WO2016030869A1 - Wearable, multi-parametric wireless system-in-patch for hydration level monitoring - Google Patents

Abstract

Wearable system based on an in-situ four-probe impedance measurement at different signal frequencies for the topical monitoring of at least one physiological parameter reflecting the hydration status such as skin conductivity, ion concentration in sweat or red blood cell characteristics. The said system is comprising a flexible substrate adapted to be directly or indirectly fixed to the skin and a plurality of conductive electrodes designed to be in contact with the body and to enable a four-probe measurements of the bio-impedance of tissue and/or skin at one or more tissue site. One embodiment includes at least a temperature sensor serving both the calibration of the impedance measurements as well as for the estimation of the temperature effect on hydration status, allowing the fine-tuning of the hydration status evaluation.

Description

Wearable, multi-parametric wireless system-in-patch for hydration level monitoring

Cross-reference to related applications

This application claims the benefit of PCT application No. PCT/IB2014/064149, filed August 29, 2014, the entire content of which is incorporated herein by reference.

Field of the invention

The present invention relates to a wearable system enabling monitoring of the hydration status of a living being. It more precisely relates to the topical monitoring of physiological parameters reflecting the hydration status.

Background of the invention

Dehydration (hypohydration) is a condition that occurs when the loss of body fluids, mostly water, exceeds the amount of the water intake. Therefore, more water is moving out of the cells and body than what an individual takes in through drinking. With dehydration, the excessive loss of body water could result in more severe effect such as disruption of metabolic processes.

The term dehydration can refer to the following two conditions:

- hypernatremia, defined by an elevated sodium level in the blood (loss/deficit of free water and the attendant "excess" concentration of salt). This is related to a disruption of the body's electrolyte- water balance (osmolarity).

- hypovolemia which is a state of decreased blood volume; more specifically, decrease in volume of blood plasma (loss of blood volume, particularly plasma). The volume loss can be isotonic and preserve the electrolyte-water balance or not (for instance hypotonic state: salt depletion). Hypovolemia is reported to be the most common dehydration form. Hypernatremia and hypovolemia can co-exist or occur independently; therefore it is important that the measurement principle of the hydration can cover both of them. Particularly, the method used for hydration estimation should be able to quantify the body water loss with an order of magnitude of a few percents (%) variations that reflect different levels of dehydration and different symptoms (see Table below).

According to the French National Institute of Health, in 2003 the heat wave in France caused 14'802 heat-related deaths, mostly among the elderly. The number of annual deaths in the UK resulting from the heat is expected to rise by 257% by 2050. The main cause of these worrying figures is acute dehydration.

In sports, dehydration during intense effort and under hot environment conditions leads to reduced performance.

Body mass is often used to assess the rapid changes of hydration in both laboratory and field environments. The level of dehydration is expressed as a percentage of starting body mass. There is evidence that body mass may be a sufficiently stable physiological marker for monitoring daily fluid balance, even over longer periods (1-2 weeks). Over longer periods, changes in body composition (fat and lean mass) are also reflected grossly as changes in body mass, thus limiting this technique for assessment of hydration. This technique is not 100% robust and cannot be used for a real-time assessment of dehydration. Experts acknowledge the difficultly in attempting to assess this true hydration and promote the use of a number of the more established methods to ensure the best representation of hydration status.

Therefore, there is a clear need and demand in terms of a low power wearable systems able to non- invasively evaluate in real time and for long periods of time the hydration level of a person in various active life scenarios.

General description of the invention

An objective of the invention is to fulfill the need and demand mentioned in the previous section.

To this effect, it relates to a wearable system for the topical monitoring of at least one physiological parameter reflecting the hydration status such as skin conductivity, ion concentration in sweat or red blood cell characteristics, said system comprising a flexible substrate adapted to be directly or indirectly fixed to the skin and comprising plurality of conductive electrodes designed to be in contact with the body, said electrodes being set in an at least four-terminal sensing configuration to detect voltages and/or currents, and determine the bio-impedance of tissue at one or more precisely defined tissue sites.

