Real-time tracing of cytokine storm in blood serum of COVID-19 patients

Patent metadata

Field	Value
Publication number	US-11175255-B2
Application number	US-202117207649-A
Country	US
Kind code	B2
Filing date	Mar 20, 2021
Priority date	Jun 1, 2020
Publication date	Nov 16, 2021
Grant date	Nov 16, 2021

Abstract

A system for diagnosing COVID-19 infection. The system includes a biosensor, an electrochemical stimulator-analyzer, and a processing unit. The biosensor is configured to be put in contact with a blood serum sample of a person suspected to be infected of COVID-19 virus. The processing unit is configured to apply an AC potential amplitude to the biosensor while sweeping a frequency range utilizing the electrochemical stimulator-analyzer, recording an electrochemical impedance spectroscopy (EIS) associated with the blood serum sample utilizing the electrochemical stimulator-analyzer, calculating a charge transfer resistance (RCT) of the recorded EIS, and detecting a COVID-19 infection of the person based on the calculated RCT if the calculated RCT is equal to or more than a threshold value.

First claim

What is claimed is:

1. A system for diagnosing COVID-19 infection, the system comprising:
a biosensor, comprising:
a substrate; and
three-integrated electrodes patterned and formed on the substrate, the three-integrated electrodes configured to be put in contact with a blood serum sample drawn from a person suspected to be infected of COVID-19 virus; the three-integrated electrodes comprising:
a working electrode configured to be an attachment site for the blood serum sample, the working electrode comprising:
a first bilayer of gold/titanium (Au/Ti) deposited on the substrate; and
a bilayer of graphene/copper adhered on the first bilayer of Au/Ti;

a counter electrode comprising a second bilayer of Au/Ti deposited on the substrate, the counter electrode configured to acquire an electrical response from the working electrode; and
a reference electrode comprising a third bilayer of Au/Ti deposited on the substrate, the reference electrode configured to adjust a specific voltage between the working and the counter electrodes;

an electrochemical stimulator-analyzer electrically connected to the biosensor; and
a processing unit electrically connected to the electrochemical stimulator-analyzer, the processing unit comprising:
a memory having processor-readable instructions stored therein; and
a processor configured to access the memory and execute the processor-readable instructions, which, when executed by the processor configures the processor to perform a method, the method comprising:
applying, utilizing the electrochemical stimulator-analyzer, an AC potential amplitude between 5 mV and 20 mV to the biosensor while sweeping a frequency range between 0.01 Hz and 100 kHz;
recording, utilizing the electrochemical stimulator-analyzer, an electrochemical impedance spectroscopy (EIS) associated with the blood serum sample responsive to the applied AC potential amplitude;
calculating a charge transfer resistance (R CT ) of the recorded EIS by measuring a diameter of a semicircular curved part of the recorded EIS; and
detecting a COVID-19 infection of the person based on the calculated R CT if the calculated R CT is equal to or more than a threshold value.

2. The system of claim 1 , wherein the threshold value comprises a R CT value of 440Ω.

3. The system of claim 1 , wherein detecting the COVID-19 infection of the person based on the calculated R CT comprises:
comparing the calculated R CT with a set of R CT values of a calibration dataset;
detecting the person is in a healthy (normal) state if the calculated R CT is within a first range of the calibration dataset, the first range of the calibration dataset comprising a first set of R CT values less than the threshold value, the first set of R CT values measured from a group of healthy people;
detecting the person is in a moderately COVID-19 infected state if the calculated R CT is within a second range of the calibration dataset, the second range of the calibration dataset comprising a second set of R CT values between the threshold value and a severity borderline value, the second set of R CT values measured from a group of COVID-19 infected patients with moderate levels of cytokines; and
detecting the person is in a severely infected state if the calculated R CT is within a third range of the calibration dataset, the third range of the calibration dataset comprising a third set of R CT values more than the severity borderline value, the third set of R CT values measured from a group of COVID-19 infected patients with high levels of cytokines.

4. The system of claim 1 , wherein detecting the COVID-19 infection of the person comprises:
detecting a healthy (normal) state for the person if the calculated R CT is less than 340Ω;
detecting a moderate COVID-19 infection of the person if the calculated R CT is between 440Ω and 610Ω; and
detecting a severe COVID-19 infection of the person if the calculated R CT is more than 715Ω.

