependent waveform, for example, using various algorithms and routines to obtain a frequency power spectrum.
In step 204, the pulse waveform is extracted using CLS data or PPG data, and the user's pulse is specified therefrom. Such processing of the initially obtained data is performed using the pulsometer / oximeter 70 component 56.
The processed CLS data and PPG data having a waveform distorted by the generation of motion artifacts are shown in FIG. 11 in a time frame of 10 seconds. Also shown at 4, 6, 8, 12 seconds. The time derivative of the PPG / IR data is plotted on the left vertical axis 300 and the CLS data is plotted on the right vertical axis 302. The CLS waveform and the PPG waveform are plotted with respect to the time axis 304.
At a branching step 206, a correlation exists between the modified PPG waveform and the resulting CLS waveform using a pulse meter / oximeter 70 over a moving time frame in which data is continuously collected. . The correlation obtained in step 206 can set specific criteria for determining the amount of motion artifact present in the pulse / oxygen concentration data.
The correlation of step 206 was found to be below a certain threshold or reference value (eg less than 0.8). The process then moves from step 206 to step 208. In step 208, a pulse regression / oximeter 70 executes a moving regression algorithm to eliminate data indicative of artifacts arising from user movement. FIG. 12 shows such a method of exclusion.
In FIG. 12, the resulting PPG-CLS correlation is plotted against the data points collected in the corresponding motion time frame on the vertical axis 350.
The correlation shown in FIG. 12 is the correlation found for the travel time frame at step 206 data points (1, 2, 3, 4, 5). . From there, an optimally sized correlation range (eg, 0.3-0.6) is selected using an adaptive algorithm, quantizing the amount of motion artifacts, and using this quantization to reduce motion artifacts. Filter or reject and screen for correct pulse / oxygen data. This therefore reduces or eliminates the properties associated with certain movements that cause false SPO2.
Therefore, at step 210, such data is provided for further processing, and the filtered data is used to calculate the actual SPO2 level using the moving histogram method.
FIG. 13 is a graph of the measured value of γ (gamma), which is pulse / oxygen concentration data and not data obtained by filtering motion artifacts.
FIG. 14 is a graph of the measured value of γ (gamma), which is pulse / oxygen concentration data and data obtained by filtering motion artifacts.
As plotted on the vertical axis 400 of FIG. 13, represents the number of plots counted versus γ on the horizontal axis. FIG. 13 is compared with FIG.
FIG. 14 represents the filtered γ measurement obtained using the above CLS-PPG correlation. This eliminates these signals resulting from motion artifacts. As shown in FIG. The first peak 404 shows true γ, which is clearly discernable when compared to the data swaying with the motion artifact of FIG.
Returning to flowchart 200, if, at branch step 206, the correlation between the modified PPG data and the CLS data is greater than a predetermined threshold, the process moves to step 210 where SPO2 is Calculated using the method.
Each step of flowchart 200 may be performed using various schemes including software and algorithms. This software and algorithm is stored and executed by the pulse meter / oximeter of the present invention.
An embodiment of the present invention is a pulse meter / oximeter in the form of a wrist band (wrist wearing). It has a strap that wraps around the user's wrist. The pulse meter / oximeter of the present invention has at least two light emitters and at least one photodetector. These are placed on a strap-type pulsometer / oxygenometer. Thus, the light emitter and the light detector are part of a structure that receives the ulna on the user's wrist. In one embodiment of the present invention, the light emitter and the light detector are placed between the light emitter and the light detector when the wrist ulna is attached to the user's wrist with a pulse meter / oximeter. Arranged so that. The light thus emitted propagates through the tissue in a propagation mode and is scattered by the bone until the light reaches the photodetector, where the light is detected and a pulse / oxygen measurement is obtained. Thus, having the desired light absorption and reflection characteristics, the ulna on the wrist provides a medium that repeats diffusion and reflection and directs light from the light emitter to the photodetector. The size and shape of the ulna provides an elongated optical path between the light emitter and the light detector. In this sense, the ulna placed between the light emitter and the photodetector functions as a specific diffuser and reflector, and the structural, scientific and physical composition of the bone and the surrounding tissue And increase the light scattering inside the bone and increase the light absorption. Such a structure can achieve measurement of the light signal of the trans-illumination by a configuration that facilitates light passing through the wrist tissue between the light emitter and the light detector. Under such a shape, a specific component of the radiated light is not detected, and only a plurality of scattered propagation components of the optical signal to be measured are detected. The present invention increases the optical path length, ie the length between the emitter and the photodetector. Accordingly, this increases the amount of scattering received by the light, and a more reliable detection light signal can be easily obtained. From there, highly reliable pulse / oxygen concentration data can be obtained.
