Biomedical sensors and related methods and manufacturing processes

Abstract

An implantable biomedical sensor (1) is disclosed which is characterized by a novel electrofluidic design based on dedicated measurement chambers (2, 3) enclosed by respective membranes (4, 5) which are permeable to water molecules and optionally typical ions found in human interstitial fluid (ISF). By this concept, the sensor (1) can perform electrical measurements in the respective chambers (2, 3), collecting data that allows conclusions to be drawn about the amount of water and ions present in the ISF around the sensor (1). In other words, such a sensor (1) enables electrical monitoring of the electrolyte state and / or hydration state in the tissue of a patient wearing the implantable sensor (1).

Description

[0001] This disclosure relates to a biomedical sensor designed for determining, particularly for (continuously) monitoring, the electrolyte and / or hydration status of a user / patient via corresponding electrical measurements. Specific use cases of such a sensor and efficient methods for electrically measuring the water content and / or ion content of aqueous media (particularly within human or animal tissues) are also disclosed, along with processes for parallel wafer-level fabrication of such a biomedical sensor and methods for evaluating the sensor signal generated by such a sensor.

[0002] Today, a large number of people aged 65 and older are hospitalized each year due to dehydration-related health deterioration. According to the World Population Prospects (UN, 2019), by 2050, people aged 65 and older will make up one-sixth of the world's population. This demographic shift, along with climate change as temperatures rise, poses significant health and economic challenges to societies.

[0003] Currently, there is no solution to the problem of accurately monitoring dehydration and electrolyte imbalance. What is desired is a continuous, preventative, and personalized healthcare monitoring solution that provides reliable access to relevant health information. This is because timely intervention and supportive health management are key to preventing health deterioration, especially for older adults.

[0004] Against this backdrop, one objective of the present invention is to provide a technology solution based on implantable technology for continuous monitoring of hydration and electrolytes with clinically relevant accuracy, aiming to personalize the prevention of health decline and improve patients' quality of life and autonomy.

[0005] According to the present invention, a biomedical sensor is provided according to claim 1, which solves the above-mentioned problems. Therefore, the present invention proposes to use an implantable biomedical sensor to accurately monitor a patient's electrolyte status and / or hydration status.

[0006] Specifically, the present invention proposes a sensor as described at the beginning, further characterized in that the sensor includes a first measuring chamber, which is enclosed by a porous first membrane (which may preferably be a rigid membrane) and communicates with the surrounding environment via the first membrane, the first membrane being resistant to ions (such as Na+). + Cl - Mg 2+ or Ca 2+ The membrane is permeable. In other words, the first measurement chamber can communicate with the environment surrounding the sensor via the first membrane.

[0007] The sensor also preferably includes a second measuring chamber, which is sealed by a water-permeable second membrane and communicates with the surrounding environment via the second membrane, the second membrane being impermeable to ions. The second membrane may preferably be elastic.

[0008] In addition, a first set of at least two measuring electrodes is arranged in a first measuring chamber, and a second set of at least two measuring electrodes is arranged in a second measuring chamber (if present).

[0009] This sensor design enables continuous and reliable electrical measurement of hydration status and electrolyte profiles, allowing for inconspicuous monitoring of these parameters via a connected digital system. This facilitates visualization, early intervention, and prevention of unnecessary hospitalizations; furthermore, it effectively avoids complications associated with deviations from ideal hydration. By incorporating implantable technology into the novel sensor, along with digital connectivity and intelligent algorithms, the sensor can measure a user's hydration and electrolyte status and transmit the corresponding measurement data to a digital monitoring platform (thus, the sensor's characteristics can lie in the necessary wireless communication device for this communication). Based on existing clinical evidence of healthy electrolyte and hydration levels, such a health platform can communicate trends and alerts in real time regarding acute or chronic cases of dehydration or electrolyte excess or deficiency. Therefore, the sensor provides an effective, reliable, minimally invasive, and implantable solution for continuous monitoring of a patient's hydration and electrolyte status. As will be described in detail below, this capability is achieved through the selection of the proposed measurement chamber design and the chosen membrane.

[0010] In other words, the sensor can be configured to perform a corresponding measurement on the corresponding resistance of a corresponding liquid contained in a corresponding measuring chamber. Thus, the sensor can perform two independent electrical measurements, namely, to determine the resistance, and in particular the impedance, of a first liquid contained in a first chamber (using a first set of electrodes arranged in a second chamber) and a second liquid contained in a second chamber (using a second set of electrodes arranged in a second chamber).

[0011] We note here that the first membrane will typically also be water-permeable. In other words, both the first and second membranes can be water-permeable, the possible difference being that the porous first membrane can be permeable to liquid water and ions, while the second membrane can be selected such that it is permeable only to single water molecules (e.g., this would be the case for a 100 μm thick PDMS membrane), but not to liquid water droplets.

[0012] The technical term "chamber enclosed or defined by a membrane" can be understood herein to mean that the corresponding membrane forms a boundary that defines (and thus limits) the volume of the corresponding measurement chamber. Thus, once the sensor is implanted in a human (or animal) body (e.g., subcutaneously), the corresponding measurement chamber can come into contact with the surrounding tissues and body fluids via the membrane.

[0013] The term "ion-impermeable" can be technically interpreted as meaning that the permeability is low enough that the number of ions that penetrate the membrane is so low that the measurement of the second resistance using the second set of at least two measuring electrodes inside the second measuring chamber is unaffected.

[0014] Based on electrical measurements performed in the first measurement chamber, when the sensor is introduced or implanted into the (user / patient's) human body, it can (indirectly) measure the electrolyte concentration in the tissue surrounding the sensor. Thus, the current electrolyte state of the patient / user can be determined using the sensor. This is because a higher electrolyte concentration in the surrounding environment results in more ions diffusing into the first measurement chamber, leading to a measurable decrease in the electrical resistance / increase in the conductivity of the first liquid contained within the first measurement chamber. We note at this point that the volume of the first liquid can be effectively constant, especially when a rigid first membrane is used.

