Patent Description:
The present application claims the benefit and priority of <CIT>.

One of the most promising and at the same time rapidly growing healthcare areas is the wearable devices that assist individuals keeping track of their everyday activities. Preventive medicine and real time monitoring services are gaining an increasing emphasis driven by the increasing need for chronic disease management, patient empowerment, wellness and aging population support.

To date, there is a plurality of applications and services supported by modern smartphones and mobile applications using embedded or external sensing devices for capturing e.g. physical activity, fitness and sleep patterns, etc..

Patent application document <CIT> describes a data processing method that comprises obtaining one or more first photoplethysmography (PPG) signals using first light sources emitting green light, and one or more PPG signals using second light sources emitting red light, wherein one or more of the first light sources and one or more of the second light sources are colocated. Patent application document <CIT> describes an apparatus and systems for providing health monitoring sensor placement, wherein the apparatus includes a sensor device that may be disposed or attached to a part of a watch. Scientific paper by <NPL>, concerns a method for detecting and removing motion artifacts (MA) in PPG signals and using highquality signal segments to calculate saturation of blood oxygen. Patent application document <CIT> describes a circuit in a mobile terminal for measuring heartbeat/stress using PPG signals, wherein the circuit includes a PPG sensor having green light-emitting diodes (LEDs), LED drivers, and a processor to control the LED drivers to alternately turn the LEDs. Internet Publication titled "<NPL>, concerns PPG for estimation of blood flow, and the development of integrated dual emitters and a detector in a single substrate. Scientific paper by <NPL>, describes that oxygen saturation in the arterial blood (SaO<NUM>) can be assessed noninvasively by pulse oximetry based on PPG pulses in two wavelengths, and that calibration of the PPG signals is performed empirically for each type of pulse-oximeter sensor.

However, most of known devices are highly inaccurate, not standardized, and not considered as medical grade devices, but rather as fitness trackers. That is, there is no known wearable device achieving highly accurate readings of vital signs such as blood oxygen levels.

In addition, known devices may comprise limited functionalities and/or may be aesthetically not appealing to users for continuous or everyday use.

In conclusion, there is a need for providing wearable devices, systems and/or methods that provide a medical grade accuracy of a complete set of vital signs via non-invasive measurements without compromising comfort or aesthetic appeal.

The present invention provides, according to a first aspect, a method for non-invasive measurements of biomarkers. The method comprises providing a case, the case being a wrist-watch back case for replacing a removable back case of a timekeeping device or to be attached thereto. The wrist-watch back case comprises a casing comprising a bottom wall and a side thereby defining an inner empty space and having at least five openings at the bottom wall. The back case also comprises an optoelectronic circuit board to be fitted in the inner space of the casing. The optoelectronic circuit board comprises at least two paired radiation sources to impinge radiation on user skin when the wrist-watch is worn by the user. Each source has a different emission wave length and at least one radiation detector to detect the reflected radiation exiting from skin and to transform it into a processable signal. The radiation sources and radiation detector are arranged in correspondence to the at least five openings. The wrist-watch back case also comprises radiation guiding elements to provide a coupling of the reflected radiation, wherein the guiding elements are arranged between the radiation detector and the user's skin.

The casing enables transforming a timekeeping wristband device into a smart medical apparatus, capable of accurately measuring a plurality of health-related biomarkers without altering the functionality and/or the characteristics of the timekeeping device. The need of an extra display may also be avoided.

In addition, the back case enables a user to choose between replacing the replaceable back case or attaching the proposed back case to an existing back case thereby the apparatus is easy to use.

The back case is simple and cost effective as the user does not need to buy a completely new device as the proposed back case permits using the user's own timekeeping device. As a result, the aesthetic design is neither altered nor compromised as the back case can also be attached to a timekeeping device (watch).

In addition, the use of aback case ensures an optimal sensor-body contact with the radiation sources.

In some examples, the back case may further comprise a temperature sensor for measuring user body temperature.

In some examples, the back case may further comprise fastening elements to attach the back case to a timekeeping device.

In some examples, the back case may further comprise a first thermally insulating layer to thermally insulate back casing.

In some examples, the radiation detector is a photodiode.

In some examples, the radiation detector may further comprise filters, e.g. optical filters. A photoplethysmogram (PPG) signal may be generated. A photoplethysmogram (PPG) is an optically obtained absorption signal. It may be acquired by using a radiation source which illuminates the skin and a radiation detector to measure changes in light absorption reflecting the volumetric variations of blood circulation.

The claimed method further comprises illuminating the skin with at least two radiation sources and capturing the radiation exiting from the skin. The method further comprises generating an absorption (PPG) signal, extracting the epochs from the PPG signal; identifying the pulses of each epoch on the PPG signal and filtering the PPG signal by rejecting non-ideal pulses. The filtering step is repeated for all pulses until each pulse is within a predetermined reliability range. The method further comprises calculating an acceptable (artefact-free) derived PPG signal (PPGd) and extracting features from the PPGd signal, wherein extracting features comprises providing a PPGd signal having a plurality of epochs comprising pulses and separating the pulses of each epoch of the PPGd signal. , further comprising for each pulse: extracting a falling edge (ePW(i)) of the pulse, discarding beginning and end tails of each ePW(i), calculating a first derivative of each ePW(i), finding zero crossings (zCx) of each ePW, determining a location of the zero crossing (zCx), retrieving all dicrotic notch/incisura positions and repeating the steps for all pulses of the PPGd signal.

By using such a method an increased accuracy of biomarkers is provided and so medical grade measurements may therefore be obtained.

In some examples, the method may further comprise illuminating the skin with a predefined wavelength until the maximum gain is reached.

