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WO2018138304A1 - Printed flow cell for photometer - Google Patents

Printed flow cell for photometer Download PDF

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Publication number
WO2018138304A1
WO2018138304A1 PCT/EP2018/052041 EP2018052041W WO2018138304A1 WO 2018138304 A1 WO2018138304 A1 WO 2018138304A1 EP 2018052041 W EP2018052041 W EP 2018052041W WO 2018138304 A1 WO2018138304 A1 WO 2018138304A1
Authority
WO
WIPO (PCT)
Prior art keywords
light
flow cell
sample
path
light source
Prior art date
Application number
PCT/EP2018/052041
Other languages
French (fr)
Inventor
Frederik FRITZSCH
Jürgen KRIEG
Frank LIEBIG
Marc Robert MIERISCH
Original Assignee
Miltenyi Biotec Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Miltenyi Biotec Gmbh filed Critical Miltenyi Biotec Gmbh
Priority to EP18705098.4A priority Critical patent/EP3574305A1/en
Publication of WO2018138304A1 publication Critical patent/WO2018138304A1/en

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/0303—Optical path conditioning in cuvettes, e.g. windows; adapted optical elements or systems; path modifying or adjustment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1456—Optical investigation techniques, e.g. flow cytometry without spatial resolution of the texture or inner structure of the particle, e.g. processing of pulse signals
    • G01N15/1459—Optical investigation techniques, e.g. flow cytometry without spatial resolution of the texture or inner structure of the particle, e.g. processing of pulse signals the analysis being performed on a sample stream
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1484—Optical investigation techniques, e.g. flow cytometry microstructural devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/05—Flow-through cuvettes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0652—Sorting or classification of particles or molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/0627—Sensor or part of a sensor is integrated
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877—Flow chambers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0883—Serpentine channels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/168—Specific optical properties, e.g. reflective coatings
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G01N15/075—Investigating concentration of particle suspensions by optical means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N2015/0042—Investigating dispersion of solids
    • G01N2015/0053—Investigating dispersion of solids in liquids, e.g. trouble
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G01N2015/0687—Investigating concentration of particle suspensions in solutions, e.g. non volatile residue
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1006—Investigating individual particles for cytology
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1434—Optical arrangements
    • G01N2015/1447—Spatial selection
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N2021/0378—Shapes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/27—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands using photo-electric detection ; circuits for computing concentration
    • G01N21/274—Calibration, base line adjustment, drift correction
    • G01N21/276—Calibration, base line adjustment, drift correction with alternation of sample and standard in optical path
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/06—Illumination; Optics
    • G01N2201/064—Stray light conditioning
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/06—Illumination; Optics
    • G01N2201/066—Modifiable path; multiple paths in one sample

Definitions

  • This invention relates to a flow cell providing a plurality of detection zones for measuring the light absorption of a liquid comprising a sample relative to a reference liquid.
  • Detecting cells by measuring light emitted or absorbed by the cells is a long known process. Such detection is utilized for cell separation by optical, mechanical or electrical means in complicated devices like FACS or TYTO machines.
  • Basis for photometric cell detection is the measurement of radiation - either by absorption or light emitted by a cell marker after excitation - which depends on the concentration of cells and the path length of the light through the sample.
  • measurement of light should be performed in the so called “linear detection range" of the detector. In other words, if the intensity of light to be measured is either too low or too high, the detection process might become unreliable.
  • Object of the invention was therefore to provide a flow cell for a photometer in which the length of the path of light through a cell sample can be adjusted in certain, discrete ranges without the need of mirrors or mechanical devices.
  • Object of the invention is a flow cell comprising a light source (4) a detector for light (5), having
  • a sample channel (1) connected to openings (2,3) for input and output of a sample
  • each the light source (4) and the detector for light (5) at least two detection zones (6,7,8), where in use, the light emitted by the light source interacts with the sample
  • sample channel is configured that
  • the detection zones are positioned in the path of light of the light source the non-detection zones are positioned out of the path of light of the light source and
  • detection zones and non-detection zones are positioned in an alternating sequence in the sample channel
  • the flow cell consists at least in the portions located in path of light from a monolithic transparent material.
  • the term "flow cell consists at least in the portions located in path of light from a monolithic transparent material” relates to a flow cell which is manufactured from a homogeneous material without (optical) interfaces between different materials. For example, placing several cuvettes into the path of light would result in several interfaces between the surfaces of the cuvettes and in the end, undesired diffraction of the light between the interfaces.