In another embodiment of the present invention, the wristband oximeter / oximeter utilizes a system that detects or mitigates (eliminates) signal artifacts resulting from user movement, thereby providing a reliable pulse rate. / Measure oxygen concentration. Specifically, the wristband type pulse meter / oximeter has a coherent light scattering CLS sensor for measuring the pulse. CLS includes scattering of light generated by coherent light. This is related to dynamic light scattering caused by multiple scattering due to the size of the moving object. As a result, dynamic speckle or Doppler scattering is obtained. CLS is related to elastic or inelastic scattering, such as Raman scattering. Although the term CLS includes the light scattering phenomenon described above, the present invention utilizes any form of dynamic light scattering DLS or other scattering processes that perform pulse measurements. One embodiment includes a sensor having a coherent light source, such as a vertical-cavity surface-emitting laser (VCSEL), or illuminates a tissue and bone region near the measurement side of a pulse meter / oximeter. Also includes other diode lasers used in The apparatus has a photodetector for making coherent light scattering response measurements. Light that responds to multiple scattering of coherent light in a flowing blood flow or a pulsed blood flow generates an instantaneous light intensity pattern on the surface of the photodetector, which allows the pulse to be calculated. Such information, in combination with pulse / oxygen concentration data, allows for specific removal filtering of artifacts resulting from user movement, thereby generating reliable pulse and SPO2 data for the user. .
Another aspect of the invention includes a system for performing the above method. Additional features and advantages of embodiments of the present invention are described herein and can be further accomplished from the specification, and further variations are possible with embodiments of the present invention.
FIG. 15A shows the difference between a conventional reflection mode and a propagation mode, and FIG. 15B shows a trans illumination mode according to one embodiment of the present invention. In contrast to conventional measurement (reflection / propagation) modes, the present invention performs measurements in a transillumination mode that incorporates multiple optical paths between the light source 50 and the optical detector 52. In the conventional reflection mode, the angle between the light emitted from the light source 50 and the light detected by the optical detector 52 (ie, the optical detector in the vicinity of the light source 50) is α = 0 °. In the propagation mode, the angle between the light emitted by the light source 50 and the light detected by the nearby optical detector 52 is α = 180 °.
The optical detector 52 of the present invention reflects at an angle different from the back reflection, ie, α is between 20 ° and 160 °. This reflection is, for example, from the convex surface of the tip of the ulna in the case of a wrist-mounted pulse meter / oximeter. A further advantage of using the tip of the ulna bone is that it can be easily worn by different users with different wrist characteristics. For example, the tip of the radius bone is also used from an optical point of view, but it is difficult for the user to properly place the pulse meter / oximeter 30 and measure it.
The exact angle α varies from user to user and from time to time of use, which varies with the shape of the wrist and the way the pulsometer / oximeter 30 is worn on the wrist. The use of transillumination on the ulna head can overcome the variation of the measurement due to the wide tolerance for the exact angle α. The pulse meter / oximeter 30 determines the position of the optical detector 52 on the dome-shaped structure 40. This structure 40 is fixed to the ulna head, and the distance d (FIGS. 16A, 17A) determines the space between the light source 50 and the structure 40 (comprising the optical detector 52). The variation in the measured value is caused by the elasticity of the wristband 32. Thus, the distance d determines the range of possible angles α for various users. The entire range can be measured using the principle of transillumination. The distance d is between 0.5 cm and 3 cm or between 1 cm and 2.5 cm, depending on the specific design, the efficiency of the optical measurement and the intended user.
