EP3359638A1 - Bioréacteur à stress mécanique pour valvules cardiaques - Google Patents

Bioréacteur à stress mécanique pour valvules cardiaques

Info

Publication number
EP3359638A1
EP3359638A1 EP16777936.2A EP16777936A EP3359638A1 EP 3359638 A1 EP3359638 A1 EP 3359638A1 EP 16777936 A EP16777936 A EP 16777936A EP 3359638 A1 EP3359638 A1 EP 3359638A1
Authority
EP
European Patent Office
Prior art keywords
construct
chamber
reactor chamber
media
ventricular
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.)
Withdrawn
Application number
EP16777936.2A
Other languages
German (de)
English (en)
Inventor
Jan Saam
Hendrik Erfurth
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.)
Ospin GmbH
Original Assignee
Ospin GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ospin GmbH filed Critical Ospin GmbH
Publication of EP3359638A1 publication Critical patent/EP3359638A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
    • A61F2/2415—Manufacturing methods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • 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
    • 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
    • C12M29/12—Pulsatile flow

Definitions

  • the technical problem underlying the present invention was to provide a bioreactor system for the improved control or adjustability of a desired modeled physiological condition for the conditioning of an in vitro heart valve construct with simultaneously low media requirements and in particular easy sterilization or interchangeability of the parts.
  • the bioreactor system should allow for flexible universal pulsatile perfusion of the in vitro construct with a dynamically adjustable or adjustable pressure curve across the heart valve over a wide range.
  • the invention solves the aforementioned technical problems and satisfies the requirements for an efficient automatic production of biogenic heart valve preparations by a novel integral bioreactor system for colonization, cultivation and, in particular, directed, pressure-controlled perfusion of an in vitro heart valve construct.
  • this contains at least the components listed and characterized below or, in a preferred embodiment, consists exclusively of:
  • the individual temporal pressure profiles in both pumping arrangements work together to simulate the desired physiological pressure course for conditioning and maturation of the construct.
  • a third function of both pumping arrangements according to the invention arises in interaction with the adjacent reactor chamber and will be described in more detail below.
  • the membrane is preferably a flat disc made of elastomeric material, which is stretched in the housing of the pump assembly, especially clamped between housing halves, wherein the elastomeric membrane can then additionally serve as a seal between the housing elements.
  • Preferred membrane material is a particularly easily sterilizable biocompatible elastomer or surface-functionalized elastomer, preferably selected from: silicone rubber, especially RTV silicone, PU, LDPE and latex.
  • material composites or bellows constructions can alternatively be used as movable membranes.
  • these three components are joined together to form an integral housing block, preferably the housings of the components are fixed to one another or they are formed together in a one-piece (one-part or multi-part) fluid block.
  • the block of the bioreactor system preferably consists exclusively of these three components.
  • the luminal compartment of the construct for the duration of this pressurization can be completed and specifically separated in each case from the residual volume of the two media chambers of the pumping arrangements and the rest of the perfusion system.
  • the movable membrane is preferably provided, at least on the side facing the media ports of the reactor chamber, with an elastically sealing and / or hydrophobic stratification or consists of such a material.
  • the in vitro heart valve construct can advantageously be colonized with cells introduced there in the form of a cell suspension and then switched seamlessly into the (pulsatile) perfusion mode. Complicated handling and opening of the reactor cycle is not required, which simplifies and automates operations while avoiding contamination.
  • bioreactor system In the context of the invention, however, an integral embodiment of the bioreactor system is preferred, wherein the pulsatile pressure-controlled perfusion takes place exclusively by the two pumping arrangements in conjunction with the return channel with check valve and throttle valve described herein and the colonization operation by interaction of the same two pumping arrangements in conjunction with the immediate interposed reactor chamber takes place.
  • the bioreactor according to the invention contains a holding device (flap holder) which is particularly suitable for colonization as well as for perfusion of the in vitro heart valve construct.
  • the holding device is advantageously physically separated from the reactor chamber and in particular for the purpose of clamping the scaffold at the beginning of production as well as the recovery of the mature heart valve from the reactor chamber removed.
  • the holding device is designed and dimensioned such that in the functional state of the reactor it sealingly engages the interior of the reactor chamber so that a luminal compartment and an extraluminal compartment are formed in the reactor chamber in connection with the fixed construct. These are preferably accessible from the outside by suitable entrances (ports) which are formed on the reactor chamber, preferably separately from one another.
  • entrances ports
  • cell suspensions can be separated from the luminal side or the extraluminal ones by these accesses Side of the construct to be colonized separately with cells.
  • a specific variant of the holding device contains on both sides of circular frame parts which are spaced apart by individual longitudinal struts.
  • the individual longitudinal struts do not form a continuous cylinder wall. This advantageously allows the cells which have fallen onto the reactor chamber wall to be resuspended by turbulence on the longitudinal struts during rotation and preferably additionally guided specifically to the outer surface of the populated construct, like a paddle wheel or a washing drum.
  • the external drive unit is a particularly static electromagnet or coil arrangement (stator), which forms a brushless internal rotor or a stepping motor with discreetly controllable angular positions together with the holding device as a permanent magnetic armature (rotor).
  • magnetic flux-conducting soft iron segments are provided in the holding device instead of the permanent magnets, which in electromagnetic interaction with correspondingly segmented stator windings in the external drive unit allow a preferably stepwise rotation with discretely controllable angular positions.
  • an annular disc is provided in the holding device in place of the permanent magnets, which allow in electromagnetic interaction with corresponding field coils in the external drive unit, a continuous rotation by eddy current effects in the annular disc.
  • drive unit and their electrical control conceivable, which can be used on known basic principles such as synchronous drive, asynchronous, reluctance and similar in conjunction with appropriately clocked power supply including variable frequency or electronic commutation.
  • step d) the active pressurization of the working chamber of the ventricle-side pumping arrangement over time follows a predetermined in vivo ventricular pressure curve and the active pressurization of the working chamber of the aortic pumping device follows a predetermined in vivo aortic pressure profile over time.
  • sealing means (47) are provided on the frame parts (44) for sealing the media ports (21, 22).
  • magnetic coupling means (49) in the frame part (44) are present, which allow a torque from the external drive unit (70) with corresponding magnetic coupling means (71).
  • a (schematically illustrated) check valve (61) and a (schematically illustrated) adjustable throttle valve (64) are integrated.
  • the main part of the reactor is a tubular, horizontally arranged and filled with culture medium vessel in the middle of which is located in a holder, the heart valve.
  • At each end of the tube there is an air chamber which is separated from the liquid phase by a flexible membrane.
  • the distal ends of the air chambers as well as the membranes are made of transparent material to allow visual observation of the function of the tissue.
  • the displaced during filling of the bioreactor air can escape as well as forming during operation gas bubbles. This is done via special ports in the pumping chambers, which have a lid with a hydrophobic sterile filter membrane (as used, for example, in cell culture bottles).
  • the diameter of the ports is at least so large that water in them can flow down by gravity alone. If the diameter is too small - as in the case of Luer Lock-based syringe filters - water once held in is held in the access by the surface tension and thus blocks the gas permeability of the membrane.
  • the device is such that a heart valve model can be sewn on, adhered or clamped.
  • the valve model is tubular, while the valve pockets / sails are approximately located centrally inside the tube.
  • the flap holder contains two connectors (connector) to which the heart valve can optionally be attached and clamped, sewn, glued, etc. can be. Spacers between the two connectors span the flap between the connectors.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Sustainable Development (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Veterinary Medicine (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Cell Biology (AREA)
  • Mechanical Engineering (AREA)
  • Dermatology (AREA)
  • Manufacturing & Machinery (AREA)
  • Molecular Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Prostheses (AREA)