The invention also relates to a method for using the above-cited system. In one preferred embodiment, the system is used with a flexible substrate, temperature co-monitoring and wireless communication of the data, which advantageously provide an almost-continuous measurement of the bio-impedance and temperature, which is necessary for real-time detection of dehydration.

An essential aspect of the invention is the evaluation of the body tissue impedance at various frequencies based on a four-probe impedance measurement removing the parasitic effect of the electrode-to-tissue contact resistance and by co-monitoring the environmental, skin and/or core body temperature. The proposed impedance measurement is particularly valuable as it can reflect both hypernatremia and hypovolemia conditions, generated by variable sodium level (ionic concentration) and volume loss, respectively. The method according to the present invention is much more accurate than any existing skin DC resistance measurements and can be flexibly adapted for both transdermal and subcutaneous electrode measurements.

In summary, the present invention offers in particular the following advantages:

• The systems is able to perform a multi-parameter measurement based on robust measurement principle. The cross analysis of multiple parameters enables to characterize and extract dehydration level related to both hypernatremia and hypovolemia.

• The system is non or minimally invasive, for instance with an embodiment being a flexible and bio-compatible electronic stamp with an area of the order of a few cm².

• The system requires no or minimal knowledge of the user to be operated.

• The system is quasi-disposable, a few days to a week

• The system is quasi-autonomous from the energy point of view, it has low power consumption and an energy source integrated.

• The system can wirelessly communicate with a personal portable hub serving as display interface.

The proposed system-in-patch (or electronic stamp) is used to non-invasively evaluate in real time the hydration level of a person by a low power multi-parameter extraction from bio-impedance measurements following well defined novel procedure and can be extended for other applications exploiting skin and sweat bio-impedance measurements.¹' ²

The data measured by the system may be advantageously wirelessly collected by a smart hub (smart phone, smart watch or any other personal mobile device) that can perform more complex signal processing and serve as interactive display interface with an end-user.

The systems is able to perform a multi-parameter bio-impedance measurement based on robust measurement principle. The cross analysis of multiple parameters enables to characterize and extract dehydration level related to both hypernatremia and hypovolemia. The system-in-a-patch embodiment permits low power consumption, autonomy and wireless connectivity. Detailed description of the invention

The invention will be better understood below with some concrete examples. It is worth noting that such examples are used only to illustrate certain forms of applications of the invention, which are much broader and of more general purpose, for any applications where related to the noninvasive measurement of the ionic content of bio-fluids and their volume. Because dehydration is directly related to these parameters, it forms a first class of major applications.

Brief description of the figures

FIG. 1 (a) shows the principle of a conventional 4-probe measurement for resistivity measurement of a substrate.

FIG. 1 (b) represents a system according to the invention in accordance with a single-site bio- impedance measurement, multi-parameter extraction and wireless communication to a smart hub (e.g. a mobile device).

FIG. 2 is a local partial cross-sectional view of a sensor of the system of FIG. 1

Numerical references used in the figures

1. Electrodes

2. Control and measurement circuitry

3. Temperature sensor

4. Radio circuit

5. Antenna

6. Flexible substrate

7. Energy source

8. Smart hub

In the principle shown on FIG. 1 (a) four metal electrodes are patterned on a substrate: between two external electrodes a DC current source is applied while the voltage drop is recorded between the middle (inner) electrodes, with the goal of removing the influence of the contact resistances and extracting the resistivity of a semiconductor substrate (typically).

