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WO2025059717A1 - Surveillance du ph - Google Patents

Surveillance du ph Download PDF

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Publication number
WO2025059717A1
WO2025059717A1 PCT/AU2024/051000 AU2024051000W WO2025059717A1 WO 2025059717 A1 WO2025059717 A1 WO 2025059717A1 AU 2024051000 W AU2024051000 W AU 2024051000W WO 2025059717 A1 WO2025059717 A1 WO 2025059717A1
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Prior art keywords
sensor
conductive coating
sensing apparatus
needle
needle body
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PCT/AU2024/051000
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English (en)
Inventor
Marimuthu Swami Palaniswami
Rana ABU UL HASSAN SARWAR
Fiona Claire BROWNFOOT
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University of Melbourne
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University of Melbourne
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Priority claimed from AU2023903038A external-priority patent/AU2023903038A0/en
Application filed by University of Melbourne filed Critical University of Melbourne
Publication of WO2025059717A1 publication Critical patent/WO2025059717A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14539—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring pH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1482—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means specially adapted for foetal tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/43—Detecting, measuring or recording for evaluating the reproductive systems
    • A61B5/4306—Detecting, measuring or recording for evaluating the reproductive systems for evaluating the female reproductive systems, e.g. gynaecological evaluations
    • A61B5/4343—Pregnancy and labour monitoring, e.g. for labour onset detection
    • A61B5/4362—Assessing foetal parameters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/302—Electrodes, e.g. test electrodes; Half-cells pH sensitive, e.g. quinhydron, antimony or hydrogen electrodes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/403—Cells and electrode assemblies
    • G01N27/4035—Combination of a single ion-sensing electrode and a single reference electrode
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/416—Systems
    • G01N27/4166—Systems measuring a particular property of an electrolyte
    • G01N27/4167—Systems measuring a particular property of an electrolyte pH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2503/00—Evaluating a particular growth phase or type of persons or animals
    • A61B2503/02—Foetus
    • A—HUMAN NECESSITIES
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    • A61B2560/00—Constructional details of operational features of apparatus; Accessories for medical measuring apparatus
    • A61B2560/02—Operational features
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0209—Special features of electrodes classified in A61B5/24, A61B5/25, A61B5/283, A61B5/291, A61B5/296, A61B5/053
    • A61B2562/0215—Silver or silver chloride containing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
    • A61B2562/125—Manufacturing methods specially adapted for producing sensors for in-vivo measurements characterised by the manufacture of electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0538—Measuring electrical impedance or conductance of a portion of the body invasively, e.g. using a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14503—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1495—Calibrating or testing of in-vivo probes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6813—Specially adapted to be attached to a specific body part
    • A61B5/6814—Head
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6848—Needles

Definitions

  • the present invention relates to a system and method for sensing pH levels in a biological subject and in particular measurement of subcuticular or blood pH levels.
  • Fetal acidosis is a medical condition in which pH levels in an unborn baby's blood are raised, typically as a result of oxygen deprivation for an extended period of time during childbirth. This can be caused by a range of different scenarios such as umbilical cord compression, positioning of the child in the womb, obstructed delivery or the like. Failure to address such issues can lead to a variety of serious complications, such as cerebral palsy, hypoxic ischemic encephalopathy, developmental delay, mental retardation, seizure disorders, paralysis or infant mortality.
  • fetal heart rate monitoring is used as a surrogate marker to assess fetal oxygen status in labour. This involves either intermittent or continuous fetal heart rate tracing cardiotocography (CTG) using an external Doppler on the maternal abdomen or a spiral bipolar electrode that attaches to the fetal scalp lodging in the subcuticular tissue to give a fetal heart rate trace.
  • CCG fetal heart rate tracing cardiotocography
  • CTG can pick up the presence of fetal hypoxia with a sensitivity (detection) of 85%, it often ‘overcalls’ fetal asphyxia - and has a low specificity at only 40% and a corresponding low positive predictive value. This means if there are concerning fetal heart rate patterns, asphyxia will only be present less than half of the time (i.e. most are actually well oxygenated babies that do not need early delivery). This has resulted in an increase in medical intervention, evidenced by a 5-fold increase in the caesarean section rate, since fetal heart rate monitoring was introduced in the 1960s.
  • the current gold standard is to perform a fetal scalp pH level measurement. This is an invasive procedure for the mum and baby. The mum must be positioned in stirrups and the fetal scalp is accessed through the vagina and cervix. A blade is used to cut the fetal scalp and a blood sample is obtained. The pH level of the blood is used to direct management. A scalp pH of >7.25 is normal, a pH between 7.25 - 7.20 is borderline and less than 7.20 indicates fetal acidosis and possible asphyxia and an urgent delivery by caesarean section or forceps is performed. Importantly the scalp pH closely correlates with the umbilical cord pH with a sensitivity of 93% and false positive rate of 6% for the detection of an arterial cord pH ⁇ 7.25.
