WO2002048247A1 - Biocompatible, porous material, method for its production and use of the same - Google Patents

Biocompatible, porous material, method for its production and use of the same Download PDF

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Publication number
WO2002048247A1
WO2002048247A1 PCT/SE2001/002778 SE0102778W WO0248247A1 WO 2002048247 A1 WO2002048247 A1 WO 2002048247A1 SE 0102778 W SE0102778 W SE 0102778W WO 0248247 A1 WO0248247 A1 WO 0248247A1
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WIPO (PCT)
Prior art keywords
cells
biocompatible
porous material
carrier
polymer phase
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Application number
PCT/SE2001/002778
Other languages
French (fr)
Other versions
WO2002048247A8 (en
Inventor
Kjell Nilsson
Original Assignee
Terminus Biotech Ab
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 Terminus Biotech Ab filed Critical Terminus Biotech Ab
Priority to AU2002222878A priority Critical patent/AU2002222878A1/en
Publication of WO2002048247A1 publication Critical patent/WO2002048247A1/en
Publication of WO2002048247A8 publication Critical patent/WO2002048247A8/en

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    • 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
    • C12N5/0068—General culture methods using substrates
    • 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
    • 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
    • A61L27/56—Porous materials, e.g. foams or sponges
    • 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
    • A61L27/60—Materials for use in artificial skin
    • 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