The method, as shown on FIG. 1 (b), is exploiting a circular design of the electrodes and an impedance measurement by an AC signal, which permits to extract skin impedance by removing the effect of the series resistances. The metal thin layer electrodes 1 are designed in a concentric manner and placed on the bottom face of a flexible substrate, in contact with the skin. The control and measurement circuit 2 includes the current source, the voltage measurement unit as well as a control measurement unit and the readout for the temperature sensor, the signals processed in this unit that is an integrated circuit placed on the top of the flexible substrate and connected by vertical metallic vias (processed through the insulating flexible substrate) to the electrodes 1 are supplied to the radio circuit. The temperature sensor 3 is included on the same flexible substrate 6 with double role: monitoring of the core body and/or skin temperature and temperature correction of the impedance measurements. The radio circuit 4, placed on the top surface of the flexible surface 6, is used to wirelessly communicate the sensor data to a smart hub. The printed antenna 5 allows a radio link. A local energy source 7 may consist of a thin-film rechargeable battery, a solar cell or a thermo-electric energy harvester with appropriate power management circuitry integrated on the flexible substrate, and, external to our smart patch embodiment. The smart hub 8 may be a mobile smart phone, a smart watch or a similar hand-held device with communication and local processing capability.

FIG. 2 is a local partial cross-sectional view of a sensor of the system of FIG. 1, which represents only the part concerning the time- or frequency- variable bio-impedance, Z(t), measurement, free of parasitic contact resistances between the skin and electrodes. The inset depicts two possible embodiments of the electrodes of important relevance for this invention: (i) a transdermal electrode embodiment, corresponding to non-invasive metal electrodes capable of measuring the impedance by a surface metal-skin contact, and, (ii) a subcutaneous embodiment, corresponding to semi-invasive 3D-patterned conductive electrodes, capable of superficially penetrating the skin in order to improve the metal-skin contact and, also, access the deeper skin layers (of the order of millimeters) for improved impedance measurement (less contact variability) and access to deeper tissue levels.

Key features of this example are listed below: The system performs a smart bio-impedance measurement based on robust four-point measurement principle at different signal frequencies, Z(f), from which multiple parameters able to characterize both hypernatremia and hypovolemia, therefore levels of any type of body (de)hydration, can be extracted. The current applied between the outer electrodes has both DC and AC components, which allows extracting all the information concerning the impedance equivalent circuit (resistive and reactive components). Moreover, our four-electrode circular design and method permits to remove the effect of the contact resistances (due to imperfect contacts and variability in skin surface, typical to all electronic patches. The circular design allows to collect all the current flow lines by the outer contact (no fringing effects), which results in a precise estimation of the form factor of the equivalent impedance (equivalent width versus length).

Such a system can be directly applied on the skin of a person and/or inside any type of garment. Its embodiment can be based on any type of insulating thin flexible substrates on which thin metal electrodes can be processed.

The system-in-patch principle can be both implemented in fully non-invasive or minimally invasive embodiments and includes temperature sensing for accurate calibration and decorrelation from any external temperature influences, on the same substrate.

The system is quasi-disposable, and can be operated for a few days to few weeks because the sensing principle require low power consumption and the embodiment on the flexible substrate includes flexible batteries and other energy harvesting devices (such as solar cells, thermoelectric, etc.) and a local power management circuit. In one

embodiment, a device on patch harvests energy from the environment, therefore the system-in-patch is autonomous from the energy point of view, having both low power consumption and an integrated energy source.

The system-in-patch is designed to wirelessly communicate with a personal portable hub serving as display interface and offers full information for hydration but also for some biological parameters characterizing body fluids and skin features. It can therefore be used for other classes of applications in health, sport and fitness exploiting these parameters.

The system comprises a flexible substrate (e.g. liquid crystal polymers, paper, polyimide, PEN, PET, PU, Silicone, Teflon, etc.) and protective insulating material, a plurality of electrodes to sense signals in a way adapted to contact human body (skin), electronics and radio to locally condition and transmit signals to a nearby mobile hub, an energy source to power the sensing device and a dual temperature sensor for sensing both the core-body temperature and the environment temperature. The system is primarily intended to monitor body hydration level but encompasses many other applications and embodiments.

The system includes a patch with a plurality of conductive electrodes, to make contact with the body, are set in a four-terminal sensing configuration to detect currents and/or voltages and determine the bio-impedance of tissue at one tissue site (in the described embodiment) but extendable to multiple body sites.