  • Microneedle pH Sensor Direct, Label-Free, Real-Time Detection of Cerebrospinal Fluid and Bladder pH, by Ganesh Kumar Mani, Kousei Miyakoda, Asuka Saito, Yutaka Yasoda, Kagemasa Kajiwara, Minoru Kimura, and Kazuyoshi Tsuchiya, ACS Appl. Mater. Interfaces 2017, 9, 21651-21659 reports the fabrication of microneedle-based direct, label- free, and real-time pH sensors.
  • the reference and working electrodes were Ag/AgCl thick films and ZnO thin films on commercially available and conductive tungsten (W) microneedles, respectively.
  • the morphological and structural characteristics of microneedles were carefully investigated through various analytical methods.
  • the developed sensor exhibited a Nemstian response of -46 mV/pH.
  • US4320764 describes an apparatus for use in measuring continuously the change in pH values of a fetus, comprising a holder made of an insulating material, a spiral electrode extending from the forward end of said holder and adapted to engage the fetus during delivery, a maternal electrode supported on said holder rearward of said spiral electrode, said electrodes including a material which forms a half cell in the presence of hydrogen ions, and means responsive to the potential difference across said first and second electrodes for continuously measuring the changes in pH of the fetus.
  • US11622705 describes an apparatus for monitoring a physiological condition of a patient.
  • the apparatus includes a body having an attachment portion configured to be inserted into the skin of a patient to affix the body to the patient.
  • the apparatus includes a sensor coupled to the body that is configured to generate sensor data corresponding to a physiological condition of the patient when the body is secured to the skin of the patient.
  • the apparatus further includes a reference sensor that is remote from the sensor coupled to the body and is configured to engage an outer surface of skin to generate reference data against which the sensor data is compared.
  • an aspect of the present invention seeks to provide a pH sensing apparatus configured to be used for sensing pH levels in a biological subject, the pH sensing apparatus including: a reference needle electrode including: a reference needle body; and, a conductive coating deposited on the reference needle body; a sensor needle electrode including: a sensor needle body; a conductive coating deposited on the sensor needle body; and, a sensor material deposited on a tip portion of the needle body; a measuring device in electrical communication with the conductive coatings of the reference needle electrode and the sensor needle electrode, wherein the needle electrodes are configured to be inserted into the biological subject, and the measuring device is configured to measure an electrical signal indicative of pH levels between the reference and sensor needle electrodes.
  • the sensor material is at least one of: a metal oxide; a metal nitride; titanium nitride (TiN); aluminium nitride (AIN); titanium dioxide (TiO ) and, zinc oxide (ZnO).
  • the sensor material has a thickness of at least one of: up to 1000 nm; up to 750 nm; at least 50 nm; 50 nm to 500 nm; 100 nm to 400 nm; 150 nm to 300 nm; and, approximately 200 nm.
  • the sensor material has a length of at least one of: 0.2 mm to 3 mm; 0.5 mm to 2 mm; 2 mm to 5 mm; and, less than 5 mm.
  • the conductive coating is at least one of: an inert metal; gold; aluminium; titanium; chromium; silver; and silver/silver chloride.
  • the conductive coating has a thickness of at least one of: up to 1000 nm; up to 750 nm; at least 50 nm; 50 nm to 500 nm; 100 nm to 400 nm; 150 nm to 300 nm; and, approximately 200 nm.
  • the conductive coating is deposited on an adhesion layer.
  • the adhesion layer includes at least one of: a metal layer; and, a titanium layer; and a chromium layer.
  • the adhesion layer is deposited on a surface of the needle body.
  • the adhesion layer has a thickness of one of: 1 nm to 20 nm; 2 nm to 10 nm; 5 nm to 15 nm; approximately 5 nm; and, approximately 10 nm.
  • the needle body is made of at least one of: stainless steel; a glass; and, boron silicate glass.
  • the sensor material and the conductive coating are deposited using the same deposition technique to reduce lattice mismatches between the sensor material and the conductive coating.
  • At least one of the sensor material, the conductive coating and an adhesion layer are deposited using sputtering deposition.
  • At least one of the sensor material, the conductive coating and an adhesion layer undergo O2 plasma treatment.
  • the measuring device is configured to measure a voltage, and wherein the voltage is correlated with pH levels.
  • the apparatus includes one or more processing devices configured to: acquire an indication of the measured electrical signal; retrieve calibration data from a memory; calculate pH levels using the measured electrical signal and the calibration data; and, generate an output indicative of pH levels.