[0015] Similarly, based on electrical measurements performed in the second measurement chamber, when the sensor is introduced or implanted in the human body, it can (indirectly) measure the water content in the (surrounding) tissue (more precisely, the interstitial fluid (ISF) contained within the tissue). Thus, the sensor can be used to determine the patient's / user's current electrolyte state. This is because the higher the water content (and therefore "hydration state") in the surrounding environment, the more water molecules will diffuse through the second membrane into the second measurement chamber, resulting in an increase in the volume of the second (aqueous) fluid contained within the second measurement chamber (note that the second membrane can expand, making the volume of the second fluid variable). However, since the second membrane is ion-impermeable, the number of ions in the second measurement chamber does not change; therefore, the injection of water molecules will lead to a decrease in ion concentration (measured in terms of the number of ions in the second fluid per milliliter of volume), resulting in a measurably increased resistance / decreased conductivity of the second fluid contained within the second measurement chamber.

[0016] Depending on the application, a simpler design of the biomedical sensor based on the inventive concept presented herein could be the biomedical sensor according to claim 2, which also solves the aforementioned problems. This sensor already allows for the electrical measurement of a patient's hydration status. Therefore, in particular, the present invention proposes a sensor as described at the outset, further characterized in that it includes a measurement chamber enclosed by a preferably resilient, water-permeable membrane and communicates with the surrounding environment via this membrane, the water-permeable membrane being resistant to ions (such as Na+). + Cl - Mg 2+ or Ca 2+It is impermeable. Furthermore, a set of at least two measuring electrodes is arranged in the chamber. It should be understood here that the measuring chamber just described can be the second measuring chamber corresponding to that described in claim 1; therefore, the mentioned set of at least two electrodes can be the second set, and the mentioned membrane can be the second membrane.

[0017] The sensors proposed so far can be further elaborated and implemented in various ways, as described in the dependent claims and below: For example, as mentioned above, the sensor is preferably designed for implantation in the human body. For this purpose, the sensor may be characterized by a biocompatible (external) encapsulation. In other words, the sensor can be designed to be introduced into the human body (permanently or temporarily, such as when the sensor is designed as part of a probe). For example, the sensor can be designed as a subcutaneous sensor and / or as part of a catheter designed for insertion into the human body. We note here that in the field of implantation technology, an implantation duration exceeding 30 days is generally considered "permanent." In other words, even if the sensor's design life is only 2 years, it can already be considered a permanent implant. In contrast, when using the sensor as part of a catheter, the implantation duration may only be a few minutes to a few hours.

[0018] To best benefit from the sensor design, it is advantageous if the sensor is configured to measure a first resistance (particularly a first impedance, most preferably the first impedance spectrum of the first liquid) using a first set of electrodes. Alternatively or additionally, it is equally advantageous if the sensor is configured to measure a second resistance (particularly a second impedance, most preferably the second impedance spectrum of the second liquid) using a second set of electrodes. This measurement can be automatically triggered by the sensor's control unit.

[0019] The appropriate selection of materials for the membrane can be as follows: the first membrane can be made of ceramic material, preferably alumina (Al2O3). Using a ceramic membrane as the first membrane is advantageous because it ensures that the first membrane exhibits very low water absorption and virtually no mechanical stress due to swelling in water (as is often observed with polymer membranes, particularly those made of polyurethane (PU)). Avoiding mechanical stress is important for achieving a reliable long-term bond between the first membrane (e.g., to the spacers forming the first measuring chamber) and for maintaining a constant / unchanging volume of the first measuring chamber (the volume should remain as constant as possible for accurate measurement).

[0020] Furthermore, the first membrane can be selected to provide nanoscale pores, preferably with a maximum pore size of less than 1 µm, and most preferably with a maximum pore size of less than 200 nm.

[0021] The first membrane may be characterized by a thickness of at least 50 µm to provide sufficient stiffness. In this case, on the other hand, it is most preferably that the thickness of the first membrane is less than 500 µm to achieve a compact design.

[0022] The electrodes of the sensor mentioned may include platinum (Pt), in the form of Pt or Pt / Ir, and / or include iridium, especially IrOx.

[0023] Most readily, the second membrane can be made of a polymer material, preferably polydimethylsiloxane (PDMS).

[0024] Furthermore, the second membrane may be characterized by a thickness of at least 100 µm, preferably at least 200 µm. In this case, it would be preferable that the thickness is also less than 500 µm to achieve a compact design.

[0025] As already mentioned, the first measuring chamber is preferably filled with a first liquid (e.g., it may be in the form of a gel). In this case, it is preferable that the first liquid cannot diffuse out of the first measuring chamber through the first membrane. In other words, the first liquid will be trapped in the first chamber.

[0026] According to a specific embodiment, the first membrane is permeable to a class of ions, wherein the class includes at least one of the following ions: K+, Na+, Cl-, Mg2+, Fe2+, Fe3+, Cu2+, and Ca2+. This design enables the sensor to specifically and electrically measure the concentration of ions belonging to the aforementioned ion class within the first measuring chamber.

[0027] Furthermore, the first membrane can be impermeable to a class of large-sized objects, wherein the second class includes at least one of the following: blood cells, proteins (e.g., proteins with a minimum diameter of x nm), and bacteria. This selection and design of the first membrane has the advantage of preventing biofouling due to the presence of such objects inside the first measuring chamber. Moreover, reliable, long-term stable, and selective (indirect) electrometry of the ion concentration in the interstitial fluid (ISF) surrounding the first measurement can be achieved without interference from cells, proteins, and other large-sized objects present in the ISF.