The four terminal sensing configuration eliminates the impedance contribution of the wiring and contact resistances of the electrodes with the body. The electrodes, as well as a temperature sensor in contact with the body, are connected to electronics and a radio that in turn condition and transmit wirelessly the signals to a data acquisition module of a nearby mobile device. This mobile device is equipped with an adequate processing unit to treat the signals, extract physiological parameters such as the water fraction of the tissue, the cardiac output, the red blood cell content and determine the hydration level.³' ⁴

The invention covers at least two embodiments that provide different levels of trade-off between accuracy and non-invasivity level:

A fully non-invasive embodiment, with electrodes presenting a flat surface for transdermal measurement of the bio-impedance.

A semi-invasive embodiment, with electrodes surface being patterned with three- dimensional (3D) microelectrode array, enabling the superficial penetration of the skin for subcutaneous measurement of the bio-impedance. This embodiment has the advantage of providing well-conditioned local impedance measurement conditions and higher accuracy of the data for hydration estimation.

The operation of the proposed system-in-patch is as follows (see Figs. 1 and 2):

An integrated current source generates a low amplitude current i(t) which is composed a DC component and an AC component with a plurality of possible frequencies. The current runs through the tissue between the outer electrodes and generates a voltage v(t) between the inner electrodes. The ratio v(t)/i(t) represents the complex bio-impedance Z(t) of the tissue between these two electrodes. Performing the measurement at least at two different frequencies: a low and a high frequency, provides information related to the extracellular bio-impedance of the tissue and the whole (intra and extracelluUar) bio-impedance of the tissue respectively. A more accurate analysis could be based on multiple-frequency measurements and an optimal combination of the results followed by appropriate signal processing.

The bio-impedance Z(t) can be divided in two components Zl(t) and Z2(t). Zl(t) contains the impedances of the tissue which can be considered as constant during the acquisition time of a single measurement point. Zl(t) varies slowly with time as a function of the tissue fluid content. Z2(t) contains a pulsatile time-varying impedance correlated with the fluid volume variation within the tissue represented by the blood flow. Each of these impedances is complex and provides two parameters: resistance and reactance, which are measured at two or more frequencies to decorrelate intra and extra cellular information. Adequate processing analysis of the waveforms of these signals enables to determine the water fraction of the tissue, the cardiac output and the red blood cell content. The water fraction is to be extracted from the signals corresponding to Zl(t) whereas the cardiac output is to be determined from the signals corresponding to Z2(t) with adequate calculations including Zl as a local constant. The decorr elation of intra and extracellular contributions using multiple measurement frequencies and the adequate analysis and processing of the real and imaginary part of the bio-impedance at all measured frequencies will enable accurate determination of the previously mentioned parameters as well as the red blood cell content. The temperature sensor is a dual temperature sensor, allows taking into account and correcting the thermal drift and/or other calibrations needed, exploiting the body core temperature and the environment temperature. The invention may be used in different fields; the following examples being of particular interest:

First responder (eg. firefighters):

First responders in general and firefighters in particular, are highly exposed to dehydration: the high temperature around them, the physical effort, and the heavy clothing they wear, make them prone to high sweat rates.

Studies have shown that dehydration leads to a loss of alertness, concentration and increased fatigue. This is particularly damaging for professionals who need to react swiftly and remain highly focused.

Athletes:

Studies have shown that as the level of dehydration increases during exercise, various physiological functions are progressively impacted: heart rate and core temperature continually increase over time, while blood volume, stroke volume, cardiac output, and skin blood flow all decrease. For athletes, dehydration is the consequence of the thermal regulation of the body through sweating, which is a mix of water and minerals. In the most intensive effort, the quantity of water lost by the human body can overpass 3,5 litres. In case this loss of water and minerals is not compensated, dehydration can lead to hypovolemia (drop in blood pressure), hypokalemia (paralysis of limbs) and hyponatremia (breathing disorder, disorientation).

