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WO2007085621A1 - Procede et dispositif pour l’injection de cellules - Google Patents

Procede et dispositif pour l’injection de cellules Download PDF

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Publication number
WO2007085621A1
WO2007085621A1 PCT/EP2007/050699 EP2007050699W WO2007085621A1 WO 2007085621 A1 WO2007085621 A1 WO 2007085621A1 EP 2007050699 W EP2007050699 W EP 2007050699W WO 2007085621 A1 WO2007085621 A1 WO 2007085621A1
Authority
WO
WIPO (PCT)
Prior art keywords
aerosol
cells
aerosols
exposure
aerosol generator
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2007/050699
Other languages
German (de)
English (en)
Inventor
Ulrich Mohr
Josef Vogel
Ulrich Deschl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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 Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Publication of WO2007085621A1 publication Critical patent/WO2007085621A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
    • C12M41/32—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of substances in solution
    • 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

Definitions

  • the present invention relates to a method for assaying the biological effect of a huable substance or composition on living cells and a device for carrying out such studies.
  • the present invention is based on the idea of using such culture devices in a standardized test system with which the biological effect of inhalable substances or substance mixtures on living cells is systematically examined, whereby the substances to be investigated are brought into direct contact as aerosols with the prokaryotic or eukaryotic biological test cultures and then examine the effects of this contact on the biological systems.
  • a system makes it possible to detect from a large number of substances those whose biological activity permits a statement about the therapeutic benefit and / or its toxicity, while at the same time the number of animal experiments and the required substance quantities are reduced.
  • the present invention thus relates to an in vitro method for investigating the biological effect of a test substance, characterized in that
  • test substance is transferred by the aerosol generator into a finely divided particle stream
  • moistening the air can be kept at a value of at least 60% relative humidity. Preference is given to saturated saturation of the clean air with water vapor, which then forms a carrier matrix for the test substance in the resulting aerosol.
  • Aerosols are understood as meaning gases which contain liquid or solid substances in extremely finely divided form. Typical particle sizes for inhalation purposes are from 0.1 ⁇ m to 10 ⁇ m, preferably from 1 ⁇ m to 5 ⁇ m aerodynamic diameter. Various possibilities of aerosol production are described in "Theory and Practice of Inhalation Therapy” by Dieter Köhler and Wolfgang Fleischer, Arcis Verlag, Kunststoff, 2000, ISBN 3-89075-140-7 and summarized in Figure 22, page 33 of the book.
  • aerosols containing liquid particles may be venturi-atomized (compressed air or steam), single-fluid nozzles (eg Respimat®), ultrasound (pressing the fluid through a vibrating perforated membrane, detaching droplets from surface waves) or vaporizing and subsequent condensation are made.
  • venturi-atomized compressed air or steam
  • single-fluid nozzles eg Respimat®
  • ultrasound pressing the fluid through a vibrating perforated membrane, detaching droplets from surface waves
  • vaporizing and subsequent condensation are made.
  • Solid particle aerosols can be generated by dispersing the powder with a suitable gas, especially air.
  • the powder can be metered in accordance with an inhalation with individual strokes (for example HandiHaler®) or in large quantities as a heap.
  • Solid particles aerosols can also be removed by one or more sharp edges of a compact of active ingredient and excipients. Evaporation and subsequent condensation can also produce aerosols with solid particles.
  • aerosol generation i. the selection of the aerosol generator takes place depending on the agent to be characterized (liquid aerosol, solid / powder aerosol) but is of minor importance for the claimed method.
  • Typical examples of aerosol generators which can be used in the present invention are known by the name of Respimat® for the production of droplets and Handihaler® for the production of solid particles.
  • Preferred aerosol generators can produce a defined aerosol concentration of the substance in the range of 1 ⁇ g / L to 20 mg / L.
  • the size of the particles produced should be in the range of 0.1 ⁇ m to 10 ⁇ m, preferably 1 ⁇ m to 5 ⁇ m.
  • test atmosphere generated by mixing the streams from the aerosol generator and possibly the humidifier in the distributor should be kept at a constant temperature. Depending on the applied cell type, the temperature should be maintained between 20 ° C and 45 ° C and preferably between 37 ° C and 42 ° C. - A -
  • the withdrawn volume flow should be able to be varied in the range from 1 ml / min to 200 ml / min, preferably from 5 ml / min to 10 ml / min.
  • Cell cultures which are cultivated in so-called CULTEX® modules are particularly suitable for charging cells with the test atmosphere generated in the distributor by mixing the streams from the aerosol generator and optionally the humidifier.
