WO2002040076A1 - Procede et dispositif pour produire des protheses biologiques - Google Patents

Procede et dispositif pour produire des protheses biologiques Download PDF

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Publication number
WO2002040076A1
WO2002040076A1 PCT/DE2001/003632 DE0103632W WO0240076A1 WO 2002040076 A1 WO2002040076 A1 WO 2002040076A1 DE 0103632 W DE0103632 W DE 0103632W WO 0240076 A1 WO0240076 A1 WO 0240076A1
Authority
WO
WIPO (PCT)
Prior art keywords
cell
cells
flow
bioreactor
ring line
Prior art date
Application number
PCT/DE2001/003632
Other languages
German (de)
English (en)
Inventor
Wolfgang Konertz
Pascal Dochmen
Original Assignee
Autotissue 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 Autotissue Gmbh filed Critical Autotissue Gmbh
Priority to AU2002210367A priority Critical patent/AU2002210367A1/en
Priority to DE10194891T priority patent/DE10194891D2/de
Publication of WO2002040076A1 publication Critical patent/WO2002040076A1/fr

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Classifications

    • 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
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
    • A61L27/3843—Connective tissue
    • 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
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2/062—Apparatus for the production of blood vessels made from natural tissue or with layers of living cells
    • 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

Definitions

  • Rinderperi ardi m manufactured prostheses that have a similarly favorable hemodynamics as the homografts and are also available in any size and number.
  • these bioprostheses do not contain living tissue and cell growth is practically impossible. Such heart valves are therefore not capable of regeneration, not capable of growth and, moreover, are subject to gradual wear. In addition, these prostheses are classified as "foreign" by the immune system of the recipient organism and are combated by immune-competent cells.
  • DE 198 28 276 already describes a process for the production of bioartificial grafts, in which a cell-free, loosened collagen matrix has been populated with autologous cells of the transplant recipient or genetically modified cells which are compatible with the recipient ,
  • this method it is difficult to coat the collagen matrix with the body's own cells of the recipient, which is as smooth as possible, and is necessary for a trouble-free blood flow through the heart valves and in the blood vessels or bypass vessels. Trouble-free function and a long lifespan of the implant are therefore not guaranteed.
  • an acellularized bioprosthesis is located in a container which can be rotated about its longitudinal axis and / or its transverse axis and which is filled with a nutrient solution which contains the body's own or genetically identical cells of the recipient is.
  • a nutrient solution which contains the body's own or genetically identical cells of the recipient is.
  • the invention is therefore based on the object of specifying a method of the type mentioned at the outset for producing biological prostheses which approximate the natural conditions with regard to cell coating, in particular heart valves and blood vessels, which improves the durability and functionality of the implant in question and the quality of life of the implant Receiver increased, as well as to develop a device for performing the method.
  • the object is achieved with a method according to the features of patent claim 1 and a device for carrying out the method characterized by the features of patent claim 8.
  • an acellularized allogeneic or xenogeneic starting product for example the collagen / elastin matrix of an aortic valve from
  • Pig by rotating in a cell suspension formed from cells of the recipient of the prosthesis, is colonized with the body's own cells
  • the basic idea of the invention is that the coating of the matrix in a cell line approximating the natural flow conditions in the organs, organ parts or vessels concerned suspension current takes place.
  • the cells to be applied already learn in the coating and first growth phase to adapt to the natural conditions during the later function of the organ (in part), such as flow conditions and wall movements or strains, with regard to their arrangement, shape and adhesion, so that a complete, all-round and fast and safely growing colonization can be achieved and the new body's own cell layer creates resistance and low-friction flow conditions in the later blood-flowed areas.
  • the process is actually characterized by three settlement steps:
  • the conditioning and resting phase can be carried out in two or more substeps, each with an increased flow rate compared to the previous phase.
  • the device according to the invention for carrying out the method comprises a bioreactor that can be handled separately, rotatable in the longitudinal and transverse directions by hand or by motor, which is filled with the cell suspension and in which the implant to be coated is fixed tightly axially to the flow direction.
