WO2013000693A1 - Détecteur de biotransformation - Google Patents

Détecteur de biotransformation Download PDF

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Publication number
WO2013000693A1
WO2013000693A1 PCT/EP2012/060989 EP2012060989W WO2013000693A1 WO 2013000693 A1 WO2013000693 A1 WO 2013000693A1 EP 2012060989 W EP2012060989 W EP 2012060989W WO 2013000693 A1 WO2013000693 A1 WO 2013000693A1
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WO
WIPO (PCT)
Prior art keywords
container
cell culture
nutrient medium
biotransformation
chemical substance
Prior art date
Application number
PCT/EP2012/060989
Other languages
German (de)
English (en)
Inventor
Ulrich Bohrn
Maximilian Fleischer
Evamaria STÜTZ
Original Assignee
Siemens Aktiengesellschaft
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 Siemens Aktiengesellschaft filed Critical Siemens Aktiengesellschaft
Publication of WO2013000693A1 publication Critical patent/WO2013000693A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
    • C12M35/08—Chemical, biochemical or biological means, e.g. plasma jet, co-culture
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/34—Internal compartments or partitions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/58—Reaction vessels connected in series or in parallel
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/02—Percolation
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/04—Filters; Permeable or porous membranes or plates, e.g. dialysis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/025—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5014—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing toxicity

