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WO2002033052A2 - Procede de production in vitro de tissu de remplacement biologique vital au moyen de cultures cellulaires et d'un substrat - Google Patents

Procede de production in vitro de tissu de remplacement biologique vital au moyen de cultures cellulaires et d'un substrat Download PDF

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Publication number
WO2002033052A2
WO2002033052A2 PCT/DE2001/003959 DE0103959W WO0233052A2 WO 2002033052 A2 WO2002033052 A2 WO 2002033052A2 DE 0103959 W DE0103959 W DE 0103959W WO 0233052 A2 WO0233052 A2 WO 0233052A2
Authority
WO
WIPO (PCT)
Prior art keywords
cell
tissue construct
tissue
cell culture
bioreactor
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/DE2001/003959
Other languages
German (de)
English (en)
Other versions
WO2002033052A3 (fr
Inventor
Ralf Sodian
Thees Lembke
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.)
Deutsches Herzzentrum Berlin
Original Assignee
Deutsches Herzzentrum Berlin
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 Deutsches Herzzentrum Berlin filed Critical Deutsches Herzzentrum Berlin
Priority to EP01987795A priority Critical patent/EP1326962A2/fr
Priority to AU2002221526A priority patent/AU2002221526A1/en
Publication of WO2002033052A2 publication Critical patent/WO2002033052A2/fr
Publication of WO2002033052A3 publication Critical patent/WO2002033052A3/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
    • 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
    • C12M35/04—Mechanical means, e.g. sonic waves, stretching forces, pressure or shear stimuli
    • 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
    • C12M21/00—Bioreactors or fermenters specially adapted for specific uses
    • C12M21/08—Bioreactors or fermenters specially adapted for specific uses for producing artificial tissue or for ex-vivo cultivation of tissue
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0062—General methods for three-dimensional culture

