Method and assembly for determining cell vitalities

• US 10,421,988 B2
• Filed: 09/29/2010
• Issued: 09/24/2019
• Est. Priority Date: 09/30/2009
• Status: Active Grant

• Current Assignee: Siemens AG
• Original Assignee: Siemens AG
• Inventors: Gumbrecht, Walter, Klopzig, Markus, Paulicka, Peter, Schmidt, Harald, Stanzel, Manfred
• Primary Examiner(s): Bowers, Nathan A
• Application Number:
  US13/499,629
• Publication Number:
  US 20120196318A1
• Time in Patent Office: 3,282 Days
• Field of Search: 4352831, 4352871, 4352872, 4352873, 435 29, 20440314
• CPC Class Codes: C12Q 1/025 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics antimicrobial activity C12Q1/18
• CPC Class Codes: C12Q 1/18 Testing for antimicrobial activity of a material
• CPC Class Codes: G01N 33/5014 for testing toxicity
• CPC Class Codes: G01N 33/502 for testing non-proliferative effects
• CPC Class Codes: G01N 35/0098 involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation magnetic particles used in immunoassays G01N33/54326; magnetic separation in general B03C

Abstract

The method includes binding living cells to magnetic particles, adding them to a sensor array, uniformly distributing over the sensor array, magnetically fixing the magnetic particles having the bound cells over the sensor array, and adding substances to maintain and/or improve the cell vitality to the sensory array, and/or adding substances to worsen the cell vitality to the sensor array. The assembly includes a sensor array composed of sensors, which are designed to be in direct fluidic contact with a fluid, and a device for generating a magnetic field over the sensor array. A layer that comprises magnetic particles and living cells is formed on the sensor array.

Claims

1. A system for determining cell vitalities, comprising:

a flow channel configured to flow a fluid with magnetic particles and living cells along a flow direction;

a measurement unit arranged along the flow channel, the measurement unit including a sensor array configured to measure a metabolism-related parameter, the sensor array including sensors having an outer surface configured to be in direct fluidic contact with a fluid, having a distance between adjacent sensors in the sensor array less than 100 μ

m;

wherein a cross-sectional dimension of the flow channel is constant along a length of the flow channel extending upstream of the measurement unit, across the measurement unit, and downstream of the measurement unit, to thereby allow an uninterrupted flow of the fluid to and from the measurement unit along the flow direction;

a controllable magnetic field generator system disposed over said sensor array, comprising at least two magnets arranged on either side of the flow channel;

wherein the controllable magnetic field generator system actuates one of the at least two magnets to alternately form (a) a magnetic field between the at least two magnets passing over the sensor array to secure a matrix of magnetic particles and embedded living cells in place on the sensor array by magnetic forces of the magnetic field acting on the magnetic particles and (b) no magnetic field passing over the sensor array;

a temperature control apparatus at a location along the flow channel with a highest magnetic field density operable to change a temperature in the flow channel; and

a control system configured to control the controllable magnetic field generator system to turn off or alter the magnetic field over the sensor array to;

(a) immobilize and collect a matrix magnetic particles and embedded liquid cells as the liquid flows through the flow channel, (b) stop the flow of liquid, turn off the magnetic field and thereby release the matrix of magnetic particles and embedded living cells to move and redistribute freely over the underlying sensor array, and (c) form a uniform magnetic field distribution over the sensor array leading to a formation of a layer of magnetic particles and embedded living cells with a uniform thickness;

wherein the sensors of said sensor array are electrochemical microsensors with a total space usage on a surface of said sensor array of substantially one micrometer.

2. The system as claimed in claim 1, wherein the layer on the sensor array has an essentially equal thickness over the sensor array.

3. The system as claimed in claim 1, wherein the layer on the sensor array has a thickness in a range from 10 micrometers to 1000 micrometers.

4. The system as claimed in claim 3, wherein the layer over the sensor array includes, between the living cells and the sensors of the sensor array, at least one closed layer of magnetic particles wherein cavities between the magnetic particles are fillable with liquid.

5. The system as claimed in claim 4, further comprising a flow cell with a support, said sensor array being located on one surface of the support in fluidic contact with the flow cell.

6. The system as claimed in claim 1, wherein the controllable magnetic field generator system comprises at least one magnetic field changer.

7. The system as claimed in claim 6, wherein the at least one magnetic field changer is at least one of a coil device and a device moving permanent magnets.

8. The system as claimed in claim 1, wherein the metabolism-related parameter is concentration of a metabolic product of a cell.

9. The system as claimed in claim 1, wherein the metabolism-related parameter is a presence or absence of a metabolic product of the cell.

10. A system for determining cell vitalities, comprising:

a flow channel configured to flow a fluid with magnetic particles and living cells, the flow channel having a continuous interior sidewall extending along a flow direction;

a measurement unit arranged along the flow channel, the measurement unit including a sensor array configured to measure a metabolism-related parameter, the sensor array including a plurality of sensors, each having an outer surface configured to be in direct fluidic contact with a fluid, the measurement unit having a distance between adjacent sensors in the sensor array less than 100 μ

m;

wherein the outer surface of each sensor in the sensor array is arranged flush with portions of the continuous interior sidewall of the flow channel upstream and downstream of the measurement unit along the flow direction;

a controllable magnetic field generator system disposed over said sensor array, comprising at least two magnets arranged on either side of the flow channel and two mu-metal bodies arranged across from one another on either side of the flow channel between the at least two magnets, concentrating a magnetic field resulting from the at least two magnets;

and configured to form a uniform magnetic field over the sensor array when a first magnet of the at least two magnets is in a first position;

a temperature control apparatus at a location along the flow channel with a highest magnetic field density operable to change a temperature in the flow channel; and

a control system configured to control the controllable magnetic field generator system to actuate the first magnet to a second position where no magnetic field caused by the interaction of the at least two magnets is present over the sensor array, the control system executing instructions to;

(a) immobilize and collect a matrix magnetic particles and embedded liquid cells as the liquid flows through the flow channel, (b) stop the flow of liquid, turn off the magnetic field and thereby release the matrix of magnetic particles and embedded living cells to move and redistribute freely over the underlying sensor array, and (c) form a uniform magnetic field distribution over the sensor array leading to a formation of a layer of magnetic particles and embedded living cells with a uniform thickness;

wherein the sensors of said sensor array are electrochemical microsensors with a total space usage on a surface of said sensor array of substantially one micrometer.