EP2155176A2 - Substrat favorisant l'angiogenèse - Google Patents

Substrat favorisant l'angiogenèse

Info

Publication number
EP2155176A2
EP2155176A2 EP08758535A EP08758535A EP2155176A2 EP 2155176 A2 EP2155176 A2 EP 2155176A2 EP 08758535 A EP08758535 A EP 08758535A EP 08758535 A EP08758535 A EP 08758535A EP 2155176 A2 EP2155176 A2 EP 2155176A2
Authority
EP
European Patent Office
Prior art keywords
gelatin
substrate
containing material
angiogenesis
substrate according
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Withdrawn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
EP08758535A
Other languages
German (de)
English (en)
Inventor
Michael Ahlers
Burkhard Schlosshauer
Lars Dreesmann
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.)
Gelita AG
Original Assignee
Gelita 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
Application filed by Gelita AG filed Critical Gelita AG
Publication of EP2155176A2 publication Critical patent/EP2155176A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • 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
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/64—Use of materials characterised by their function or physical properties specially adapted to be resorbable inside the body
    • 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
    • A61L27/222—Gelatin
    • 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
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/045—Gelatin
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/26—Web or sheet containing structurally defined element or component, the element or component having a specified physical dimension

Definitions

  • the present invention relates to an angiogenesis-promoting substrate.
  • endothelial cells that line existing blood vessels form new capillaries wherever they are needed.
  • the endothelial cells have the remarkable ability to adapt their number and arrangement to local requirements. Tissues are dependent on the blood supply that occurs through the blood vessel system.
  • the vascular system in turn depends on the endothelial cells.
  • the endothelial cells create an adaptive life assurance system that ramifies into almost all parts of the body.
  • angiogenesis Cells in tissues release oxygen deficient angiogenesis factors that stimulate the growth of new capillaries.
  • Local (mechanical) irritation and infection also causes the proliferation of new capillaries, most of which retract and disappear as soon as the inflammation subsides.
  • the newly developing blood vessels always arise first as capillaries, which sprout on existing small vessels. This process is called angiogenesis.
  • Angiogenesis-stimulating factors are well known and include e.g. the factors HGF, FGF, VEGF and others more.
  • the object of the present invention is to provide an angiogenesis-promoting substrate which can be produced simply and inexpensively.
  • angiogenesis-promoting substrate which comprises a non-porous shaped body which is formed from a physiologically-insoluble, absorbable, gelatin-containing material.
  • Gelatin-based materials have long been used for medical applications because of their good biocompatibility, for example, as a matrix material for the release of pharmaceutical agents or as a carrier material for colonization with cells.
  • collagen In contrast to collagen, gelatine can be produced in reproducible quality and high purity. Furthermore, it is essentially completely absorbable in the body.
  • the gelatin-containing material as such exhibits an angiogenesis-promoting effect, i. stimulates the formation of new blood vessels in its immediate vicinity, without any further angiogenesis-promoting factors, such as e.g. the signal molecules VEGF, FGF or HGV mentioned above are needed.
  • angiogenesis-promoting factors such as e.g. the signal molecules VEGF, FGF or HGV mentioned above are needed.
  • angiogenesis-promoting effect of the present invention is observed in a non-porous shaped body formed of the gelatin-containing material.
  • an angiogenesis-promoting effect on porous shaped articles of gelatin-containing material had first been found, with angiogenesis taking place primarily within the shaped articles, i. ingrowth of blood vessels into the pores, cavities or spaces of the molding has been observed.
  • the pro-angiogenic effect was therefore attributed primarily to the porous structure of the molded article (see German Patent Application No. 10 2005 054 937). Examples of such structures are sponges, fabrics or nonwovens.
  • a non-porous shaped body as angiogenesis promoting substrate can be used, wherein the blood vessel formation is not in the molding, but in its spatial environment.
  • this effect is caused by a release of soluble components of the gelatin and therefore is largely independent of the structure of the shaped body.
  • Non-porous shaped articles made of a gelatin-containing material are generally easier to produce than those having a porous structure.
  • the use of a shaped body of an insoluble material, which is absorbed or degraded only after a certain time, compared to the use of soluble or dissolved gelatin has the advantage that the targeted angiogenesis at a certain place, namely the environment inserted molding, can be stimulated.