Definitions

  • the invention relates to a method for the in vitro production of vital, biological replacement tissue using cell cultures and a carrier material, and to an apparatus for carrying out the method.
  • tissue engineering for the production of artificial connective and epithelial tissues and neuronal organoids on the basis of cultivated cells and with the aid of various biomatrices outside the body “in vitro” and then to implant the cultivated cells.
  • Tissue engineering combines findings from medicine and biology with methods of engineering science, and enables spatially defined tissues and organoid structures to be built up for implantation.
  • tissue engineering is to apply the body's own cells to suitable matrices, to control their multiplication and to direct their three-dimensional spread in order to produce a vital and functional tissue replacement.
  • the body's own cells are anchored on a carrier material, in particular on individually selected filter pads, fleeces, biodegradable scaffolding materials or sponge-like matrices and in culture containers with nutrients and others Additives supplied.
  • the body's own cells which are increased in accordance with tissue differentiation and consolidated in vitro to a stable structure, theoretically lead to a vital replacement tissue suitable for implantation.
  • tissue engineering In addition to tissue-typical differentiation and optimal cell anchoring, easy handling, high functional reliability with the least possible expenditure on equipment and the guarantee of sterile conditions during the production of the biological replacement tissue are important for the application of tissue engineering.
  • the object of the present invention is therefore to provide a method for the in vitro production of vital, biological replacement tissue using cell cultures and a carrier material, with which in particular a flat, so-called patch tissue can be produced in vitro, which has a high and controllable line multiplication rate while maintaining the desired cell properties, which is easy to handle and functionally reliable, and can be used with little outlay on equipment while ensuring sterile conditions.
  • This object is achieved by a method for the in vitro production of vital, biological replacement tissue using cell cultures and a carrier material, in which a cell-tissue construct formed from the carrier material and the cell cultures is exposed to a changing mechanical stress.
  • the solution according to the invention ensures the production of a vital, stable and fractional replacement tissue, in particular a flat patch tissue in vitro, which enables a high and controllable cell multiplication rate while maintaining the desired cell properties and which is easy to handle and functionally reliable and with little equipment and under the protection of sterile conditions is applicable.
  • the method according to the invention is particularly suitable for the production of sheet-like tissue pieces for cardiovascular structures.
  • the cell-tissue construct is preferably subjected to a periodically changing mechanical stress, in particular a pulsating pressure stress, exposed.
  • the cell-tissue construct is exposed to a tissue-stimulating flow of the cell culture medium by a combination of a pulsating flow and a pulsating movement of the cell-tissue construct on the Cell-tissue construct acts.
  • the pulsating movement acting on the cell-tissue construct is preferably carried out alternately on both sides of the cell-tissue construct, in particular in the case of a horizontally arranged cell-tissue construct, by raising and lowering the cell-tissue construct.
  • a particularly suitable carrier material has proven to be an absorbable or biodegradable tissue scaffold, in particular a resorbable scaffold material, for optimal cell anchoring and thus for maintaining tissue-typical properties.
  • the amplitude of the pulsating movement preferably directed perpendicular to the surface of the cell-tissue construct, and the flow rate of the cell culture medium can be changed, ie the amount of liquid pumped can be varied as desired by setting the frequency and the pump volume • of an appropriate drive unit for the cell culture medium.
  • An advantageous embodiment of the method according to the invention for the production of vital and functional replacement tissue pieces (patch tissue) according to the principle of tissue engineering using a resorbable carrier material that colonizes with vascular cells and in vitro to form a cell-tissue construct to form an adequate, Conditioned extracellular matrix, in particular for the reconstruction of cardiovascular structures, is characterized in that the cell-tissue construct is a pulsating moving the cell-tissue construct in alternating directions pulsatile flow of a cell culture fluid is exposed.
  • the pulsatile flow preferably acts on the cell-tissue construct both perpendicularly and essentially parallel to the surface of the cell-tissue construct.
  • a direction of flow of the cell culture fluid moving past the cell-tissue construct is preferably specified.
  • the Zeil-tissue is. Constructed mechanically in such a way that the cell culture fluid flows along one surface of the cell-tissue construct, while the other surface of the cell-tissue construct or the tissue structure is moistened with cell culture fluid.
  • This cell culture fluid which moistens the tissue structure, is aspirated and exchanged at predetermined intervals.
  • a device is suitable for carrying out the method according to the invention, which comprises a bioreactor for receiving the cell-tissue construct, a drive unit connected to the bioreactor and acting on the cell culture medium, and a container for the bioreactor connected via a supply and an outlet line Cell culture medium exists.
  • Such a device enables a compact structure and a maximum degree of sterility in the production of a vital replacement tissue as well as simple handling and optimal influence on the control mechanisms during the growth of the vital replacement tissue.
  • the drive unit is designed so that it directly or indirectly changes the pressure on the cell-tissue construct and on the cell culture medium to produce a mechanical alternating movement of the cell-tissue construct and one pulsatile flow of the cell waist medium.
  • the drive unit can act directly on the cell-tissue construct, for example, in such a way that the carrier material populated with cell cultures and contained in a cell culture fluid is moved mechanically and, in addition to a mechanical alternating movement, also causes a flow movement of the cell culture fluid, which is caused by appropriate control means is converted into a pulsatile flow.
  • the drive unit preferably consists of a membrane pump arranged essentially parallel to the alignment of the cell-tissue construct, between which and the cell-tissue construct the cell culture medium is located.
  • a holding device of the bioreactor which clamps the cell-tissue construct at its edge region, is used, so that both surfaces of the cell-tissue construct can be suitably loaded with the cell culture medium.
  • An advantageous embodiment of the bioreactor according to the invention is characterized in that it has a plurality of chambers arranged one above the other, of which a lower chamber forms the membrane pump, a middle chamber from the lower chamber through the membrane of the membrane pump and from an upper chamber through the cell tissue.
  • the construct is separated and connected to the reservoir for the cell culture medium via the feed and drain line and thus contains cell culture medium and that the upper chamber contains the holding device which clamps the cell-tissue construct and cell culture medium.
  • the middle chamber has two diametrically arranged hose connections and lead from the hose connections to the cell-tissue construct
  • a check valve is arranged in bores and at least in the feed or drain line.
  • a mechanical load and a pulsatile flow Membrane pump consisting of the membrane separating the lower chamber from the middle chamber and a respirator connected to the lower chamber via a pressure line, an infusion pump or the like for periodically generating an overpressure and underpressure in the lower chamber.
  • the holding device provided for fixing the cell-tissue construct preferably consists of a cylindrical stamp, the circular base of which presses the cell-tissue construct against an upper edge of the middle chamber, a support cover which is connected to a housing part of the bioreactor, and one Adjusting element which supports the cover surface opposite the circular base surface of the cylindrical stamp on the support cover.