[0028] On the other hand, the second measuring chamber can be filled with a second liquid, preferably aqueous, containing a defined and constant amount / quantity of ions. By virtue of this feature, the number / concentration of ions present in the second liquid will be well-defined and / or constant over time. Therefore, the osmotic pressure (drop) across the second membrane can be well-defined. Another result is that the sensor can then specifically and electrically measure the amount of water contained in the second measuring chamber at a specific time point (particularly after water has diffused through the second membrane into or out of the second measuring chamber), as previously explained. Since this diffusion depends on the water content of the surrounding ISF, i.e., the hydration state of the user / patient, this method allows for indirect but accurate (particularly without any significant time delay) electrical measurement of hydration state.

[0029] One embodiment proposes that the sensor includes a substrate, and a first set of electrodes and / or a second set of electrodes includes at least two planar electrodes deposited (respectively) on the substrate. In this design, preferably, the electrodes are electrically connected to corresponding conductive vias formed in an electrically insulating substrate. This allows for a highly electrically reliable sensor design, ideally suited for implantation. Most preferably, the planar electrodes can be constructed by laser processing, most preferably by laser ablation, or by screen printing or photolithography. All these techniques allow sufficient resolution to accurately define the necessary electrode geometry.

[0030] For example, the substrate can be a ceramic substrate or a silicon substrate. As mentioned above, depending on the application, the electrode structuring can be accomplished by screen printing based on thick film technology or by any photolithography method based on thin film technology.

[0031] Another design, which can be combined with the features mentioned above, proposes that the sensor includes a substrate (particularly the substrate having the aforementioned through-holes), and that the first and second measurement chambers are specifically defined by spacers attached freely to the substrate. In other words, one or at least two spacers may be present. The respective spacers may define the sidewalls of the respective chambers. Additionally, the respective spacers may provide (preferably flat) surfaces that are bonded to the first and / or second membranes.

[0032] The sensor may also include a controller configured to: (i) perform a first impedance measurement of the first liquid using a first set of electrodes disposed within a first measuring chamber, and / or (ii) perform a second impedance measurement of the second liquid using a second set of electrodes disposed within a second measuring chamber. Based on these measurements, the controller can calculate derived data indicating the current hydration state and / or electrolyte state. The controller may also be configured to preferably wirelessly transmit such data or measurement results to an external communication device (computer, smartphone, etc.). The use of impedance measurement particularly allows for a more accurate assessment of the hydration state and / or electrolyte state, as a greater number of measurement points will be available.

[0033] Of course, the sensor can then include the necessary hardware for performing such impedance measurements, such as an AC current source with an adjustable frequency. Therefore, the sensor can include a current source configured to deliver alternating current to the first set of electrodes and / or the second set of electrodes, specifically enabling AC measurements of impedance to be performed by the sensor.

[0034] According to a preferred design, the sensor may include a controller (particularly the aforementioned controller) configured to perform frequency variations of the alternating current applied to the first or second set of electrodes within a frequency range, most preferably continuous scanning, to perform impedance spectroscopy (EIS). In this case, preferably, the controller is configured to calculate the real and imaginary parts from such recorded impedance spectra.

[0035] The sensor may include a voltmeter configured to perform voltammetry measurements using a first set of electrodes and / or a second set of electrodes, and / or an ammeter configured to perform ammeter measurements using a first set of electrodes and / or a second set of electrodes, and / or a potentiometer configured to perform potentiometry measurements using a first set of electrodes and / or a second set of electrodes.

[0036] The sensor may also include a controller (particularly the aforementioned controller) configured to calculate the ion concentration of the second fluid contained in the second measurement chamber and / or calculate the currently closed / contained water content in the second measurement chamber (based on an assumed constant amount of ions contained in the second measurement chamber). An (indirect) electrical measurement of the water content in the second measurement chamber (since the amount of ions contained in the second chamber is constant, a measured low ion concentration will be equivalent to a high water content) can be valuable in determining the patient's / user's hydration status: the more water contained in the interstitial fluid (ISF) and the lower the ion content of the ISF, the greater the likelihood of water diffusing from the ISF into the second measurement chamber due to the decrease in osmotic pressure across the second membrane. Therefore, a high water content / low ion concentration determined in the second measurement chamber will indicate a high hydration status for the patient / user.

[0037] The first membrane can have such stiffness that the volume of liquid contained in the first measuring chamber, particularly the volume of the first liquid that completely fills the first chamber, remains constant within a range of less than 1%, especially even if ions and / or water can freely diffuse through the first membrane.

[0038] In contrast, the volume of liquid contained in the second measuring chamber and defined by the second membrane, particularly the volume of the second liquid that completely fills the second chamber, can vary, especially due to water diffusion through the second membrane.

[0039] In a preferred design, the first set of electrodes and / or the second set of electrodes (each) comprise at least four electrodes. In this case, the sensor can be configured to perform a 4-electrode resistance measurement using the first set of electrodes and / or the second set of electrodes.

[0040] To achieve a compact design suitable for implantation, the first and second sets of electrodes can be microelectrodes with sub-millimeter dimensions. Furthermore, the first and / or second measurement chambers can each comprise less than 1 × 1 mm. 2 A volume of ×0.3mm = 0.3 µL is provided to give a possible example.

[0041] In more advanced designs, the sensor is characterized by at least two independent first measurement chambers, one of which is sealed and isolated from the surrounding environment by a porous type A membrane that is impermeable to a class (particularly a second class) of large-sized ions. Preferably, the second class includes at least one of the following ions: Ca 2+ Mg 2+ The other of the two first chambers can be sealed off and isolated from the surrounding environment by a porous type B membrane, which is permeable to the first class of large ions, particularly the second class of large ions. Therefore, the ion concentration of the first class of ions can be measured electrically and specifically when the first chamber (2a) is covered by a type A membrane, and / or the ion concentration of the second class of ions can be measured electrically and specifically when the first chamber is covered by a type B membrane. Thus, this sensor design allows for the collection of even more information regarding the current electrolyte state and specific measurements of certain ion classes.