  • the flow cell consists at least in the portions located in path of light from an optical homogenous material without interfaces or voids having a different refraction index as the transparent material.
  • the detection zones are located in path of light and are not considered as different material.
  • the flow cell according to the invention can be used for detecting, i.e. determining the amount or the concentration of any sample solved or suspended in a liquid as long as the sample absorbs light emitted from the light source i.e. an absorption relative to a reference liquid can be measured.
  • the flow cell is provided with an appropriate light source and a detector for the light emitted by the light source.
  • the light source is preferable an LED with a small angle like 1 - 5° of the light cone.
  • the detector measures the absorption of cells provided to at least one detection zone relative or in a ratio to the absorption of a reference liquid.
  • another object of the invention is a process for detecting cells in a liquid sample wherein the liquid sample and a reference liquid are directed through the sample channel of a flow cell as disclosed herein, provided with a light source and a detector for light characterized in that the absorption of the light emitted by the light source by the liquid sample provided to at least one detection zone is measured with the detector relative to the reference liquid.
  • Fig. 1 shows the dependency of light absorption of a typical cell suspension from the cell concentration.
  • FIG. 2 shows a schematic view of the flow cell with sample channel (1) having openings (2,3) for input and output of liquid, openings (4,5) for a light source and a detector for light, detection zones (6,7,8) and non-detection zones (9,10).
  • FIG. 3 shows a schematic flow chart of the process of the invention
  • Fig. 4 shows the position of the sample liquid in the flow cells during the process of the invention, where the marks (1) to (10) have the same meaning as in Fig.2.
  • (11) stands for the light emitted by light source (4), (12) for the sample liquid, (13) for the reference liquid and (14) for the air bubble separating sample and reference liquid.
  • Fig. 5, 6 and 7 show embodiments of the flow cell, with (1) to (8) having the same meaning as in Fig. 2.
  • Fig. 7, (15) and (16) indicate positions of light-absorbing barriers or layers.
  • the flow cell In order to achieve maximum yield of the light emitted by the light source, the flow cell should be at least in the portions located in path of light transparent for the light emitted by the light source. For example, most polymers have an absorption maximum at about 400 nm and 1600 - 1800 nm. On the other hand, most cells have an absorption maximum at around 250 to about 600 nm and around 1500 nm. Accordingly, the transparent material of the flow cell has preferable a transmittance for light having a wavelength of 450 to 900 nm of at least 70%. Furthermore, the transparent material of the flow cells of the invention may have transmission for light having a wavelength between 250 and 350 nm and/or 1450 to 1550 nm of at least 50%. Accordingly, the flow cell is preferable provided with a light source emitting light with a wavelength between 400 and 900 nm, and/or between 1450 to 1550 nm and/or between 250 and 350 nm.
  • the transparent material may have a refractive index of 1.4 to 1.6.
  • the length of the path of light is adjusted be the flow cell of the invention. This is achieved by combining at least two, preferred 3 to 8 detection zones and the appropriate non-detection zones as already disclosed.
  • the detection zones may provide different lengths or the same length for the path of light, i.e. detection zones have the same or a different length in the direction of the light emitted by the light source (or perpendicular to the direction of flow of the liquid through the sample channel.
  • detection zones (6) in Fig. 5 provide the same length for the path of light
  • detection zones (6) and (7) in Fig. 6 provide different lengths for the path of light.
  • the sample channel In order to provide the detection zones within the path of light and the non- detection zones out of the path of light, the sample channel needs to change direction (in view of the direction). This may be achieved by a helix-shaped sample channel, where at least two turns of the helix are located in the path of light and serve as detection zone. All parts or turns of the helix not located in the path of light can be used as non-detection zone.
  • Fig. 5 shows a flow cell provided with a helix-shaped sample channel.
  • the surfaces of the flow cell are provided with a light-absorbing coating.
  • the light-absorbing coating may be applied to the whole external surface of the flow cell.
  • any black lacquer may be utilized.
  • the flow cell of the invention may be manufactured by any method known to a person skilled in the art from polymers such as polyamide, polystyrene, polyolefins like polyethylene and polypropylene, polycarbonate, polyoxymethylene, polymethylmethacrylate, poly lactic acid or polyamides.
  • polymers such as polyamide, polystyrene, polyolefins like polyethylene and polypropylene, polycarbonate, polyoxymethylene, polymethylmethacrylate, poly lactic acid or polyamides.