  • the bioreactor is integrated in a ring line which is connected to a diaphragm pump in order to generate a pulsating, variable-speed liquid flow.
  • Fig. 1 is a schematic view of a device according to the invention for coating an acellularized porcine aortic valve in a flow circuit from a body with endothelial cells of the intended recipient
  • tr rt d ⁇ ⁇ 0 tr 3 LQ rt tr ⁇ CQ Cb tr ⁇ ⁇ dt 0 et 3 ⁇ tr ⁇ ⁇ 3 d ⁇ tr ⁇ . ⁇ • ⁇ tr o rt ⁇ ⁇ Cb ⁇ 3 H o ⁇ ⁇ - ⁇ tr & tr d ⁇ - ⁇ ⁇ 3 ⁇ tö ⁇ TJ ⁇ - P ⁇ - tr CQ N ⁇ - ⁇ 3 ⁇ ⁇ - Hi ⁇ - 3 H ⁇ ) ti rt 3 3 3
  • a second seal 19 is provided for liquid-tight fastening.
  • the aortic valve 8 is introduced into the hollow cylinder 9 in such a way that the direction of flow in the device corresponds to the natural direction of flow through the implant in the human body. Due to the fact that two quasi-identical valves are connected in series with the outlet valve 6 and the aortic valve 8, the outlet valve 6 of the diaphragm pump 3 could be dispensed with in this case. However, if blood vessels are coated with body cells in the same way, the outlet valve 6 in the diaphragm pump 3 is still required.
  • the endothelial cells proven to be viable are available from the cell cultivation described above in a number of at least 8 million in the medium also used in cell cultivation, which is 20% from the serum of the recipient commercially available cell growth agents DMEM and bFGF as well as antibiotics, L-glutamine and possibly a HEPES buffer.
  • This cell suspension is filled into the bioreactor 2 via one of the connecting pieces 12, 13 detached from the ring line 1 or a fill and drain valve 24, 25.
  • the bioreactor 2 held in a rotating device is rotated both around its longitudinal axis and around as a first step of the settlement its transverse axis and intermediate settling phases distribute the endothelial cells on the surfaces of the aortic valve 8, both under the effect of gravity and centrifugal forces.
  • the turning can preferably also be carried out manually with simultaneous visual observation.
  • a first cell conditioning step then takes place in that a pulsating cell suspension flow is generated via the membrane pump 3 at a flow rate of 11 / min in the direction of the arrow.
  • the direction of flow of the cell suspension corresponds to the direction of flow of the blood in the implanted state of the bioprosthesis.
  • Inner surfaces (flow surfaces) of the aortic valve 8 are gradually adapted in shape and orientation of the endothelial cells in shape and orientation to the flow direction and forces as well as the movements of the implant walls, ie the cells are conditioned and learn, at initially low flow velocity to be designed and arranged in such a way that in the growth phase a smooth, single-layer endothelial cell surface which opposes the flow as little as possible arises. That is, in the resting phase following the first cell conditioning step phase, which can be connected with a discontinuous rotation of the bioreactor 2, the endothelial cells have the opportunity to grow on the collagen matrix in the shape and direction learned by the previously entered flow stimuli. Cells that may have been detached when flowing through are resettled in this phase.
  • Information stimuli are provided to develop and grow in accordance with these changing flow conditions.
  • the entire previously described process of cell coating in the bioreactor 2 takes place in an incubator (not shown) in which the temperature is constantly 37 ° C. and an air humidity of 98% and a CO 2 content of 5% are maintained ,
  • the access of this atmosphere or the corresponding media to the bioreactor 2 is realized via at least one semi-permeable membrane valve 26 which is gas-permeable from the outside, but is not liquid-permeable in the opposite direction.
  • the membrane valves 26 can be arranged at a suitable point on the bioreactor 2, for example in the inserts 10, 11 or also in the ring line 1.
  • Growth phases are created under physiological flow conditions corresponding to the functions of the human heart on the collagen matrix of the bioprosthesis (aortic valve 8) provided with a submatrix of fibronectin -Recipient largely corresponds to the shape, size and location of the cells and the strength and flatness of the cell layer.
  • Implants for cardiac and vascular surgery are thus provided, the use of which is not associated with the risk of immune reactions and viral infections.
  • the cell layer applied to the implant is largely designed to approximate the physiological processes in the human organism, here the specific dynamics in the area of the heart and vessels.
  • the formation of the endothelial cell layer achieved with the method according to the invention and the corresponding device ensures, in the implanted state of the bioprosthesis, flow conditions which correspond to the natural conditions, so that the signs of wear are significantly minimized and the life of the implant can thus be increased.
  • porcine aortic valve treated as an example pulmonary or mitral valves or vessels, generally from allogeneic, xenogeneic or artificial starting material, can also be produced in the manner described.
  • Aortic valve (bioprosthesis)