In some examples, the method may further comprise outputting a feature set for calculating biomarkers.

In another aspect, a method for calculating blood oxygen level (SpO<NUM>) is provided. The method comprises providing a PPGd signal, separating the PPGd signal into pulse waves and calculating the absorption/emission peaks. The method also comprises calculating RatioR from the absorption/emission peaks, calculating extinction coefficients of oxyhemoglobin and deoxyhemoglobin, and calculating unique wave propagation calibration coefficient (α).

In another aspect a method for calculating blood pressure (BP) is provided. The method comprises ensuring an ideal noise free environment, contacting the skin with a device according to aspects disclosed herein and estimating BP. Then BP is compared with a predetermined range, and the user is suggested to measure BP with conventional sphygmomanometer when the BP is out of the predetermined range.

In another aspect a system for non-invasive measurements of biomarkers is provided. The system comprises an illumination module comprising at least two paired radiation sources, a capture module comprising at least one radiation detector and a calculation module for calculating an absorption signal. The system also comprises a feature extraction module for extracting features from the absorption signal and a communication module for managing the communications between the calculation and feature extraction modules.

In another aspect a watchband to be attached around a wrist of a user in an adjustable manner for non-invasive measurements of biomarkers is provided. The watchband comprises a textile layer having perforations to adapt the degree of fixation, coupling elements for coupling the watchband to a watch face and a buckle coupled to an end of the wristband. The buckle has a frame and a pivoting prong coupled to the frame. The watchband also comprises a tightening mechanism for obtaining a predefined fixation on the wrist. The tightening mechanism comprises a ratchet gear having locking teeth in a predetermined angular range and a pivoting strut to engage the ratchet gear. The tightening mechanism may be arranged at a side of the buckle of a wristband or one tightening mechanism may be arranged at each side for better stability.

A tighten fixation and thus, an optimized sensor-body contact is thereby facilitated which improves and assures the accuracy of the measurements i.e. of the calculated biomarkers.

In another aspect a timekeeping device is provided. The timekeeping device comprises a case according to aspects disclosed hereinbefore and a wristband according to aspects disclosed hereinbefore.

In another aspect system for non-invasive measurements of biomarkers is provided. The system comprises a time keeping device according to aspects disclosed hereinbefore, an interface module, and a mobile device for controlling signal acquisition procedure, acquisition mode and acquisition parameters as well as processing all the signals and performing the calculation methods as disclosed herein.

<FIG> shows a back case <NUM> to be attached to an existing back case of a timekeeping device. The back case <NUM> may comprise a bottom wall <NUM> and a side wall <NUM> surrounding the bottom wall thereby forming an inner empty space for fitting an electronics circuit board (later on disclosed).

The back case <NUM> may be made of e.g. plastic, metal, carbon fiber or any other suitable material.

The bottom wall <NUM> may comprise openings <NUM>, <NUM> for receiving an element of a circuit board and openings <NUM> for attaching the circuit board to the bottom wall <NUM>.

The bottom wall may comprise a central opening, a pair of openings surrounding the central opening and openings near the periphery of the bottom wall.

In an example, the bottom wall <NUM> may comprise openings <NUM> for receiving radiation sources, an opening <NUM> for receiving a radiation detector and other elements e.g. a temperature sensor and openings <NUM> for fastening the electronics circuit board to the bottom wall. The diameter of each opening <NUM> - <NUM> may vary depending on the element to be received therein. For instance, openings <NUM> for receiving radiation sources may comprise a diameter smaller than the diameter of opening <NUM> for receiving a radiation detector.

In an example, the back case <NUM> may comprise an opening <NUM> for receiving a radiation detector arranged in the bottom wall <NUM> and four radiation source openings <NUM> arranged around and in the proximity of the opening <NUM> for receiving the detector. The four radiation source openings <NUM> may be arranged at <NUM> degrees with respect to each other and. A pair of such opposite, i.e. arranged at <NUM> degrees with respect to each other, radiator source openings <NUM> may be situated at a closer distance to the opening <NUM> than the other opposing radiator opening sources.

The bottom wall <NUM> may comprise any shape e.g. substantially rounded, elliptical, etc., for adapting to the watch face of a certain timekeeping device and therefore avoid part of the back case <NUM> from protruding out of the timekeeping face which may be uncomfortable and may even cause injuries to the user. In an example, the bottom wall <NUM> may be substantially circular and its diameter, i.e. the diameter of the back case <NUM>, may be of about <NUM> - <NUM>. In an example, the diameter may be <NUM>. In another example, the diameter may be about <NUM>.

The back case <NUM> may, after inserting a circuit board therein, be attached to an existing back case of a timekeeping device by an adhesive provided on the surface of the side wall or by any other suitable method.

In some examples, the back case <NUM> may replace the existing back case of a timekeeping device.

<FIG> depicts an example of a back case <NUM> which differs from the back case <NUM> of <FIG> in that the side wall <NUM> may comprise fastening elements, e.g. laterally protruding flaps <NUM> to fasten the back case to the timekeeping device. In an example, the fastening elements may comprise screws (not shown) to provide a secure fastening of the back case to the timekeeping device.

In addition, the height of the side wall <NUM> may be different than that in the example of <FIG>, thereby forming a deeper or shallower inner space.

The back case <NUM>, <NUM> according to any of the disclosed examples may further comprise a first insulating layer (not shown) to insulate the inner space. In an example, the first insulating layer may be thermally insulating layer and/or a moisture insulating layer. The first insulating layer may be arranged at the sidewall, i.e. at the periphery of the back casing, thereby thermally and/or hermetically sealing the inner space there between when coupling the back case to a timekeeping device. A thermally conductive ring may be in contact with the skin and conduct the heat to the sensor, which is inside the casing. In an example, the conductive ring may be made of metal.