  • Preferred methods of manufacture are injection molding and 3D printing, for example by extrusion deposition, fused deposition modeling, stereolithography or photopolymer digital light processing.
  • the flow cell according to the invention may be produced by extrusion deposition printing of a support structure comprising water soluble polymers, then extrusion deposition printing of the surface structure comprising water in soluble polymers and removing the support structure comprising water soluble polymers by a solving in an aqueous medium.
  • a person skilled in the art is familiar with such 3D printing processes and the necessary equipment.
  • a suitable 3D printer is for example Ml 20 Scan-LED Printer from Innovation MediTech GmbH, with FotoMed® LED.A as printing photoresist polymer.
  • the flow cell according to invention consists preferable of layers arranged perpendicular to the path of light. If the flow cell is produced by 3D printing, care should be taken that the build-up of the flow cell is performed in a way that the layers are printed perpendicular to the (later) path of light.
  • the flow cell may be provided with one or more light-absorbing barriers or layers positioned between the light source and the detector and at least in part covering a plane perpendicular to the path of light and or the sample channel.
  • the light-absorbing barriers or layers may be layers similar to the layers from which the flow cell is build, but produced from a material having no or a very low transparency for the emission of the light source.
  • the same material as used for the transparent layers of the flow cell may be tinted or pigmented with appropriate inorganic particles.
  • the light-absorbing barriers or layers may be a void introduced during manufacturing of the flow cell which can be filled with a material having no or a very low transparency for the emission of the light source like a black lacquer.
  • Fig. 7 shows with (15) and (16) light-absorbing barriers or layers which prevent undesired scattered radiation from entering the detector.
  • the flow cell according to the invention can be advantageously used for detecting a sample or liquid.
  • the sample may be any compound or particle solved or suspended in a fluid, like cells, particles (inorganic particles like silica or carbon black), microbeads (magnetic dextran-covered particles with an iron core), dyes, antibodies, antibody-dye conjugates, fabs, polymers, aqueous systems like cell medium, pharmaceutical solutions, crystal solutions, biomolecule solutions like protein solutions, complex mixtures for food production, diverse matters in suspensions, animal oils, vatable oils, petrochemical oils and other nonpolar and polar chemical solutions All references to "cell suspensions” are synonym for other liquids to be detected like “particle suspensions" or "solutions of sample”.
  • the sample to be detected is suspended or solved in a liquid.
  • the liquid to solve or suspend the sample is the same or has the same absorption is used as reference liquid against the absorption of the sample is measured.
  • the liquid containing the sample hereinafter referred to a liquid sample
  • the reference liquid are then - separated by an bubble of air - directed through the sample channel (1) of the flow cell according to the invention.
  • the liquids and the air bubble may be pumped into the flow cell by appropriate pumping mechanism providing a constant fiuidic flow through the channel/the flow cell.
  • the liquids and the air bubble are sucked into the into the flow cell by a device generating vacuum like a syringe, preferable a motor driven syringe to assure a precise metering of liquid.
  • the liquids are directed through the sample channel sequentially separated by a medium which has a different absorption of light than the liquids and which immiscible with the liquids.
  • a bubble of air is introduced in the sample channel to first provide a detectable interface (or border) between reference medium and sample liquid and second to prevent mixing of the liquids.
  • any liquid which is immiscible with the reference liquid and cell suspension can be used.
  • the reference liquid is directed before the sample liquid in the flow cell to remove any traces of a preceding measurement. Since the absorption of the sample is mathematically the ratio between sample liquid and reference liquid, it is possible to first direct the sample liquid into the flow cell, followed by the air bubble and the reference liquid. [0038] The absorption of the light emitted by the light source by the liquid sample provided to at least one detection zone is measured with the detector relative to the reference liquid.
  • step a the reference liquid is provided to the liquid channel and into the first detection zone (in direction of flow) and the absorption of reference liquid is measured as blank measurement or reference measurement. Then, in step b) sample liquid is directed into the first detection zone, separated from the reference liquid by an air bubble.
  • the liquids may be provided in appropriate vessels like a titer plate and can be introduced into the flow cell with a needle or pipetting automate as indicated in Fig. 2 and 4.
  • the progress of the liquid in the channel may by monitored by measuring absorption in the first detection zone: When the absorption indicates that the air bubble left the first detection zone downstream, the detection zone must be filled with sample liquid. Then, absorption of sample liquid is measured relative to the previous reference
  • the process can be stopped and the cell concentration may be calculated.
