WO2003080141A1 - Biomatrice et procede de production de cette biomatrice - Google Patents

Biomatrice et procede de production de cette biomatrice Download PDF

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Publication number
WO2003080141A1
WO2003080141A1 PCT/DE2003/000904 DE0300904W WO03080141A1 WO 2003080141 A1 WO2003080141 A1 WO 2003080141A1 DE 0300904 W DE0300904 W DE 0300904W WO 03080141 A1 WO03080141 A1 WO 03080141A1
Authority
WO
WIPO (PCT)
Prior art keywords
biomatrix
collagen
matrix
solution
cells
Prior art date
Application number
PCT/DE2003/000904
Other languages
German (de)
English (en)
Inventor
Thomas Graeve
Original Assignee
Ars Arthro Ag
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
Priority claimed from DE10241817A external-priority patent/DE10241817A1/de
Application filed by Ars Arthro Ag filed Critical Ars Arthro Ag
Priority to JP2003577965A priority Critical patent/JP2005520638A/ja
Priority to US10/508,224 priority patent/US20060014284A1/en
Priority to DE10391674T priority patent/DE10391674D2/de
Priority to EP03720209A priority patent/EP1485139A1/fr
Priority to AU2003223880A priority patent/AU2003223880A1/en
Publication of WO2003080141A1 publication Critical patent/WO2003080141A1/fr

Links

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
    • A61L27/3804—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 specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3817—Cartilage-forming cells, e.g. pre-chondrocytes
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • 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
    • A61L27/3852—Cartilage, e.g. meniscus
    • 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