<FIG> depicts a circuit board <NUM>, e.g. an optoelectronic circuit board, to be fitted within a back case <NUM>, <NUM> according to any of the disclosed examples. The optoelectronic circuit board <NUM> may comprise a base plate <NUM> e.g. a printed circuit board (PCB), in which different electronic and/or optoelectronic elements may be arranged. The optoelectronic circuit board <NUM> may have a shape corresponding to the shape of the bottom wall <NUM>, <NUM> of a back case <NUM>, <NUM> to be easily fitted therein.

The optoelectronic circuit board <NUM> may comprise at least two paired radiation sources 303A, 303B for generating emissions having two different wavelengths e.g. visible, near infrared (NIR), infrared (IR) or any combination thereof, thereby obtaining a different penetration degree into the skin.

The first paired radiation sources 303A may emit radiation of a first wavelength λ1 that may achieve a deeper skin penetration, i.e. may reach large arteries. Such first wavelength λ1 may be less sensitive to oxyhemoglobin content thereby yielding a more stable signal over the time and less dependent on temperature. The second paired radiation sources 303B may emit radiation of a second wavelength λ2. Such radiation may penetrate less in the tissues but may capture large intensity variations, i.e. may comprise greater absorptivity.

The at least two paired radiation sources 303A, 303B may emit radiation subsequently, i.e. the emission may not be simultaneous.

The paired radiation sources 303A, 303B may impinge the body in a pulsed, continuous, frequency modulated, amplitude modulated, polarization or phase modulated mode in order to detect the intrinsic components of the tissue. In an example, the radiation sources 303A, 303B may be LED emitters or laser diodes.

The optoelectronic circuit board <NUM> may also comprise at least a radiation detector <NUM> e.g. a photodiode, to detect the light exiting from the body. The radiation source may also be provided with filters, i.e., dielectric coatings, diffractive elements or any type of wavelength selection element (not shown) and may generate a photoplethysmogram (PPG) signal.

The optoelectronic circuit board <NUM> may comprise a first set of radiation guiding elements (not shown) to be arranged between the radiation detector <NUM> and patient skin for providing a coupling of the radiation exiting from the user skin and thereby improve the accuracy and reliability of measurements. The optoelectronic circuit board <NUM> may comprise a second set of radiation guiding elements (not shown) to be arranged between each of the paired radiation sources 303A and 303B and user skin for providing an optimum coupling of the radiation entering the user skin and thereby improve the accuracy and reliability of measurements. The guiding elements may be microlenses, Fresnel lenses, diffraction elements, optical fibers, waveguides, photonic structures, etc..

The optoelectronic circuit board <NUM> may also comprise a power module comprising rechargeable battery <NUM> e.g. a lithium-ion polymer battery, and a battery charging element <NUM> which may charge the battery through wireless electromagnetic induction. The battery charging element <NUM> e.g. a charging coil, may be arranged on the periphery, i.e. around, the optoelectronic circuit board <NUM>. Such power module may further comprise at least two voltage regulators to stabilize voltages of all electronic and optoelectronic components.

The optoelectronic circuit board <NUM> may comprise an analog to digital front end (AFE) <NUM>, e.g. a system on chip (SoC). The AFE <NUM> may comprise an analog to digital converter (ADC) which may transform the detected exiting radiation analogic signal of the radiator detector into a digital signal e.g. of <NUM> bits. The AFE <NUM> may further control timings, sampling and radiation intensity parameters of the data acquisition, i.e. of the radiation entering and exiting the user body.

In some examples, the AFE <NUM> may not drive more than two different paired radiation sources (emitters) simultaneously, therefore the AFE <NUM> may comprise a selection circuit (not shown) for selecting paired radiation sources to impinge radiation on user skin. The selected paired radiation sources may emit radiation having Visible wavelength only, Near Infrared (NIR) wavelength only, Infrared (IR) wavelength only, Visible and NIR wavelength interchanged, NIR and IR wavelength interchanged, and Visible and IR wavelength interchanged.

In an example, there may be as many selection circuits as radiation source pairs.

In addition, the optoelectronic circuit board <NUM> may comprise a temperature and inertial measurement unit (TIMU) <NUM>, e.g. a low power integrated microelectromechanical system (MEMS).

The TIMU <NUM> may comprise a temperature sensor and also an inertial measurement unit, e.g. an inertial sensor, which may comprise a plurality of magnetic field channels and a plurality of acceleration channels, each having adjustable scales. The measured signals of both magnetic field and acceleration channels may be used e.g. as artefact rejection, PPG signal quality assessment.

In an example, the adjustable scales may be ± <NUM>, ± <NUM>, ± <NUM> and ± <NUM> gauss magnetic full scale, and ± <NUM>, ± <NUM>, ± <NUM>, ± <NUM> or ± <NUM> linear acceleration full scale.

In an example, the TIMU may comprise <NUM> magnetic field channels and <NUM> acceleration channels.

The inertial sensor of the TIMU <NUM> may measure the acceleration of the optoelectronic board and thus of the back case.

The temperature sensor may comprise a second thermally insulating layer (not shown) arranged for thermally decoupling the temperature sensor from remaining electronic components of the optoelectronic circuit board <NUM>. By thermally decoupling the temperature sensor and together with the first thermally insulating layer, arranged between the back case and a timekeeping device the temperature measurement accuracy is improved. A thermally conductive ring is in contact with the skin and conducts the heat to the sensor, which is inside the casing.