  • a person skilled in the art is aware about the necessary calibration measurements and calculations to establish the correct physical and mathematical correlation between the absorption measured and the concentration or amount of the sample to be detected.
  • the process can be stopped. If not, further sample liquid is directed into the channel until filling up the next detection zone in direction of flow. This loop (as indicated by step c and d in Fig. 3) may be repeated until the last detection zone is reached and/or the absorption is sufficiently high.
  • the liquid sample may be separated by an appropriate device like a vent from the reference liquid and stored for further use.
  • the reference liquid is identical to the liquid used to suspend or solve the compound, particle or cells yielding the sample liquid.
  • the chemical nature of the sample and reference liquid is not particular limited and may include water or aqueous systems or organic solvents like alcohols.
  • any aqueous liquid with pH values, osmolality and ion concentrations in the physiological range can be used.
  • Preferred buffers are PBS, D-PBS, HBSS (Hanks' balanced salt solution), EBSS, DMEM (Dulbecco's Modified Eagle Medium), DMEM/F12, IMDM, RPMI, RPMI-1640, either in a complete form or in variants thereof, with or without phenol red, with or without HEPES, with or without glucose, optionally including a protein component like FCS (fetal calf serum), FBS (fetal bovine serum), HSA (human serum albumin), or BSA (bovine serum albumin).
  • FCS fetal calf serum
  • FBS fetal bovine serum
  • HSA human serum albumin
  • BSA bovine serum albumin
  • the process of the invention can be applied to detect all type of inorganic or organic particles or living or dead cells, especially epithelial cells, endothelial cells, fibroblasts, myofibroblasts, hepatocytes, hepatic stellate cells, cardiomyocytes, podocytes, keratinocytes, melanocytes, neuronal cells including neurons, astrocytes, microglia and oligodendrocytes, leukocytes including dendritic cells, neutrophils, macrophages and lymphocytes, including T cells, B cells, NK cells, NKT cells and innate lymphoid type 1-3 cells, tissue stem cells including MSCs and progenitor cells of cells mentioned above.
  • epithelial cells especially epithelial cells, endothelial cells, fibroblasts, myofibroblasts, hepatocytes, hepatic stellate cells, cardiomyocytes, podocytes, keratinocytes, melanocytes, neuronal cells including

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Dispersion Chemistry (AREA)
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  • General Physics & Mathematics (AREA)
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  • Pathology (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Optical Measuring Cells (AREA)

Abstract

The invention is directed to a flow cell comprising a sample channel (1) having • - openings (2,3) for input and output of a sample • - at least one opening for a light source (4) and a detector for light (5) • - at least two detection zones (6,7,8), where the light emitted by the light source interacts with the sample • - at least one non-detection zone (9,10) characterized in that the sample channel is configured that • - the detection zones are positioned in the path of light of the light source • - the non-detection zones are positioned out of the path of light of the light source and • - detection zones and non-detection zones are positioned in an alternating sequence in the sample channel. • - and wherein the flow cell consists at least in the portions located in path of light from a monolithic transparent material. The flow cell may be used for detecting the concentration of cells in a sample liquid.

Description

PRINTED FLOW CELL FOR PHOTOMETER
FIELD OF THE INVENTION
[0001] This invention relates to a flow cell providing a plurality of detection zones for measuring the light absorption of a liquid comprising a sample relative to a reference liquid.
BACKGROUND
[0002] Detecting cells by measuring light emitted or absorbed by the cells is a long known process. Such detection is utilized for cell separation by optical, mechanical or electrical means in complicated devices like FACS or TYTO machines.
[0003] Basis for photometric cell detection is the measurement of radiation - either by absorption or light emitted by a cell marker after excitation - which depends on the concentration of cells and the path length of the light through the sample. In order to obtain reproducible and reliable data, measurement of light should be performed in the so called "linear detection range" of the detector. In other words, if the intensity of light to be measured is either too low or too high, the detection process might become unreliable.
[0004] To avoid this, a lot of techniques are known which improve the measurement conditions by shifting the intensity of light to be measured into the "linear detection range" of the detector. Especially for flow cytometry applications, it is known to increase the path length of the light by mirroring the light several times through a sample as described in US 5268736.
[0005] Furthermore, it is known to increase the length of the detection cell in order to increase the path length of the light, for example by mechanically varying the length of path light of light as disclosed in US5168367, US 4786117 or DT159907.
