WO2005003332A2 - Appareil et procede de culture cellulaire tridimensionnelle magnetique - Google Patents

Appareil et procede de culture cellulaire tridimensionnelle magnetique Download PDF

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Publication number
WO2005003332A2
WO2005003332A2 PCT/US2004/020908 US2004020908W WO2005003332A2 WO 2005003332 A2 WO2005003332 A2 WO 2005003332A2 US 2004020908 W US2004020908 W US 2004020908W WO 2005003332 A2 WO2005003332 A2 WO 2005003332A2
Authority
WO
WIPO (PCT)
Prior art keywords
core particles
culture chamber
culture
magnetized core
diamagnet
Prior art date
Application number
PCT/US2004/020908
Other languages
English (en)
Other versions
WO2005003332A3 (fr
Inventor
Jeanne L. Becker
Susan B. Coffin
Original Assignee
University Of South Florida
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 University Of South Florida filed Critical University Of South Florida
Publication of WO2005003332A2 publication Critical patent/WO2005003332A2/fr
Publication of WO2005003332A3 publication Critical patent/WO2005003332A3/fr
Priority to US12/330,071 priority Critical patent/US20090137018A1/en
Priority to US14/096,791 priority patent/US9752139B2/en

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Classifications

    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
    • H01F7/00—Magnets
    • 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
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/14—Scaffolds; Matrices
    • 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
    • C12M25/00—Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/16—Particles; Beads; Granular material; Encapsulation
    • 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
    • C12M35/06—Magnetic means
    • 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
    • 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
    • C12N2529/00—Culture process characterised by the use of electromagnetic stimulation
    • 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
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/10—Mineral substrates
    • 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
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/50—Proteins
    • C12N2533/54—Collagen; Gelatin
    • 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
    • C12N2533/00—Supports or coatings for cell culture, characterised by material
    • C12N2533/90—Substrates of biological origin, e.g. extracellular matrix, decellularised tissue