Definitions

  • Biotransformation sensor The invention relates to a device for evaluating at least one chemical substance with respect to its harmfulness to living cells and a corresponding use of this device. Since the earliest days of toxicology, knowledge of the metabolic pathways of toxins has been shown to be a critical step in the evaluation of pharmacological and toxicological data. Non-toxic substances can be prepared by biotransformation, i.e. by Metabolisie- tion, which is a chemical conversion, to be converted into a toxic sub ⁇ substance. Examples include the Encrypt ⁇ development of methanol to formaldehyde, the conversion of Parathi- on in paraoxon and the conversion of CCI4 in CCl3 radicals.
  • Main verstoff ungsorgan in the human body is the liver, since it has the highest expression level of biotransformie ⁇ leaders enzymes.
  • Other tissues, as, for example, the nasal mucosa, as well show such Capable ⁇ ness.
  • liver extracts such as the so-called S9 for biotransformation.
  • Such Leberex ⁇ extracts contain high amounts of hepatogenous enzymes, namely, for example, cytochromes, namely, for example, cytochrome P450, which effect a biotransformation to a very large extent.
  • cytochromes namely, for example, cytochrome P450
  • the actual rate of biotransformation can not be determined because the enzymes are outside the hepatocytes, which are liver cells, and thus outside their natural environment.
  • liver slices are a known possibility.
  • tissue organization is at least partially maintained.
  • cell-cell interactions that need to be considered.
  • cytochrome overexpressing mammalian cells is known, as is the case for example with HepG2.
  • Intact mammalian cells represent a suitable compromise between reductionist approaches and the need to be as close as possible to the in vivo situation.
  • the object is achieved by a device according to the main claim and a use of the device according to the independent claim.
  • Harmfulness provided for living cells wherein the device is designed as a flow system, the first dissolved in a nutrient medium chemical substance in contact with a chemical substance in a biotransformed chemical substance metabolizing Biotransform- ons cell culture and subsequently the biotransformed chemi ⁇ cal Substance in contact with a detection cell culture having living cells adjoined by at least one sensor which measures physiological changes simultaneously upon contact of the biotransformed chemical substance with the cells of the detection cell culture to determine the harmfulness of the biotransformed chemical substance to living cells.
  • a device according to the invention and a corresponding use enable the observation of physiological changes of the living cells of the detection cell culture when subjected to biotransformed substances in real time.
  • the sensor detects physiological changes in these cells at the same time as their contact with the biotransformed substances.
  • a real-time measurement of the physiological changes is created.
  • the metabolization that is to say the biotransformation, of the chemical substances is not effected by means of enzyme solutions or cell isolates. In this way, ei ⁇ ne device according to the invention and a use of the invention, which is closer to the actual situation in vivo.
  • the cells can be applied over a longer period of time with the same concentration of chemical substances in the nutrient medium.
  • the accumulated and metabolized substances accumulate over time, which in turn interact with the cell culture.
  • the effects of the biotransformation of chemical substances on living cells can be read off by a measurement signal based on physiological changes.
  • the flow system can drive the nutrient medium through a first container containing the biotransformation cell cultures and subsequently through a second container containing the sensor carrying the detection cell culture.
  • the flow system may comprise the first container having an inlet arranged at the top in the direction of gravity for the nutrient medium flowing in the direction of gravity to the biotransformation cell culture and in the second container in the direction of gravity below the sensor carrying the detection cell culture and an outlet for discharging the Form nutrient media.
  • the flow system can form the first container as an upper region in the direction of gravity and the second container as a lower region of a culture vessel in the direction of gravity and separate by means of a lower water-permeable bottom of the first container in the direction of gravity. In this way, the flow system uses energy ⁇ saving gravity to drive the nutrient medium.
  • the flow system from the first container to the second container ter a connecting line form, with the nutrient medium is pumped by means of a pumping device from the first container into the second container.
  • a pumping device By means of the pump, it is possible with particular advantage to set a flow velocity from the first to the second container.
  • the flow system can have an inlet into the connecting line below a bottom of the first container and an outlet from the first container. forming a connection line through a lid as an inlet of the second container.
  • the pumping action of the pump is special ⁇ for assistance are due to gravity easy.
  • the bottom of the first container may be formed as a filter, which only lets through the biotransformed nutrient medium.
  • the biotransformation cell culture may be formed on the bottom of the first container and the bottom of the first container as a membrane from ⁇ .
  • the membrane is particularly advantageous biokom ⁇ patible, that is, in particular chemically stable upon contact with the biochemical substances.