These cases are extreme, but what is sure to be a consequence of dehydration is underperforming. Glucose is the gas of the body and glycogen is made of three molecules of water. Thus, without water, an athlete will not be able to use its reserves of glucose. It is estimated that a water loss of 1% to 2% leads to a drop in performance of 10%.

Elderly and infants: Fragile segments of the population, like the elderly and infants, are also at risk of dehydration, particularly during extreme heat. The summer 2003 heat wave in France for example caused 14' 802 heat-related deaths, mostly among the elderly, according to the French National Institute of Health. Furthermore a recent study predicts that the number of annual deaths in the UK that occur as a result of the heat will rise by 257% by 2050.⁵· ⁶

References

1. X. Huang, H. Cheng, K. Chen, Y. Zhang, Y. Zhang, Y. Liu, C.i Zhu, et al. 2013. « Epidermal Impedance Sensing Sheets for Precision Hydration Assessment and Spatial Mapping ». IEEE Transactions on Biomedical Engineering 60 (10): 2848-2857. doi: 10.1109/TBME.2013.2264879.

2. J. Beck , V. R. Sattiraju, A. M. Niknejad, L. C. Yun, R. Lee, S. Magar, et L. M. Fisher. 2014. « Integrated wireless patch for physiological monitoring ». patent US 8718742 B2

3. M. V Malahov, A. V. Smirnov, D. V. Nikolaev, A. A. Melnikov, and A. D. Vikulov. 2010. "Bioimpedance Spectroscopy as Technique of Hematological and Biochemical Analysis of Blood." Journal of Physics: Conference Series 224 (1): 012130. doi: 10.1088/1742- 6596/224/1/012130.

4. J.F. Brun, E. Varlet-Marie and J. Mercier. 2010. "Whole body bioimpedance as a mirror of the influence of hemorheological factors on electric properties of blood: a step forward with Hanai's mixture conductivity theory". Series on Biomechanics: Vol 25, No 1-2 (2010), 100-104

5. J. Holstein, F. Canoui^'-Poitrine, A. Neumann, E. Lepage, and A. Spira, "Were less disabled patients the most affected by 2003 heat wave in nursing homes in Paris, France?," Journal of public health (Oxford, England), vol. 27, no. 4, pp. 359-65, Dec. 2005.

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Claims

Wearable system based on a four-probe skin and/or body tissue impedance measurement at different signal frequencies, for the topical monitoring of at least one physiological parameter reflecting the hydration status such as skin conductivity, ion concentration in sweat or red blood cell characteristics, said system comprising a flexible substrate (6) adapted to be directly or indirectly fixed to the skin and comprising plurality of conductive electrodes (1) designed to be in contact with the body, said electrodes (1) being set in an at least four-terminal sensing configuration to detect voltages and/or currents and determine the bio-impedance of tissue at one or more tissue sites.

System according to claim 1 furthermore comprising electronics and radio (2,4) to locally condition and transmit signals to a nearby mobile hub (8), a current source (7) for generating a current between at least two of said electrodes(l) and a dual temperature sensor (3) for sensing both the core-body temperature and the environment temperature.

System according to claim 1 or 2 for non-invasive use and wherein said electrodes (1) show a flat surface for transdermal measurement of the bio-impedance.

System according to claim 1 or 2 for a semi-invasive use and wherein the electrode surface is 3D patterned such as a microelectrode array for subcutaneous measurement of the bio- impedance.

Method for using a wearable system as defined in anyone of the previous claims, said method comprising the following steps : - generating a low amplitude current i(t) (time variable) which is composed a DC component and an AC component with a plurality of possible frequencies, well controlled by a control and measurement circuit;

- Measuring the bio-impedance for at least one low and one high frequency via a voltage measurement unit embodied as an integrated circuit connected to the patterned inner electrodes of four-electrode design.

- Obtaining the hydration status from the bio-impedance measurement.