[0006] For such adjustment, precise and expensive mechanical means are necessary. Although this technique offers the greatest flexibility to adjust measurement conditions for any given cell suspension, in praxis such flexibility is not needed: The concentration of a sample like cells to be detected and subsequently the intensity of light to measured varies in certain known ranges only. So, a mechanically simpler device might solve the problem sufficiently.
[0007] Object of the invention was therefore to provide a flow cell for a photometer in which the length of the path of light through a cell sample can be adjusted in certain, discrete ranges without the need of mirrors or mechanical devices.
SUMMARY [0008] The detection of cells in a liquid sample by absorption depends besides the absorption characteristics of the cells on the concentration of cells and the length of the path of light. As can be seen from Fig. 1, if the concentration of cells is too low and/or the length of the path of light is too small, absorption is low. Since any detector has only a range or a window of sensitivity (so called "linear range" of the detector), too low absorption leads to greater error in measurement. The same applies to high concentrations and/or great length of the path of light. With the device of the invention, the length of the path of light and hence, the absorption can be adjusted to fit into the "linear range" of the detector used.
[0009] Object of the invention is a flow cell comprising a light source (4) a detector for light (5), having
a sample channel (1) connected to openings (2,3) for input and output of a sample
at least one opening for each the light source (4) and the detector for light (5) at least two detection zones (6,7,8), where in use, the light emitted by the light source interacts with the sample
at least one non-detection zone (9,10)
wherein the sample channel is configured that
the detection zones are positioned in the path of light of the light source the non-detection zones are positioned out of the path of light of the light source and
detection zones and non-detection zones are positioned in an alternating sequence in the sample channel
and wherein the flow cell consists at least in the portions located in path of light from a monolithic transparent material.
[0010] The term "flow cell consists at least in the portions located in path of light from a monolithic transparent material" relates to a flow cell which is manufactured from a homogeneous material without (optical) interfaces between different materials. For example, placing several cuvettes into the path of light would result in several interfaces between the surfaces of the cuvettes and in the end, undesired diffraction of the light between the interfaces. In other words, the flow cell consists at least in the portions located in path of light from an optical homogenous material without interfaces or voids having a different refraction index as the transparent material. Of course, the detection zones are located in path of light and are not considered as different material.
[0011] The flow cell according to the invention can be used for detecting, i.e. determining the amount or the concentration of any sample solved or suspended in a liquid as long as the sample absorbs light emitted from the light source i.e. an absorption relative to a reference liquid can be measured.
[0012] In the following, the function of the flow cell is explained by way of example at an aqueous cell suspension as sample. It should be noted the same process may be utilized to measure the absorption of any particle or compound suspended or solved in in any liquid like a polymer solution in an organic solvent. All references to "cell suspensions" are synonym for other liquids to be detected like "particle suspensions" or "solutions of sample".
[0013] To measure the absorption of a liquid, the flow cell is provided with an appropriate light source and a detector for the light emitted by the light source. The light source is preferable an LED with a small angle like 1 - 5° of the light cone. The detector measures the absorption of cells provided to at least one detection zone relative or in a ratio to the absorption of a reference liquid.
[0014] Accordingly, another object of the invention is a process for detecting cells in a liquid sample wherein the liquid sample and a reference liquid are directed through the sample channel of a flow cell as disclosed herein, provided with a light source and a detector for light characterized in that the absorption of the light emitted by the light source by the liquid sample provided to at least one detection zone is measured with the detector relative to the reference liquid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Fig. 1 shows the dependency of light absorption of a typical cell suspension from the cell concentration.
[0016] Fig. 2 shows a schematic view of the flow cell with sample channel (1) having openings (2,3) for input and output of liquid, openings (4,5) for a light source and a detector for light, detection zones (6,7,8) and non-detection zones (9,10).
[0017] Fig. 3 shows a schematic flow chart of the process of the invention
[0018] Fig. 4 shows the position of the sample liquid in the flow cells during the process of the invention, where the marks (1) to (10) have the same meaning as in Fig.2. (11) stands for the light emitted by light source (4), (12) for the sample liquid, (13) for the reference liquid and (14) for the air bubble separating sample and reference liquid.
[0019] Fig. 5, 6 and 7 show embodiments of the flow cell, with (1) to (8) having the same meaning as in Fig. 2. In Fig. 7, (15) and (16) indicate positions of light-absorbing barriers or layers.
[0020] It should be understood that the drawings are not necessarily to scale, and that like numbers may refer to like features.