  • the biotransformation cell culture may substrate on loose bodies, which can be spherical, as well as beads referred who can ⁇ , in the first container and the bottom of the first container be formed as a membrane.
  • the membrane is particularly advantageous biocompatible.
  • the biotransformation cell culture may be formed as a sol-gel suspension in the first container and the bottom of the first container as a water-permeable and impermeable to the sol-gel suspension pad.
  • a membrane or overlay according to the invention is provided in such a way that it allows only the biotransformed nutrient medium to pass therethrough.
  • the nutrient medium can be produced as a liquid cell culture medium.
  • This is a particularly simple embodiment, for example, in comparison to a gaseous nutrient medium.
  • a liquid nutrient medium is easier to handle.
  • the outlet of the second container and / or an outlet of the Ver ⁇ connecting line can each have a drain valve for contamination ⁇ free removal of the nutrient medium.
  • an inventive flow system is provided as a CLOSED ⁇ senes system. That is, the removal of a liquid amount of the one or two times biotrans ⁇ formed nutrient medium can be carried out in a closed system, so that the risk of fungal or bacterial contamination, for example, with respect to long-term applications, effectively reduced.
  • the first container of the culture vessel in the direction of gravity at the top can have an opening into which a vertically relatively displaceable flow head is accommodated, which has the inlet and a pressure equalization opening.
  • the detection cell culture carrying sensor may only cover a portion of a bottom of the second container so that out ⁇ forms a drain for removal of only biotransformed nutrient medium on the other part of the bottom of the second container. Such a decrease of the nutrient medium can be carried out without contamination when the drain is provided with a drain valve.
  • the first container may have a cap having the inlet, wherein the inlet may be an outlet of a reservoir of the nutrient medium mixed only with the substance to be evaluated, arranged above the lid.
  • a heating and / or cooling device can regulate a temperature at at least one position of the flow system. In this way, it is particularly easy to provide an environmental condition of living cells.
  • the substrate spheres, or beads of polystyrene, glass, Gela ⁇ tine, dextran or magnetic materials may have.
  • the cells of the biotransformation cell culture and / or the detection cell culture can be animal, plant, from a human or from an insect.
  • the cells may be Hep-G2, Hep-3B, SK-HEP-1, PLC-PRF-5, Chang-liver, BRL-3A, AS-30-D, A549 and RPMI2650 cells.
  • the chemical substance to be evaluated can be a drug, a toxin, a drug, a household chemical or Fermentationspro ⁇ domestic product.
  • Figure 1 shows a first embodiment of a erfindungsge ⁇ MAESSEN device
  • FIG. 2 shows the first embodiment of the invention
  • FIG. 3 shows the first embodiment of the invention
  • Figure 4 shows a second embodiment of a erfindungsge ⁇ MAESSEN device
  • Figure 5 shows a third embodiment of a erfindungsge ⁇ MAESSEN device
  • Figure 6 shows a fourth embodiment of a erfindungsge ⁇ MAESSEN device.
  • 1 shows a first embodiment of a device OF INVENTION ⁇ to the invention.
  • FIG. 1 shows a cross section of an unfilled, closed, vertical device for the online measurement of physiological changes in a cell culture in contact with biotransformed chemical substances.
  • FIG. 1 shows an initial state in which no nutrient medium with dissolved chemical substances to be investigated covers cells of a detection cell culture 9 and a biotransformation cell culture 3.
  • biotransformation cell cultures 3 for example, the following cellular test systems, in which an intracellular metabolic capacity is ⁇ taken are:
  • Isolates of primary cells with differently defined and depending on the respective isolation technique and the isolation batch different metabolic capabilities or capacities, namely hepatocytes of the rat liver or human biopsies.
  • FIG. 1 shows a culture vessel 1 having in a vertically mitt ⁇ sized region, a membrane 2 on which the biotransformation formations cell culture is grown. 3 Below the membrane 2, the culture vessel 1 forms a drainage reservoir 5. The culture vessel 1 forms in the direction of gravity above a first container and below the membrane 2 from a second container which generates the discharge reservoir 5. The first container has in the direction of gravity above an opening in which a flow head 6 is received. This has an inlet 7 and a pressure compensation opening 13.
  • the passage head 6 and the first container may be vertically displaceable relative to each other, so that the volume of the first container corresponds to the volume of a nutrient medium 4 that has flowed into the first container.
  • a foot of the culture vessel 1 are at least one sensor on a substrate 15 10 out ⁇ forms on which the detection cell culture is grown.
  • an outlet 8 is provided, which can be opened and closed by means of a drain valve 14.
  • a measuring surface of the sensor 10 faces the detection cell culture 9.
  • Figure 2 shows the first embodiment of a device according to Inventive ⁇ according to Figure 1, this time filled with a Nährme- dium.
  • Figure 2 shows a cross section of the filled j ⁇ th, closed vertical Device for online measurement of physiological changes in a cell culture in contact with biotransformed chemical substances.
  • the first exemplary embodiment illustrated in FIG. 2 comprises, as a receiving unit for cells, the culture vessel 1 with a multiplicity of
  • the flow head 6 is arranged to be displaceable relative to the culture vessel 1 in the vertical direction.
  • Several planar chemical, electrochemical and physical sensors 10 are formed on the bottom of the culture vessel 1.
  • Proton activity sensors, oxygen sensors, and impedance sensors are embodiments of a erfindungsge ⁇ MAESSEN sensor 10.