Definitions

  • the present invention relates to a method for preparing a biocompatible, porous material as carrier for cells, to said biocompatible, porous material prepared by means of said method and to use of the biocompatible, porous material .
  • Carrier materials can be used for, for instance, chromatographic separation purposes, as ion exchanger in affinity chromatography or in gel filtration and as carrier material in implantation.
  • the carriers that are currently available for cells are not optimal in every respect.
  • Macroporous particles which can be used, for instance, in cultivation of cells are described in
  • the particles in said patent publication are spherical and are mainly used for cultivation of cells on a large scale for preparation of vaccines.
  • the technique for producing the macroporous particles differs from the method according to the invention.
  • An object of the present invention therefore is to provide a method for preparing a biocompatible, porous material as carrier for cells, which comprises casting a dispersion containing a polymer phase and a solvent phase, removing the solvent and crosslinking the polymer phase.
  • Another object of the invention is a biocompatible, porous material as carrier for cells, prepared by cast- ing a dispersion containing a polymer phase and a solvent phase, removing the solvent and crosslinking the polymer phase.
  • One more object of the invention is use of a biocompatible, porous material, prepared as described above, as carrier for cells.
  • An additional object of the present invention is a method for implanting a biocompatible, porous material as carrier for cells in an individual for production of substances, comprising injecting said biocompatible, porous material into the individual and then letting the cells on the biocompatible, porous material produce said substances .
  • the biocompatible, porous material according to the present invention may be used both as carrier for cells in cultivation of cells and as carrier for existing cells for production of a desirable substance before/after implantation in an individual.
  • the cells can either be the individual's own cells or cells from another source (characteristic of the species or foreign to the species) .
  • the cells as such can be the desirable product, for instance attached initial stages of adipocytes (preadipocytes) on the carrier which after implantation can propagate so as then to be converted into adipocytes (fat cells) .
  • preadipocytes adipocytes
  • One field of application for this is for instance plastic surgery.
  • myoblasts muscle cells which can be used in treatment of e.g. cardiac infarction.
  • hepato- cytes liver cells
  • more complex structures such as the islets of Langerhans, can be attached to and/or in the porous carrier.
  • the islets of Langerhans are composed of a plurality of different cell types and constitute the system that regulates the blood sugar content. These islets are considerably larger and require a pore size of the carrier of 50-200 ⁇ .
  • the term "substance” used herein relates to the substances that can be produced by various cells or microorganisms, for instance antibiotics, pharmaceutical substances, e.g. dopamine which is a key substance in Parkinson's disease, and different interferons which are active substances in treatment of cancer.
  • the decomposability of the biocompatible, porous material is determined by the degree of crosslinking of the polymer phase .
  • an agent is added for enhancing or changing the adhesion of cells to said biocompatible, porous material during casting of the dispersion, or the agent is bound chemically to the polymer or added later.
  • Agents affecting the cell adhesion can be either single molecules or proteins.
  • the former are positively or negatively charged substances, such as hexamethylene diamine and amino caproic acid.
  • Examples of more complex struc- tures are peptides containing the amino acid sequence Arginine-glycine-aspargine or derivatives thereof. This sequence promotes the adhesion of cells to the carrier.
  • proteins are fibronectin and la inin. Also non-defined mixtures of proteins (obtained by extraction of tissues) such as ECM (extracellular matrix) can be used.
  • the polymer phase is preferably selected among gelatin, polysaccharides and synthetic polymers, gelatin being particularly preferred.
  • the polymer phase is cross- linked preferably chemically or by heating.
  • the polymer phase is preferably aqueous.
  • the dispersion can be cast into membranes, tubes or other convenient forms. Larger forms can be required, for instance, in production of artificial skin or other three-dimensional forms.
  • the dispersion is cast according to the present invention into membranes.
  • the biocompatible, porous material can be used for production of artificial skin, artificial organs, fatty tissue, blood vessels etc.
  • the biocompatible, porous material is prepared so that the cells are present both inside and on the outside of the biocompatible, porous material. This results in optimal use of the material .
  • carrier for cells is intended to comprise carriers that can be used in cultivation of various cells, and carriers which can be used for cells to achieve production of desirable substances.
  • carrier for cells also includes medical implants for implantation in the human body.
  • a surprising effect in the preparation of the biocompatible, porous material according to the invention is that the pores obtained in the material are uniformly distributed through the cross-section of the material. Thus, a more uniform distribution of the cells in the biocompatible, porous material is achieved.
  • the form is separated and the formed gelatin membrane is washed with acetone until all the water and Tween 80 have been removed. After that the membrane is allowed to air-dry and obtains the appearance of white paper.
  • the membrane formed must be crosslinked so as not be dissolved at temperatures above 25°C. Crosslinking
  • a suitable form/size is cut out from the dried mem- brane by means of a pair of scissors.
  • 0.97 g membrane is rehydrated in 39 ml 0,1 M phosphate buffer, pH 8.0. To this, 97 ⁇ l hexamethylene diisocyanate (crosslinking agent) and 0.5 ⁇ l triethylamine (catalyst) are added. The crosslinking reaction is allowed to proceed for two hours at 25°C under agitation. The reaction is stopped by adding 0.24 g glycine. Then the mixture is allowed to stand over night. The membrane is washed with deionised water, hot (70°C) deionised water and finally with acetone. The membrane is dried in air. The crosslinked membrane can now be autoclaved at 120°C without being dissolved.
  • the example above results in a membrane having an ideal pore size of 20-30 ⁇ m, which pore size is optimal for cultivation of cells and adhesion of cells.
  • the example above is applied, except that 7.9 g Tween 80 is added to the gelatin solution. After cooling as described above, a mixture of 6.6 ml cyclohexane and 0.8 g Tween 80 is added.
  • crosslinking reagents that are used in the preparation can be, for instance, bifunctional, such as diisocyanates and aldehydes.

Abstract

The present invention relates to a method for preparation of a biocompatible, porous material as carrier for cells. The method comprises casting a dispersion containing a polymer phase and a solvent phase, removing the solvent and crosslinking the polymer phase. The invention also relates to use of said material for cultivation of different cell types and use of said material as carrier for cells for production of substances.