DETAILED DESCRIPTION [0021] In order to achieve maximum yield of the light emitted by the light source, the flow cell should be at least in the portions located in path of light transparent for the light emitted by the light source. For example, most polymers have an absorption maximum at about 400 nm and 1600 - 1800 nm. On the other hand, most cells have an absorption maximum at around 250 to about 600 nm and around 1500 nm. Accordingly, the transparent material of the flow cell has preferable a transmittance for light having a wavelength of 450 to 900 nm of at least 70%. Furthermore, the transparent material of the flow cells of the invention may have transmission for light having a wavelength between 250 and 350 nm and/or 1450 to 1550 nm of at least 50%. Accordingly, the flow cell is preferable provided with a light source emitting light with a wavelength between 400 and 900 nm, and/or between 1450 to 1550 nm and/or between 250 and 350 nm.
[0022] It is further preferred to avoid scatting or mirroring of the light at the surfaces of the sample channel i.e. at the interface between the liquid and the flow cell. To this end, it is preferred that the surfaces of the sample channel in the detection zones are perpendicular to the path of light. For further reducing undesired scattering effects at the interface between the liquid and the transparent material, the transparent material may have a refractive index of 1.4 to 1.6.
[0023] In order to adjust the absorption to the "linear range" of the detector used, the length of the path of light is adjusted be the flow cell of the invention. This is achieved by combining at least two, preferred 3 to 8 detection zones and the appropriate non-detection zones as already disclosed.
[0024] The detection zones may provide different lengths or the same length for the path of light, i.e. detection zones have the same or a different length in the direction of the light emitted by the light source (or perpendicular to the direction of flow of the liquid through the sample channel. For example, detection zones (6) in Fig. 5 provide the same length for the path of light, whereas detection zones (6) and (7) in Fig. 6 provide different lengths for the path of light.
[0025] In order to provide the detection zones within the path of light and the non- detection zones out of the path of light, the sample channel needs to change direction (in view of the direction). This may be achieved by a helix-shaped sample channel, where at least two turns of the helix are located in the path of light and serve as detection zone. All parts or turns of the helix not located in the path of light can be used as non-detection zone. Fig. 5 shows a flow cell provided with a helix-shaped sample channel.
[0026] In a preferred embodiment, the surfaces of the flow cell are provided with a light-absorbing coating. The light-absorbing coating may be applied to the whole external surface of the flow cell. As light-absorbing coating, any black lacquer may be utilized. Process of manufacture of the device
[0027] The flow cell of the invention may be manufactured by any method known to a person skilled in the art from polymers such as polyamide, polystyrene, polyolefins like polyethylene and polypropylene, polycarbonate, polyoxymethylene, polymethylmethacrylate, poly lactic acid or polyamides.
[0028] Preferred methods of manufacture are injection molding and 3D printing, for example by extrusion deposition, fused deposition modeling, stereolithography or photopolymer digital light processing.
[0029] For example, the flow cell according to the invention may be produced by extrusion deposition printing of a support structure comprising water soluble polymers, then extrusion deposition printing of the surface structure comprising water in soluble polymers and removing the support structure comprising water soluble polymers by a solving in an aqueous medium.
[0030] A person skilled in the art is familiar with such 3D printing processes and the necessary equipment. A suitable 3D printer is for example Ml 20 Scan-LED Printer from Innovation MediTech GmbH, with FotoMed® LED.A as printing photoresist polymer.
Usually, layers of polymer having a thickness of 25 - 100 μιη are cured by UV radiation with subsequent removal of the liquid uncured FotoMed® LED.A. by shaking. After the final layer is printed /cured, the uncured FotoMed® LED.A is removed by flushing the object in ultrasonic bath filled with isopropanol. Finally, post curing in nitrogen atmosphere e.g. in the post curing unit PCU 90 (Innovation MediTech GmbH) may be performed to reach an appropriate shore hardness of the flow cell.
[0031] The flow cell according to invention consists preferable of layers arranged perpendicular to the path of light. If the flow cell is produced by 3D printing, care should be taken that the build-up of the flow cell is performed in a way that the layers are printed perpendicular to the (later) path of light.