  • Part of the test atmosphere in the distributor is preferably via a flow guide with an inlet for introducing the
  • Test atmosphere i n the flow guide and an opening above the cell culture output opening in the Kutur / exposure device forcibly guided and comes into direct contact with the cells in order to develop a possibly biological effect can.
  • the flow guidance is characterized in that the outlet orifice of the flow guide opens in the direction of flow corresponding to the bell of a trumpet (hereinafter "trumpet-shaped"), thereby ensuring an intensive loading of the cells with the test atmospheres opening starting orifice opposite a circular cylindrical inlet pipe is that in particular difficult to control
  • the flow guide can be designed in such a way that the flow flow of the test atmosphere is generated over the surface of the cell culture and through an annular gap existing between the flow guide and the culture inner wall, for example by means of a vacuum pump arranged downstream of said annular gap. She leaves the admission area, for example, via holes in a circle around the Inlet nozzles of the flow guide are arranged and the output side are bundled in an output port.
  • the flow guide may be connected on the input side to an intake manifold, which is connected to the generation source of the test atmosphere.
  • the exposure attachment includes one or more, for example, three separate flow guides that allow separate loading of the cells in separate cell culture vessels of the exposure device.
  • various materials can be used, which are based on the properties of the test atmosphere, e.g. Teflon, metallic materials, polished stainless steel and specially non-stick or glass-coated trumpet-shaped flow guides, which allow application of cultured cells, such as cells of the respiratory tract, with ultrafine particles.
  • Prokaryotic test systems are usually cultured on media solidified with agar or chelatine, while eukaryotic cells are preferentially cultured on membranes for direct loading. These are basally supplied with culture medium via the membrane, so that the cells grow without medium (apical).
  • eukaryotic cells are cells of the animal or human respiratory tract; macrophages; endothelial cells; or fibroblasts.
  • cells of the respiratory tract for example, nasal, bronchial or alveolar epithelial cells come into question for the investigations.
  • the cells grow apically and come into direct contact with the test atmosphere at the air / liquid boundary layer. They can be cultured on microporous membranes (see DE 198 01 763 A1).
  • suitable microporous membranes are coated membranes, for example the companies Becton Dickinson (FALCON) and Corning (Costar), which ensure appropriate cell growth on account of their membrane properties.
  • a special culture guide not only allows the study of the drugs with the above cell types, but also allows their combination with other cells, such as macrophages, endothelial cells and fibroblasts, which may play a role in the development of the effect of the respective substance. This takes place in so-called co-cultures, wherein the cells are grown on both sides of a membrane.
  • Such a culture device in combination with the method after direct exposure of the apical cell type to the test atmosphere, allows an analysis of the interactions between the various cell types present on the membrane in order to obtain further information on the effect of the test substance.
  • Vessels which receive cells grown on microporous membranes and cultured to be exposed to the test atmosphere are preferably in a separate subset, with each vial being individually supplied with nutrients.
  • the supply of nutrients takes place via a feed line which is connected via a suitable connection, e.g. a hose connection is connected to the nutrient reservoir, and via an inlet nozzle allows a supply of nutrients in the relevant vessel of the pedestal.
  • the vessel can be filled to a certain level with medium to supply the cells over the time of exposure.
  • Another nozzle opens up the possibility of a constant medium flow in which the inflowing volume flows off or is removed in an analogous manner via the outlet nozzle.
  • the medium flow may e.g. controlled by a peristaltic pump.
  • test method described makes it possible, for example, to apply different target cells of the respiratory tract or suitable bacterial test systems to potentially therapeutically active substances which are taken up by inhalation and act directly.
  • This is not limited to gaseous and liquid aerosols, but also includes agents that are administered as solid aerosol particles.
  • the procedure ensures an immediate Loading the cultured cells or bacteria with a test atmosphere and allows a precise analysis of the resulting cellular reaction pattern to describe the expected therapeutic and possibly unwanted toxic effect.
  • the bioavailability and efficacy of substances applied in solid particulate form can be studied depending on particle size and support material, an aspect that can not be realized under conventional conditions.
  • Another advantage of the method is the ability to test not only individual substances, but also combinations thereof in different mixing ratios of cells to select therapeutically relevant agents or combinations thereof.