  • an aspect of the present invention seeks to provide a method of manufacturing pH sensing apparatus configured to be used for sensing pH levels in a biological subject, the method including: manufacturing a reference needle electrode by depositing a conductive coating on a reference needle body; manufacturing a sensor needle electrode by: depositing a conductive coating on a sensor needle body; and, depositing a sensor material on a tip portion of the needle body.
  • the method includes depositing the conductive coating on an adhesion layer deposited on a surface of the sensor needle body.
  • the method includes using sputtering to deposit at least one of: an adhesion layer; the conductive coating; and, the sensor material. [0032] In one embodiment the method includes using the same deposition technique to deposit the conductive coating and sensor material to reduce lattice mismatches between the sensor material and the conductive coating.
  • the method includes performing O2 plasma treatment of at least one of: a needle surface; an adhesion layer; the conductive coating; and, the sensor material.
  • the method includes, prior to depositing a material: cleaning a surface; annealing the surface; and, performing O2 plasma treatment.
  • the sensor material is at least one of: a metal oxide; a metal nitride; titanium nitride (TiN); aluminium nitride (AIN); titanium dioxide (TiO2) and, and, zinc oxide ZnO.
  • the conductive coating is at least one of: an inert metal; gold; aluminium; titanium; chromium; silver; and, silver/silver chloride.
  • conductive layer is deposited on an adhesion layer, and wherein the adhesion layer includes at least one of: a metal layer; a titanium layer and, a chromium layer.
  • the needle body is made of at least one of: stainless steel; a glass; and, boron silicate glass.
  • Figure 1 is a schematic diagram of an example of an apparatus for pH monitoring
  • Figure 2 is a flow chart of an example of a method for performing pH monitoring using the apparatus of Figure 1;
  • Figures 3A and 3B are a flow chart of a process for manufacturing an apparatus for pH monitoring
  • Figure 4A is a scanning electron microscope image of an example of a uniform metallic coating on a needle
  • Figure 4B is a scanning electron microscope image of an example of a Zinc Oxide (ZnO) coating on a needle tip;
  • Figure 4C is a scanning electron microscope image of an example of interface between the metallic coating of Figure 4 A and the ZnO coating of Figure 4B;
  • Figure 4D is a high magnification scanning electron microscope image of an example of ZnO thin film deposition
  • Figure 5A is a graph illustrating an example of structural characteristics and defects of a ZnO sensor via X-Ray diffraction (XRD) analysis
  • Figure 5B is a graph illustrating an example of structural characteristics and defects of a ZnO sensor via Energy-dispersive X-ray spectroscopy (EDS) analysis;
  • EDS Energy-dispersive X-ray spectroscopy
  • Figure 6A is a graph illustrating an example of pH sensor calibration in a buffer solution with Ag/AgCl
  • Figure 7A is a graph illustrating an example of pH sensor performance in a buffer solution with Ag/AgCl
  • Figure 7B is a graph illustrating an example of pH sensor performance in a buffer solution without Ag/AgCl
  • Figure 7C is a graph illustrating an example of pH sensor performance in cord blood with Ag/AgCl
  • Figure 7D is a graph illustrating an example of pH sensor performance in cord blood without Ag/AgCl
  • Figure 8 A is a graph illustrating an example of pH sensor performance for 12 hours in a buffer solution
  • Figure 8B is a graph illustrating an example of pH sensor performance for 4 hours in cord blood
  • Figure 9 is a schematic diagram illustrating an example of an experimental configuration for monitoring pH sensor performance in buffers or blood;
  • Figure 10 is a graph illustrating an example of pH sensor performance inserting the sensor on baby sheep's head
  • Figure 11A is a first schematic diagram illustrating an example of a configuration for in utero measurement.
  • Figure 1 IB is a second schematic diagram illustrating an example of a configuration for in utero measurement
  • Figure 12A is a schematic diagram of an example of apparatus being used to perform measurements of blood pH levels.
  • Figure 12B is a schematic diagram of an example of apparatus being used to perform measurements of subcuticular pH levels.
  • the apparatus 100 includes a reference needle electrode 111 and a sensor needle electrode 112.
  • the reference needle electrode and the sensor needle electrodes are shown as substantially straight in this illustration, but this is for the purpose of example only and is not intended to be limiting.
  • at least one of the needles could be helically shaped, and other shapes could be used depending on the preferred implementation.
  • the reference needle electrode 111 includes a reference needle body 113 and a conductive coating 115 deposited on the reference needle body.
  • the sensor needle electrode 112 includes a sensor needle body 114 and a conductive coating 116 deposited on the sensor needle body. Additionally, the sensor needle electrode 112 includes sensor material 118 deposited on a tip portion of the needle body.