Description

BIOCOMPATIBLE, POROUS MATERIAL, METHOD FOR ITS PRODUCTION AND USE OF THE SAME
Field of the Invention
The present invention relates to a method for preparing a biocompatible, porous material as carrier for cells, to said biocompatible, porous material prepared by means of said method and to use of the biocompatible, porous material . Background Art
Carrier materials can be used for, for instance, chromatographic separation purposes, as ion exchanger in affinity chromatography or in gel filtration and as carrier material in implantation.
The carriers that are currently available for cells are not optimal in every respect.
Macroporous particles which can be used, for instance, in cultivation of cells are described in
SE 464,816. The particles in said patent publication are spherical and are mainly used for cultivation of cells on a large scale for preparation of vaccines. The technique for producing the macroporous particles differs from the method according to the invention.
The drawback of previously used macroporous particles for cells is that the particles are not optimal, or even usable, in implantation of the particles in the body of an individual. If any step in the implantation of the macroporous particles should cause serious consequences and it should be desirable to remove the particles, this would be impossible owing to the spherical and minimal structure .
In cultivation of different cells for preparing tissues, entire organs or other three-dimensional structures on different carriers, there is thus a need for a material, the form of which may be varied within wide limits for the specific application. In cultivation of e.g. skin cells for preparing artificial skin or other three-dimensional forms, it is necessary to have large carriers .
In implantation of the material it is important, for instance, to be able to remove it from the individual's body when required. Important properties of the material are that it is biocompatible and that it is possible to vary the form of the material for the specific purpose. Both the cell types and the different applica- tions determine the form of the carrier. Summary of the Invention
An object of the present invention therefore is to provide a method for preparing a biocompatible, porous material as carrier for cells, which comprises casting a dispersion containing a polymer phase and a solvent phase, removing the solvent and crosslinking the polymer phase.
Another object of the invention is a biocompatible, porous material as carrier for cells, prepared by cast- ing a dispersion containing a polymer phase and a solvent phase, removing the solvent and crosslinking the polymer phase.
One more object of the invention is use of a biocompatible, porous material, prepared as described above, as carrier for cells.
An additional object of the present invention is a method for implanting a biocompatible, porous material as carrier for cells in an individual for production of substances, comprising injecting said biocompatible, porous material into the individual and then letting the cells on the biocompatible, porous material produce said substances .
The biocompatible, porous material according to the present invention may be used both as carrier for cells in cultivation of cells and as carrier for existing cells for production of a desirable substance before/after implantation in an individual. The cells can either be the individual's own cells or cells from another source (characteristic of the species or foreign to the species) . In some cases, the cells as such can be the desirable product, for instance attached initial stages of adipocytes (preadipocytes) on the carrier which after implantation can propagate so as then to be converted into adipocytes (fat cells) . One field of application for this is for instance plastic surgery. Another example is myoblasts (muscle cells) which can be used in treatment of e.g. cardiac infarction. One more example is hepato- cytes (liver cells) which can be used to render toxic substances in liver lesions harmless. Also more complex structures, such as the islets of Langerhans, can be attached to and/or in the porous carrier. The islets of Langerhans are composed of a plurality of different cell types and constitute the system that regulates the blood sugar content. These islets are considerably larger and require a pore size of the carrier of 50-200 μ .
The term "substance" used herein relates to the substances that can be produced by various cells or microorganisms, for instance antibiotics, pharmaceutical substances, e.g. dopamine which is a key substance in Parkinson's disease, and different interferons which are active substances in treatment of cancer. According to an embodiment of the inventive method, the decomposability of the biocompatible, porous material is determined by the degree of crosslinking of the polymer phase .
According to yet another embodiment of the inventive method, an agent is added for enhancing or changing the adhesion of cells to said biocompatible, porous material during casting of the dispersion, or the agent is bound chemically to the polymer or added later. Agents affecting the cell adhesion can be either single molecules or proteins. Examples of the former are positively or negatively charged substances, such as hexamethylene diamine and amino caproic acid. Examples of more complex struc- tures are peptides containing the amino acid sequence Arginine-glycine-aspargine or derivatives thereof. This sequence promotes the adhesion of cells to the carrier. Examples of proteins are fibronectin and la inin. Also non-defined mixtures of proteins (obtained by extraction of tissues) such as ECM (extracellular matrix) can be used.
The polymer phase is preferably selected among gelatin, polysaccharides and synthetic polymers, gelatin being particularly preferred. The polymer phase is cross- linked preferably chemically or by heating. The polymer phase is preferably aqueous.
To obtain a form that fits the specific application, for instance in cultivation of skin cells on the biocom- patible, porous material for production of artificial skin, the dispersion can be cast into membranes, tubes or other convenient forms. Larger forms can be required, for instance, in production of artificial skin or other three-dimensional forms. Preferably, the dispersion is cast according to the present invention into membranes.
In cultivation of cells, the biocompatible, porous material can be used for production of artificial skin, artificial organs, fatty tissue, blood vessels etc.
The biocompatible, porous material is prepared so that the cells are present both inside and on the outside of the biocompatible, porous material. This results in optimal use of the material .
In this description, the expression "carrier for cells" is intended to comprise carriers that can be used in cultivation of various cells, and carriers which can be used for cells to achieve production of desirable substances. The expression "carrier for cells" also includes medical implants for implantation in the human body. A surprising effect in the preparation of the biocompatible, porous material according to the invention is that the pores obtained in the material are uniformly distributed through the cross-section of the material. Thus, a more uniform distribution of the cells in the biocompatible, porous material is achieved. Description of Preferred Embodiments Example 1
6.7 g gelatin is dissolved in 53 ml deionised water by heating to 50°C. To this solution 11.0 g Tween 80 (polyoxyethylene (20) sorbitanmonooleate) is added. The mixture is agitated. Then the mixture is cooled to 35°C. At this temperature, a mixture of cyclohexane (18 ml) and Tween 80 (0.6 g) is added. The resulting mixture is agitated vigorously. Then this mixture is poured onto a glass slide with a 1-mm-thick packing along the periphery, then another glass slide is placed on top, after which the two glass slides are pressed together by means of clips. The form is chilled with cold water until the temperature is below 20°C. The form is separated and the formed gelatin membrane is washed with acetone until all the water and Tween 80 have been removed. After that the membrane is allowed to air-dry and obtains the appearance of white paper. The membrane formed must be crosslinked so as not be dissolved at temperatures above 25°C. Crosslinking
A suitable form/size is cut out from the dried mem- brane by means of a pair of scissors. 0.97 g membrane is rehydrated in 39 ml 0,1 M phosphate buffer, pH 8.0. To this, 97 μl hexamethylene diisocyanate (crosslinking agent) and 0.5 μl triethylamine (catalyst) are added. The crosslinking reaction is allowed to proceed for two hours at 25°C under agitation. The reaction is stopped by adding 0.24 g glycine. Then the mixture is allowed to stand over night. The membrane is washed with deionised water, hot (70°C) deionised water and finally with acetone. The membrane is dried in air. The crosslinked membrane can now be autoclaved at 120°C without being dissolved. The example above results in a membrane having an ideal pore size of 20-30 μm, which pore size is optimal for cultivation of cells and adhesion of cells.
To obtain a membrane having a pore size in the range 10-20 μm, the example above is applied, except that 7.9 g Tween 80 is added to the gelatin solution. After cooling as described above, a mixture of 6.6 ml cyclohexane and 0.8 g Tween 80 is added.
In the production of the membrane above, larger pores can be obtained by using a higher Tween concentration. An increase of the amount of cyclohexane also results in larger pores and simultaneously a larger total pore volume. An increase of the agitation speed results in smaller pores . There are thus great possibilities of varying the porosity of the membrane within wide limits. The resistance of the biocompatible, porous material to heat, enzymes etc. is proportional to the crosslinking degree. An increased concentration of crosslinking agent, for instance hexamethylene diisocyanate, results in increased resistance. An increasing crosslinking time also results in increased resistance.
The crosslinking reagents that are used in the preparation can be, for instance, bifunctional, such as diisocyanates and aldehydes.