Definitions

  • the present invention relates in general to the fields of biophysics, tissue regeneration, tissue culture and neurobiology. More specifically, the present invention relates to a method and apparatus for potentiation of or controlling the growth of biological cells and tissue in vitro.
  • Typical cell culturing involves placing a small number of cells into a nutrient rich media, commonly in a Petri dish or tube, and allowing the cells to grow and multiply. The result is two dimensional growth of cells offering limited insight as to how the cells would actually grow and multiply in vivo. Without a proper three-dimensional assembly, epithelial and mesenchymal cells, which are the basic cells that differentiate tissue into specific organ functions, would lack the proper indicators for growing into a variety of cells that make up a specific tissue. It is known that cells self-associate in the body, meaning that replication involves associating with the proper connections in the surrounding environment, as in the body, for proper growth clues to naturally form. It is therefore desirable to have a culture environment that is able to simulate tissue assembly in the body to enable the cells with the proper growth clues.
  • the present invention is a culture apparatus and method for growing cells and tissue in a three-dimensional configuration using magnetic, paramagnetic, ferromagnetic and diamagnetic forces, alone or in combination.
  • the cells/tissue are grown on magnetized core particles and are suspended via magnetic forces in a native, non-restricted, three-dimensional configuration, while being maintained in an earth gravity (1g) growth environment, thus without rotational alteration of the gravity vector.
  • the cellular constructs generated in the culture device of the present invention can be utilized for applications including, but not limited to, pharmacological testing and development of new types of biologic and therapeutic agents, cellular factor/protein production, generation of tissue for transplant to replace damaged tissue and development of functional three-dimensional cellular constructs for bio-sensing activities.
  • the system and method of the invention are utilized in combination with known tissue culture processes to produce enhanced three-dimensionally directed cell growth and tissue formation organization.
  • a system for cultivating three-dimensional biological cells includes an upper lifter magnet, stabilizing diamagnets and a culture chamber containing a culture medium and a plurality of bioattractive magnetized core particles, the culture chamber is positioned relative to the upper lifter magnet and diamagnets to facilitate levitation of the magnetized core particles.
  • a variety of diamagnets are encompassed by the invention.
  • a single magnet as in the form of a toroid, may supply the diamagnetic force.
  • two diamagnetic plates may supply the diamagnetic force, with the culture chamber being positioned substantially between the two plates.
  • the system may also include a plurality of diamagnets positioned to provided the diamagnetic force for the levitation of the magnetized core particles.
  • the culture chamber in accordance with the present invention contains a culture medium and a plurality of bioattractive magnetized core particles. As biological cells to be cultivated are introduced into the culture chamber, they adhere to the bioattractive magnetized core particles. The subsequent growth of the cells provides a three- dimensional cellular construct.
  • the culture chamber in accordance with the invention may be gas permeable to allow for the exchange of oxygen, carbon dioxide and other gases through the chamber. Additionally, the culture chamber may include an influx port allowing the introduction of new culture media into the chamber and an outflux port to allow for the removal of spent culture media.
  • the magnetized core particles within the culture chamber may be coated with a cellular adhesive material such as a collagen or other matrix component, to facilitate cellular adherence and three-dimensional growth.
  • a cellular adhesive material such as a collagen or other matrix component
  • the matrix components used may be biodegradable or non-biodegradable. Other methods and materials designed to encourage cellular adhesion to the magnetized core particles are within the scope of the invention.
  • the magnetized core particles may be shaped to achieve a predetermined cellular construct shape, such as the form of skin or other tissue.
  • the upper lifter magnet can also be used as a removal magnet to remove the magnetized core particles subsequent to a predetermined culture cultivation period.
  • the magnetized core particles can be dissociated from the cellular aggregates by adherence to this removal magnet at the desired termination of the culture period.
  • the method steps include inoculating a plurality of biological cells into a culture chamber, the culture chamber containing culture medium and a plurality of bioattractive magnetized core particles, thereby initiating the adherence of the biological cells to the magnetized core particles, positioning the culture chamber relative to the upper lifter magnet and the diamagnets to facilitate levitation of the magnetized core particles, and monitoring the growth of the cells.
  • the method of the present invention includes the steps of introducing new culture media into the culture chamber through an influx port and removing spent culture media from the culture chamber through an outflux port.
  • the magnetized core particles are removed from the culture chamber by positioning the upper lifter magnet relative to the culture chamber, and using the upper removal magnet effectively in the removal of the magnetized core particles.
  • the present invention provides a solution to in vitro three-dimensional suspension culture of cells under quiescent growth conditions characterized by zero shear and turbulence while maintaining a 1g, normal gravity and not simulated microgravity, environment, thus facilitating cellular co-localization and three-dimensional aggregate formation akin to an in vivo configuration.
  • the present invention provides many advantages over other systems and methods for three-dimensional cell growth know in the art, including a more realistic and in wVo-like growth condition from which to develop in vitro models of cell and tissue biology and functionality that replicate the conditions in the body in which the cells/tissue normally grow.
  • the present invention additionally serves to eliminate the problems associated with altering gene, and thus protein, expression by means of simulated microgravity associated with continuous rotation of the culture chamber which produces constant randomization of the gravity vector, as is known in the prior art.
  • the present invention provides a system and method affording these advantages in a three-dimensional culture that does not require electrically conductive channels to create electromagnetic fields or waveforms.
  • FIG. 1 is a diagrammatic illustration of the experimental setup demonstrating the principle of magnetic/diamagnetic levitation in accordance with the present invention.
  • FIG. 2 is a diagrammatic illustration of the experimental magnetic culture device setup demonstrating levitation of magnetic microcarriers within a culture bag in accordance with the present invention.
  • FIG. 3 is a diagrammatic illustration of the experimental magnetic culture device further illustrating the influx and outflux ports in accordance with the present invention.
  • a system including an in vitro culture device utilizing magnetic, paramagnetic, ferromagnetic and diamagnetic fields to create a suspension culture in which to grow cells and/or tissue.
  • a culture chamber in accordance with the present invention may be comprised of a plastic or plastic-like material, which may be gas permeable, within which cells are grown as three- dimensional tissue-like aggregate constructs under conditions of zero shear and turbulence, and in a 1g, normal gravity, environment.
  • the present invention utilizes this approach to establish a very stable permanent magnet levitator that is operational at room temperature without superconductors and without energy input.
  • a culture bag or chamber 30 is positioned between the two stabilizing diamagnetic plates 25, the plates supported by diamagnetic supports 20.
  • the culture chamber 30 contains magnetized core particles, culture medium and biological cells to be cultivated.
  • the three-dimensional cellular constructs, that are adhered to magnetized core particles, are held in suspension in the magnetic field provided by the upper lifter magnet 35 stabilized by repelling forces supplied by the diamagnets 25, which may exist as two single or several small diamagnets dispersed over a surface.
  • a single diamagnet may be effective in the system of the present invention, such as a toroidal shaped diamagnet.
  • the magnetic cell culture device may have a culture media flow-through system, such that new media is slowly infused into the vessel, while at the same time, spent culture media is removed.
  • the flow through system comprises an influx port 40 on one end of the magnetic cell culture device, with the outflow port 45 located substantially opposite the influx port.
  • Other configurations of the influx port and the outflow port are within the scope of the present invention.
  • the culture media flow through system of the present invention is adapted to be attached to a supply of fresh media, while spent media is collected into a reservoir for subsequent removal. From this spent media, further purification may be employed to provide purified cell-produced factors and proteins derived from the growing three- dimensional cellular constructs.
  • cells will be grown on magnetized core particles which have been coated with cellular adhesive material, such as collagen and other matrix components, to facilitate cellular adherence and three-dimensional grown.
  • the cells grown in this manner may either be cultured in the device while adhered to the magnetized core particles, or the magnetized core particles may exist within the cells themselves.
  • the matrix material on these particles may be non-degradable by the cells which are growing on said material or may be biodegradable such that growing cellular aggregates actually degrade the matrix as cell growth continues, thus the cells fall away from the core particles after a significant period of time in culture.
  • the magnetized core particles are eliminated from the three- dimensional cellular constructs by upper adherence magnet 35.
  • the cellular constructs are dispersed from the magnetized core particles by enzymatic digestion techniques common to those skilled in the art of cell culture, and the magnetized core particles are eliminated from the dissociated cellular aggregates by adherence to magnet 35.
  • the magnetized core particles may be shaped to specific dimensions, so as to achieve desired cellular construct shapes, for example, in the case of molding to create replacement bone joints and cartilage.
  • cellular construct shapes are created that are specified sized and shaped pieces of skin, or any other type of organ-specific tissue, for uses including but not limited to pharmacological testing of new types of biologic and therapeutic agents, and for transplant to replace damaged tissue.
  • the magnetic cell culture device may be utilized to enhance specific cellular geometries associated with particular biological functions, including but not limited to drug uptake, transport and metabolism, cellular factor/protein production, and bio-sensing activities.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Sustainable Development (AREA)
  • Cell Biology (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Electromagnetism (AREA)
  • Power Engineering (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