  • a measuring device 120 is provided in electrical communication with the conductive coatings of the reference and sensor needle electrodes 111, 112.
  • the needle electrodes 111, 112 are inserted into the biological subject.
  • the manner in which this is performed will depend on the circumstances and the nature of the measurement being performed.
  • the needle electrodes 111, 112 are inserted into the scalp of a fetus, for example by attaching the needle electrodes 111, 112 to an intrauterine catheter, which is then inserted into the vaginal tract and through the cervix, so that the needles can penetrate the scalp S of the fetus in utero.
  • the sensing apparatus could be used in other manners, for example inserting the needle electrodes 111, 112 into a blood vessel to perform direct measurements of blood pH levels, or by inserting the needle electrodes 111, 112 into the dermis and/or subcuticular tissue, in order to perform pH measurements therein.
  • the measuring device 120 measures an electrical signal, such as an open circuit voltage, indicative of pH levels between the reference and sensor needle electrodes, with this being optionally used to provide an output indicative of the pH levels, for example by way of visual, audible or electronic indication at step 220. This in turn can be used to allow a clinician or other individual to determine if an intervention is required at step 230.
  • an electrical signal such as an open circuit voltage
  • the above-described arrangement provides a straightforward sensor configuration for performing measurements of pH levels in biological subjects.
  • this can be used for performing in utero measurement of fetal pH levels, allowing these to be monitored continuously and/or semi continuously during labour, which in turn can be used as an indicator of oxygen deprivation, so as to enable targeted intervention if required.
  • the above configuration is particularly beneficial as the conductive coating and sensor material are both deposited, which can help reduce lattice mismatching between the sensor material and the conductive coating, as well as ensuring the coatings are impurity free. This in turn helps ensure efficient electron transfer between the materials, which increases the magnitude of the electrical signal generated between the electrodes, and hence increases sensitivity to changes in pH and reduces the impact of noise. In one example, this can result in a Nemst response of ⁇ 60 mV/pH, and a sensitivity to pH changes of approximately 0.05 units, which is significantly better than that achieved by prior art arrangements.
  • the above-described configuration can also help reduce response time, corresponding to the time between a change in pH levels and a corresponding change in the electrical signal, as well as recovery times. Specifically, in one example, this allows response / recovery times of the order of milli / micro seconds, again better than prior art configurations.
  • sensing apparatus allows smaller surface areas of sensing material to be employed, which can in turn help maintain needle tip sharpness, facilitating easy penetration of the biological subject, for example penetrating the fetal scalp.
  • the deposition of the conductive and sensor material coatings, together with the materials used, can also ensure the resulting coatings are durable, allowing the sensor to function over long time periods, such as 12 or more hours, corresponding to a typical period of labour. This in turn allows a single sensor to be used for the entire period of labour, avoiding the need for multiple interventions to perform monitoring throughout labour.
  • the senor can be more sensitive to changes in pH levels, respond more quickly, and be more suited for long term use, thereby improving the outcomes for subjects, such as the fetus and mother during labour.
  • the method of manufacturing includes manufacturing a reference needle electrode by depositing a conductive coating on a reference needle body, and manufacturing a sensor needle electrode by depositing a conductive coating on a sensor needle body and depositing a sensor material on a tip portion of the needle body.
  • the apparatus could be used to measure pH levels in blood and subcuticular tissue. This has application in a side variety of situations, for example providing continuous and/or semi continuous monitoring for use in trauma, diabetes or cancer patients. Other applications will also be apparent to persons skilled in the art, and it will therefore be appreciated that reference to measuring fetal pH levels is not intended to be limiting.
  • the sensor material is a metal oxide.
  • metal oxides are sensitive to pH levels, and specifically when arranged as part of two half cells, can lead to the generation of electrical potentials in the presence of either acidic or alkali environments.
  • the metal oxide is Zinc Oxide (ZnO), which is beneficial as it is widely available, is biocompatible, durable and is suitable for deposition on the conductive coating, using suitable deposition techniques such as sputtering.
  • ZnO Zinc Oxide
  • other materials with similar electrical and amphoteric properties could be used.
  • metal nitrides such as titanium nitride (TiN) and/or aluminium nitride (AIN), have similar semi-conductor properties, and in particular a similar band gap eV range, which facilitates the amphoteric nature. Accordingly, it will be appreciated that whilst metal oxides such as ZnO and/or titanium dioxide (Ti O2 ) are particularly suited to this application and may provide beneficial results as discussed in more detail below, other similar semiconductor materials having similar band gaps could also be used.