Definitions

  • the invention relates to a biomatrix and a method for its production.
  • DE 100 26 789 AI describes a cartilage replacement that allows good regeneration of a treated cartilage defect.
  • the application mentioned makes use of a 3D biomatrix that can be adapted in shape and size to the defect to be replaced ,
  • the state of the art also includes many other suggestions for implants in the area described.
  • the materials used here are either three-dimensional, but porous, for example in the case of a configuration as a sponge or fleece; or they are solid, but have no three-dimensional structure, for example in the case of an embodiment as a film.
  • special requirements must be placed on implants that are to replace parts of the mechanical body structure.
  • a defect to be repaired generally has at least a certain three-dimensionality, so that the implant should also be three-dimensional.
  • the implant due to its density or, in particular, its pressure stability, the implant must be able to take into account the mechanical loads when used in the body structure. In particular, the pressure stability of the previously known materials is not sufficient for use, for example, in the cartilage area.
  • the inventor has also set himself the task of developing a Biomatrix so that the Biomatrix as an implant can also cope with the high loads that occur in mechanical matters.
  • the inventor has set himself the task of developing a method with which such a biomatrix can be produced.
  • the task is solved to a surprisingly good degree by a biomatrix in which the matrix is compressed or solidified.
  • a collagen biomatrix as described in DE 100 26 789 AI can be three-dimensional per se.
  • the biological material becomes so strong that the dynamometric requirements in the mechanical body structure can be met.
  • the compressive strength of the compressed or solidified material in particular can meet very high demands. But tensile strength also increases compared to known biomatrices. ge with an increasing resistance to transverse contraction associated with the higher compressive strength.
  • the invention thus opens up far-reaching uses for implants, for example as cartilage replacement with high compressive strength, ligament replacement, selmen replacement, meniscus replacement, ligament disc replacement, nucleus replacement and / or annulus replacement.
  • implants for example as cartilage replacement with high compressive strength, ligament replacement, selmen replacement, meniscus replacement, ligament disc replacement, nucleus replacement and / or annulus replacement.
  • Such an implant can even be used as a bone replacement or as a replacement for bone-cartilage constructs.
  • the biomatrix compressed or solidified according to the invention can advantageously be characterized in that it has a density gradient.
  • the biomatrix can be homogeneously compressed, but the collagen structure can also be produced in gradient form.
  • the resulting implant can be adapted in a special way to the defect on the body trunk in accordance with the dynamometric requirements. It is also possible to economically manufacture implants with reinforced areas for special requirements.
  • the density gradient is stepped.
  • a biomatrix according to the invention is generally relatively easy to produce with a step-shaped density gradient.
  • the density gradient can also have a continuous transition.
  • a biomatrix designed in this way is relatively complex to manufacture, but can be adapted to the mechanical requirements at a defective location to an outstanding degree.
  • the biomatrix according to the invention can particularly preferably be distinguished in that the density gradient forms a body with a firmer outer shell and a softer core.
  • a softer core is also understood to mean a much softer core, including a core without its own hardness.
  • the core can be filled with a fluid or in particular a gas, so that a mechanical effect similar to that of an air cushion is achieved.
  • the properties of the implant are particularly well matched to the neighboring structures.
  • the soft core ensures sufficient flexibility of the Biomatrix when it is in use, while the solid outer shell protects particularly well against mechanical damage to the Biomatrix. In this way, the Biomatrix can still be sufficiently elastic with a long service life and great robustness.
  • biomatrix with a density gradient is also advantageous and inventive, regardless of an explicit compression or consolidation of the biomatrix.
  • the matrix according to the invention is combined with inert materials.
  • the inert materials can be of both biological and non-biological origin. Collagen fleeces are mentioned here as examples.
  • the biomatrix according to the invention has aligned fibers, in particular collagen fibers.
  • aligned fibers in particular collagen fibers.
  • the combination of compression and simultaneous application of changing pressure and tensile loads enables the collagen fibers to be aligned in the matrix.
  • this is also possible by applying physical AC voltages or by other physical methods.
  • Aligned fibers have a particularly advantageous effect on the physical properties of the biomatrix. If collagen fibers are used for this, both the physical and the biochemical properties experience a significant improvement.
  • an embodiment variant of the biomatrix according to the invention is particularly preferred in which the starting solution has 1 to 10 mg protein per ml gel solution and this starting solution is compressed to more than 50 times the original protein content, preferably more than 50 times.
  • the protein content can even up to Hundred times the original protein content. This creates a very pressure-stable matrix with high strength.
  • the task also solves a method for producing a biomatrix, in which the matrix is compressed or solidified.
  • the method according to the invention is preferably characterized in that the matrix is produced using a method for redifferentiating and / or multiplying dedifferentiated cartilage cells, in which undifferentiated cartilage cells are embedded in a three-dimensional, gel-like biomatrix containing at least 1.5 mg / l collagen in buffered serum-containing cell culture medium, to be cultured.