Abstract

La présente invention concerne un nouveau système de bioréacteur pour la production de tissus par génie génétique, spécialement conçu pour la formation in vitro d'une valvule cardiaque en vue d'obtenir une prothèse de valvule cardiaque biogène, ainsi que des procédés et des applications dudit système de bioréacteur.
EP16777936.2A 2015-10-06 2016-09-21 Bioréacteur à stress mécanique pour valvules cardiaques Withdrawn EP3359638A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102015219313.6A DE102015219313B3 (de) 2015-10-06 2015-10-06 Herzklappenmechanobioreaktor
PCT/EP2016/072368 WO2017060081A1 (fr) 2015-10-06 2016-09-21 Bioréacteur à stress mécanique pour valvules cardiaques

Publications (1)

Publication Number Publication Date
EP3359638A1 true EP3359638A1 (fr) 2018-08-15

Family

ID=56889898

Family Applications (1)

Application Number Title Priority Date Filing Date
EP16777936.2A Withdrawn EP3359638A1 (fr) 2015-10-06 2016-09-21 Bioréacteur à stress mécanique pour valvules cardiaques

Country Status (3)

Country Link
EP (1) EP3359638A1 (fr)
DE (1) DE102015219313B3 (fr)
WO (1) WO2017060081A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110037831B (zh) * 2019-05-02 2020-10-09 武汉唯柯医疗科技有限公司 一种猪心包瓣叶处理装置
CN111925939B (zh) * 2020-09-08 2023-07-04 华中科技大学同济医学院附属协和医院 一种动态加压组织工程瓣膜细胞接种器的使用方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7348175B2 (en) * 2002-03-15 2008-03-25 St3 Development Corporation Bioreactor with plurality of chambers for conditioning intravascular tissue engineered medical products
DE10322024A1 (de) * 2003-05-16 2004-12-02 Symetis Ag Bioreaktor zum Herstellen einer Gewebeprothese, insbesondere Herzklappe
EP1693025A1 (fr) * 2005-02-17 2006-08-23 Universität Zürich Procédé pour la production d'une prothèse par génie tissulaire
EP2085054A1 (fr) * 2008-02-01 2009-08-05 Technische Universiteit Eindhoven Procédé de fabrication de construction créée par tissu
EP2399986A1 (fr) * 2010-06-22 2011-12-28 Ludwig-Maximilians-Universität München Bioréacteur et procédé de création et/ou de conditionnement de tissus biologiques

Also Published As

Publication number Publication date
DE102015219313B3 (de) 2016-09-29
WO2017060081A1 (fr) 2017-04-13

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