The optoelectronic circuit board <NUM> may further comprise a control and communication module (MCUBT) <NUM>, e.g. a system on chip (SoC), which may communicate with the AFE and the TIMU to enable a fast data acquisition i.e. at sampling rates of at least <NUM> for the AFE and at least <NUM> for the TIMU. The control and communication module <NUM> may further communicate with an external (mobile) device, e.g. a smartphone, a tablet, a computer, etc., to provide the acquired data. Such an external device may control the signal processing and the measuring process. In some example, an external device may also control the selection circuit of the AFE.

The control and communication module <NUM> may comprise a microprocessor and a communication module, e.g. Bluetooth.

In an example, the optoelectronic circuit board <NUM> may further comprise optoacoustic emitters and receivers (not shown). The acoustic emitters and radiation sources may be multiplexed.

In an example, the optoelectronic circuit board <NUM> may further comprise an interface module (not shown). The optoelectronic board may comprise a control module for initiating and controlling the data acquisition parameters, a communication module for managing the communications with an external mobile device and two voltage regulators. The optoelectronic board may additionally comprise an analogue to digital front end for managing the conversion of the analogue signal received by the radiation detector to a digital one, and for controlling the radiation sources.

In an example, the optoelectronic circuit board <NUM> may be fixed to the bottom wall <NUM>, <NUM> of the back case <NUM>, <NUM> by adhesive, by coupling elements or any other suitable method.

Once the optoelectronic circuit board <NUM> is assembled within the inner space of the housing of a back case <NUM>, <NUM> according to any of the disclosed examples, the resulting back case may be ready to be attached to or to replace an existing back case of a wrist watch or other timekeeping device. When the proposed back case is to be attached to an existing back case a thin cover may be placed between the case and the watch body for protection, e.g. against moisture accumulation.

The assembled back case, i.e. the back case having the optoelectronic circuit board within the housing, may have a thickness determined by the thickness of the height of the side wall. In an example, the battery may have a thickness of about <NUM>, the charging coil may have a thickness of about <NUM> and the side wall a height of about <NUM> - <NUM>.

In an example, the optoelectronic circuit board <NUM> may comprise more than two paired radiation sources e.g. near infrared, short wave infrared, infrared, mid-infrared, etc. for measuring tissue constituents such as water, lipids e.g. yellow and brown fat, and glucose. Additional and related biomarkers, e.g. hydration, lipid metabolic activity, blood sugar levels and glucose metabolic activity, may also be then calculated.

The back case and the optoelectronic circuit board may be manufactured e.g. by CNC machining, milling, moulding, press fitting, 3D printing, etc. Any suitable material such as metal e.g. stainless steel, titanium, aluminium, gold, silver; plastic, composite materials, carbon fibre or any combination may be used to manufacture a back case and/or an optoelectronic circuit board according to any of the disclosed examples.

<FIG> depicts the bottom view of a watchband or a timekeeping band <NUM> to be attached around a user wrist in an adjustable manner. The watchband <NUM> may comprise a flexible layer <NUM> e.g. made of fabric, plastic, leather, metal, etc., that may have a first <NUM> and a second portions <NUM> to be coupled to the watch body <NUM> of a timekeeping device. The watchband <NUM> may further comprise coupling elements <NUM> for coupling the watch face <NUM> to the flexible layer <NUM>.

The first portion <NUM> may comprise adjusting elements <NUM>, e.g. perforations, in order to enable the user to adapt the watchband to the size of user wrist. The second portion <NUM> may comprise a buckle <NUM> arranged at an end <NUM> of the flexible layer. The buckle <NUM> may comprise a frame <NUM> and a pivoting prong <NUM> coupled to the frame. The pivoting prong <NUM> may be introduced in a specific adjusting element to adjust the watchband to the user wrist.

In order to ensure a proper counterforce when fastening the watchband <NUM> i.e. when pulling up the buckle, around the wrist of the user, the watchband may further comprise a solid plate <NUM> e.g. made of metal, which may be arranged below the flexible layer.

The watchband <NUM> may replace the existing fastening system of a timekeeping device thereby ensuring a tighten fixation which aids to maintain the sensor-body contact pressure and improves the signal while avoiding vasoconstriction and/or user discomfort.

Additionally, the watchband <NUM> may further comprise a tightening mechanism <NUM> that may be arranged in the frame of the buckle <NUM>. The use of the tightening mechanism <NUM> enables obtaining a predefined fixation on the wrist and thereby improving the sensor-skin contact and the accuracy of measurements.

<FIG> shows a tightening mechanism <NUM> that may be arranged at a side of the buckle. The tightening mechanism <NUM> may comprise a ratchet gear <NUM> having a plurality of locking teeth arranged at the periphery, over a predetermined angular range and facing a pivoting strut <NUM> that may engage the teeth. The mechanism <NUM> may further comprise an unlocking mechanism <NUM>, e.g. a knob, and compression spring (not shown) for holding the unlocking mechanism <NUM> against the pivoting strut against the ratchet gear <NUM>.

In order to unlock the mechanism, the user may press the unlocking mechanism and release the pivoting strut.

The buckle can freely move in the opposite direction to locking thereby allowing the watch band to form a circular shape around the wrist when no measurement is taken.

In an example, the watchband <NUM> may comprise two tightening mechanisms <NUM> arranged at opposite sides of the buckle.

<FIG> depicts a system <NUM> which may comprise an illumination module <NUM> comprising at least two paired radiation sources according to any of the disclosed examples for illuminating user skin, a capture module <NUM> comprising at least one radiation detector for detecting the light exiting from the user according to any of the disclosed examples and a calculation module <NUM> for calculating an absorption signal. The system <NUM> may further comprise a feature extraction module <NUM> for extracting features from the absorption signal and a communication module <NUM> for managing the communications between the calculation and feature extraction modules. In an example, the communication module may further manage communications between the system <NUM> and an external communication device <NUM>.