  • the main problem of degenerative or traumatic joint diseases is that the damaged articular cartilage shows only a slight ability to regenerate. A major task therefore consists in permanently inserting cartilage cells with the implant at the site of the defect enable the cartilage to regenerate. If the matrix is produced using the described method, the dedifferentiated cartilage cells in the biomatrix can redifferentiate and resume their cell-typical metabolic performance.
  • the biomatrix should contain a collagen structure newly composed of a preferably fresh collagen solution with a concentration of at least 1.5 mg collagen per ml biomatrix.
  • the term “culturing cells” is understood to mean maintaining the vital functions of cells in a suitable environment, preferably taking place in vitro, for example by supplying and removing metabolic educts and products, in particular also an increase of cells, Cartilage cells are understood to mean naturally occurring or genetically modified cartilage cells or their precursors, which can be of animal or human origin.
  • the process according to the invention is characterized in that the matrix is produced by a process comprising the isolation of collagen-containing tissue
  • the matrix according to the invention is produced without cells. This is particularly useful when there are no suitable cells available to produce the matrix.
  • the resulting implant is simpler and cheaper to manufacture, but also meets the requirements for mechanical strength.
  • the compression is effected by withdrawing liquid. If the matrix is one
  • the matrix can be pressurized physically, for example, or a negative pressure can be applied. Liquid can also be reliably extracted from the matrix using capillary forces or a combination of the described possibilities. In most cases, the easiest way to do this is to remove water. Such liquid withdrawal can be achieved particularly effectively by pressurizing or applying a negative pressure. Alternatively and cumulatively, it is advantageous if the compaction is brought about by chemical bonding. Chemical bonding represents a further possibility of removing water and / or other liquid from the biomatrix and thereby compressing or solidifying the biomatrix in order to achieve the desired properties.
  • the method according to the invention can also be used to produce a collagen thread with a diameter between 0.005 and 4 mm, preferably between 0.01 and 2 mm.
  • a collagen thread opens up many new possibilities for insertion into the human or animal body. In particular, it can even have a connection functionality.
  • the collagen solution pass through a nozzle.
  • the biomatrix is also compulsorily compressed.
  • the liquid collagen can be pressed through the nozzle with or without a buffer solution, which withdraws liquid from the collagen. This can be done by applying positive or negative pressure. After compaction, the collagen thread can be dried, whereby a proportion of approx. 10% residual moisture is readily permitted.
  • a collagen solution as described in DE 100 26 789 AI, with a protein concentration of 6 mg / ml gel solution serves as the starting material.
  • a buffer solution is used to buffer the acidic collagen solution,
  • the two liquids are combined in equal parts at 4 ° C and mixed together.
  • the mixed solution therefore has a collagen concentration of approximately 3 mg / ml.
  • This solution is now filled into a glass cylinder with a diameter of approx. 2 cm.
  • approx. 35 ml of collagen buffer solution mixture are filled into the cylinder, resulting in a filling height of approx. 10 cm.
  • the lower part of the glass cylinder is in a glass cover, which ensures a reliable seal.
  • the lower end of the glass cylinder is closed with a porous, liquid-permeable membrane.
  • the collagen buffer solution mixture is incubated in the cylinder for 20 minutes at 37 ° C., during which it gels completely.
  • a pressure stamp is then applied to the gelled matrix, which is inserted through the upper, open end of the glass cylinder and the matrix pressurized along the cylinder axis.
  • the pressure here is approximately 0.2 Pa and is maintained for 20 minutes.
  • the pressure compresses the matrix and squeezes liquid out of it. This happens first at the upper end of the matrix, to which the Daick is originally applied; a short time later there is also a liquid outlet at the lower opening which is closed by the liquid-permeable membrane.
  • the pressure stamp is carried along with the compressed matrix in order to maintain the applied pressure as unchanged as possible,
  • the protein content of collagen increases and the biomatrix solidifies according to the invention.
  • the pressure stamp is removed and the glass cylinder is removed from the base. The leaked liquid simply flows away, the compressed matrix remains.
  • the matrix still has a height of approx. 2 cm after compaction, the protein content has quintupled compared to that in the starting mixture and is approx. 15 mg / ml.
  • protein contents of collagen of, for example, 30 mg / ml gel and more can also be easily achieved,
  • the compressed matrix is then mechanically cleaned and opened, for example cut, according to the later application.
  • the graft is then ready for cultivation.
  • the wall of the standing cylinder can consist of non-porous material, for example glass, or of porous material, for example an ultrafiltration membrane.
  • the shape of a cylinder is not binding here, the compression or consolidation of the biomatrix can also take place in any other shape, for example also in the shape of a sphere or in the form of a strand.
  • the compressed matrix is shaped in accordance with the later application.
  • the compressed matrix can also be adapted to the later shape by mechanical methods such as cutting or punching and by physical methods, for example lasers.
  • the diameter and the thickness of the compressed matrix are variable.
  • the diameter can range from 1 mm to 200 mm, the thickness from 1 mm to 50 mm.
  • a collagen solution 1 as described above is again used as the starting material. This is pressed by a pump 2 via a line 3 a, 3 b through a nozzle 4 with a cylindrical section 5 and a conical section 6.
  • a auxiliary pump 7 can be used to Council container 8 and a buffer solution 9 are introduced into the line 3b and are passed through the nozzle 4 together with the collagen solution 1.
  • the collagen solution undergoes a strong compression, in which the liquid is extracted from it (in the figure illustrated by the arrows numbered 10 as an example).
  • a collagen thread 12 emerges, which essentially has the average of the outlet opening 11. The collagen thread 12 can then be dried