16A-E show the structure of a pulse meter / oximeter 30 of one embodiment of the present invention.
FIG. 16A is a wrist cross section showing the distal ends of the radius and ulna. The CLS device 72 (including the light source 71 and the CLS detector 73) is disposed at a location away from the structure 40. The light source 71 emits coherent light 74A, and this coherent light 74A is measured by the CLS detector 73 as reflected light 74B. PPG is measured in a region 41 above the tip of the ulna fixed by the structure 40. At least one optical detector 52 is disposed above the fixed region 41, and a plurality of light sources 50 </ b> A and 50 </ b> B having different wavelengths are disposed around the fixed 41. The optical detector 52 is arranged to measure the light 51 </ b> B reflected from the distal end of the ulna by the emitted light 51 </ b> A. This is emitted from at least two light sources 50A and 50B. The reflected light 51B is at an angle between 20 ° and 160 ° from the emitted light 51A. In one embodiment, the optical detector 52 has two light sources 50A, 50B arranged to detect light 51B reflected from the light emitted from the light source 50A at an angle between 70 ° and 110 °. Is done.
In FIG. 16B, the light source 71 of the CLS device 72 is used for two purposes. The first purpose is to emit coherent light 74A as a coherent light source for the CLS device 72, the CLS detector 73 detects the reflected light 74B, and the CLS device 72 calculates pulses therefrom.
The second objective is to use one of two PPG light sources (instead of light source 50B in FIG. 16B) as a non-coherent light source (coherency is lost due to the combination of different optical paths and movement through tissue). Function as.
FIG. 16C shows an embodiment in which the CLS device 72 is disposed in the vicinity of the light sources 50A and 50B, but it is not used as one of the light sources due to frequency limitations. In another embodiment, both light sources 50A and 50B are laser diodes, and optical detector 52 detects the light emitted therefrom to determine PPG data.
Utilizing the measurement of the transillumination mode of the present invention, light loses coherency through reflection from the ulnar head through tissue and is used only in relation to its strength dependence on wavelength. This represents the amount of oxygen saturation in the blood.
In one embodiment, the light sources 50A, 50B are further used as a reflection mode to measure pulses using their coherency, ie, the light source 50B functions as the light source 71 of the CLS device 72.
In one embodiment, the plurality of light sources 50 includes the following options: (X) two LEDs having different wavelength ranges, (Y) two laser diodes of different wavelengths, (Z) a combination of one LED and one laser diode outside the wavelength of this LED.
In the configuration of FIG. 16D, the light source 50 is in the structure 40 and includes a coherent light source 71 including, for example, another LED 50 </ b> B or a CLS detector 73. With this configuration, the light reflected to the optical detector 52 by the ulna propagates.
In another configuration, one light source 50 </ b> A is in the structure 40 and another light source 50 </ b> B (or the light source 71 having the CLS detector 73) is outside the structure 40.
In the configuration of FIG. 16E, the light source 50 (the light sources 50 </ b> A and 50 </ b> B or the coherent light source 71) is in the structure 40, and the optical detector 52 is outside the structure 40. In any combination of the light source 50 and the optical detector 52, measurement by trans-illumination at the tip of the ulna is realized by the pulse meter / oximeter 30.
FIG. 17A is a perspective view of a pulse meter / oximeter 30 in an unmounted state in one embodiment of the present invention. FIG. 17B is a partially enlarged view of FIG. 17A.