  • the top surface of the cylindrical plunger and the support cover have at least one hole and a cylindrical or pot-shaped cover which extends over the support cover and can be connected to the housing part of the bioreactor closes off the upper chamber.
  • the bioreactor advantageously consists of a transparent material, preferably of acrylic.
  • the bioreactor, the reservoir for the cell culture medium and the connecting lines are arranged in an incubator and the bioreactor is connected via the pressure line to the ventilator, the infusion pump or the like arranged outside the incubator ,
  • FIG. 5 shows a section through a bioreactor which is particularly suitable for producing a vital patch tissue
  • FIG. 6 shows a section through the bioreactor according to FIG. 5 along the line VI-VI;
  • Fig. 7 - a section through the bioreactor according to FIG. 5 along the line VII-VII and
  • Fig. 8 - a schematic representation of an experimental setup for the production of biologically functional replacement tissue.
  • FIGS. 1 and 2 are intended to explain the principles of the new flow system for the production of a patch tissue in vitro by a combined mechanical stress of a cell-tissue construct in connection with a tissue-stimulating flow to induce an adequate extracellular matrix formation.
  • the cell-tissue construct 1 clamped in a holding device 7 preferably consists of a carrier material in the form of a resorbable tissue framework, which is populated, for example, with vascular cells.
  • the cell-tissue construct 1 is subjected to an overpressure P j from the underside, so that the cell-tissue construct 1 is arched upwards.
  • a tissue-stimulating flow F is generated, which flows from an inlet line 41 to an outlet line 42 and thereby flows along the underside of the cell-tissue construct 1.
  • the cell-tissue construct 1 is exposed both to a pulsatile flow F and to a changing pressure Pi or P 2 and thus to a mechanical stress.
  • An example of the generation of this changing, mechanical stress on the cell-tissue construct 1 is explained in more detail below in connection with the description of a bioreactor according to FIG. 5.
  • FIG. 3 shows a typical course of the pressure loading of the cell-tissue construct with an overpressure and underpressure acting alternately after a sinus function on the cell-tissue construct.
  • FIG. 3 illustrates that the overpressure acting on the cell-tissue construct reaches higher pressure values than the negative pressure acting on the cell-tissue construct.
  • FIG. 4 shows a temporal representation of the pulsatile flow acting on the cell-tissue construct, the flow velocity of which also increases sinusoidally with increasing overpressure acting on the cell-tissue construct, while it essentially increases with negative pressure acting on the cell-tissue construct drops to zero, the vibrations shown being caused by the systemic friction due to the laminar flow of the cell culture fluid and the movement of the cell-tissue construct.
  • FIG. 5 shows a section through a bioreactor 2 for producing a patch tissue in vitro, with the aid of which the cell-tissue construct is subjected to both mechanical stress and a tissue-stimulating, pulsatile flow in order to induce adequate extracellular matrix formation.
  • the bioreactor 2 has a lower chamber 3, which is delimited by a first housing part 30 and a silicone membrane 6.
  • the lower chamber 3 is filled with air or a suitable gas and has a hose connection 31 to which one is connected
  • Hose a drive unit, for example in the form of a ventilator, an infusion pump or the like is connected.
  • a corresponding drive unit can consist, for example, of a so-called “dual phase control fan” or an infusion pump which can be found in WO 96/25963.
  • a middle chamber 4 which is delimited by a second housing part 40, the silicone membrane 6 and by the cell-tissue construct 1.
  • cell culture liquid with a volume of, for example, 370 ml.
  • two bores 41, 42 which communicate with hose connections 43, 44 which are fastened to the second housing part 40 of the bioreactor 2 , The two bores 41, 42 are arranged diametrically to one another and directed towards the underside of the cell-tissue construct 1.
  • the two tube connections 43, 44 are connected to a reservoir 15 for cell culture fluid via silicone tubes.
  • An upper chamber 5 is delimited by a third housing part 50, a cover 10 which closes and seals the bioreactor 2 at the top and on its underside by the cell-tissue construct 1.
  • a holding device for fixing the cell-tissue construct 1 which consists of a cylindrical stamp 7 and a clamping device 8, 9.
  • a knurled screw 9 which presses the top surface 71 of the cylindrical stamp 7 against one on the third housing part 50 of the bioreactor 2 supported support cover 8 biased.
  • a lock nut 90 is provided, which secures the position of the knurled nut 9.
  • cell culture liquid with a volume of, for example, 40 ml, the accessibility of which is through bores 72 to 74 or 81-83 (FIGS. 6 and 7) in the top surface 71 of the cylindrical stamp 7 or in the support cover
  • the sealing of the interior of the bioreactor 2 to maintain sterile conditions for the cell-tissue construct 1 is achieved by a silicone O-ring 11 on the abutting end faces of the second housing part 40 and the third housing part 50, which are the middle chamber 4 and the upper chamber 5 limit and guaranteed by the silicone membrane 6.
  • Acrylic is used as the material for the housing parts 30, 40, 50 and for the pot-shaped cover 10, and the connection connections and connections of the housing parts are effected using stainless steel screws.
  • FIGS. 6 and 7 are top views of the support cover 8 and the top surface 71 of the cylindrical stamp 7 with the bores 72 to 74 and 81 to 83 arranged therein for the exchange of cell culture fluid.
  • FIG. 8 shows a schematic diagram of an experimental setup with the bioreactor 2, which is arranged in an incubator 12 together with the reservoir 15 for cell culture fluid and a ring line 16 made of silicone tubes for supplying and draining cell culture fluid.
  • the bioreactor 2 is connected via a pressure line 17 to a respirator 11 as the drive unit, which is arranged outside the incubator 12.
  • check valves 13, 14 are arranged, which prescribe a direction of flow of the cell culture fluid.
  • the bioreactor 2 has the following functions:
  • the silicone membrane 6 In the idle state, the silicone membrane 6 is arched downward, ie into the lower chamber 3, due to the force of gravity and the cell culture liquid located in the middle chamber 4. If the drive unit 12 generates an overpressure in the lower chamber 3, this overpressure causes a movement of the membrane pump Silicone membrane 6 upwards, ie into the middle chamber 4 and thus a volume reduction of the middle chamber 4 filled with cell culture liquid. According to FIG. 1, this curvature of the silicone membrane 6 causes a pressure on the cell from the middle chamber 4 to the upper chamber 5 Tissue construct 1 exerted so that the cell-tissue construct 1 bulges into the upper chamber 5.
  • a negative pressure is generated in the lower chamber 3 by means of the drive unit 12 and the silicone membrane 6 is thereby drawn into the lower chamber 3.
  • the resulting increase in volume in the middle chamber 4 ensures that cell culture fluid is drawn in from the reservoir 15 via one of the two bores 41, 42.
  • Cell culture fluid flows along the underside of the cell-tissue construct 1 or patch tissue through the predetermined flow direction and the bores 41, 42 directed towards the underside of the cell-tissue construct 1 and bulges the cell-tissue construct downwards the middle chamber 4 according to FIG. 2 by.
  • the cycle starts again when the drive unit 12 again generates an overpressure in the lower chamber 3 and as a result causes the silicone membrane 6 to bulge into the middle chamber 4.
  • the cell-tissue construct 1 bulges into the upper chamber 5 or middle chamber 4 and is exposed in parallel to a pulsatile flow of the cell culture liquid which, as a result of the non-return flaps 13, 14 according to FIG Cell tissue construct 1 flows along. In this way, the cell-tissue construct is exposed to both mechanical (pressure) stress and a pulsatile flow.
  • the cell culture liquid located in the upper chamber 5 serves to moisten the carrier material and is at certain intervals via the bores 72 to 74 and 81 sucked up to 83 in the support cover 8 or in the cover surface 71 of the cylindrical stamp 7 and exchanged.

