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EP-4736756-A2 - BIOMEDICAL SENSOR AND ASSOCIATED METHODS AND FABRICATION PROCESS

EP4736756A2EP 4736756 A2EP4736756 A2EP 4736756A2EP-4736756-A2

Abstract

An implantable biomedical sensor (1) is disclosed which features a novel electrofluidic design based on dedicated measurement chambers (2, 3) which are closed up by respective membranes (4, 5), which are permeable to water molecules and optionally also to typical ions which are found in the human interstitial fluid (ISF). Through this concept, the sensor (1) can perform electrical measurements in the respective chamber (2, 3) and thereby collect data which allow conclusions to be drawn about the amount of water and ions present in the ISF surrounding the sensor (1). In other words, such a sensor (1) enables electrical monitoring of an electrolyte status and/or a hydration status of the patient wearing the implanted sensor (1) in his tissue.

Inventors

  • Ordóñez, José Andrés Leal

Assignees

  • Ordóñez, José Andrés Leal

Dates

Publication Date
20260506
Application Date
20230829

Claims (15)

  1. Biomedical sensor (1) for determining, in particular for monitoring, a hydration state of a user or patient through an electrical measurement, the sensor (1) comprising - a measurement chamber (3), which is closed by and in communication with the ambient via a, preferably elastic, water-permeable membrane (5) which is impermeable to ions, - wherein a set of at least two measurement electrodes (6) is arranged in the measurement chamber (3), - in particular wherein the measurement chamber (3) is a second measurement chamber (3) and the set of at least two electrodes (8) is a second set and the membrane (5) is a second membrane (5).
  2. Biomedical sensor (1) according to claim 1, for determining, in particular for monitoring, an electrolyte status and a hydration status of a user or patient through respective electrical measurements, the sensor (1) comprising, - a first measurement chamber (2), which is closed by and in communication with the ambient (27) via a, preferably stiff, porous first membrane (4) which is permeable to ions, and - said measurement chamber (3) closed by said membrane (5) which is impermeable to ions, which is a second measurement chamber (3), and wherein said membrane (5) impermeable to ions is a second membrane (5), - wherein a first set of at least two measurement electrodes (6) is arranged in the first measurement chamber (2) and a second set of at least two measurement electrodes (6) is arranged in the second measurement chamber (3).
  3. Sensor (1) according to claim 1 or 2, wherein the sensor (1) is designed for implantation into the human body, - in particular wherein the sensor (1) features a biocompatible encapsulation (12) for this purpose, or - wherein the sensor (1) is designed to be introduced, permanently or temporarily, into the human body, - in particular as a subcutaneous sensor (1) and/or as part of a catheter designed for insertion into the human body.
  4. Sensor (1) according to one of the preceding claims, - wherein the sensor (1) is configured to measure a first electrical resistance, in particular a first electrical impedance, most preferably a first electrical impedance spectrum, with the first set of electrodes (8) and/or - wherein the sensor (1) is configured to measure a second electrical resistance, in particular a second electrical impedance, most preferably a second electrical impedance spectrum, with the second set of electrodes (8).
  5. Sensor (1) according to one of the preceding claims, - wherein the first membrane (4) is made from a ceramic material, preferably from aluminum oxide (Al2O3) and/or - wherein the first membrane (4) offers nanoscale pores, preferably with a maximum pore size below 1 µm, most preferably with a maximum pore size below 200 nm, and/or - wherein the first membrane (4) features a thickness of at least 50 µm for providing sufficient stiffness, most preferably and wherein the thickness of the first membrane (4) is below 500 µm and/or - wherein said electrodes (8) comprise platin (Pt), either in the form of Pt or Pt/Ir, and/or Iridium, in particular IrOx.
  6. Sensor (1) according to one of the preceding claims, - wherein the second membrane (5) is made from a polymer material, preferably from polydimethylsiloxane (PDMS), and/or - wherein the second membrane (5) features a thickness of at least 100 µm, preferably of at least 200 µm, most preferably and below 500 µm, and/or - wherein the first measurement chamber (2) is filled with a first liquid (7), preferably wherein said first liquid cannot diffuse through said first membrane (4) out of the first measurement chamber (2).
  7. Sensor (1) according to one of the preceding claims, - wherein the first membrane (4) is permeable to a class of ions, wherein said class comprises at least one of the following ions: K+, Na + , Cl - , Mg 2+ , Fe 2+ , Fe 3+ , Cu 2+ , Ca 2+ and/or - wherein the first membrane (4) is impermeable to a class of large-sized objects, wherein said second class comprises at least one of the following objects: blood cells, proteins with a minimum diameter of x nm, bacteria; - in particular such that the sensor (1) is capable of specifically and electrically measuring concentrations of ions belonging to said class of ions within the first measurement chamber (2).
  8. Sensor (1) according to one of the preceding claims, - wherein the second measurement chamber (3) is filled with a, preferably aqueous, second liquid (7) containing a defined and constant amount of ions, - in particular such that an amount of ions present in the second liquid (7) is well-defined and/or constant over time and/or - such that an osmotic pressure via the second membrane (5) is well-defined and/or - such that the sensor (1) is capable of specifically and electrically measuring the amount of water contained in the second measurement chamber (3) at a certain point in time, in particular after water has diffused into or out of the second measurement chamber (3) through the second membrane (5).
  9. Sensor (1) according to one of the preceding claims, - wherein the first membrane (4) is so stiff that a liquid volume contained in the first measurement chamber (2), in particular a volume of said first liquid (6) filling up the first chamber (2), is invariable within less than 1%, in particular even though ions and/or water can freely diffuse through said first membrane (4), and/or - wherein a liquid volume contained in the second measurement chamber (3) and delimited by the second membrane (5), in particular a volume of said second liquid (7) filling up the second chamber (3), can vary, in particular as a result of water diffusing through said second membrane (5).