  • the treatment of cultured cells with therapeutic aerosols by direct application contains no limitation with regard to the determinable biological endpoints or effects. Typically certain parameters are e.g. Viable cell count, metabolic activity, membrane integrity, energy status, or oxidative stress.
  • a comprehensive characterization of the treated cells for example with respect to the cytotoxic and genotoxic activity of the test atmosphere, their inflammatory potential or molecular biology aspects (Genomics, Metabono mics) is fully possible, as well as receptor studies, the determination of mediators or other biomarkers, the analysis of signal transduction pathways and bioavailability conditions of the test atmosphere.
  • the investigations preferably carried out in the context of the method relate to the biological effect of aerosols / test atmosphere on cells cultured in vitro. They are typically aimed at
  • Examples of molecular biology studies include receptor studies, determination of mediators or other biomarkers, or analysis of signal transduction pathways.
  • Another object of the invention relates to a device based on the method just described.
  • Such a device is used to study the biological effect of an inhaled substance comprises
  • the device described additionally comprises on-line analyzers for measuring aerosol parameters, which are connected to the distributor via sampling points and, like the cell culture units, are supplied with samples from the distributor.
  • cold traps or activated carbon filters for gaseous components particle filters for aerosol particles or impactors for defined particle sizes can be connected as sampling devices.
  • devices for determining the particle concentration devices for determining the particle size distribution or devices for determining the concentration of certain gaseous constituents can be connected as online analysis devices.
  • Typical examples of aerosol generators which can be used in the context of the present invention are known under the names Respimat® and Handihaler®.
  • a suitable culture and exposure unit are those available as CULTEX® modules.
  • a conditioning to a fixed temperature value between 20 ° C and 45 ° C and preferably between 37 ° C and 42 ° C.
  • FIGS. 1 and 6 show the aerosol exposure structure.
  • the complete construction consists of at least two such constructions, which are used for the simultaneous exposure of A549 cultures on microporous membranes to a control substance (aerosolized PBS) and a test substance (eg aerosolized tertiary butyl hydroperoxide).
  • a control substance e.g aerosolized PBS
  • a test substance eg aerosolized tertiary butyl hydroperoxide
  • Example 1 Apparatus for the Generation and Exposure of Droplet Aerosols on a Cell Culture Scale
  • a modular construction in parallel arrangement allows the simultaneous operation of several nebulizers.
  • the simultaneous, parallel exposure of cells to microporous membranes is e.g. to a test aerosol and a control aerosol (e.g., PBS as the vehicle or solvent of the test substance) in an experiment.
  • a control aerosol e.g., PBS as the vehicle or solvent of the test substance
  • nebulizers of the "Miniheart Low Flow Nebulizer” brand (Westmed Inc., Arlington, USA) are used, which are continuously pumped into the nebulizer storage vessel by means of a perfusor pump for constant levels in the nebulizer 37 ° C, 2 l / min)
  • the aerosols are sampled for cell exposures immediately above the outlet
  • the sampling position for an online aerosol analysis before the test aerosol is passed through a cold trap and a combined activated carbon / particulate filter.
  • the parallel operated position de s Kontrollaerosols be extended by such a cleaning unit and online aerosol analysis.
  • the entire flow path of the aerosols above the Nebulizer is heated by an electric winding heater to approx. 37 ° C constantly thermostated.
  • A549 culture DSMZ, Braunschweig cells are harvested during the routine culture split and seeded on membranes (BD Falcon). After a 72 h attachment and growth phase under standard culture conditions, the cells on the membranes are microscopically controlled and provided with fresh medium. Eighteen hours before the actual exposure, the adherently-growing cells become submerged in culture spent in an air / lifted cultural tour. The cells conditioned in this way are used for exposure to the test aerosol or the control aerosol or as incubator control. Following the exposure period, the cells are worked up or post-cultured under submerged conditions in the incubator for further analysis.
  • WST-1 dye reagent (Boehringer, Mannheim) is added to the culture medium supernatant. The cells are reincubated under cell-type-specific conditions in the incubator for 30 min. The measurement of the absorption in the microtiter plate reader at the wavelengths 450 nm / 630 nm is then carried out from the medium.
  • a trypsin / EDTA solution is added and the cells are reincubated at 37 ° C for 5 min in the incubator. Subsequently, the trypsin effect is stopped by addition of trypsin inhibitor and the cells are carefully suspended.
  • an electronic cell analyzer (CASY, Fa. Sharp) an aliquot of cell trypsinate is suspended in a weak electrolyte and sucked at a constant flow rate through a capillary of defined geometry. Each cell suspension is subjected to a triple measurement.