[0042] The sensor may also feature a completely sealed reference measurement chamber, preventing ions and water from permeating into the chamber from the surrounding environment. A third set of at least two measuring electrodes is arranged within this chamber to perform electrical reference measurements. Preferably, a third liquid with a defined conductivity, most preferably in the form of a hydrogel, may be contained within the reference measurement chamber. The advantage of this reference measurement chamber is that the sensor can be configured to perform electrical reference measurements using the third set of electrodes. Based on the results of such reference measurements, temperature drift and other variations can be detected and compensated for (e.g., via the sensor's controller).

[0043] To address the aforementioned problems, the method of the present invention can also lead to specific uses of sensors as proposed herein (which may have the features claimed and / or described herein). This use is characterized by the sensor being used to monitor the hydration and / or electrolyte status of a user / patient. This monitoring can be performed continuously and / or repeatedly (e.g., at preset time intervals). In this use case, the sensor can be implanted or introduced into the user's body simultaneously with / before the performance of monitoring. Furthermore, the sensor can be configured to autonomously perform electrical measurements.

[0044] As outlined at the beginning, we also propose a method for electrically determining the water content and / or ion content of an aqueous medium, particularly in human or animal tissues, using a biomedical sensor (which may have features as claimed or described herein). The sensor should be in contact with the medium, particularly with the tissue. The method differs in that, in the first measurement, the ion concentration in a first measuring chamber containing a first liquid is electrically measured by the sensor using a first set of electrodes to determine the ion content in the medium / tissue. Specifically, as previously described, this can be accomplished by electrically measuring the resistance and / or impedance of the first liquid. It should be understood that during such a measurement, ions can freely diffuse through the described first membrane into and out of the first measuring chamber.

[0045] Alternatively, according to the method described above, in a second measurement (preferably independent of the first measurement), the water content or ion concentration in a second measurement chamber containing the second liquid can be electrically measured by a sensor using a second set of electrodes to determine the water content in the medium / tissue. Specifically, this can be accomplished by electrically measuring the resistance and / or impedance of the first liquid.

[0046] As described above, ions and / or water can diffuse into the first measurement chamber through the porous first membrane during the first measurement, and / or water molecules can diffuse into the second measurement chamber through the second membrane during the second measurement. The respective chambers can be isolated / separated from the surrounding environment, particularly from adjacent human or animal cells, via corresponding membranes.

[0047] In this method, an alternating current supplied by a current source of the sensor can be used to perform a first measurement and / or a second measurement, respectively: for example, the first measurement and / or the second measurement may therefore include a change in the frequency of the corresponding alternating current, in particular a scanning, such that impedance spectroscopy is performed, respectively.

[0048] This method can also be designed and applied to allow autonomous monitoring of a patient's hydration and electrolyte status. For example, after the sensor is introduced or implanted in the patient, it can transmit data of the first and / or second measurements, or data related to the first and / or second measurements, to an external monitoring device (tablet, smartphone, etc.). This monitoring device outputs current (i.e., measured at that specific point in time) measurements related to the patient's hydration and electrolyte status based on the data transmitted by the sensor, particularly measurement trends. Preferably, the monitoring device can trigger the sensor, for example, by transmitting instructions to the sensor to perform new first and second measurements. This instruction can, of course, depend on the data previously transmitted from the sensor to the monitoring device; that is, the monitoring device can autonomously decide whether to trigger further measurements.

[0049] Finally, we also present a specific process for parallel wafer-level fabrication of biomedical sensors (which have the features claimed and / or described herein), wherein each fabricated sensor can be designed or later configured as an implantable sensor. The process includes the following steps: - Electrodes are formed, preferably laser-processed, deposited on a wafer that forms a common substrate for the sensor; in other words, the sensors can share the substrate and can later be separated from each other by singulation. - Bonding the spacer-wafer to the substrate or picking and placing the spacer onto the substrate, the spacer forming the sidewall of the corresponding measurement chamber of the sensor; - Dispense the first liquid into a plurality of first measurement chambers formed on the substrate; - The second liquid is formed in each of the plurality of second measurement chambers by distributing a liquid (particularly a second liquid containing ions of a defined concentration) into each of the multiple second measurement chambers formed on the same substrate; we note that in the case where salt crystals are already present in each chamber, such formation can be achieved simply by distributing water, for example by deposition via a pick-and-place machine; - At least one first film is bonded (preferably multiple first films are bonded). For example, this bonding can be accomplished using a pick-and-place robot. Bonding can be performed on spacer-wafers or the aforementioned spacer(s). - Preferably, a pick-and-place robot is used to bond at least one second membrane (preferably multiple second membranes) to the spacer-wafer or spacer; - The resulting wafer-level stack, including the substrate, is monolithized into individual dies; each die corresponds to one of the sensors in the sensor suite.

[0050] The second liquid can be formed by first depositing an ionic substance (e.g., a certain amount of ionic salt) in each measurement chamber, and then dispensing the liquid into the corresponding second measurement chamber. Alternatively, the final second liquid can be pre-prepared and directly dispensed into the corresponding second measurement chamber.

[0051] The process may also include the step of encapsulating the wafer with a biocompatible soft encapsulation material to form a separate biomedical sensor. Of course, the first and second membranes may each be at least partially free of the encapsulation material. Therefore, the transfer of ions and / or water molecules through the respective membranes will still be possible.

[0052] The manufactured sensors can each present a planar design. Furthermore, the sensors can be cable-free, as all necessary wiring can be integrated into or on a common substrate, particularly via conductive vias formed in an electrically insulating substrate. These vias can connect measuring electrodes on the upper side of the substrate to current sources and voltmeters (particularly as separate electronic components) arranged on the lower side of the substrate.

[0053] In detail, each of the individual wafers can be bonded to a corresponding lower microelectronic package, which includes corresponding microelectronic circuitry electrically connected to electrodes formed on the top side of the substrate (in a corresponding chamber). This connection can be formed via conductive vias formed in an electrically insulating substrate.

[0054] Preferably, the microelectronic circuitry can implement an electronic controller for the sensor, wherein the controller is configured to perform a first electrical measurement and a second electrical measurement within the chamber to which the sensor's circuitry belongs.