<FIG> depicts a system <NUM> for non-invasive measurements of biomarkers which may comprise a back case <NUM> according to any of the disclosed examples and wherein the back case may comprise an optoelectronic circuit board <NUM> according to any of the disclosed examples. The system <NUM> may comprise an interface module <NUM> and a mobile device <NUM> for controlling signal acquisition procedure, acquisition mode and acquisition parameters. In an example, the system <NUM> may further comprise a detachable device for obtaining measurements in a different body position. The detachable device may be adhered to user body e.g. in a removable manner. In an example, the detachable device may be a sticker.

<FIG> depicts a block diagram of a method <NUM> for non-invasive measurements of biomarkers which may be implemented with a back case comprising an optoelectronic circuit according to any of the disclosed examples. Firstly, the at least two paired radiation sources having different wave lengths λ1, λ2 may be provided.

In an example, the first wave length λ1 may achieve deeper penetration than the second wave length λ2 which may only achieve superficial penetration. The first wave length λ1 may be, e.g. red light, infrared (IR) or near infrared (NIR), and when comparing with second wave length λ2, it may be less sensitive to oxyhemoglobin and therefore more stable over time, and less sensitive to temperature. The second wave length λ2, e.g. green light, may capture large intensity variations as it may have greater absorption of oxyhemoglobin and deoxyhemoglobin and so the cardiac cycle may be better reflected. By using such different wave lengths a better signal to noise ratio (SNR) may therefore be achieved. In addition, the second wave length λ2 may be more sensitive to temperature and vasodilatation/constriction.

Once a back case is attached or coupled to a timekeeping device and the latter fastened e.g. around user wrist, the user skin may be illuminated, in block <NUM>, with at least two paired radiation sources having different wave lengths. The acquired signal and the skin penetration may therefore be improved. In an example, the skin may be interchangeably illuminated by the two paired radiation sources. In an example, the skin may be firstly illuminated by an IR or NIR radiation wave length to get robust PPG signal in reflectance mode.

Then, in block <NUM>, the radiation exiting from the skin, i.e. the reflected radiation, may be captured, e.g. by a radiation detector arranged on the optoelectronic circuit board of the back case, and an absorption signal, e.g. a PPG signal, may be generated, in block <NUM>, by the radiation detector. Then, in block <NUM>, the signal epochs or epochs of the PPG signal may be extracted. Signal epochs are signal segments or signal frame lengths of a predefined length which may be long enough to facilitate robust statistical information and short enough to capture non-stationary information. In an example, the length of each epoch may be of about <NUM> seconds to accommodate <NUM>-<NUM> heart cycles within.

Pulses and/or pulse morphology of the PPG signal may then, in block <NUM>, be identified and the PPG signal may then be filtered, in block <NUM>, to get ideal artefact free PPG signal. In an example, the filtering may comprise rejecting whole pulses.

The filtering may then be repeated for all pulses of every signal epoch until each signal epoch is within a predetermined reliability range.

Then, in block <NUM>, filtered pulsed, i.e. non-removed pulses, may be collated thereby forming an acceptable (artefact free or ideal) derived PPG signal. The derived PPG signal (PPGd) may then be used for calculating the biomarkers (later on disclosed).

In an example, the method <NUM> may further comprise assessing SNRPPG of the PPG signal to verify whether SNRPPG is within an acceptable range of values. The SNRPPG of the PPG signal may indicate the level of the clinically useful signal to the level of background noise. In an example, the SNRPPG may be the ratio of filtered PPG signal variance to the unfiltered raw signal, i.e. noise, variance.

In an example, the method may further comprise assessing the PPG signal quality which may be performed e.g. by Kurtosis, Skewness or any other suitable method. The Skewness (SPPG) is defined as: <MAT> where x is the raw, i.e. unfiltered, PPG signal, µ× and σx are the empirical estimates of the mean and standard deviation of x, and E is the expected value operator.

In an alternative example, Perfusion index (PIPPG) of the PPG signal may be used to calculate PPG signal quality. The PIPPG is the ratio of the pulsatile blood flow (AC) to the non-pulsatile or static blood in peripheral tissue (DC), and represents the represents the difference of the amount of light absorbed through the pulse of when light is transmitted through the tissue. The PIPPG may be calculated as: <MAT>.

Wherein µx is the raw unfiltered signal mean, and emission and absorption peaks are calculated on the filtered signal.

In case the SNR is out of the predefined range of values, the skin may be further illuminated with a predefined wave length radiation e.g. <NUM> - <NUM>, IR/NIR wavelength, until the maximum possible gain limits of the illumination driver is reached. The SNRPPG, PIPPG or SPPC may then be re-evaluated and, in the event that a non-working signal persists and no further gain increase may be achieved, the skin may be illuminated by alternative radiation having a wave length of e.g. <NUM> - <NUM>, corresponding to green colour wavelength. The amplification gain can be also increased in order to ensure better SNR.

In an example, temperature may also be closely monitored, since cold temperature conditions may significantly reduce PPG signal quality, whereas warm temperature conditions may improve the quality of the PPG signal e.g. up to four times. Warm temperature conditions ensure reliable measurements related to peripheral extraction and circulation.