[0032] In order to reduce the impact of radiation detected by the detector which did not pass through the detection zones like undesired scattered radiation, the flow cell may be provided with one or more light-absorbing barriers or layers positioned between the light source and the detector and at least in part covering a plane perpendicular to the path of light and or the sample channel. The light-absorbing barriers or layers may be layers similar to the layers from which the flow cell is build, but produced from a material having no or a very low transparency for the emission of the light source. For example, the same material as used for the transparent layers of the flow cell may be tinted or pigmented with appropriate inorganic particles. In another embodiment, the light-absorbing barriers or layers may be a void introduced during manufacturing of the flow cell which can be filled with a material having no or a very low transparency for the emission of the light source like a black lacquer. Fig. 7 shows with (15) and (16) light-absorbing barriers or layers which prevent undesired scattered radiation from entering the detector.
Process of detecting the sample
[0033] The flow cell according to the invention can be advantageously used for detecting a sample or liquid. As already pointed out, the sample may be any compound or particle solved or suspended in a fluid, like cells, particles (inorganic particles like silica or carbon black), microbeads (magnetic dextran-covered particles with an iron core), dyes, antibodies, antibody-dye conjugates, fabs, polymers, aqueous systems like cell medium, pharmaceutical solutions, crystal solutions, biomolecule solutions like protein solutions, complex mixtures for food production, diverse matters in suspensions, animal oils, vatable oils, petrochemical oils and other nonpolar and polar chemical solutions All references to "cell suspensions" are synonym for other liquids to be detected like "particle suspensions" or "solutions of sample".
[0034] In the process of the invention, the sample to be detected is suspended or solved in a liquid. Preferable, the liquid to solve or suspend the sample is the same or has the same absorption is used as reference liquid against the absorption of the sample is measured. The liquid containing the sample (hereinafter referred to a liquid sample) and the reference liquid are then - separated by an bubble of air - directed through the sample channel (1) of the flow cell according to the invention.
[0035] The liquids and the air bubble may be pumped into the flow cell by appropriate pumping mechanism providing a constant fiuidic flow through the channel/the flow cell. In a preferred embodiment, the liquids and the air bubble are sucked into the into the flow cell by a device generating vacuum like a syringe, preferable a motor driven syringe to assure a precise metering of liquid.
[0036] The liquids are directed through the sample channel sequentially separated by a medium which has a different absorption of light than the liquids and which immiscible with the liquids. Preferable, a bubble of air is introduced in the sample channel to first provide a detectable interface (or border) between reference medium and sample liquid and second to prevent mixing of the liquids. Instead of a bubble of air, any liquid which is immiscible with the reference liquid and cell suspension can be used.
[0037] Usually, the reference liquid is directed before the sample liquid in the flow cell to remove any traces of a preceding measurement. Since the absorption of the sample is mathematically the ratio between sample liquid and reference liquid, it is possible to first direct the sample liquid into the flow cell, followed by the air bubble and the reference liquid. [0038] The absorption of the light emitted by the light source by the liquid sample provided to at least one detection zone is measured with the detector relative to the reference liquid.
[0039] The general process to use the flow cell for detecting cells is shown in Fig 3 and the corresponding position of the sample, the reference liquid and a bubble is shown in Fig. 4. Referring to Figs 3 and 4, in step a), the reference liquid is provided to the liquid channel and into the first detection zone (in direction of flow) and the absorption of reference liquid is measured as blank measurement or reference measurement. Then, in step b) sample liquid is directed into the first detection zone, separated from the reference liquid by an air bubble.
[0040] The liquids may be provided in appropriate vessels like a titer plate and can be introduced into the flow cell with a needle or pipetting automate as indicated in Fig. 2 and 4.
[0041] The progress of the liquid in the channel may by monitored by measuring absorption in the first detection zone: When the absorption indicates that the air bubble left the first detection zone downstream, the detection zone must be filled with sample liquid. Then, absorption of sample liquid is measured relative to the previous reference
measurement.
[0042] If the absorption is acceptable for further processing (i.e. is in a predefined range), the process can be stopped and the cell concentration may be calculated. A person skilled in the art is aware about the necessary calibration measurements and calculations to establish the correct physical and mathematical correlation between the absorption measured and the concentration or amount of the sample to be detected.
[0043] If the absorption is not acceptable for further processing (i.e. is not in the predefined range), further sample liquid is directed into the channel until filling up the next detection zone in direction of flow. Again, the absorption of the sample liquid is measured relative to the previous reference measurement. As the path of light is now extended by a further detection zone, absorption should increase.
[0044] If the absorption is now in the predefined range, the process can be stopped. If not, further sample liquid is directed into the channel until filling up the next detection zone in direction of flow. This loop (as indicated by step c and d in Fig. 3) may be repeated until the last detection zone is reached and/or the absorption is sufficiently high.