  • Incubator controls are incubated in the incubator for the period of exposure under air-liquid culture conditions.
  • Exposure controls are cultures that are exposed simultaneously and simultaneously to the aerosol exposure under the same conditions as the cells in aerosol exposure. The only difference with aerosol exposure is that this exposure occurs exclusively against aerosolized PBS. In aerosol exposure, the cultures are exposed for 30 minutes to various concentrations of a freshly generated droplet aerosol of a model substance.
  • Various concentrations of a model substance are used.
  • the cells are exposed to the generated aerosols at an exposure flux of 5 ml / min / cm 2 for 30 min each.
  • the deposition of the aerosol is quantified using Na fluorescein (10 ⁇ g / ml in the Nebulizer filling) on the microporous membranes. Under conditions of cell exposure, they are overflowed with exposure fluxes of 5 ml / min for periods of 10 to 30 minutes.
  • the membranes are removed, cut out of the holders, extracted with ultrapure water and quantified the fluorescence of the extract at the wavelengths 435 nm (ex.) 510 nm (em.) against reference solutions of Na-fluorescein in ultrapure water. By cutting out the membranes, only the growth areas are included in the measurement, on which the adherent cell cultures will be located.
  • the volumes of PBS deposited during the exposure time can be determined by staining the Nebulizer filling with sodium fluorescein and detecting in cell-free experiments.
  • the maximum deposited volume is within 30 minutes at 1 ul / cm 2 .
  • the medium level (“medium level”) below the membrane can also be an influence on the exposure situation of apically adherently cultivated cells when using microporous membranes. Therefore, cell-grown membranes are exposed to the aerosolized model substances or the corresponding PBS control for the duration of exposure as a function of the medium level in up to three different variations: (1) under the conditions of a "high” medium level, and a resulting maximum hydrostatic level Pressure on the microporous membrane (2) minimal “contact” between the membrane and the basal medium, and (3) no membrane and medium contact, a so-called “low” medium level ( Figure 2-2).
  • Exposure controls are used concurrently with each aerosol exposure in parallel construction and are the reference for the aerosol exposure results as they are subject to all exposure factors, except for the effect of the test substance.
  • the cell-grown originating from the respective control situations are used concurrently with each aerosol exposure in parallel construction and are the reference for the aerosol exposure results as they are subject to all exposure factors, except for the effect of the test substance.
  • Membranes are processed in parallel with the membranes derived from the aerosol exposures.
  • the results for the incubator controls and the exposure controls depending on the respective exposure day are shown separately after endpoints.
  • the results of the tetrazolium salt conversion (WST-1) after exposure of the A549 cells to a PBS droplet aerosol as a control situation for the aerosol exposures carried out with model substances are shown in FIG. 2 for two exposure days (Di and Mi) as a function of the exposure situation (mean values with standard deviation for medium high, medium contact and medium deep).
  • the data are related to the respective incubator controls currently carried out during each exposure.
  • the values are in the fluctuation range of the incubator controls and document that the exposure situation has no influence on the tetrazolium salt conversion of the cells.
  • the results of the living cell count determination, which was recorded as a further vitality parameter following the exposure, are compiled in FIG.
  • the values on both days of exposure coincide on average Exposure controls in all exposure situations with incubator control values.
  • the medium level "contact” is used.
  • FIG. 4 shows the results of this series of experiments.
  • the results from the study of the tetrazolium salt conversion at the median level "contact" against the dose determined by the deposition study are shown: Measurement points taken into account for the regression are marked with "x", not taken into account with "o.”
  • the plotted curves correspond to the regression line with The corresponding confidence limits (95%)
  • a dose-response relationship is calculated which describes the complete vitality range of 100% to 0% within the investigated doses compared to the PBS-exposed control.
  • characteristic values for example ED 50 values (value at which the measured signal of an end point, eg metabolic activity in the WST-1 assay, is reduced by 50% compared to the control culture) can be calculated allow a direct comparison of effects of different substances.
  • ED 50 values value at which the measured signal of an end point, eg metabolic activity in the WST-1 assay, is reduced by 50% compared to the control culture
  • tBuOOH this value, based on the measurement of the metabolic activity (WST-1 assay) under the conditions mentioned, is 0.05 ⁇ mol / cm 2 or 0.08 ⁇ mol / cm 2 for the cell number.