  10. Sensor (1) according to one of the preceding claims, - wherein the sensor (1) features a reference measurement chamber (13) which is fully closed such that no ions and no water can penetrate from the ambient into the reference measurement chamber (13) and wherein a third set of at least two measurement electrodes (6) is arranged in the reference measurement chamber (13) for performing electrical reference measurements, - preferably wherein a third liquid (14) with a defined electrical conductivity, most preferably in the form of a hydrogel, is contained in the reference measurement chamber (13).
  11. Use of a sensor (1) according to one of the preceding claims for, preferably continuously and/or repeatedly, monitoring the hydration status, preferably and the electrolyte status, of a user, - wherein the sensor (1) is implanted in or introduced into the user's body while the monitoring is performed, - preferably wherein the sensor (1) performs the electrical measurements autonomously.
  12. Method for electrical determination of - a water content and/or of - an ionic content of an aqueous medium, respectively, in particular within human or animal tissue, - using a biomedical sensor (1) according to one of the claims 1 to 10, which is in touch with the medium, in particular in touch with said tissue, - wherein a water content within a second measurement chamber (3) of the sensor (1), which contains a second liquid (7) and which is closed by and in communication with an ambient (27) via the water-permeable second membrane (5) which is impermeable to ions, is electrically measured by the sensor (1) with a second set of electrodes (8) in a second measurement, in particular by electrically measuring an electrical resistance and/or an electrical impedance of said second liquid (7), for determining the water content in the medium / tissue, - preferably wherein an ionic concentration within a first measurement chamber (2) of the sensor (1), which contains a first liquid (6) and which is closed by and in communication with an ambient (27) via a porous first membrane (4) which is permeable to ions, is electrically measured by the sensor (1) with a first set of electrodes (8) in a first measurement, in particular by electrically measuring an electrical resistance and/or an electrical impedance of said first liquid (6), for determining the ionic content in the medium / tissue - in particular wherein - water molecules diffuse through the second membrane (5) into the second measurement chamber (3) during said second measurement and/or wherein - ions and/or water diffuse(s) through the porous first membrane (4) into the first measurement chamber (2) during said first measurement, - most preferably wherein the respective chamber (2, 3) is shielded from the ambient, in particular from neighboring cells, by the respective membrane (4, 5).
  13. Method according to the previous claim, - wherein the first measurement and/or the second measurement are performed using an alternating current, respectively, which is provided by a current source of the sensor (1), - in particular wherein the first measurement and/or the second measurement includes a variation, in particular a sweep, of a frequency of the respective alternating current, such that an impedance spectroscopy (EIS) is performed, respectively and/or - wherein the method is applied for achieving autonomous monitoring of a hydration state and a electrolyte state of a patient, wherein the sensor (1) has been introduced or implanted into the body of the patient and - the sensor (1) transmits data of said first and/or second measurement to an extracorporeal monitoring device (15), which outputs a current measurement value, in particular a measurement trend, related to the hydration status and the electrolyte status of the patient, based on the data transmitted by the sensor (1), - preferably wherein the monitoring device (15) triggers the sensor (1), in particular by transmitting an instruction to the sensor (1), to perform a new first and second measurement.
  14. Process for parallel wafer-level-fabrication of a multitude of biomedical sensors (1), - wherein each sensor (1) is designed according to one of the claims 2 to 10, the process comprising the following steps: - formation, preferably laser machining, of electrodes (8) deposited on a wafer forming a common substrate (18) for the sensors (1); - bonding of a spacer-wafer onto the substrate (18) or pick-and-place assembly of spacers onto the substrate (18), the spacer(s) forming sidewalls of respective measurement chambers (2,3) of the sensors (1); - dispensing of a first liquid (6) into a plurality of the first measurement chambers (2) formed on the substrate (18); - formation of a second liquid (7) containing a defined concentration of ions in each of a plurality of second measurement chambers (3) formed on the same substrate (18) by dispensing a liquid, in particular said second liquid (7), into each of the second measurement chambers (3); - bonding of at least one, preferably bonding of a multitude of, first membrane(s) (4), preferably using a pick-and-place robot, to the spacer-wafer or to the spacers; - bonding of at least one, preferably of a multitude of, second membrane(s) (5), preferably using a pick-and-place robot, to the spacer-wafer or to the spacer; - singulation of the resulting wafer-level-stack comprising said substrate (18) into individual dies, which each die corresponds to one of said sensors (1);
  15. Method for evaluating a sensor signal delivered by a biomedical sensor (1) according to one of the claims 1 to 10, - wherein an alternating current of variable frequency is employed by the sensor (1) for measuring an electrical impedance spectrum of a liquid (6,7) contained in a measurement chamber (2,3) of said sensor (1), - in particular wherein said chamber (2, 3) is closed by and separated from the ambient by a water-permeable membrane (4,5), - wherein the impedance spectrum, in particular a real and an imaginary part of a measured impedance curve, is/are evaluated using a method of machine learning, in particular by employing an artificial intelligence, and - wherein, based on said evaluation, ion concentrations of specific ions are computed, - in particular - wherein said evaluation is executed by a controller (9) integrated in the sensor (1), in particular such that the sensor (1) transmits data relating to the computed specific ion concentrations or - wherein the evaluation is executed by an external controller (9) belonging to an extracorporeal monitoring device which, preferably wirelessly, receives measurement data from said sensor (1).