<FIG> schematically illustrates a detailed implementation of the method of <FIG>. In block <NUM> the method may be initiated when a condition is met (e.g. user selection, a predetermined time interval is reached, a time of the day etc.). In block <NUM> the skin may be illuminated using e.g. IR/NIR wavelengths. In block <NUM> a PPG signal may be captured and epochs may be extracted. The SNR may be assessed based on the absorption properties of the skin and the tightness of the strap around the wrist of the user. In decision box <NUM>, it may be determined if the SNR assessed is acceptable. If the SNR is determined to be not acceptable then in decision box <NUM> it may be determined if the gain or frequency of the signal may be increased. If the gain can be increased, then in block <NUM> the amplifier gain is increased and the method moves back to block <NUM>. If in decision box <NUM> it is determined that the gain or frequency cannot be further increased, then the skin may be illuminated using a green wavelength in box <NUM> and the process moves back to box <NUM>. Now, if after the aforementioned feedback control loop involving optimizing timing, intensity, gain or switching wavelength, the SNR is determined to be acceptable in decision box <NUM>. Then in box <NUM> the distinct pulses' morphology may be identified to meet a predefined PPG signal template considered as ideal. By using a plurality of template matching algorithms, such as the Common Spatial Patterns (CSP) technique, template subtraction, Principal/Independent Component Analysis (PCA/ICA), simple Correlation or alternative, that may compare the actual signal with the template signal a similarity may be identified. A dynamic time warping may be used to stretch each beat to match the ideal running template. This process may be repeated for every pulse in each signal epoch until an ideal PPG derived signal (PPGd) is captured in box <NUM>. The process may then end in box <NUM>. As mentioned, the epoch is defined as the signal frame length able to accommodate about <NUM> to <NUM> heart cycles, long enough to capture robust statistical signal information, yet short enough to capture nonstationary information. Decision box <NUM> may determine if pulse is acceptable and in box <NUM> suboptimal pulses may be rejected.

<FIG> depicts a block diagram of a method <NUM> for extracting a feature output set which may be used to calculate biomarkers. Biomarkers may include Heart Rate (HR), Heart Rate Variability (HRV), Blood Oxygen Level (SpO<NUM>), Cardiac Output (CO), Blood Pressure (BP), Respiratory Rate (RR), Arterial Stiffness (AS), Blood Flow Volume (BFV), Temperature and Activity tracking, etc..

Firstly, a PPGd signal e.g. the signal calculated from method <NUM>, comprising a plurality of epochs having pulses may be provided, in block <NUM>. The pulses of the PPGd signal may, in block <NUM>, be separated.

In addition, the falling edge ePW(i) of each pulse (i denotes each pulse) may be extracted, in block <NUM>, and the beginning and end tails of each ePW(i) may be discarded, in block <NUM>, to eliminate edge discrepancies. To that end an empirically defined threshold value, e.g. equal to a length segment of <NUM>*HR seconds, may be used.

The first derivative of each ePW(i) may then be calculated, in block <NUM>, and filtered, in block <NUM>, e.g. by low pass filter, in order to smooth out high frequency content. In an example, a moving average filtering with windows size of <NUM> samples may be used for filtering the first derivative.

The filtered first derivative may then be used to find the zero crossings (zCx), in block <NUM>, e.g. using a step by step zero-crossing adaptive/non-adaptive technique.

In the event the zero crossings are found, their location may be determined and a respective ePW(i) dicrotic notch/ incisura position may be found and assigned, in block <NUM>, and such value stored in a memory device. The algorithm may be moved to the subsequent pulse, in block <NUM>. The process may be repeated for all the pulses of the PPGd signal. We use the terms dicrotic notch and incisura to refer descriptively to the two possible positions of the notch. In the first case, (if the position is matched with an upstroke) we name it to be a "dicrotic notch", whether in the latter case, (if the position matches an inflection of the waveform) we will refer to it as an incisura.

On the contrary, in the event the zero crossings are not found, the peaks of first derivative of ePW(i) may be found, in block <NUM>, and may be used to analyse each peak position in a descending order thereby to locating the peak corresponding to the incisura peak, in block <NUM>. In an example, the selection of the peak may be based on position criteria with respect to the inter-beat time.

The output of block <NUM>, may then be evaluated and used to determine the incisura position if it fulfils certain inclusion criteria, as follows: Disjoint pulses (<NUM>) are identified to be: upstrokes (upslope), or downstrokes (downslope) and inflections - based on the bending pattern of the pulse under study. The "dicrotic notch and/or incisura peak" is identified if one or more of the following criteria are met: a downstroke followed by a small upstroke and/or a downstroke followed by an inflection and an upstroke and/or a downstroke followed by an inflection and another downstroke. If more than one of these is identified, we select the one with the higher slope (negative/positive) curvature in the respected segment of question.

The algorithm may be moved to the subsequent pulse, in block <NUM>.

In parallel to the separation of the pulses of the PPGd signal, the emission and absorption peaks of the PPGd signal may similarly be detected, in blocks <NUM> and <NUM>, respectively, e.g. by using an algorithm based on geometric definition of signal trends and the statistical definition of peaks and valleys.

Additionally, the method <NUM> may further comprise calculating the second derivative of the PPGd signal, in block 914a, after separating the pulses of the PPGd signal. Then, the maximum and minimum peaks of the second derivative of the PPGd signal may be found, in block 916a, and the ratio of the maximum peak to the minimum peak may be calculated.

After processing all PPGd's pulses, all epoch's dicrotic notch/incisura may be retrieved, in block <NUM>, and a feature output set may be calculated, in block <NUM>, by adding the emission and absorption peaks latency and amplitude, the peak and valley latency of the PPGd's second derivative, as well as the computed epoch's HR (<NUM>) that may be calculated using e.g. dominant frequency extraction techniques or time domain detection techniques (i.e. autocorrelation).