5. The system of claim 1 , wherein the bilayer of graphene/copper comprises a layer of graphene sheets with a thickness between 0.1 nm and 1 nm deposited on a layer of copper with a thickness between 1 μm and 30 μm.

6. The system of claim 1 , wherein each of the bilayers of Au/Ti comprises a layer of gold with a thickness between 10 nm and 50 nm deposited on a layer of titanium with a thickness between 3 nm and 10 nm.

7. The system of claim 1 , wherein:
the working electrode comprises a circular-shaped sensing part, the circular-shaped sensing part configured to be the attachment site for the blood serum sample;
the counter electrode comprises a partially annular-shaped part placed around the working electrode; and
the reference electrode comprising an active part placed adjacent to both the working electrode and the counter electrode, the active part configured to adjust a specific voltage between the working electrode and the counter electrode.

8. The system of claim 1 , wherein:
the substrate comprises an electrically insulator material, the substrate comprising at least one of a glass substrate, a silicon substrate, a ceramic substrate, and combinations thereof; and
the substrate has a thickness between 0.5 mm and 5 mm.

9. The system of claim 1 , wherein the electrochemical stimulator-analyzer comprises a potentiostat.

10. A system for measuring a level of total cytokines in a blood serum sample, the system comprising:
a biosensor, comprising:
a substrate; and
three-integrated electrodes patterned and formed on the substrate, the three-integrated electrodes configured to be put in contact with a blood serum sample; the three-integrated electrodes comprising:
a working electrode configured to be an attachment site for the blood serum sample, the working electrode comprising:
a first bilayer of gold/titanium (Au/Ti) deposited on the substrate; and
a bilayer of graphene/copper adhered on the first bilayer of Au/Ti;

a counter electrode comprising a second bilayer of Au/Ti deposited on the substrate, the counter electrode configured to acquire an electrical response from the working electrode; and
a reference electrode comprising a third bilayer of Au/Ti deposited on the substrate, the reference electrode configured to adjust a specific voltage between the working and the counter electrodes;

an electrochemical stimulator-analyzer electrically connected to the biosensor; and
a processing unit electrically connected to the electrochemical stimulator-analyzer, the processing unit comprising:
a memory having processor-readable instructions stored therein; and
a processor configured to access the memory and execute the processor-readable instructions, which, when executed by the processor configures the processor to perform a method, the method comprising:
applying, utilizing the electrochemical stimulator-analyzer, an AC potential amplitude between 5 mV and 20 mV to the biosensor while sweeping a frequency range between 0.01 Hz and 100 kHz;
recording, utilizing the electrochemical stimulator-analyzer, an electrochemical impedance spectroscopy (EIS) associated with the blood serum sample responsive to the applied AC potential amplitude;
calculating a charge transfer resistance (R CT ) of the recorded EIS by measuring a diameter of a semicircular curved part of the recorded EIS; and
determining the level of total cytokines in the blood serum sample based on the calculated R CT by comparing the calculated R CT with a calibration dataset comprising a set of total cytokine mass values respective to a set of R CT values.

11. The system of claim 10 , wherein determining the level of total cytokines in the blood serum sample based on the calculated R CT furth

Assignees

• Khayamian Mohammad Ali
• Abdolahad Mohammad
• Ghaderinia Mohammad Reza
• Parizi Mohammad Salemizadeh
• Abadijoo Hamed
• Vanaei Shohreh
• Simaee Hossein
• Shalileh Shahriar
• Darzini Mahsa Faramarzpour

Inventors

• Khayamian Mohammad Ali
• Abdolahad Mohammad
• Ghaderinia Mohammad Reza
• Parizi Mohammad Salemizadeh
• Abadijoo Hamed
• Vanaei Shohreh
• Simaee Hossein
• Shalileh Shahriar
• Darzini Mahsa Faramarzpour

Classifications

• G01N27/026

  Dielectric impedance spectroscopy (electrochemical impedance spectroscopy for measuring corrosion G01N17/02) · CPC title

• G01N33/48714 Primary

  for determining substances foreign to the organism, e.g. drugs or heavy metals (drugs by chemical analysis G01N33/94) · CPC title

• G01N33/48771

  Coding of information, e.g. calibration data, lot number · CPC title

• A61B10/0051

  for taking saliva or sputum samples (devices for receiving spittle A61J9/00) · CPC title

• G01N27/3275 Primary

  Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction · CPC title