The structure 40 including the optical detector 52, the CLS device 71, and the plurality of light sources 50 are mounted on the wristband 32 in a functional positional relationship. The structure 40 hits the tip of the ulna as a reference point. The structure 40 incorporates a soft material inside to allow good contact and fitting with the ulna and gently press against the area to remove venous blood flow movement from that area and to reduce the s / n ratio. Improve.
FIG. 17A shows a structure having an optical detector 52 within the structure 40, a light source 50, and a coherent light source 71 outside the structure 40. The light source 50 is located at a distance d from the structure 40. The coherent light source 71 replaces the light source 50 by arranging the optical detector 52 so that the light emitted from the light source 71 is measured and reflected by the ulna. The reflected light loses coherency.
FIG. 17A shows another structure having a light source 50 in structure 40 and having a structure similar to that shown in FIG. 16D.
FIG. 17B shows a structure similar to that shown in FIG. 16E, with an optical detector 52 outside the structure 40 and a light source 50 outside the structure 40.
FIG. 18 is a flowchart of a method 500 for measuring oxygen concentration according to the present invention.
The present invention 500 includes the following steps.
Step 510: Fix the predetermined region (42) above the distal end of the ulna (38).
Step 520: Arrange the photodetector (52) above the fixed area (42).
Step 524: A plurality of light sources (50) having different wavelengths are arranged in the fixed region (42).
Step 540: Light is emitted from the light source (50) to the wrist.
Step 550: Detect light in a state where light from the light source (50) is reflected by the distal end portion of the ulna.
The angle between the emitted light and the detected reflected light is between 20 ° -160 °.
The method 500 of the present invention further includes the step of placing a light source within the dome and a detector inside or outside the dome (step 530). This is an alternative to steps 520 and 525.
The method 500 of the present invention further measures the pulse by reflecting a coherent light source from the ulna (step 560). Further, the coherent light is emitted by a coherent light source coupled to a detector and a strap holding at least two light sources. Light obtained from the emitted coherent light is detected by at least one photodetector. Coherent light scattering (CLS) data is obtained based on the detected light obtained from the emitted coherent light. Based on the CLS data, the pulse and pulse waveform used to perform the SPO2 calculation are obtained. Here, at least one coherent light source and at least one photodetector are coupled to the strap.
The method 500 further includes using a coherent light source as one of the plurality of light sources (step 535).
The above description relates to one embodiment of the present invention, and those skilled in the art can consider various modifications of the present invention, all of which are included in the technical scope of the present invention. The The numbers in parentheses described after the constituent elements of the claims correspond to the part numbers in the drawings, are attached for easy understanding of the invention, and are not intended to limit the invention. Absent. Even in the case of the same number, the part names in the specification and the claims are not necessarily the same. This is for the reason described above. “At least one or more” and “and / or” are not limited to one of them. For example, “at least one of A, B, and C” is not only “A”, “B”, and “C” but also “A, B or B, C, and also A, B, and C”. A combination of A, B, A, B, and C may be used. “A, B and / or C” may include not only A, B and C alone, but also two of A and B, or all of A, B and C. In this specification, “including A” and “having A” may include other than A. Unless stated otherwise, the number of devices or means may be singular or plural.
10: Sensor 12: Finger 14, 16: Part 18: Cable 30: Pulse meter / oximeter 31: Wrist 32: Wrist band 34: Casing 36: Display unit 37: Button 38: Ulna 40: Dome-shaped structure 42: Portion 44: Opening 50: Light source 51B:
52: Optical detector 56: Component 70: Pulse meter / oximeter 71: Light source 72: CLS device 73: CLS detector 74B; Reflected light
202: Detect CLS and PPG data streams.
204: Process the CLS and PPG data stream, extract the waveform, and identify the pulse.
206: Correlate the CLS and the modified PPG signal over the travel time frame.
Correlation value> = criteria 208: A moving regression algorithm is used to exclude motion artifact data from the SPO2 calculation routine.
210: Perform the SPO2 calculation routine using the moving histogram method.