  • Such sensors may be any combinatorial ⁇ defined.
  • the scope of protection of the invention numbers of sensors 10.
  • a sensor chip can be fixed, for example, with a lever, not shown, on contacts of the operating circuit.
  • the detection cell culture 9 is formed in the culture vessel 1 on the chemical, electrochemical and / or physical sensors 10.
  • the sensors 10 form the bottom of theVolge ⁇ vessel 1, so that the cells of the detection cell culture 9 adhere directly to the sensors.
  • Below the sensors 10, the substrate 15 is formed.
  • Above the bottom of the culture vessel 1 is a biocompatible membrane 2 at a distance from the
  • the resulting state is shown in FIG.
  • the biotransformation cell culture 3 metabolizes the chemical substances dissolved in the nutrient medium 4 and returns them to the nutrient medium 4.
  • the enriched with biotransformed chemical substances nutrient medium 4 can slowly drip into the drainage reservoir 5.
  • the discharge reservoir 5 fills with the nutrient medium 4 and comes into direct contact with the detection cell culture 9.
  • the biotransformed chemical substances in the nutrient medium 4 trigger a cell reaction of the detection cell culture 9, which can be detected via the sensors 10 in the culture vessel 1.
  • the nutrient medium 4 which has come into contact with the biotransformation cell culture 3 and the detection cell culture 9, can be drained from the drainage reservoir 5.
  • FIG. 3 shows the first exemplary embodiment of a device according to the invention according to FIG. 2 with a modification.
  • FIG. 3 shows a cross-section of a filled, closed, vertical device for the online measurement of physiological changes in a cell culture on contact with biotransformed chemical substances, wherein a second outlet 12 is additionally formed from the outflow reservoir 5.
  • FIG. 3 shows a modification of the system shown in FIG. A partial elevation of the bottom of the culture vessel 1 passes the dripping through the membrane 2 biotransformed medium via the second outflow 12 from the apparatus and allowed separate biological, chemical and / or physical Analy ⁇ sen of the biotransformed nutrient medium 4, which is only in contact with the biotransformation Cell culture 3 has come.
  • FIG. 4 shows a second embodiment of an inventive device.
  • FIG. 4 shows a cross section of a filled, two-part, horizontal device for online measurement of physiological changes in a cell culture in contact with biotransformed chemical substances, namely with a nutrient medium reservoir 18, a pump 16 and a connecting line 19 designed as a connecting tube.
  • the device forms the connecting line 19 from a first container to a second container.
  • a pumping device 16 the nutrient medium 4 is pumped from an outlet 8 of the first container and the connecting line 19 into the second container.
  • the outlet 8 from the first container corresponds to an inlet into the connecting line 19 and is formed or positioned at a bottom of the first container ⁇ relationship, in a bottom of the first container.
  • the first Benzol ⁇ ter also has an inlet 7 having lid 17, said inlet 7 is an output of a lid 17 arranged above the reservoir 18 of the nutrient medium.
  • the biotransformation cell culture 3 may be formed directly on the bottom of the first container.
  • the Biotransformati ⁇ ons-3 cell culture may alternatively be on a membrane 2 which is not shown in Figure 4, above the bottom of the first Be formed container.
  • the biotransformation cell culture 3 may alternatively be formed on a filter, which can reach the link ⁇ line 19 only the biotransformed nutrient medium.
  • the connecting line 19 can have an outlet 12, which has a drain valve 14 for the contamination-free removal of the nutrient medium 4.
  • the second container has an outlet 8 with a drain valve 14 for the contamination-free removal of the nutrient medium 4.
  • the respective cover 17 of the first and second containers are loosely on these ⁇ sets. They can be clamped with the respective container.
  • the second container can thus be formed a culture vessel 1, in the foot of which a substrate 15 is formed, on which the one or more sensors 10 carrying the detection cell culture 9 are positioned.
  • the drain valves 14 each of which ⁇ stays awhile filling level of the nutrient medium 4 may be set in the respective container.
  • FIG. 5 shows a third embodiment of an inventive device.
  • FIG. 5 shows a cross section of an unfilled, closed vertical device for online measurement of physiological changes of a cell culture on contact with biotransformed chemical substances, wherein the biotransformation cell culture 3 is produced as a suspension in a sol-gel 20.
  • this embodiment corresponds to the first embodiment, wherein instead of a membrane 2 for water permeable and impermeable to the sol-gel suspension 20 edition 21 is also. By means of this overlay 21, the biotransformed nutrient medium 4, not shown here, may drip.
  • the reference symbols in FIG. 5 correspond to those of the first exemplary embodiment according to FIG. 1.
  • FIG. 6 shows a fourth exemplary embodiment of a device according to the invention.
  • FIG. 6 shows a cross-section of an unfilled, closed, vertical device for online measurement of physiological changes in a cell culture in contact with biotransformed chemical substances, where in the biotransformation cell culture 3 is produced on loose substrate bodies 22.
  • the loose substrate bodies 22 may be spherical and may also be referred to as beads.
  • the substrate body 22 form a suspension with the nutrient medium 4, not shown here.
  • the cells of the biotransformation cell culture 3 overgrow these substrate bodies 22 or beads.
  • the substrate balls 22 are loosely positioned on a membrane 2 in the unfilled state of the device.