The output feature set (f1 - f8) may comprise: Pulse Transit Time (PTT), defined by the difference in latency within each pulse between the dicrotic notch and the absorption peak of the same pulse (f1), Amplitude/ Latency of emission peak (f2), Amplitude/ Latency of absorption peak (f3), Amplitude/ Latency of dicrotic notch/incisura peak (f4), Heart Rate (HR) (f5), Time span between Maximum peak of first derivative and dicrotic notch/incisura peak of PPGd pulse (f6), the second derivative time span between maximum and minimum peak (f7) and PPGdlR ratio of PPGd epoch emission and absorption peak amplitude (f8).

In an example, the output features may then be used to compute the biomarkers for instance by method <NUM> (later on disclosed).

<FIG> depicts a block diagram of method <NUM> for calculating biomarkers, which may be subsequent to method <NUM> of <FIG>. Firstly, the features may be extracted from the PPGd signal, in block <NUM>, and, in block <NUM>, the extracted features may be compared with previously stored features. In the event of statistically significant non-matching features, such features may be rejected.

The biomarkers may then be calculated, in block <NUM>, and calculated biomarkers may be compared, in block <NUM>, with values of previous measures e.g. of previous day, week, month, etc., in search or variability patterns i.e. capture at same time and similar activity level.

<FIG> depicts a method <NUM> for calculating Blood Pressure (BP) which may accurately estimate the BP using an output feature set f1 - f8 calculated according to any of the disclosed examples. Firstly, an ideal noise free environment may be secured, in block <NUM>.

To get a noise free environment and improve the measurements, the user may be in a resting position, e.g. sitting upright on a chair. The user may use a system for non-invasive measurements according to any of the disclosed examples, i.e. comprising at least a back case, an interface module and a mobile device, attached thereto. In an example, the device may be levelled with the user heart and the feet flat on the floor.

In order to avoid obstructing blood flow, the excess of clothing or anything that could possibly block unobstructed blood flow in the arm may be removed. As a precautionary measure, reading or talking while taking measurements should be avoided for ensuring proper measurements. Before taking the first measurement, the user may tighten the watchband, in block <NUM>, e.g. via a tightening mechanism according to any of the disclosed examples, and thereby ensure a firm contact to the skin without risking overtightening. A first measurement may then be taken, after e.g. <NUM> minutes to allow for the individual to relax and the BP may then be estimated, in block <NUM>.

Blood Pressure (BP) is related to multiple factors such as blood hemodynamics, blood density and arterial physical properties i.e. thickness, diameter, and elasticity, stroke volume, heart rate, cardiac output, peripheral resistance, circulating blood volume, blood vessels, nervous system, circulatory system, respiration, emotion and other anthropic factors.

In an example, the method <NUM> for calculating BP i.e. both systolic (SBP) and diastolic (DBP) blood pressures, relates to the features f1 - f8 which may be closely selected to match different physiological properties of the cardiovascular system under study e.g. for reflecting peripheral resistance, vessel elasticity, cardiac output, blood volume and contribute to both the SBP and DBP calculation. Contrary to known PPT-based models, method <NUM> is heavily depended on the dicrotic notch identification that carries significant physiological information. In method <NUM> a particular attention may be paid on getting optimal signal quality from the wrist. All measurements and calculations may be performed by using a noise free, high quality PPGd signal.

The output features f1 - f8 may be subjected to both linear and nonlinear multivariate analysis to build a BP estimation model.

In an example, Mean Square Error (MSE) loss function of either Multi-Layer Perceptron (MLP) or Regression Forests (RF), may be used to perform machine learning. Thereby an improved performance over time may be achieved, as compared to the faster Multivariate Linear Regression method (GLR).

In another example, ensemble learning may be used, that is, MLP, RF and GLR may be combined in order to improve the confidence of the BP estimation using majority voting. All BP models may be trained, i.e. calibrated, to output the widely used mmHg sphygmomanometer scale.

In another example, the user height, age, gender and health status may also be taken into account to derive BP measurements in each PPGd epoch.

For the training and validation phase, a static BP estimation experiment on <NUM> healthy normotensive adults (<NUM> men and <NUM> women) with an age range <NUM>-<NUM> may be used. Assuming that the user was not exercising just before taking the measurement, the activity state may automatically be extracted from the TIMU sensor of the device, in block <NUM>, BP estimation may be evaluated and in the event that BP moves outside of the bounds of normalcy, the user may be advised, in block <NUM>, to get an additional measurement with conventional sphygmomanometer.

In such a case, the values of three successive sphygmomanometer measurements, e.g. taken with an interval of <NUM> minute, may then entered e.g. manually, into a user interface, e.g. via a mobile app. In an example, the system may be retrained i.e. recalibrated, to take account for the manually entered measurements and the difference with respect to estimated BP values, in block <NUM>.

The estimation error is found to increase one day after model training, with no further significant increase, afterwards. A bit shifted (erroneous) blood pressure value may be provided the first day after initial calibration. Hence, the user may be prompted to recalibrate the system after one day in order to properly account for possible BP prediction power loss.

In the event the method is used while exercising, the system may be capable of evaluating BP in the recovery phase to estimate, in block <NUM>, the hypertension tendency of the user. In an example, the recovery phase, blood pressure may be hypertensive if a value of <NUM>/<NUM> Hg is exceeded in the fifth minute.

<FIG> depicts a block diagram <NUM> of a method for calculating the tissue Blood Oxygen Level (SpO2) from PPG readings.