La présente invention concerne un appareil et un procédé de culture pour la croissance de cellules et de tissus dans une configuration tridimensionnelle dans laquelle sont utilisées des forces magnétiques, paramagnétiques, ferromagnétiques et diamagnétiques. Les cellules/tissus se développent dans ledit appareil de culture à l'aide de particules de noyau magnétisées, et sont suspendus par des forces magnétiques dans une configuration tridimensionnelle naturelle non limitée, tout en restant dans un environnement de croissance de 1g sans altération rotative du vecteur de gravité.
PCT/US2004/020908 2003-06-30 2004-06-30 Appareil et procede de culture cellulaire tridimensionnelle magnetique WO2005003332A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/330,071 US20090137018A1 (en) 2003-06-30 2008-12-08 Magnetic three-dimensional cell culture apparatus and method
US14/096,791 US9752139B2 (en) 2003-06-30 2013-12-04 Magnetic three-dimensional cell culture apparatus and method

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US48104203P 2003-06-30 2003-06-30
US60/481,042 2003-06-30

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US30647805A Continuation 2003-06-30 2005-12-29

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WO2005003332A3 WO2005003332A3 (fr) 2005-09-09

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010036957A1 (fr) * 2008-09-25 2010-04-01 William Marsh Rice University Systèmes et procédés de guidage et de modelage magnétique de cellules et de matériaux
US20120020885A1 (en) * 2010-07-26 2012-01-26 Searete Llc, A Limited Liability Corporation Of The State Of Delaware MHC-Less cells
EP2665807A1 (fr) * 2011-03-29 2013-11-27 Zhang, Yongxin Système de bioréacteur multifonctionnel et procédés pour le triage et la culture cellulaires
US9476025B2 (en) 2003-07-23 2016-10-25 University Of South Florida Ferromagnetic cell and tissue culture microcarriers
EP2909303A4 (fr) * 2012-10-18 2017-01-18 Yongxin Zhang Système de bioréacteur et procédés de culture cellulaire alternant entre un état statique et un état dynamique
US9752139B2 (en) 2003-06-30 2017-09-05 University Of South Florida Magnetic three-dimensional cell culture apparatus and method
US10288603B2 (en) 2011-02-01 2019-05-14 Greiner Bio-One North America, Inc. 3D cell viability assay
US10407660B2 (en) 2010-08-10 2019-09-10 Greiner Bio-One North America, Inc. Hardware for magnetic 3D culture
WO2020150556A1 (fr) 2019-01-18 2020-07-23 Voyager Therapeutics, Inc. Procédés et systèmes de fabrication de particules aav
EP3467093A4 (fr) * 2016-05-27 2020-08-05 Hitachi High-Tech Corporation Dispositif et procédé de fabrication d'une structure tridimensionnelle à partir de cellules
EP3819374A4 (fr) * 2018-07-04 2022-03-30 Yokogawa Electric Corporation Procédé de production de structure cellulaire, support, et procédé de production de support
WO2022094255A2 (fr) 2020-10-29 2022-05-05 Regenxbio Inc. Anticorps de facteur xii vectorisés et leur administration