  • the sensor material typically has a thickness of approximately 50 nm to 500 nm, which provides a good balance of electrical and mechanical properties. For example, this is sufficient to generate an electrical signal, without risk of the material detaching and without adversely affecting the sharpness of the tip. More typically, the sensor material has a thickness of approximately 100 nm to 400 nm and more typically 150 nm to 300 nm. In one particular example, the thickness could be approximately 200 nm. However, in some situations thicker materials might be required, and so the sensor material could be up to 1000 nm, or 750 nm, and typically is at least 50 nm in thickness. In this situation, a greater thickness can result in additional noise, degrading the signal to noise ratio, meaning an increased thickness might require noise cancellation processing is implemented when processing measured signals.
  • the sensor material typically has a length of approximately 0.2 mm to 3 mm, which again balances electrical and mechanical properties, as well as allowing penetration of the sensor material into the scalp, to thereby ensure measurement of pH levels. More typically the sensor material has a length of approximately 0.5 mm to 2 mm, or 2 mm to 5 mm, and in one specific example is less than approximately 5 mm.
  • the conductive coating is a metallic coating, and could for example be an inert metal, such as gold, aluminium, titanium, chromium, silver or silver/silver chloride. These materials have good electrical and mechanical properties, and are also durable and biocompatible, making these suitable for insertion into biological subjects, such as the uterus and the fetal scalp.
  • gold is used as this is biocompatible, although alternatively aluminium can be used as this is readily available and cost effective.
  • the conductive coating typically has a thickness of approximately 50 nm to 500 nm, which similarly to the sensor material provides a good balance between mechanical and electrical properties.
  • the thickness is approximately 100 nm to 400 nm and more typically approximately 150 nm to 300 nm, with a thickness of approximately 200 nm being preferred in some applications.
  • coating thicknesses of up to 1000 nm, or 750 nm, and typically at least 50 nm in thickness could be used, which again may necessitate that noise cancellation is performed when processing measured signals.
  • the conductive coating can be deposited on an adhesion layer, which can be a metal layer, such as a titanium layer or a chromium layer.
  • the adhesion layer is also typically deposited on the needle body, and typically has a much lower thickness, in the vicinity of approximately 1 nm to 20 nm, 2 nm to 10 nm, 5 nm to 10 nm, and in one example, approximately 10 nm or approximately 5 nm.
  • the reference needle electrode could additionally and/or alternatively include Ag/AgCl conductive coating, for example including Ag/AgCl on the needle tip only.
  • the needle body can be made of a variety of materials but is typically substantially electrically non-conductive.
  • suitable materials include glasses, such as boron silicate glass and alloys, such as stainless steel.
  • stainless steel is used due to its tensile strength and widespread use in surgical needles, meaning it is familiar to clinicians, and readily available for manufacture of the needle electrodes.
  • the sensor material and the conductive coating are deposited using the same deposition technique, and optionally similar deposition parameters, to reduce lattice mismatches between the sensor material and the conductive coating. Reducing lattice mismatches helps improve electron transfer between the materials, which as outlined above can improve sensor performance.
  • the sensor material, the conductive coating and an adhesion layer could be deposited using a variety of techniques, examples of which include hydrothermal fabrication, microwave assisted growth, atomic layer deposition or chemical vapour deposition.
  • the sensor material, conductive coating and adhesion layer are deposited using sputtering.
  • sputtering techniques such as ion-beam sputtering, reactive sputtering, ion-assisted deposition, high-target- utilization sputtering (HiTUS), high-power impulse magnetron sputtering (HiPIMS), radio frequency (RF) magnetron sputtering, or gas flow sputtering.
  • AC/DC sputering is used, as it has been found that this generates particularly effective sensors, and more details of such an approach will be described in more detail below.
  • the senor material, conductive coating and adhesion layer typically undergo O2 plasma treatment, and optionally additional treatments such as washing and annealing. Such treatments can assist with removing impurities, which again helps improves lattice quality, and hence electron transfer.
  • the measuring device is configured to measure a voltage, and specifically an open circuit voltage, with the voltage being correlated with pH levels.
  • the apparatus will typically undergo some form of calibration so that the voltage can be correlated to a particular pH value.
  • the apparatus can include one or more processing devices that are configured to acquire an indication of the measured electrical signal, retrieve calibration data from a memory and then calculate pH levels using the measured electrical signal and the calibration data.
  • the one or more processing devices can be part of the measuring device, or alternatively could be part of a separate device, such as a computer system, which is configured to receive the measurement data indicative of measured voltages from the measuring device.
  • the processing device can be further configured to generate an output indicative of pH levels, for example displaying a pH level indication on a display, or communicating an indication of the pH level to another device, such as a remote computer system, or the like, allowing this to be displayed remotely.
  • the processing device could be configured to perform basic analysis, for example comparing pH levels and/or changes or rates of change in pH levels to one or more thresholds, optionally generating an alert or notification depending on results of the comparison.