The PPGd signal may be used as the basis for extracting meaningful measures. The emission (f2) and absorption (f3) peaks may be detected as described before in blocks <NUM> and <NUM>, respectively. Then, in block <NUM>, the PPGd signal calculated according to any of the disclosed examples may be provided and the epochs of the PPGd may be segmented, in block <NUM>, into disjoint pulse waves which may be used to calculate, in block <NUM>, the latency, i.e. the amplitude, of emission and absorption peaks.

The user skin may, in an example, be illuminated with at least two different wavelengths e.g. Green light and IR radiation. The use of the at least two different wavelengths penetrating and then exiting the user tissue enables obtaining different absorption with distinct extinction coefficients. Light extinction coefficients of blood components, i.e. oxyhemoglobin (HbO) and deoxyhemoglobin (Hb) may be calculated from extinction coefficients as a function of wavelength measurements. Such light extinction coefficients are unique for each tissue impinging light wavelength.

The method <NUM> for calculating the tissue blood oxygen level (SpO2) may further comprise calculating the RatioR, in block <NUM>, from the absorption and emission peaks of the PPGd signal. RatioR may be calculated by: <MAT>.

Then, in block <NUM>, the extinction coefficients of oxyhemoglobin and deoxyhemoglobinmay i.e. HbO1, HbO2 and Hb1, Hb2, of impinging first wavelength λ1 and second wavelength λ2, respectively, may be calculated. In an example, the first wavelength may correspond to green light and the second wavelength may be IR.

In block <NUM>, the unique wave propagation calibration coefficient α may be calculated according to predefined light propagation models accounting for different absorption and scattering of first and second wavelengths λ1, λ2 resulting to a difference of light propagation path length (L1, L2) within the illuminated tissue. Therefore, α may be calculated as: <MAT>.

Then, in block <NUM>, the value of SpO<NUM> may be calculated by the following formula: <MAT>.

In an alternative example, the Perfusion Index PIPPC of each signal epoch may be used to calculate the RatioR for the two wavelengths by dividing PIPPG(wave1) / PIPPG(wave2).

However, a single measurement of a biomarker cannot allow a precise determination of user health status. In an example, the system according to any of the disclosed examples used to implement any of the disclosed methods, may comprise a Personal Health Record (PHR) e.g. on the mobile device, thereby enabling short-term i.e. previous day, and/or long-term, i.e. previous week and month, comparative/ contrasting vital signs monitoring.

The Cardiac Output (CO) may be calculated as the reciprocal ratio of the systolic and diastolic area of the PPGd pulse signals. The systolic area, in a pulse, is defined as the area under the curve bounded by the beginning of pulse and the dicrotic notch, whereas the diastolic area is bounded by the dicrotic notch and the end (absorption peak) of the pulse.

The Blood Flow Volume (BFV) is the volume of the blood measured considering a specific PTT, physiological parameters of a human body, and measurement position, where according to one example the device may be positioned on the posterior side of the wrist of a subject.

The Respiration Rate (RR) may be calculated using band pass filtering on Fast Fourier Transform (FFT) peak detection over noisy quasi-periodic signals selecting, according to one example, the dominant or most important frequency prior to the cardiac frequency.

The Heart Rate Variability (HRV) may be calculated by jointly measuring the interval time between emission, absorption and dicrotic notch/incisura peaks, according to one example the SD (standard deviation) and RMSSD (root mean square of successive differences of beat to beat intervals in time domain).

The Arterial Stiffness (AS, ASI), an independent screening measure for cardiovascular risk, related to aging and elastic properties of the arteries shows the contribution of wave reflection to systolic arterial pressure, and according to one example may be approximated by the ratio of the maximum peak to the minimum peak of the second derivative.

Claim 1:
A method for non-invasive measurements of biomarkers, comprising:
providing a case, wherein the case is a wrist-watch back case (<NUM>) to replace a removable back case of a timekeeping device or to be attached thereto, the wrist-watch back case comprising:
a casing comprising a bottom wall (<NUM>) and a side wall (<NUM>) thereby defining an inner empty space, at least five openings (<NUM>; <NUM>) at the bottom wall, an optoelectronic circuit board (<NUM>) to be fitted in the inner space of the casing the board comprising, at least two paired radiation sources (303A; 303B) to impinge radiation on a user's skin when the wrist-watch is worn by the user, each source having a different emission wave length to obtain a different degree of skin penetration, at least one radiation detector (<NUM>) to detect a reflected radiation signal exiting from the skin and to transform the reflected radiation signal into a processable signal, wherein the radiation sources and the radiation detector are arranged in correspondence to the at least five openings, and the wrist-watch back case also comprises radiation guiding elements to provide a coupling of the reflected radiation, wherein the guiding elements are arranged between the radiation detector and the user's skin;
illuminating a skin with the at least two radiation sources;
capturing the radiation exiting from the skin;
generating an absorption (PPG) signal;
extracting the epochs from the PPG signal;
identifying the pulses of each epoch on the PPG signal;
filtering the PPG signal by rejecting non-acceptable pulses;
repeating the filtering step for all pulses until each pulse is within a predetermined reliability range;
calculating an artefact-free derived PPG signal (PPGd), and extracting features from the PPGd signal, wherein extracting features comprises:
providing a PPGd signal having a plurality of epochs comprising pulses;
separating the pulses of each epoch of the PPGd signal,
further comprising for each pulse:
extracting a falling edge (ePW(i)) of the pulse;
discarding beginning and end tails of each ePW(i);
calculating a first derivative of each ePW(i);
finding zero crossings (zCx) of each ePW;
determining a location of the zero crossings (zCx);
retrieving all dicrotic notch/ incisura positions; and
repeating the steps for all pulses of the PPGd signal.