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  • General Engineering & Computer Science (AREA)
  • Sustainable Development (AREA)
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  • Toxicology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

L'invention concerne un dispositif pour l'évaluation d'au moins une substance chimique en ce qui concerne sa nocivité pour des cellules vivantes et son utilisation correspondante. Dans un système d'écoulement, un milieu nutritif biotransformé (4) est mis en contact avec une culture cellulaire de détection (9), à laquelle est adjacent au moins un détecteur (10) qui mesure simultanément les modifications physiologiques des cellules de la culture cellulaire de détection (9).
PCT/EP2012/060989 2011-06-28 2012-06-11 Détecteur de biotransformation WO2013000693A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102011078184.6 2011-06-28
DE201110078184 DE102011078184B3 (de) 2011-06-28 2011-06-28 Biotransformationssensor

Publications (1)

Publication Number Publication Date
WO2013000693A1 true WO2013000693A1 (fr) 2013-01-03

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014131590A1 (fr) * 2013-02-26 2014-09-04 Siemens Aktiengesellschaft Capteur pour fluides corporels et procédé pour mesurer les propriétés des fluides corporels

Citations (4)

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Publication number Priority date Publication date Assignee Title
US6104495A (en) * 1997-05-28 2000-08-15 Micronas Intermetall Gmbh Measuring apparatus
US20050101010A1 (en) * 2003-11-10 2005-05-12 Li Albert P. Cell culture tool and method
US20070166816A1 (en) * 2002-03-12 2007-07-19 Surface Logix, Inc. Assay device that analyzes the absorption, metabolism, permeability and/or toxicity of a candidate compound
DE102009043527A1 (de) * 2009-09-30 2011-04-07 Siemens Aktiengesellschaft Anordnung und Verfahren unter Verwendung von Mikrosensoren zum Messen von Zell-Vitalitäten

Family Cites Families (3)

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Publication number Priority date Publication date Assignee Title
DE19526533C2 (de) * 1995-07-20 1997-06-05 Fraunhofer Ges Forschung Expositionsvorrichtung
US6982152B2 (en) * 2002-04-17 2006-01-03 Promega Corporation Cytotoxicity assay
GB0211963D0 (en) * 2002-05-24 2002-07-03 British American Tobacco Co An exposure device

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6104495A (en) * 1997-05-28 2000-08-15 Micronas Intermetall Gmbh Measuring apparatus
US20070166816A1 (en) * 2002-03-12 2007-07-19 Surface Logix, Inc. Assay device that analyzes the absorption, metabolism, permeability and/or toxicity of a candidate compound
US20050101010A1 (en) * 2003-11-10 2005-05-12 Li Albert P. Cell culture tool and method
DE102009043527A1 (de) * 2009-09-30 2011-04-07 Siemens Aktiengesellschaft Anordnung und Verfahren unter Verwendung von Mikrosensoren zum Messen von Zell-Vitalitäten

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014131590A1 (fr) * 2013-02-26 2014-09-04 Siemens Aktiengesellschaft Capteur pour fluides corporels et procédé pour mesurer les propriétés des fluides corporels

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