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Botany (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Biophysics (AREA)
  • Vascular Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Prostheses (AREA)
  • Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne une biomatrice et un procédé de production de celle-ci. Selon l'invention, pour que l'on puisse obtenir un produit présentant une action biologique et une action mécanique satisfaisantes, qui permette de remplacer par exemple des cartilages malades, la biomatrice est condensée ou compactée. L'invention concerne en outre un procédé correspondant.
PCT/DE2003/000904 2002-03-21 2003-03-19 Biomatrice et procede de production de cette biomatrice WO2003080141A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2003577965A JP2005520638A (ja) 2002-03-21 2003-03-19 バイオマトリックスならびにその製造方法
US10/508,224 US20060014284A1 (en) 2002-03-21 2003-03-19 Biomatrix and method for producting the same
DE10391674T DE10391674D2 (de) 2002-03-21 2003-03-19 Biomatrix sowie Verfahren zu deren Herstellung
EP03720209A EP1485139A1 (fr) 2002-03-21 2003-03-19 Biomatrice et procede de production de cette biomatrice
AU2003223880A AU2003223880A1 (en) 2002-03-21 2003-03-19 Biomatrix and method for producing the same

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
DE10212715 2002-03-21
DE10212715.8 2002-03-21
DE10233291 2002-07-22
DE10233291.6 2002-07-22
DE10241817.9 2002-09-06
DE10241817A DE10241817A1 (de) 2002-03-21 2002-09-06 Biomatrix sowie Verfahren zu deren Herstellung
US40996102P 2002-09-11 2002-09-11
US60/409,961 2002-09-11

Publications (1)

Publication Number Publication Date
WO2003080141A1 true WO2003080141A1 (fr) 2003-10-02

Family

ID=28457805

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE2003/000904 WO2003080141A1 (fr) 2002-03-21 2003-03-19 Biomatrice et procede de production de cette biomatrice

Country Status (5)

Country Link
EP (1) EP1485139A1 (fr)
JP (1) JP2005520638A (fr)
AU (1) AU2003223880A1 (fr)
DE (1) DE10391674D2 (fr)
WO (1) WO2003080141A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007060459A2 (fr) * 2005-11-25 2007-05-31 Ucl Business Plc Matériaux bio-artificiels à propriétés d’ajustement
JP2008504921A (ja) * 2004-07-05 2008-02-21 ユーシーエル ビジネス ピーエルシー 組織等価物の細胞非依存的製造

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6566290B2 (ja) * 2014-12-04 2019-08-28 学校法人北里研究所 軟骨再生用移植材料、軟骨再生用移植材料の製造方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044119A (en) * 1973-05-03 1977-08-23 Cutter Laboratories, Inc. Method of controlling release of medicament and bolus therefor
US5263984A (en) * 1987-07-20 1993-11-23 Regen Biologics, Inc. Prosthetic ligaments
WO1995025481A1 (fr) * 1992-05-11 1995-09-28 Li Shu Tung Systemes d'obturation pour tissus mous
WO2000029484A1 (fr) * 1998-11-17 2000-05-25 Biocomposites, Llc Procede de preparation de matiere collagene insoluble haute densite mecaniquement resistante sous ses formes pure et combinee
US6090996A (en) * 1997-08-04 2000-07-18 Collagen Matrix, Inc. Implant matrix

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044119A (en) * 1973-05-03 1977-08-23 Cutter Laboratories, Inc. Method of controlling release of medicament and bolus therefor
US5263984A (en) * 1987-07-20 1993-11-23 Regen Biologics, Inc. Prosthetic ligaments
WO1995025481A1 (fr) * 1992-05-11 1995-09-28 Li Shu Tung Systemes d'obturation pour tissus mous
US5571181A (en) * 1992-05-11 1996-11-05 Li; Shu-Tung Soft tissue closure systems
US6090996A (en) * 1997-08-04 2000-07-18 Collagen Matrix, Inc. Implant matrix
WO2000029484A1 (fr) * 1998-11-17 2000-05-25 Biocomposites, Llc Procede de preparation de matiere collagene insoluble haute densite mecaniquement resistante sous ses formes pure et combinee

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008504921A (ja) * 2004-07-05 2008-02-21 ユーシーエル ビジネス ピーエルシー 組織等価物の細胞非依存的製造
US9101693B2 (en) 2004-07-05 2015-08-11 Ucl Business Plc Cell-independent fabrication of tissue equivalents
WO2007060459A2 (fr) * 2005-11-25 2007-05-31 Ucl Business Plc Matériaux bio-artificiels à propriétés d’ajustement
WO2007060459A3 (fr) * 2005-11-25 2008-05-22 Ucl Business Plc Matériaux bio-artificiels à propriétés d’ajustement
EP2184078A3 (fr) * 2005-11-25 2010-05-19 UCL Business PLC Matériaux bio-artificiels à propriétés d'ajustement
US8343758B2 (en) 2005-11-25 2013-01-01 Ulc Business Plc Bio-artificial materials with tuneable properties
CN101355974B (zh) * 2005-11-25 2013-04-10 Ucl商业有限公司 具有可调整性质的人造生物材料

Also Published As

Publication number Publication date
DE10391674D2 (de) 2005-05-25
EP1485139A1 (fr) 2004-12-15
JP2005520638A (ja) 2005-07-14
AU2003223880A1 (en) 2003-10-08

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