[0055] Finally, within the context of the biomedical sensor presented herein, we also propose a method for evaluating the sensor signal transmitted by such a biomedical sensor (which may be manufactured as described above and / or have the features claimed and / or described herein). In this method, the sensor uses alternating current with a variable frequency to measure the impedance spectrum of a liquid contained in a measurement chamber of the sensor. Specifically, as previously mentioned, the chamber may be sealed by a water-permeable membrane and isolated from the surrounding environment. Machine learning methods can then be used to evaluate the impedance spectrum (particularly the real and imaginary parts of the measured impedance curve). In particular, this can be achieved by employing artificial intelligence (AI) to perform the evaluation, which can be implemented in software and / or hardware.

[0056] Based on such an assessment, the ion concentration of a specific ion can be calculated. For example, the assessment can be performed by a controller integrated into the sensor, specifically causing the sensor to transmit data related to the calculated concentration of the specific ion. Alternatively, the assessment can also be performed by an external controller belonging to the in vitro monitoring device; in this case, the AI ​​can be implemented by software running on the monitoring device. The monitoring device can preferably receive measurement data wirelessly from the sensor.

[0057] Preferred embodiments of the invention will now be described in more detail, but the invention is not limited to these examples: it will be apparent to those skilled in the art that other examples of the invention can be obtained by combining features of one or more of the patent claims with each other and / or with one or more features of the examples described or shown herein.

[0058] Referring to the accompanying drawings, features having corresponding technical functions are represented by the same numerals, even if these features differ in shape or design: Figure 1 This is a top view of the biomedical sensor according to the present invention. Figure 2 It shows Figure 1 A schematic cross-sectional view of the sensor, and Figure 3 It shows Figure 1 and Figure 2 How can the sensors communicate with in vitro monitoring devices to form a digital biomedical monitoring platform?

[0059] Figure 1 A possible embodiment of the sensor 1 according to the invention is shown, characterized by three separate measuring chambers 2, 3, and 13: as shown in Figure 2 As can be seen more precisely in the cross-sectional view, the first measuring chamber 2 is sealed by a ceramic first membrane 4 with nanoscale pores. When the sensor 1 is subcutaneously implanted into human tissue, ions and water molecules present in the interstitial fluid (ISF) adjacent to the sensor 1 can freely diffuse from the surrounding environment 27 through the first membrane 4 into the first liquid 6, which is sealed within the first measuring chamber 2 by the first membrane 4. Because the first membrane 4 is rigid, the volume of the liquid 6 contained in the first measuring chamber 2 cannot change over time. This is also because the first liquid 6 is selected such that it cannot diffuse out of the first chamber 2 through the first membrane 4. Therefore, the ion concentration present inside the first liquid 6 will rapidly adapt to the corresponding ion concentration present in the surrounding ISF at a given time point. This is because when the ion concentration outside the first chamber 2 is higher than the ion concentration inside the chamber 2, ions will tend to diffuse through the first membrane 4 into the first liquid 6, thereby balancing the difference in ion concentration.

[0060] from Figure 2 As can be seen, the design of the second measuring chamber 3 is similar to that of the first measuring chamber 2; however, the second liquid 7 contained in chamber 2 (which may differ from the first liquid 6) is sealed by a second deformable polymer membrane 5, which is impermeable to ions but permeable to individual water molecules. The second aqueous liquid 7 is chosen such that its ion concentration is well known. If the amount of water in the ISF increases due to a high hydration state, more water molecules will permeate the second membrane 5, and since the membrane 5 is flexible, the volume of the second liquid 7 will increase due to water intake. A further result is that the conductivity of the second liquid 7 will decrease because water intake leads to an effective reduction in the ion concentration within the second measuring chamber 3 (note that all ions present in the second liquid 7 are trapped in the second chamber 3), since the number of ions within the chamber 3 does not change / will remain constant. By measuring the conductivity and / or resistance of the second liquid 7 at regular time intervals (which are, of course, technically equivalent), the hydration state in the surrounding environment 27 can be indirectly determined / monitored by sensor 1.

[0061] Please note that a simpler design for sensor 1 could use only such a second measuring chamber 3 without the first measuring chamber 2. This would be sufficient for monitoring hydration status.

[0062] Figure 2 The sensor 1 also includes an internal non-conductive substrate 18, which forms the bottom of each of the three chambers 2, 3, and 13. Spacers 20 are attached to the upper side of the substrate 18, forming corresponding sidewalls 21 for each chamber 2 / 3 / 13. On the upper side of the substrate 18, at the bottom of each chamber 2 / 3 / 13, corresponding measurement electrodes 8 are deposited, which are electrically connected via vias 19 to a complex microelectronic package 17, which also forms part of the sensor 1. All these components are encapsulated in a biocompatible encapsulation material 12 forming the outer surface of the sensor 1. Note that the membrane 4 of the first measurement chamber 2 and the membrane 5 of the second measurement chamber 3 remain partially open, while the third measurement chamber 13, serving as a reference measurement chamber, is completely sealed by a cover 22 that is impermeable to both water and ions. In other words, there is no exchange between the surrounding environment 27 and the third liquid 14 contained in the reference measurement chamber 13. We note that... Figure 2 The sensor design shown can be fabricated using the previously explained wafer-level processes; in this case, Figure 2 The size of the sensor 1 shown schematically will be approximately equal to the size of the wafer cut from the carrier wafer 18 / main substrate 18 used in the process.

[0063] The microelectronic package 17 (which can be soldered to the through-hole 19 before or after the substrate 18 is individualized into a single wafer) includes a controller 9 that operates a current source 10, a voltmeter 11, and an ammeter 24 to perform various electrical measurements using a corresponding set of electrodes 8 present in each of the chambers 2, 3, and 13. Note that these components 9, 10, 11, and 24 are all electrically connected to each other via electrical interconnects of the package 17. The controller can also electrically address the electrodes 8 via the through-hole 21.