  • a notification could be generated if pH levels fall below a particular threshold, such as 7.25, with an alert being generated if there is a further fall to be below 7.2.
  • a scalp pH of >7.25 is normal, whilst a pH between 7.25 - 7.20 is borderline, so this threshold can be used to indicate a potential issue and abnormal, in turn signally an intervention might be required.
  • a rapidly changing pH level might also be indicative of an issue requiring an intervention, and so again an alert and/or notification could be generated if the rate of change of the pH levels exceeds a threshold.
  • the measuring device includes at least one processing device, such as a microprocessor 121, connected to a memory 122, an input/output device 123, and an interface 124.
  • the interface 124 is used for connecting the measuring device 120 to the needle electrodes, and/or may be used for communication with other computer systems, via a communication network or the like.
  • a single interface is described, in practice functionality may be provided by several distinct interfaces 123, such as a serial interface, a network interface, wireless interface, USB interface, or the like.
  • the input/output device 123 can be used to receive input user commands and/or display information, and may therefore be in the form of a touch screen, or display and separate input buttons.
  • the processing device 121 executes applications software stored in the memory 122, allowing the processing device 121 to perform necessary functions, including acquiring readings from the needle electrodes, converting these to pH levels, and optionally comparing pH levels to thresholds, or similar.
  • processing can be performed by any one or more of the devices, and/or distributed between the processing devices as necessary.
  • the measuring device measure voltages and then transfer corresponding voltage data to a computer system for analysis and optional alerting or notification.
  • reference to a singular processing device should be understood to encompass multiple processing devices and vice versa, with processing being distributed between the devices as appropriate.
  • needles are cleaned, dried and annealed to ensure the needles are free from contaminants, with the cleaned needles optionally undergoing O2 plasma treatment to remove any impurities from the needle surface at step 305, which helps with adherence of subsequent layers to the needle body.
  • the needles are coated with an adhesion layer, typically of titanium or chromium or another similar metal, using a DC sputtering process.
  • the adhesion layer could undergo cleaning and O2 plasma treatment, although alternatively the conductive material, such as gold or aluminium, could be applied directly to the adhesion layer, again using a DC sputtering process at step 315.
  • Example parameters used in the sputtering process are discussed in more detail below, although it will be appreciated that these will vary depending on a number of factors, such as the machine used, the specific configuration and material of the needles, or the like.
  • the coated needles are cleaned, dried and annealed, before being treated with O2 plasma treatment to remove impurities at steps 320, 325.
  • the reference needle is completed, and no further manufacturing steps are required.
  • the sensor needle undergoes further processing, specifically to coat the tip of the sensor needle with mentioned sensing materials, such as ZnO, using a DC sputtering process, with the coated needle then being cleaned, dried and annealed, before O2 plasma treatment is performed at step 335 and 340.
  • sensing materials such as ZnO
  • a calibration process is performed at step 345. Specifically, this will involve placing the needles in solutions with different known pH levels over a range of values excepted to be encountered in a practical situation, for example between pH 6.8 and pH 7.6.
  • the open circuit voltage generated between the electrodes is then recorded and used to generate calibration data at step 350, which can be subsequently used to correlate voltage measurements performed in utero with specific pH values.
  • the responsiveness of the needle electrodes will vary depending on minor variations in the manufacture of the electrodes.
  • electrodes are typically manufactured in batches, with each electrode in the batch being exposed to the same conditions, meaning that typically electrodes will only need to be calibrated on a per batch basis.
  • This allows the calibration data to be stored based on batch identifiers, so that the correct calibration data can be used based on a corresponding batch identifier provided with the needle electrodes.
  • the sensors can be fabricated in experimental setup, and it is possible to calibrate a single sensor for multiple batches of sensor fabrication where a controlled fabrication equipment is used in an industrial setup.
  • electrochemical potentiometric sensors in the form of the needle electrodes are fabricated. Whilst a three-cell model could be used for electrochemical potentiometric sensing, in this example, a two-cell model is used to reduce the number of electrodes required, which is important in invasive applications.
  • the apparatus employs a metallic working (sensor) electrode with the sensor material on its tip and a metallic reference electrode.
  • a metallic working (sensor) electrode with the sensor material on its tip and a metallic reference electrode.
  • the electrodes should be conductive and at the same time have only a few microns diameter at the tip. This narrows down the choice of suitable materials for the needle body to glass (quartz or borosilicate) microneedles, metallic wires and stainless-steel clinical needles.
  • stainless-steel clinical needles are used because of their stiffness and strength, common use in the medical industry and easy availability. Additionally, this avoids the need for specified training of medical staff, as they are familiar with the use of such clinical needles.
  • needle electrodes were manufactured using each of 18, 20 and 22 G clinical needles. However, for the purpose of illustration, the following explanation will explain the manufacturing procedure for only one sensor using a single type of clinical needles.