510: A predetermined region is fixed above the tip of the ulna.
520: Arrange the photodetector above the fixed predetermined area.
525: A plurality of light sources having different wavelengths are arranged around the fixed region.
530: A light source is arranged in the dome, and a photodetector is arranged inside or outside the dome.
535: A coherent light source is used as one of the plurality of light sources.
540: The light is emitted to the wrist with the arranged light source.
550: Detect reflected light reflected at the tip of the ulna.
560: The pulse is measured by reflecting the coherent light source on the bone.
(A) a dome-shaped structure (40);
The structure (40) fixes a predetermined region (42) on the tip of the ulna (38), removes the influence of venous blood flow from the predetermined region,
(B) having a plurality of light sources (50) of different wavelengths and a photodetector (52) responsive to the different wavelengths;
The photodetector (52) measures the light emitted from the light source (50);
The pulsometer / oximeter, wherein the light is trans-illumination light from the tip of the ulna (38) through the predetermined region (42).
The photodetector (52) is disposed above the fixed region (42),
The light source (50) is arranged around the fixed area (42),
The light detector (52) measures the reflected light reflected from the tip of the ulna (38) by the light emitted from the light source (50),
The pulsometer / oximeter according to claim 1, wherein the reflection is performed at an angle between 20 ° and 160 ° from the emitted light.
(C) further includes a processor;
2. The pulse meter / oximeter according to claim 1, wherein the processor calculates pulse / oxygen concentration data from the measured reflected light.
(D) having a coherent light source (72) and a photodetector (52);
The pulse detector / oximeter according to claim 1, wherein the photodetector (52) measures coherent light scattering (CLS) data to calculate a pulse.
The pulsometer / oximeter according to claim 1, wherein the coherent light source (72) is used as one of the plurality of light sources (50).
The plurality of light sources (50) are:
1. Two LEDs of different wavelengths,
2. Two laser diodes of different wavelengths;
3. The pulse meter / oximeter according to claim 1, wherein the pulse meter / oximeter is one of one LED and one laser diode having a wavelength other than the wavelength of the LED.
2. The pulse meter / oximeter according to claim 1, wherein the pulse meter / oximeter is mounted on a strap (32).
The said photodetector (52) and said light source (50) are arranged such that the emitted light is reflected at an angle between 70 ° -110 °. Pulse meter / oximeter.
A strap (32) attached to the user's wrist;
A member having the dome-shaped structure (40) coupled to the strap (32);
The light source (50) is coupled to the strap (32) in the vicinity of the member;
The photodetector (52) is coupled to a portion of the member and the strap (32);
The light source (50) and the photodetector (52) are arranged such that light emitted from the light source is scattered by the ulna (38) before reaching the photodetector. The pulsometer / oximeter according to claim 1.
The strap (32) further comprises a casing (34),
The casing (34) has a coherent light source (72) and a photodetector (52),
2. The pulsometer / oximeter according to claim 1, wherein coherent light scattering (CLS) data is obtained in order to obtain a pulse and a pulse waveform used for SPO2 calculation.
The pulsometer / oximeter according to claim 1, characterized in that the light source (50) is separated from the dome-shaped structure (40) by a distance between 0.5-3 cm.
(A) fixing the predetermined region (42) above the distal end of the ulna (38);
(B) disposing a photodetector (52) above the fixed region (42);
(C) arranging a plurality of light sources (50) of different wavelengths in the fixed region (42);
(D) emitting light from the light source (50) to the wrist;
(E) detecting light in a state in which light from the light source (50) is reflected by a distal end portion of the ulna,
The method for measuring oxygen level in blood, wherein the angle between the emitted light and the detected reflected light is between 20 ° -160 °.
The method of claim 12, further comprising the step of: (F) measuring the pulse by detecting the reflection of light from the coherent light source (72) by the ulna.