Claims

1. A method for preparation of a biocompatible, porous material as carrier for cells, which comprises casting a dispersion containing a polymer phase and a solvent phase, removing the solvent and crosslinking the polymer phase .
2. A method as claimed in claim 1, wherein the deco posability of the biocompatible, porous material is determined by the degree of crosslinking of the polymer phase .
3. A method as claimed in claim 1 or 2 , wherein an agent for enhancing or changing the adhesion of cells to said biocompatible, porous material is added during casting of the dispersion, or the agent is bound chemically to the polymer or is added later.
4. A method as claimed in claim 3, wherein said agent is selected from the group consisting of positive- ly or negatively charged substances and peptides.
5. A method as claimed in claim 4, wherein said agent is selected from the group consisting of hexamethylene diamine, amino caproic acid, peptides containing the amino acid sequence arginine-glycine-aspargine, fibronectin and laminin.
6. A method as claimed in any one of claims 1-5, wherein the polymer phase is selected among gelatin, polysaccharides and synthetic polymers.
7. A method as claimed in any one of claims 1-6, wherein the polymer phase is crosslinked chemically or by heating.
8. A biocompatible, porous material as carrier for cells, prepared according to any one of claims 1-7.
9. Use of a biocompatible, porous material, prepared by means of the method according to any one of claims 1-7 or according to claim 8 as carrier for cells.
10. Use as claimed in claim 9, for production of substances .
11. Use as claimed in claim 9, for cultivation of cells.
12. Use as claimed in claim 11, wherein the biocompatible, porous material is used for cultivation of artificial skin, artificial organs, fatty tissue and blood vessels.
13. Use as claimed in any one of claims 10-12, wherein the cells are present both inside and on the outside of the biocompatible, porous material.
14. A method for implanting a biocompatible, porous material as carrier for cells in an individual for production of substances, comprising injection of said bio- compatible, porous material, prepared by means of the method according to any one of claims 1-7 or 8, into the individual and then letting the cells on the biocompatible, porous material produce said substances.
PCT/SE2001/002778 2000-12-14 2001-12-14 Biocompatible, porous material, method for its production and use of the same WO2002048247A1 (en)