  • the fabrication was performed in a class 1000 clean room facility.
  • the substrate should be clean and dirt-free.
  • the needles were sufficiently cleaned with acetone, isopropyl alcohol (IP A) and deionized (DI) water in a sonicator and dried with nitrogen blow.
  • IP A isopropyl alcohol
  • DI deionized
  • the needles were then annealed in an oven at 100 degrees for one hour to evaporate any remaining solution on the needle surface.
  • the needles were subjected to oxygen plasma treatment to remove any residue on the needle surface and to improve the deposition/adhesion characteristics of the needles.
  • the stainless-steel non-conductive needles are now ready for metal deposition for electrochemical sensing.
  • the needles were coated with both e-beam evaporator (Intlvac Nanochrome II) and AC/DC sputter (Intlvac Nanochrome).
  • sputtering provided the better results, as well as being more economically viable, having a lesser coating time and an easier coating process.
  • the needles were coated with 5 nm Cr, used as an adhesion layer, and 200 nm Al with deposition parameters of 30 SCCM (Standard cubic centimeters per minute) Argon (Ar) flow rate, 150 W sputtering power, 1.9 Pa pressure for 16 minutes.
  • SCCM Standard cubic centimeters per minute
  • Argon (Ar) flow rate 150 W sputtering power
  • 1.9 Pa pressure for 16 minutes.
  • the needles were then removed from the vacuum chamber and again annealed in an oven at 100 degrees for an hour.
  • the next step is the sensor material deposition on the very tip ( ⁇ 2 mm) of the sensor needle electrode.
  • zinc oxide (ZnO) is used as a sensing material because of its amphoteric nature and its biocompatibility, although other metal oxides could also be used.
  • ZnO deposition the sensor needles electrode is masked using a hard mask so only the tip was left open. The masked needle was again subjected to oxygen plasma treatment to assist ZnO deposition on a very small surface area.
  • Possible ZnO deposition methods available include sputtering, hydrothermal fabrication, microwave assisted growth, atomic layer deposition and chemical vapour deposition.
  • sputtering is used for consistency with the conductive Al coating, with deposition parameters of 30 SCCM Ar flow, 20 SCCM oxygen flow, 200 W sputtering power, 1.9 Pa pressure and 22 minutes time.
  • the needles were removed from the vacuum chamber, rinsed in deionised water, dried with nitrogen, annealed in an oven at 100 degrees for an hour and cured in a clean desiccator.
  • silver/silver-chloride (Ag/AgCl) is a generic reference electrode material because of its effective transfer characteristics, Ag/AgCl has objections on its biocompatibility. Furthermore, an ineffective fabrication process coats a very thick Ag/AgCl layer on the needle compromising the needle sharpness on the tip which is an obstacle to penetrate through the skin in this application. Nevertheless, two reference electrodes, one with bare Al and the other with Ag/AgCl were manufactured for effective comparison.
  • the fabrication process for Ag/AgCl included using a dip coating method.
  • Commercially available Ag/AgCl paste purchased from Merck Australia and was used without any further processing.
  • the needle was attached to a Misumi dunking rug and the shutter speed was fixed to 30 seconds with the paste placed in a way that only the tip of the needle ( ⁇ 2 mm) is immersed in the paste. After 3 minutes, the needle was removed from the dunking rug and dried overnight (12-hours).
  • FIG. 4A shows the metallic coating on the needle and Figure 4B shows the Zinc Oxide (ZnO) coating on a needle tip.
  • Figure 4C shows the interface between the metallic coating of Figure 4A and the ZnO coating of Figure 4B, whilst Figure 4D is a high magnification of the ZnO coating.
  • the film thickness was also double checked with a profilometer (Ambios XP 200).
  • the ZnO film deposition/presence on the needle tip and its elemental characteristics were confirmed with the energy dispersive x-ray spectroscopy (EDS: Hitachi TM3030) attached with an SEM equipment.
  • the ZnO film’s structural parameters and crystalline quality was studied via x-ray diffraction (XRD).
  • XRD x-ray diffraction
  • PL photoluminescence
  • the electrodes 111, 112 were attached to a support 150 to make a sensing device, with top ends of the electrodes clipped with copper wires 151, 152 for electrical connections with the myDaq system which was connected to a computer 160 to record the data, with the myDaq system converts the continuous electronic signal into digital data.
  • a sample solution S was placed in a container allowing the measurements to be performed.
  • This setup also allows arterial blood samples (250pl) to be obtained to determine arterial fetal pH.
  • the maternal internal iliac artery is identified, and a sterile mechanical clamp placed around the artery to enable restriction of blood supply to the uterus.