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Abstract

L’invention concerne un procédé et un dispositif destinés à l’examen de l’action biologique d’une substance testée, caractérisés en ce que (a) de l’air pur est introduit dans un générateur d'aérosol et éventuellement dans un humidificateur, (b) la substance à tester est transformée en un flux de particules finement divisées par le générateur d’aérosol, (c) le flux issu du générateur d’aérosol et éventuellement de l’humidificateur est mélangé de manière appropriée avec un aérosol et transmis dans un distributeur et (d) des volumes définis du flux issus du distributeur sont prélevés et sont mis en contact direct avec des cultures in vitro procaryotes ou eucaryotes dans un dispositif d’exposition/de culture.
PCT/EP2007/050699 2006-01-27 2007-01-24 Procede et dispositif pour l’injection de cellules Ceased WO2007085621A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06001687 2006-01-27
EP06001687.0 2006-01-27

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WO2007085621A1 true WO2007085621A1 (fr) 2007-08-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010040473A3 (fr) * 2008-10-06 2010-12-29 Ulrich Mohr Dispositif de culture/d'exposition notamment pour des cultures de cellules et/ou de bactéries
DE102022000616A1 (de) 2022-02-19 2023-09-07 Photonion Gmbh Verfahren und Vorrichtung zur optischen Kontrolle der Exposition von biologischen Systemen mit Partikeln, Aerosolen und Gasen

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5612188A (en) * 1991-11-25 1997-03-18 Cornell Research Foundation, Inc. Automated, multicompartmental cell culture system
DE10014057A1 (de) * 2000-03-22 2001-10-04 Ulrich Mohr Vorrichtung und Verfahren zum Beaufschlagen einer in einem Kulturgefäss aufgenommenen Kultur mit einem gasförmigen Medium sowie Expositionsvorrichtung
DE10211324A1 (de) * 2002-03-14 2003-10-02 Ulrich Mohr Kultur/Expositionsvorrichtungen, Bausatz für den Zusammenbau einer solchen sowie Verfahren zur Kultivierung und Exposition von Prokaryonten
WO2005061694A1 (fr) * 2003-12-16 2005-07-07 Hepahope, Inc. Systeme d'essai de medicaments utilisant un foie bioartificiel

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5612188A (en) * 1991-11-25 1997-03-18 Cornell Research Foundation, Inc. Automated, multicompartmental cell culture system
DE10014057A1 (de) * 2000-03-22 2001-10-04 Ulrich Mohr Vorrichtung und Verfahren zum Beaufschlagen einer in einem Kulturgefäss aufgenommenen Kultur mit einem gasförmigen Medium sowie Expositionsvorrichtung
DE10211324A1 (de) * 2002-03-14 2003-10-02 Ulrich Mohr Kultur/Expositionsvorrichtungen, Bausatz für den Zusammenbau einer solchen sowie Verfahren zur Kultivierung und Exposition von Prokaryonten
WO2005061694A1 (fr) * 2003-12-16 2005-07-07 Hepahope, Inc. Systeme d'essai de medicaments utilisant un foie bioartificiel

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010040473A3 (fr) * 2008-10-06 2010-12-29 Ulrich Mohr Dispositif de culture/d'exposition notamment pour des cultures de cellules et/ou de bactéries
US9096824B2 (en) 2008-10-06 2015-08-04 Ulrich Mohr Culture/exposure device, in particular for cell and/or bacteria cultures
DE102022000616A1 (de) 2022-02-19 2023-09-07 Photonion Gmbh Verfahren und Vorrichtung zur optischen Kontrolle der Exposition von biologischen Systemen mit Partikeln, Aerosolen und Gasen

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