[0064] For example, controller 9 can be programmed to electrically measure the complex impedance spectra of each liquid 6, 7, 14 using components 9, 10, 11, 24 and electrode 8, respectively. By taking into account the data generated by the electrical measurements performed in reference measurement chamber 13, controller 9 can compensate for temperature drift. Note that the composition and volume of the third liquid 14 do not change over time.

[0065] like Figure 3 As shown, sensor 1 can transmit this measurement data and / or data derived from such measurement via controller 9 using wireless communication module 23, which is also part of the microelectronic package 17. Data is transmitted from sensor 1 to a monitoring device 15, such as a tablet computer, located outside the patient's body. The monitoring device 15 can then further evaluate the transmitted data, particularly based on algorithms that implement artificial intelligence, and can, for example, calculate the current trends in the patient's electrolyte and hydration states. These trends can then be visualized on the screen of device 15, and the patient can be instructed to take appropriate actions, such as drinking more water.

[0066] In summary, an implantable biomedical sensor 1 is disclosed, characterized by a novel electrofluid design based on dedicated measurement chambers 2, 3, which are sealed / closed by corresponding membranes 4, 5, which are permeable to water molecules and, in the case of the first membrane 4, also permeable to typical ions found in human interstitial fluid (ISF). Through this concept, the sensor 1 can perform electrical measurements within the corresponding chambers 2, 3, thereby collecting data that allows for conclusions regarding the amount of water and ions present in the ISF surrounding the sensor 1. In other words, this sensor 1 enables the electrical monitoring of the electrolyte and / or hydration status in the tissues of a patient wearing the implantable sensor 1.

[0067] List of reference numerals 1. Sensor (to be implanted in the human body, especially subcutaneously) 2 First measuring chamber 3. Second measuring chamber (permeable to ions smaller than a specific size) 4. First membrane (porous, and preferably rigid) 5. Second membrane (elastic, permeable) 6 First Liquid 7 Second Liquid 8 electrodes (for measuring resistance and / or impedance) 9. Controller (can control the current source and voltmeter included in 1) 10 Current Sources (preferably AC current sources) 11 Voltmeter 12 Packaging Materials 13 Reference Measurement Chamber 14 Third Liquid 15 monitoring devices 16 Microelectronic Circuits 17 Microelectronic Packages 18 substrate 19 Through-hole (conductive, formed in 18) 20 spacers 21 sidewalls (sidewalls of 2 and 3; formed by 20) 22. Cover (impermeable to water and ions) 23 Wireless Communication Module 24 Ammeter 25 Electrical interconnects (formed in 17) 26 Wireless Communication 27. Surrounding environment (organization and ISF).

Claims

1. A biomedical sensor (1) for determining, in particular monitoring, the electrolyte and hydration status of a user or patient by means of corresponding electrical measurements, said sensor (1) comprising: A first measuring chamber (2), which is preferably sealed by a rigid, porous first membrane (4) and communicates with the surrounding environment (27) via the first membrane, the first membrane being permeable to ions, and A second measuring chamber (3) is sealed by a preferably elastic, water-permeable second membrane (5) and communicates with the surrounding environment (27) via the second membrane, which is impermeable to ions. In this configuration, at least two measuring electrodes (6) of the first group are arranged in the first measuring chamber (2), and at least two measuring electrodes (6) of the second group are arranged in the second measuring chamber (3).

2. A biomedical sensor (1) for determining, particularly monitoring, the hydration status of a user or patient by electrical measurement, particularly the sensor according to claim 1, wherein the sensor (1) comprises: The measuring chamber (3) is preferably enclosed by a flexible, water-permeable membrane (5) and communicates with the surrounding environment through the membrane, the water-permeable membrane being impermeable to ions. In this process, at least two measuring electrodes (6) are arranged in the measuring chamber (3). Specifically, the measuring chamber (3) is the second measuring chamber (3), the set of at least two electrodes (8) is the second set of at least two measuring electrodes, and the membrane (5) is the second membrane (5).

3. The sensor (1) according to claim 1 or 2, wherein, The sensor (1) is designed for implantation in the human body, and in particular, the sensor (1) is characterized by a biocompatible package (12) for this purpose, or The sensor (1) is designed to be introduced into the human body permanently or temporarily, particularly as a subcutaneous sensor (1) and / or as part of a catheter designed for insertion into the human body.

4. The sensor (1) according to any one of the preceding claims. in, The sensor (1) is configured to measure a first resistance using the first set of electrodes (8), particularly a first impedance, most preferably a first impedance spectrum, and / or The sensor (1) is configured to measure a second resistance using the second set of electrodes (8), particularly a second impedance, and most preferably a second impedance spectrum.

5. The sensor (1) according to any one of the preceding claims. in, The first membrane (4) is made of ceramic material, preferably alumina (Al2O3), and / or Wherein, the first membrane (4) provides nanoscale pores, preferably with a maximum pore size of less than 1µm, most preferably with a maximum pore size of less than 200nm, and / or The first membrane (4) is characterized by having a thickness of at least 50 µm to provide sufficient stiffness, most preferably, and wherein the thickness of the first membrane (4) is less than 500 µm, and / or The electrode (8) contains platinum (Pt) in the form of Pt or Pt / Ir, and / or contains iridium, especially IrOx.

6. The sensor (1) according to any one of the preceding claims. in, The second membrane (5) is made of a polymer material, preferably polydimethylsiloxane (PDMS), and / or The second membrane (5) is characterized by a thickness of at least 100µm, preferably at least 200µm, and most preferably less than 500µm.

7. The sensor (1) according to any one of the preceding claims. in, The first measuring chamber (2) is filled with a first liquid (7), preferably wherein the first liquid cannot diffuse out of the first measuring chamber (2) through the first membrane (4).