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  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
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  • Biomedical Technology (AREA)
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  • Mechanical Engineering (AREA)
  • Molecular Biology (AREA)
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Abstract

L'invention concerne un procédé de production in vitro de tissu de remplacement biologique vital au moyen de cultures cellulaires et d'un substrat. Ce procédé consiste à soumettre une construction cellules-tissu, constituée du substrat et des cultures cellulaires, à une sollicitation mécanique fluctuante qui associe notamment un écoulement pulsé d'un milieu de culture cellulaire et un mouvement pulsé de la construction cellules-tissu.
PCT/DE2001/003959 2000-10-17 2001-10-17 Procede de production in vitro de tissu de remplacement biologique vital au moyen de cultures cellulaires et d'un substrat Ceased WO2002033052A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP01987795A EP1326962A2 (fr) 2000-10-17 2001-10-17 Procede de production in vitro de tissu de remplacement biologique vital au moyen de cultures cellulaires et d'un substrat
AU2002221526A AU2002221526A1 (en) 2000-10-17 2001-10-17 Method for producing vital, biological substitute tissue in vitro using cell cultures and a support

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10053014.1 2000-10-17
DE10053014A DE10053014A1 (de) 2000-10-17 2000-10-17 Verfahren zur In-vitro-Herstellung von vitalem, biologischem Ersatzgewebe unter Verwendung von Zellkulturen und einem Trägermaterial

Publications (2)

Publication Number Publication Date
WO2002033052A2 true WO2002033052A2 (fr) 2002-04-25
WO2002033052A3 WO2002033052A3 (fr) 2002-11-28

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PCT/DE2001/003959 Ceased WO2002033052A2 (fr) 2000-10-17 2001-10-17 Procede de production in vitro de tissu de remplacement biologique vital au moyen de cultures cellulaires et d'un substrat

Country Status (4)