Description

The present disclosure relates to a biomedical sensor, which is designed for determining, in particular for (continuously) monitoring, an electrolyte status and/or a hydration status of a user/patient through respective electrical measurements. A specific use case of such a sensor and an efficient method for electrical determination of a water content and/or of an ionic content of an aqueous medium, respectively, in particular within human or within animal tissue, are also disclosed as well as a process for parallel wafer-level-fabrication of such biomedical sensors and a method for evaluating a sensor signal produced by such a sensor. Today, a substantial amount of people over the age of 65 are hospitalized yearly for dehydration-related health deterioration. According to the World Population Prospects (United Nations, 2019), by the year 2050, the world will count 1 in 6 people over the age of 65. This demographic development as well as the climate change with elevated temperatures presents a major health and economic challenge to society. No solution exists today to address the problem of accurately monitoring dehydration and electrolyte imbalances. Desirable would be a continuous, preventive and personalized healthcare monitoring solution that provides trustworthy access to the relevant health information. This is because enabling timely intervention and supporting health management is key to avoid the deterioration of health, in particular for elderly people. Starting out from this background, it is one objective of the invention to provide a technical solution based on an implantable technology for continuous monitoring of hydration and electrolytes with clinically relevant accuracy intended for personalized prevention of health decay and for increased quality of life and autonomy of the patient. In accordance with the present invention, a biomedical sensor is provided according to claim 1, which solves the afore-mentioned problem. The present invention thus proposes to employ an implantable biomedical sensor for accurately monitoring the electrolyte status and/or the hydration status of a patient. In particular, the invention proposes a sensor as introduced at the beginning, which, in addition, is characterized in that the sensor comprises a first measurement chamber, which is closed by and in communication with the ambient via a porous first membrane (which may be preferably a stiff membrane), which is permeable to ions (such as Na+, Cl-, Mg2+ or Ca2+). In other words, the first measurement chamber can communicate via the first membrane with an ambient surrounding the sensor. The sensor further preferably comprises a second measurement chamber, which is closed by and in communication with the ambient via a water-permeable second membrane which is impermeable to ions. The second membrane may be preferably elastic. Furthermore, a first set of at least two measurement electrodes is arranged in the first measurement chamber and a second set of at least two measurement electrodes is arranged in the second measurement chamber (if present). With such a sensor design, a continuous, reliable electrical measurement of the hydration status and of the electrolyte profile becomes possible with the proposition for unobtrusive monitoring of these parameters through connected digital systems, thereby facilitating visualisation, early intervention and prevention of unnecessary hospitalisations; moreover, associated comorbidities when deviating from ideal euhydration can be effectively avoided. By combining implantable technologies into a novel sensor, together with digital connectivity and intelligent algorithms, this sensor can measure the user's hydration status and electrolyte status and transmit corresponding measurement data to a digital monitoring platform (accordingly the sensor may feature necessary wireless communication means for such communications). Based on existing clinical evidence of healthy electrolyte and hydration levels, such a health platform can communicate tendencies and alarms in acute or chronic cases of dehydration or electrolyte excess or deficiencies in real-time. The sensor thus offers an efficient, reliable minimally invasive, and implantable solution to continuously monitor hydration and electrolyte status of a patient. This capability is enabled by the proposed choice of the measurement chamber design and the chosen membranes, as will be detailed below. In other words, the sensor may be configured to perform a respective measurement of a respective electrical resistance of a respective liquid that is contained in the respective measurement chamber. Hence, the sensor can perform two independent electrical measurements, namely for determining the electrical resistance, in particular an impedance, of a first liquid contained in the first chamber (using a first set of electrodes arranged in the second chamber) and of a second liquid contained in the second chamber (using a second set of el