(F1) emitting coherent light by a coherent light source (72) coupled to the strap;
(F2) holding the photodetector and the light source;
(F3) detecting light obtained from the emitted coherent light with a photodetector;
(F4) obtaining coherent light scattering (CLS) data based on detection light obtained from the emitted coherent light;
(F5) obtaining a pulse and a pulse waveform necessary for performing the SPO2 calculation based on the CLS data,
The method of claim 12, wherein the coherent light source and the photodetector are coupled to a strap.
The method of claim 12, further comprising: (G) using the coherent light source as one of a plurality of light sources.
The method according to claim 12, wherein the step (A) is performed by a dome-shaped structure that fits a tip of the ulna.
JP2014527775A 2011-08-30 2012-08-26 Pulse meter / oximeter that can be worn on the body Pending JP2015503933A (en)
GB1114881.4 2011-08-30
GB1114881.4A GB2494622A (en) 2011-08-30 2011-08-30 Wearable pulse oximetry device
PCT/IB2012/054349 WO2013030744A1 (en) 2011-08-30 2012-08-26 Wearable pulse oximetry device
JP2015503933A true JP2015503933A (en) 2015-02-05
ID=44838863
JP2014527775A Pending JP2015503933A (en) 2011-08-30 2012-08-26 Pulse meter / oximeter that can be worn on the body
US (2) US9314197B2 (en)
EP (1) EP2750604B1 (en)
JP (1) JP2015503933A (en)
KR (1) KR20140069055A (en)
CN (1) CN103906468B (en)
AU (1) AU2012303702A1 (en)
BR (1) BR112014004744A2 (en)
CA (1) CA2882683A1 (en)
DK (1) DK2750604T3 (en)
ES (1) ES2661709T3 (en)
GB (1) GB2494622A (en)
IL (1) IL231133D0 (en)
NO (1) NO2812096T3 (en)
PL (1) PL2750604T3 (en)
SG (1) SG11201402545QA (en)
WO (1) WO2013030744A1 (en)
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2011-08-30 GB GB1114881.4A patent/GB2494622A/en not_active Withdrawn
2012-08-26 KR KR1020147008246A patent/KR20140069055A/en not_active Application Discontinuation
2012-08-26 PL PL12827666T patent/PL2750604T3/en unknown
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2012-08-26 EP EP12827666.4A patent/EP2750604B1/en active Active
2012-08-26 ES ES12827666.4T patent/ES2661709T3/en active Active
2012-08-26 BR BR112014004744A patent/BR112014004744A2/en active Search and Examination
2012-08-26 AU AU2012303702A patent/AU2012303702A1/en not_active Abandoned
2012-08-26 DK DK12827666.4T patent/DK2750604T3/en active
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2012-08-26 JP JP2014527775A patent/JP2015503933A/en active Pending
2012-08-26 CN CN201280053389.5A patent/CN103906468B/en active IP Right Grant
2012-08-26 WO PCT/IB2012/054349 patent/WO2013030744A1/en active Application Filing
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2014-02-24 IL IL231133A patent/IL231133D0/en active IP Right Grant
2016-04-12 US US15/096,611 patent/US9730622B2/en active Active
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GB201114881D0 (en) 2011-10-12
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US20160278676A1 (en) 2016-09-29
US20140200423A1 (en) 2014-07-17
IL231133D0 (en) 2014-03-31
CN103906468A (en) 2014-07-02
AU2012303702A1 (en) 2014-04-10
PL2750604T3 (en) 2018-05-30
BR112014004744A2 (en) 2017-03-28
DK2750604T3 (en) 2018-01-15
KR20140069055A (en) 2014-06-09
US9730622B2 (en) 2017-08-15
WO2013030744A1 (en) 2013-03-07
US9314197B2 (en) 2016-04-19
ES2661709T3 (en) 2018-04-03
CA2882683A1 (en) 2013-03-07
EP2750604B1 (en) 2017-10-04
US20140031650A1 (en) 2014-01-30 Sine saturation transform