Country Link
EP (1) EP1326962A2 (fr)
AU (1) AU2002221526A1 (fr)
DE (1) DE10053014A1 (fr)
WO (1) WO2002033052A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1550716A1 (fr) * 2004-01-05 2005-07-06 fzmb Forschungszentrum für Medizintechnik und Biotechnologie e.V. Procédé pour la fabrication de structures de tissu tridimensionnelles, et structures de tissu fabriqués avec ce procédé
US8399243B2 (en) 2005-02-17 2013-03-19 Universitaet Zuerich Method of manufacturing a tissue-engineered prosthesis
US20210355430A1 (en) * 2019-02-04 2021-11-18 Fujifilm Corporation Cell culture device, method for culturing cells, and method for producing product
IT202000021847A1 (it) * 2020-09-16 2022-03-16 React4Life S R L Dispositivo per l’esecuzione di esperimenti in vitro su materiale biologico

Families Citing this family (9)

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Publication number Priority date Publication date Assignee Title
DE10249903B4 (de) * 2002-10-22 2007-10-11 Cytonet Gmbh & Co. Kg Mechanischer Bioreaktor
DE10322024A1 (de) * 2003-05-16 2004-12-02 Symetis Ag Bioreaktor zum Herstellen einer Gewebeprothese, insbesondere Herzklappe
DE102008050424B4 (de) 2008-10-08 2010-11-25 Universität Leipzig Verfahren und Vorrichtung zur homogenen Verteilung einer zellulären Suspension in porösem Trägermaterial für die Herstellung von vitalem biologischem Ersatzgewebe
DE102009039535B4 (de) * 2009-09-01 2015-08-20 Corlife Ohg Behälter, Vorrichtung und Verfahren zur Behandlung von Gewebe unter Reinraumbedingungen
EP2399986A1 (fr) 2010-06-22 2011-12-28 Ludwig-Maximilians-Universität München Bioréacteur et procédé de création et/ou de conditionnement de tissus biologiques
EP2468846A1 (fr) 2010-12-22 2012-06-27 Ludwig-Maximilians-Universität München Procédé pour examiner la croissance tissulaire et le conditionnement de cellules sur un support et bioréacteur à perfusion
EP2500410A1 (fr) 2011-03-18 2012-09-19 Ludwig-Maximilians-Universität München Bioréacteur avec supports de stimulation mécanique et électrique
CZ2012376A3 (cs) 2012-06-05 2013-12-18 Institut Klinické A Experimentální Medicíny Způsob výroby perikardiální náhrady srdeční chlopně, perikardiální náhrada srdeční chlopně vyrobená tímto způsobem, zařízení pro kondicioning a modifikaci tkáně autologního perikardu pro perikardiální náhradu srdeční chlopně
CN113249211A (zh) * 2021-05-26 2021-08-13 庆开雄 一种可改变箱内压力的细胞培养箱及其压力调节方法

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US5153136A (en) * 1988-07-22 1992-10-06 Vandenburgh Herman H Apparatus for growing tissue specimens in vitro
US5217899A (en) * 1990-08-24 1993-06-08 The General Hospital Corporation Cell stretching apparatus
US5792603A (en) * 1995-04-27 1998-08-11 Advanced Tissue Sciences, Inc. Apparatus and method for sterilizing, seeding, culturing, storing, shipping and testing tissue, synthetic or native, vascular grafts

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1550716A1 (fr) * 2004-01-05 2005-07-06 fzmb Forschungszentrum für Medizintechnik und Biotechnologie e.V. Procédé pour la fabrication de structures de tissu tridimensionnelles, et structures de tissu fabriqués avec ce procédé
US8399243B2 (en) 2005-02-17 2013-03-19 Universitaet Zuerich Method of manufacturing a tissue-engineered prosthesis
US20210355430A1 (en) * 2019-02-04 2021-11-18 Fujifilm Corporation Cell culture device, method for culturing cells, and method for producing product
US12331280B2 (en) * 2019-02-04 2025-06-17 Fujifilm Corporation Cell culture device, method for culturing cells, and method for producing product
IT202000021847A1 (it) * 2020-09-16 2022-03-16 React4Life S R L Dispositivo per l’esecuzione di esperimenti in vitro su materiale biologico
WO2022058909A1 (fr) * 2020-09-16 2022-03-24 React4Life S.R.L. Appareil pour effectuer des expériences in vitro sur un matériau biologique

Also Published As

Publication number Publication date
DE10053014A1 (de) 2002-04-18
WO2002033052A3 (fr) 2002-11-28
AU2002221526A1 (en) 2002-04-29
EP1326962A2 (fr) 2003-07-16

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