[0045] After measurement, the liquid sample may be separated by an appropriate device like a vent from the reference liquid and stored for further use.
Reference liquid [0046] Preferable, the reference liquid is identical to the liquid used to suspend or solve the compound, particle or cells yielding the sample liquid. The chemical nature of the sample and reference liquid is not particular limited and may include water or aqueous systems or organic solvents like alcohols.
[0047] As reference and sample liquid for cell measurements, any aqueous liquid with pH values, osmolality and ion concentrations in the physiological range can be used. Preferred buffers are PBS, D-PBS, HBSS (Hanks' balanced salt solution), EBSS, DMEM (Dulbecco's Modified Eagle Medium), DMEM/F12, IMDM, RPMI, RPMI-1640, either in a complete form or in variants thereof, with or without phenol red, with or without HEPES, with or without glucose, optionally including a protein component like FCS (fetal calf serum), FBS (fetal bovine serum), HSA (human serum albumin), or BSA (bovine serum albumin). The pH of the buffer is between 6,0 and 8,0, preferably between 7,0 and 7,5.
Particles, compounds or cells to be detected
[0048] The process of the invention can be applied to detect all type of inorganic or organic particles or living or dead cells, especially epithelial cells, endothelial cells, fibroblasts, myofibroblasts, hepatocytes, hepatic stellate cells, cardiomyocytes, podocytes, keratinocytes, melanocytes, neuronal cells including neurons, astrocytes, microglia and oligodendrocytes, leukocytes including dendritic cells, neutrophils, macrophages and lymphocytes, including T cells, B cells, NK cells, NKT cells and innate lymphoid type 1-3 cells, tissue stem cells including MSCs and progenitor cells of cells mentioned above.

Claims

WHAT IS CLAIMED
1. Flow cell comprising a light source (4) a detector for light (5), having
a sample channel (1) connected to openings (2,3) for input and output of a sample
at least one opening for each the light source (4) and the detector for light (5) at least two detection zones (6,7,8), where in use, the light emitted by the light source interacts with the sample
at least one non-detection zone (9,10)
characterized in that the sample channel is configured that
the detection zones are positioned in the path of light of the light source the non-detection zones are positioned out of the path of light of the light source and
detection zones and non-detection zones are positioned in an alternating sequence in the sample channel
and wherein the flow cell consists at least in the portions located in path of light from a monolithic transparent material.
2. Flow cell according to claim 1 characterized in that the transparent material has a transmittance for light having a wavelength of 450 to 900 nm of at least 70%.
3. Flow cell according to claim 1 or 2 characterized in that the transparent material has a refractive index of 1.4 to 1.6.
4. Flow cell according to any of the claims 1 to 3 characterized in that the surfaces of the sample channel in the detection zones are perpendicular to the path of light.
5. Flow cell according to any of the claims 1 to 4 characterized in that the detection zones provide different lengths for the path of light.
6. Flow cell according to any of the claims 1 to 4 characterized in that the detection zones provide the same length for the path of light.
7. Flow cell according to any of the claims 1 to 6 characterized in that the flow cell consists of layers arranged perpendicular to the path of light.
8. Flow cell according to any of the claims 1 to 7 characterized in that the surfaces of the flow cell are provided with a light-absorbing coating.
9. Flow cell according to any of the claims 1 to 8 characterized in that the flow cell is provided with one or more light-absorbing barriers or layers positioned between the light source and the detector, covering and at least in part a plane perpendicular to the path of light and/or the sample channel.
10. Use of the flow cell according to any of the claims 1 to 9 for detecting cells in a liquid sample.
11. Process for detecting cells in a liquid sample wherein the liquid sample and a reference liquid are directed through a the sample channel (1) of a flow cell according to any of the claims 1 to 9 provided with a light source and a detector for light characterized in that the absorption of the light emitted by the light source by the liquid sample provided to at least one detection zone is measured with the detector relative to the reference liquid.
12. Process for manufacturing the flow cell according to any of the claims 1 to 9 by
injection molding or 3D printing 3D printing of polyamide, polystyrene, polyolefins like polyethylene and polypropylene, polycarbonate, polyoxymethylene,
polymethylmethacrylate, poly lactic acid or poly amides.
PCT/EP2018/052041 2017-01-30 2018-01-29 Printed flow cell for photometer WO2018138304A1 (en)

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