8. The sensor (1) according to any one of the preceding claims. in, The first membrane (4) is permeable to a class of ions, wherein the class includes at least one of the following ions: K + Na + Cl - Mg 2+ Fe 2+ Fe 3+ Cu 2+ Ca 2+ , and / or The first membrane (4) is impermeable to a class of large objects, wherein the second class includes at least one of the following objects: blood cells, proteins with a minimum diameter of x nm, and bacteria. In particular, it enables the sensor (1) to specifically and electrically measure the concentration of ions belonging to the first type of ions in the first measurement chamber (2).

9. The sensor (1) according to any one of the preceding claims. in, The second measuring chamber (3) is filled with a second liquid (7), preferably containing water, the second liquid containing a defined and constant amount of ions. In particular, the amount of ions present in the second liquid (7) is clearly defined and / or constant over time, and / or This makes the osmotic pressure across the second membrane (5) clearly defined, and / or This enables the sensor (1) to specifically and electrically measure the amount of water contained in the second measuring chamber (3) at a specific time point, particularly after water has diffused through the second membrane (5) into or out of the second measuring chamber (3).

10. The sensor (1) according to any one of the preceding claims, wherein, The sensor (1) includes a substrate (18), and the first set of electrodes and / or the second set of electrodes (8) includes at least two planar electrodes deposited on the substrate (18). Preferably, the electrode (8) is electrically connected to a corresponding conductive via (19) formed in the electrically insulating substrate (18). Most preferably, the planar electrode (8) has been structured by laser processing, most preferably by laser ablation, or by screen printing or photolithography.

11. The sensor (1) according to any one of the preceding claims, wherein, The sensor (1) includes a substrate (18), and the first measurement chamber (2) and the second measurement chamber (3) are specifically each freely attached to a spacer (20) defined by the substrate (18), wherein the respective spacer (20) defines a sidewall (21) of the respective chamber (2, 3), and / or The first membrane (4) and / or the second membrane (5) are bonded to the spacer (20).

12. The sensor (1) according to any one of claims 7 to 9, wherein, The sensor (1) includes a controller (9) configured to perform the following actions: A first impedance measurement is performed on the first liquid (6) using the first set of electrodes (8) arranged in the first measuring chamber (2), and / or The second set of electrodes (8) arranged in the second measuring chamber (3) is used to perform a second impedance measurement on the second liquid (7).

13. The sensor (1) according to the preceding claim, wherein, The sensor (1) includes a current source (10) configured to deliver alternating current to the first set of electrodes and / or the second set of electrodes (8), in particular enabling AC measurements of impedance to be performed by the sensor (1).

14. The sensor (1) according to any one of the preceding claims. in, The sensor (1) includes a controller (9), particularly the controller (9) mentioned above, which is configured to perform frequency changes of an alternating current applied to the first set of electrodes or the second set of electrodes (8) within a certain frequency range, most preferably continuous scanning, to perform impedance spectroscopy (EIS). Preferably, The controller (9) is configured to calculate the real and imaginary parts from the recorded impedance spectrum.

15. The sensor (1) according to any one of the preceding claims. in, The sensor (1) includes a voltmeter configured to perform voltammetry measurements using the first set of electrodes and / or the second set of electrodes (8), and / or The sensor (1) includes an ammeter (24) configured to perform amperometric measurements using the first set of electrodes and / or the second set of electrodes (8), and / or The sensor (1) includes a potentiometer configured to perform potentiometric measurements using the first set of electrodes and / or the second set of electrodes (8).

16. The sensor (1) according to any one of the preceding claims. in, The sensor (1) includes a controller (9), and in particular the aforementioned controller (9), which is configured to: Calculate the ion concentration of the second liquid (7) contained in the second measuring chamber (3), and / or Based on the assumed constant amount of ions contained in the second measuring chamber (3), the water content currently enclosed / contained in the second measuring chamber (3) is calculated.

17. The sensor (1) according to any one of the preceding claims. in, The first membrane (4) has a certain stiffness such that the volume of liquid contained in the first measuring chamber (2), particularly the volume of the first liquid (6) filling the first chamber (2), remains constant within a range of less than 1%, especially even if ions and / or water can freely diffuse through the first membrane (4), and / or The volume of liquid contained in the second measuring chamber (3) and defined by the second membrane (5), particularly the volume of the second liquid (7) filling the second chamber (3), can vary, especially due to the diffusion of water through the second membrane (5).

18. The sensor (1) according to any one of the preceding claims. in, The first set of electrodes and / or the second set of electrodes (8) includes at least four electrodes (8), and the sensor (1) is configured to perform a 4-electrode resistance measurement using the first set of electrodes and / or the second set of electrodes (8).

19. The sensor (1) according to any one of the preceding claims. in, The electrodes (8) in the first and second groups are microelectrodes with sub-millimeter dimensions, and / or Wherein, the first measuring chamber (2) and / or the second measuring chamber (3) each comprise a component smaller than 1×1mm. 2 ×0.3mm = 0.3µL volume.

20. The sensor (1) according to any one of the preceding claims. in, The sensor is characterized by at least two separate first measurement chambers (2a, 2b). One of the two first chambers (2a) is sealed by a porous type A membrane (4) and isolated from the surrounding environment by the membrane. The porous type A membrane is impermeable to a class of large ions, particularly a second class of large ions. Preferably, the second class includes at least one of the following ions: Ca... 2+ or Mg 2+ ; Of the two first chambers (2a), the other is sealed by a porous type B membrane (4) and isolated from the surrounding environment by the membrane. The porous type B membrane is permeable to the first type of large ions, especially the second type of large ions. In particular, it enables the electrical and specific measurement of the concentration of the first type of ion / the first type of ion while the first chamber (2a) is covered by the type A membrane (4), and / or The concentration of the second type of ions can be measured electrically and specifically when the first chamber (2a) is covered by the type B membrane (4).

21. The sensor (1) according to any one of the preceding claims. in, The sensor (1) is characterized by a reference measurement chamber (13) that is completely sealed, allowing no ions or water to permeate into the reference measurement chamber (13) from the surrounding environment, and wherein a third set of at least two measuring electrodes (6) are arranged in the reference measurement chamber (13) for performing electrical reference measurements. Preferably, a third liquid (14) having a defined conductivity is contained in the reference measurement chamber (13), and the third liquid is most preferably in the form of a hydrogel.