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WO2005010139A2 (fr) * 2003-07-23 2005-02-03 University Of South Florida Microtransporteurs ferromagnetiques de culture cellulaire et tissulaire

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US5026650A (en) * 1988-06-30 1991-06-25 The United States Of Amercia As Represented By The Administrator Of The National Aeronautics And Space Administration Horizontally rotated cell culture system with a coaxial tubular oxygenator
US6054319A (en) * 1998-02-03 2000-04-25 Board Of Trustees Operating Michigan State University Method and apparatus for growing cells using gas or liquid aphrons
WO2002051985A2 (fr) * 2000-12-22 2002-07-04 Keele University Culture de tissus au moyen de contraintes mecaniques generees de maniere magnetique
WO2005010139A2 (fr) * 2003-07-23 2005-02-03 University Of South Florida Microtransporteurs ferromagnetiques de culture cellulaire et tissulaire

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GEIM A: "Everyone's magnetism" PHYSICS TODAY, September 1998 (1998-09), pages 36-39, XP008048406 ISSN: 0031-9228 *
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9752139B2 (en) 2003-06-30 2017-09-05 University Of South Florida Magnetic three-dimensional cell culture apparatus and method
US9476025B2 (en) 2003-07-23 2016-10-25 University Of South Florida Ferromagnetic cell and tissue culture microcarriers
US8815231B2 (en) * 2008-09-25 2014-08-26 William Marsh Rice University Systems and methods for magnetic guidance and patterning of materials
US20110286975A1 (en) * 2008-09-25 2011-11-24 Souza Glauco R Systems and methods for magnetic guidance and patterning of materials
WO2010036957A1 (fr) * 2008-09-25 2010-04-01 William Marsh Rice University Systèmes et procédés de guidage et de modelage magnétique de cellules et de matériaux
US9909116B2 (en) 2008-09-25 2018-03-06 William Marsh Rice University Systems and methods for magnetic guidance and patterning of materials
US20120020885A1 (en) * 2010-07-26 2012-01-26 Searete Llc, A Limited Liability Corporation Of The State Of Delaware MHC-Less cells
US10407660B2 (en) 2010-08-10 2019-09-10 Greiner Bio-One North America, Inc. Hardware for magnetic 3D culture
US10288603B2 (en) 2011-02-01 2019-05-14 Greiner Bio-One North America, Inc. 3D cell viability assay
EP2665807A1 (fr) * 2011-03-29 2013-11-27 Zhang, Yongxin Système de bioréacteur multifonctionnel et procédés pour le triage et la culture cellulaires
EP2665807A4 (fr) * 2011-03-29 2015-04-15 Zhang Yongxin Système de bioréacteur multifonctionnel et procédés pour le triage et la culture cellulaires
EP2909303A4 (fr) * 2012-10-18 2017-01-18 Yongxin Zhang Système de bioréacteur et procédés de culture cellulaire alternant entre un état statique et un état dynamique
EP3467093A4 (fr) * 2016-05-27 2020-08-05 Hitachi High-Tech Corporation Dispositif et procédé de fabrication d'une structure tridimensionnelle à partir de cellules
EP3819374A4 (fr) * 2018-07-04 2022-03-30 Yokogawa Electric Corporation Procédé de production de structure cellulaire, support, et procédé de production de support
US12037571B2 (en) 2018-07-04 2024-07-16 Yokogawa Electric Corporation Method of producing cell structure, carrier, and method of producing carrier
WO2020150556A1 (fr) 2019-01-18 2020-07-23 Voyager Therapeutics, Inc. Procédés et systèmes de fabrication de particules aav
WO2022094255A2 (fr) 2020-10-29 2022-05-05 Regenxbio Inc. Anticorps de facteur xii vectorisés et leur administration

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