Abstract

Selon un procédé pour recouvrir des implants biologiques avec des cellules autologues du receveur, la colonisation de la matière étrangère allogène ou xénogène, dépourvue de cellule, s'effectue dans un flux de suspension de cellules pulsé, à débit variable, proche des conditions naturelles dans l'organe ou la partie d'organe concerné(e). Le conditionnement des cellules ainsi provoqué permet d'obtenir de manière rapide et sûre un revêtement cellulaire complet, dont la formation s'effectue dans des conditions proches des conditions naturelles et qui confère à l'implant une fonction sans faille ainsi qu'une longue durée de vie. Le dispositif pour mettre en oeuvre ledit procédé comprend un bioréacteur (2) qui est inséré dans une conduite annulaire (1) et rempli de suspension cellulaire, et dans lequel l'implant (8) est fixé de manière centrée et axialement dans le sens d'écoulement. Cette conduite annulaire (1) est raccordée à une pompe (3) servant à produire un flux de substance pulsé, traversant l'implant (8). Ce revêtement constitué de cellules autologues peut également être appliqué à des prothèses artificielles.
PCT/DE2001/003632 2000-11-17 2001-09-19 Procede et dispositif pour produire des protheses biologiques WO2002040076A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002210367A AU2002210367A1 (en) 2000-11-17 2001-09-19 Method and device for producing biological prostheses
DE10194891T DE10194891D2 (de) 2000-11-17 2001-09-19 Verfahren und Vorrichtung zur Herstellung biologischer Prothesen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10058240A DE10058240A1 (de) 2000-11-17 2000-11-17 Verfahren und Vorrichtung zur Herstellung biologischer Prothesen
DE10058240.0 2000-11-17

Publications (1)

Publication Number Publication Date
WO2002040076A1 true WO2002040076A1 (fr) 2002-05-23

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Family Applications (1)

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PCT/DE2001/003632 WO2002040076A1 (fr) 2000-11-17 2001-09-19 Procede et dispositif pour produire des protheses biologiques

Country Status (3)

Country Link
AU (1) AU2002210367A1 (fr)
DE (2) DE10058240A1 (fr)
WO (1) WO2002040076A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052417A1 (fr) * 2002-12-06 2004-06-24 Auto Tissue Gmbh Procede de realisation de protheses biologiques
US8399243B2 (en) 2005-02-17 2013-03-19 Universitaet Zuerich Method of manufacturing a tissue-engineered prosthesis

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10130512B4 (de) * 2001-06-25 2007-08-16 Bionethos Holding Gmbh Vorrichtung zur Druckperfusion für das Züchten und/oder für das Behandeln von Zellen
DE10211106B4 (de) * 2002-03-12 2004-12-09 Bio-Energie-Consult Innovations- Und Technologie Gmbh Verfahren zur Verbesserung der Sauerstoffzufuhr für Zellkulturen in Bioreaktoren
GB0410177D0 (en) * 2004-05-07 2004-06-09 Univ Wales Medicine Engineered tubular tissue structures
DE102009008923B4 (de) * 2009-02-13 2011-05-05 Hennig, Jörn, Dipl.-Ing. Zellbesiedelungskammer