22. Use of a sensor (1) according to any one of the preceding claims, the sensor being used to preferably continuously and / or repeatedly monitor the following of a user: Hydration state, and Electrolyte state, in, While performing monitoring, the sensor (1) is implanted or introduced into the user's body. Preferably, The sensor (1) performs electrical measurements autonomously.

23. A method for the electrical determination of water content and / or ion content in aqueous media, particularly in human or animal tissues. The use of a biomedical sensor (1), particularly the sensor according to any one of claims 1 to 21, wherein the sensor is in contact with the medium, particularly with the tissue. in, In the first measurement, the ion concentration within the first measuring chamber (2) containing the first liquid (6) of the sensor (1) is electrically measured by the sensor (1) using the first set of electrodes (8), specifically by electrically measuring the resistance and / or impedance of the first liquid (6) to determine the ion content in the medium / tissue. and / or In a second measurement, preferably independent of the first measurement, the water content or ion concentration in a second measurement chamber (3) containing a second liquid (7) of the sensor (1) is electrically measured by the sensor (1) using a second set of electrodes (8), and in particular by electrically measuring the resistance and / or impedance of the first liquid (6) to determine the water content in the medium / tissue. Specifically, ions and / or water diffuse into the first measurement chamber (2) through the porous first membrane (4) during the first measurement, and / or water molecules diffuse into the second measurement chamber (3) through the second membrane (5) during the second measurement. In the most preferred embodiment, the corresponding chambers (2, 3) are isolated from the surrounding environment, particularly from adjacent cells, by corresponding membranes (4, 5).

24. The method according to the preceding claim, wherein, The first measurement and / or the second measurement are performed using alternating current supplied by the current source of the sensor (1), respectively. In particular, The first measurement and / or the second measurement includes a change in the frequency of the corresponding alternating current, in particular a scan, such that impedance spectroscopy (EIS) is performed respectively.

25. The method according to any one of the preceding claims, particularly applied to enabling autonomous monitoring of a patient's hydration and electrolyte status. in, The sensor (1) has been introduced or implanted into the patient's body, and The sensor (1) transmits the data of the first measurement and / or the second measurement to an external monitoring device (15), which outputs current measurements, particularly measurement trends, related to the patient's hydration and electrolyte status based on the data transmitted by the sensor (1). Preferably, The monitoring device (15) triggers the sensor (1), in particular by transmitting instructions to the sensor (1) to perform a new first measurement and a second measurement.

26. A method for parallel wafer-level fabrication of multiple biomedical sensors (1), particularly wherein, Each sensor (1) is designed to be implantable and / or according to any one of claims 1 to 21 above, the method comprising the following steps: Electrodes (8) are formed, preferably laser-processed and deposited on a wafer, the wafer forming a common substrate (18) for the sensor (1). The spacer-wafer is bonded to the substrate (18) or the spacer is pick-and-place assembled to the substrate (18), the spacer forming the sidewall of the corresponding measurement chamber (2, 3) of the sensor (1); The first liquid (6) is dispensed into a plurality of first measuring chambers (2) formed on the substrate (18); The second liquid (7) is formed in each of the plurality of second measurement chambers (3) by distributing a liquid, particularly a second liquid (7) containing ions of a defined concentration, into each of the plurality of second measurement chambers (3) formed on the same substrate (18). Preferably, a pick-and-place robot is used to bond at least one first film (4), preferably multiple first films (4), to the spacer-wafer or the spacer; Preferably, a pick-and-place robot is used to bond at least one second film (5), preferably multiple second films (5), to the spacer-wafer or the spacer; The resulting wafer-level stack, including the substrate (18), is monolithized into individual wafers, each wafer corresponding to one of the sensors (1).

27. The method (1) according to the preceding claim, wherein, The method further includes the following steps: The wafer is encapsulated with a biocompatible soft encapsulation material (12) to form a separate biomedical sensor (1), but each of the first membrane (4) and the second membrane (5) is at least partially free of the encapsulation material (12).

28. The method (1) according to any one of the preceding two claims, wherein, The manufactured sensors (1) are each: Presenting graphic design, and / or There are no cables because all the necessary wires are integrated in or on the common substrate (18), particularly based on conductive vias formed in the electrically insulating substrate (18).

29. The method (1) according to any one of claims 26 to 28, wherein, Each of the individual wafers (1) is bonded to a corresponding lower microelectronic package (17), the package including a corresponding microelectronic circuit (16), the microelectronic circuit being electrically connected to an electrode (8) formed on the top side of the substrate (18) in the corresponding chamber (2, 3) via a conductive via (18) formed in the electrically insulating substrate (18). Preferably, The microelectronic circuit (16) implements a controller (9) for the sensor (1), which is configured to perform a first electrical measurement and a second electrical measurement in the chamber (2, 3) to which the circuit (16) of the sensor (1) belongs.

30. A method for evaluating sensor signals transmitted by a biomedical sensor (1), particularly a sensor (1) according to any one of claims 1 to 21, or a sensor (1) manufactured using the method according to claims 26 to 29, in, The electrical impedance spectrum of the liquid (6, 7) contained in the measurement chambers (2, 3) of the sensor (1) is measured using alternating current with a variable frequency. In particular, The chambers (2, 3) are sealed by a water-permeable membrane (4, 5) and separated from the surrounding environment by the membrane. Among these methods, machine learning is used, particularly artificial intelligence, to evaluate the impedance spectrum, especially the real and imaginary parts of the measured impedance curve. Based on the assessment, the ion concentration of a specific ion is calculated. Specifically, the evaluation is performed by a controller (9) integrated in the sensor (1), particularly causing the sensor (1) to transmit data related to the calculated specific ion concentration, or The evaluation is performed by an external controller (9) belonging to an external monitoring device, which preferably receives measurement data wirelessly from the sensor (1).

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