  • the clamp is tightened to achieve mild, moderate or severe hypoxia determined by an oxygen saturation of 40-50%, 30- 40% and 20-30% respectively over a 4-hour period.
  • the sensing apparatus 1100 includes reference and sensing electrodes mounted to a support, which is in turn attached to an intrauterine catheter 1154, held in place by a leg plate adaptor 1101.
  • the catheter 1154 is connected via a lead 1155 to a measuring device 1120, which is in turn connected to an external computer system 1160, such as a tablet or the like, which can display results of the measurement process.
  • the above-described arrangements can be used to provide a sensing apparatus that is capable of measuring pH levels in utero.
  • the sensing apparatus uses needle electrodes having a conductive layer applied thereto, with the sensor needle electrode also including a sensor material on the needle tip.
  • the sensing apparatus uses needle electrodes having a conductive layer applied thereto, with the sensor needle electrode also including a sensor material on the needle tip.
  • the sensing apparatus includes reference and sensing electrodes 1211, 1212 mounted to a support 1214, allowing the reference and sensing electrodes 1211, 1212 to be inserted into a blood vessel BV, thereby facilitating direct measurement of blood pH levels.
  • the sensing apparatus includes reference and sensing electrodes 1211, 1212 mounted to a support 1214, allowing the reference and sensing electrodes 1211, 1212 to be inserted into the skin, and in particular through the epidermis 1281 and into the dermis 1282 and subcuticular layer 1283, enabling pH levels therein to be measured, and without penetrating the muscle 1284.

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Abstract

Un appareil de détection de pH pour détecter des niveaux de pH dans un sujet biologique comprend une électrode d'aiguille de référence comprenant un corps d'aiguille de référence et un revêtement conducteur déposé sur le corps d'aiguille de référence, et une électrode d'aiguille de capteur comprenant un corps d'aiguille de capteur, un revêtement conducteur déposé sur le corps d'aiguille de capteur et un matériau de capteur déposé sur une partie de pointe du corps d'aiguille. L'invention propose un dispositif de mesure qui est en communication électrique avec les revêtements conducteurs de l'électrode d'aiguille de référence et de l'électrode d'aiguille de capteur, les électrodes d'aiguille étant configurées pour être insérées dans le sujet biologique, et le dispositif de mesure étant configuré pour mesurer un signal électrique indiquant des niveaux de pH entre les électrodes d'aiguille de référence et de capteur.
PCT/AU2024/051000 2023-09-21 2024-09-18 Surveillance du ph Pending WO2025059717A1 (fr)

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AU2023903038A AU2023903038A0 (en) 2023-09-21 pH MONITORING
AU2023903038 2023-09-21

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4320764A (en) * 1980-06-13 1982-03-23 American Home Products Corporation Fetal electrode
WO2000073763A2 (fr) * 1999-05-28 2000-12-07 E-Monitors, Inc. Procedes et systemes de surveillance du ph d'un tissu
US20200337605A1 (en) * 2019-04-25 2020-10-29 National Chiao Tung University Miniaturized sensing probe and manufacturing method thereof
WO2020217056A1 (fr) * 2019-04-23 2020-10-29 Oxford University Innovation Limited Procédé de détermination de ph sanguin humain
US20210054493A1 (en) * 2019-08-21 2021-02-25 Endress+Hauser Conducta Gmbh+Co. Kg Method of manufacturing a sensor element for a potentiometric sensor
WO2021232109A1 (fr) * 2020-05-20 2021-11-25 Commonwealth Scientific And Industrial Research Organisation Détection et surveillance de bioanalyte
US20230113717A1 (en) * 2021-10-08 2023-04-13 Mahla POUDINEH Microneedle Electrodes for Biosensing

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4320764A (en) * 1980-06-13 1982-03-23 American Home Products Corporation Fetal electrode
WO2000073763A2 (fr) * 1999-05-28 2000-12-07 E-Monitors, Inc. Procedes et systemes de surveillance du ph d'un tissu
WO2020217056A1 (fr) * 2019-04-23 2020-10-29 Oxford University Innovation Limited Procédé de détermination de ph sanguin humain
US20200337605A1 (en) * 2019-04-25 2020-10-29 National Chiao Tung University Miniaturized sensing probe and manufacturing method thereof
US20210054493A1 (en) * 2019-08-21 2021-02-25 Endress+Hauser Conducta Gmbh+Co. Kg Method of manufacturing a sensor element for a potentiometric sensor
WO2021232109A1 (fr) * 2020-05-20 2021-11-25 Commonwealth Scientific And Industrial Research Organisation Détection et surveillance de bioanalyte
US20230113717A1 (en) * 2021-10-08 2023-04-13 Mahla POUDINEH Microneedle Electrodes for Biosensing

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