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0320441A1 (fr) * 1987-12-07 1989-06-14 GebràœDer Sulzer Aktiengesellschaft Appareil et procédé de conditionnement d'un support en plastique recouvert de cellules vivantes
WO1996008213A1 (fr) * 1994-09-12 1996-03-21 Advanced Tissue Sciences, Inc. Cultures tridimensionnelles de cellules humaines sur des structures de valvules cardiaques, et leurs utilisations
US5846828A (en) * 1995-06-07 1998-12-08 Advanced Tissue Sciences Apparatus and method for sterilizing, seeding, culturing, storing, shipping, and testing tissue, synthetic, or mechanical heart valves orvalve segments
DE19828726A1 (de) * 1997-06-27 1999-01-07 Augustinus Dr Bader Bioartifizielles Transplantat und Verfahren zu seiner Herstellung
WO2000037123A1 (fr) * 1998-12-21 2000-06-29 Cell-Lining Gesellschaft Für Zellkultivierung Mbh Protheses cardiovasculaires a surface revetue d'une couche stable de cellules endotheliales
DE19915610A1 (de) * 1999-04-07 2000-10-19 Augustinus Bader Verfahren zur Besiedlung von Substraten mit biologischen Zellen und dafür verwendbare Besiedlungsvorrichtungen
DE19938518A1 (de) * 1999-04-23 2000-10-26 Vascular Biotech Gmbh Gewebekultursystem zur Epithelialisierung bzw. Endothelialisierung und zur funktionellen Untersuchung und Anlieferung natürlichen oder künstlicher Hohlorgane bzw. Gefäße unter kontrollierbaren Sterilbedingungen für chirurgische Implantationszwecke

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Publication number Priority date Publication date Assignee Title
JPH09510108A (ja) * 1994-03-14 1997-10-14 クリオライフ，インコーポレイティド 移植用処理組織及び調製方法
DE19919625C2 (de) * 1999-04-29 2002-10-31 Symetis Ag Zuerich In-vitro-Verfahren zum Herstellen einer homologen Herzklappe und durch dieses Verfahren herstellbare Klappe

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0320441A1 (fr) * 1987-12-07 1989-06-14 GebràœDer Sulzer Aktiengesellschaft Appareil et procédé de conditionnement d'un support en plastique recouvert de cellules vivantes
WO1996008213A1 (fr) * 1994-09-12 1996-03-21 Advanced Tissue Sciences, Inc. Cultures tridimensionnelles de cellules humaines sur des structures de valvules cardiaques, et leurs utilisations
US5846828A (en) * 1995-06-07 1998-12-08 Advanced Tissue Sciences Apparatus and method for sterilizing, seeding, culturing, storing, shipping, and testing tissue, synthetic, or mechanical heart valves orvalve segments
DE19828726A1 (de) * 1997-06-27 1999-01-07 Augustinus Dr Bader Bioartifizielles Transplantat und Verfahren zu seiner Herstellung
WO2000037123A1 (fr) * 1998-12-21 2000-06-29 Cell-Lining Gesellschaft Für Zellkultivierung Mbh Protheses cardiovasculaires a surface revetue d'une couche stable de cellules endotheliales
DE19915610A1 (de) * 1999-04-07 2000-10-19 Augustinus Bader Verfahren zur Besiedlung von Substraten mit biologischen Zellen und dafür verwendbare Besiedlungsvorrichtungen
DE19938518A1 (de) * 1999-04-23 2000-10-26 Vascular Biotech Gmbh Gewebekultursystem zur Epithelialisierung bzw. Endothelialisierung und zur funktionellen Untersuchung und Anlieferung natürlichen oder künstlicher Hohlorgane bzw. Gefäße unter kontrollierbaren Sterilbedingungen für chirurgische Implantationszwecke

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004052417A1 (fr) * 2002-12-06 2004-06-24 Auto Tissue Gmbh Procede de realisation de protheses biologiques
US8399243B2 (en) 2005-02-17 2013-03-19 Universitaet Zuerich Method of manufacturing a tissue-engineered prosthesis

Also Published As

Publication number Publication date
DE10194891D2 (de) 2004-01-15
DE10058240A1 (de) 2002-05-29
AU2002210367A1 (en) 2002-05-27

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