Priority Applications (1)

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SE0004612A SE0004612D0 (en) 2000-12-14 2000-12-14 Biocompatible, porous material, process for its preparation and use thereof
SE0004612-8 2000-12-14

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4522753A (en) * 1980-07-17 1985-06-11 Massachusetts Institute Of Technology Method for preserving porosity in porous materials
EP0222718A2 (en) * 1985-10-15 1987-05-20 Kjell G.C. Nilsson Macroporous particles
US4955893A (en) * 1988-05-09 1990-09-11 Massachusetts Institute Of Technologh Prosthesis for promotion of nerve regeneration
US5290494A (en) * 1990-03-05 1994-03-01 Board Of Regents, The University Of Texas System Process of making a resorbable implantation device
US5686091A (en) * 1994-03-28 1997-11-11 The Johns Hopkins University School Of Medicine Biodegradable foams for cell transplantation
US5723508A (en) * 1996-01-25 1998-03-03 Northwestern University Method of fabricating emulsion freeze-dried scaffold bodies and resulting products
US5856367A (en) * 1994-02-18 1999-01-05 Minnesota Mining And Manufacturing Company Biocompatible porous matrix of bioabsorbable material
US5939323A (en) * 1996-05-28 1999-08-17 Brown University Hyaluronan based biodegradable scaffolds for tissue repair
WO2000062829A1 (en) * 1999-04-16 2000-10-26 Rutgers, The State University Porous polymer scaffolds for tissue engineering

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4522753A (en) * 1980-07-17 1985-06-11 Massachusetts Institute Of Technology Method for preserving porosity in porous materials
EP0222718A2 (en) * 1985-10-15 1987-05-20 Kjell G.C. Nilsson Macroporous particles
US4955893A (en) * 1988-05-09 1990-09-11 Massachusetts Institute Of Technologh Prosthesis for promotion of nerve regeneration
US5290494A (en) * 1990-03-05 1994-03-01 Board Of Regents, The University Of Texas System Process of making a resorbable implantation device
US5856367A (en) * 1994-02-18 1999-01-05 Minnesota Mining And Manufacturing Company Biocompatible porous matrix of bioabsorbable material
US5686091A (en) * 1994-03-28 1997-11-11 The Johns Hopkins University School Of Medicine Biodegradable foams for cell transplantation
US5723508A (en) * 1996-01-25 1998-03-03 Northwestern University Method of fabricating emulsion freeze-dried scaffold bodies and resulting products
US5939323A (en) * 1996-05-28 1999-08-17 Brown University Hyaluronan based biodegradable scaffolds for tissue repair
WO2000062829A1 (en) * 1999-04-16 2000-10-26 Rutgers, The State University Porous polymer scaffolds for tissue engineering

Non-Patent Citations (1)

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Title
KIM KEA YONG ET AL.: "Synthesis and properties of polymeric skin substitute (1) evaluation of bilayer membrane composed of crosslinked gelatin och polyurethane", POLYMER, vol. 11, no. 3, June 1987 (1987-06-01), KOREA, pages 246 - 253 *

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AU2002222878A1 (en) 2002-06-24
SE0004612D0 (en) 2000-12-14

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