  • the gelatin-containing material is a gelatin-based material and consists predominantly of gelatin. This means that the gelatin makes the largest contribution to any other components of the material used.
  • a gelatin-based material is used which consists essentially completely of gelatin.
  • Particularly suitable gelatin types are pork rind gelatin, which is preferably of high molecular weight and has a bloom value of about 160 to about 320 g.
  • an angiogenesis-stimulating effect is also observed with low molecular weight, water-soluble gelatin having an average molecular weight of less than 6 kDa, but such an effect is comparatively nonspecific when compared to other also less stimulatory agents.
  • the gelatin used therefore preferably has an average molecular weight of more than about 6 kDa.
  • a gelatin with a particularly low content of endotoxins is preferably used as starting material. Endotoxins are metabolic products or fragments of microorganisms found in the animal raw material. The endotoxin content of gelatin is expressed in international units per gram (IU / g) and determined according to the LAL test described in the fourth edition of the European Pharmacopoeia (Ph. Eur. 4).
  • the endotoxin content of gelatin can be drastically reduced by certain measures in the manufacturing process.
  • measures include, first and foremost, the use of fresh raw materials (e.g., pork rind) to avoid storage times, the thorough cleaning of the entire production line just prior to the start of gelatine production, and, if necessary, the replacement of ion exchangers and filtration systems at the production line.
  • the gelatin used in the present invention preferably has an endotoxin content of about 1,200 I.U./g or less, more preferably about 200 I.U./g or less. Optimally, the endotoxin content is about 50 I.U./g or less, each determined according to the LAL test. In comparison, some commercially available gelatins have endotoxin levels of more than 20,000 I.U./g.
  • the non-porous shaped body of the angiogenesis-promoting substrate is formed from a material that is insoluble under physiological conditions, so that it has a certain period of time maintains its structural integrity and angiogenesis can be localized to the desired target area.
  • the gelatin-containing material is preferably crosslinked.
  • rapid dissolution can be counteracted by using the gelatin together with other slower dissolving components (examples of such resorbable biopolymers are chitosan and hyaluronic acid).
  • Such components may be used for the purpose of temporarily immobilizing the gelatin moieties.
  • the crosslinking is selected to stabilize the material, in particular the gelatin portion of the gelatin-containing material may be crosslinked, it being possible to resort to chemical crosslinking as well as enzymatic crosslinking.
  • Preferred chemical crosslinking agents are aldehydes, dialdehydes, isocyanates, carbodiimides and alkyl dihalides. Particularly preferred is formaldehyde, which simultaneously causes a sterilization of the molding.
  • the enzymatic crosslinking agent used is preferably the enzyme transglutaminase, which brings about linkage of the glutamine and lysine side chains of proteins, in particular also of gelatin.
  • the stability to resorption under the aforementioned physiological conditions to which the material is exposed when used can be reconstituted in vitro under standard physiological conditions.
  • a PBS buffer (pH 7.2) at 37 0 C is used and under these conditions, the substrates can be tested for their time-dependent stability behavior and compare.
  • the gelatin-containing material has a predetermined degree of crosslinking. By specifying the degree of crosslinking, in particular the absorption stability of the shaped body can be adjusted, ie the time during which it receives its structural integrity under physiological conditions.
  • non-porous moldings can be used as angiogenesis-promoting substrates, which are stable depending on the degree of crosslinking of the gelatin-containing material, for example, one, three, six or twelve weeks under physiological standard conditions, depending on the period over which an angiogenic effect of attending physician is desired.
  • the non-porous shaped body is preferably stabilized in its structure by means of a two-stage cross-linking, wherein in a first stage the gelatin-containing material is subjected in solution to a first cross-linking reaction, and then a molded article produced from this material is further cross-linked in a second cross-linking step.
  • crosslinking in the gas phase is particularly suitable for the second crosslinking stage, for example using formaldehyde.
  • the two-stage cross-linking has the particular advantage that overall a higher degree of cross-linking can be achieved, which then also moreover can be realized substantially uniform over the entire cross section of the molded body. This has the consequence that the degradation properties of the shaped body during absorption are homogeneous, so that it retains substantially its structural integrity for the intended time dependent on the degree of crosslinking and then completely absorbed in a relatively short time with loss of structural integrity.
  • the degree of cross-linking should be such that, during 7 days, about 20% by weight or less of the gelatin-containing material degrades under the standard physiological conditions mentioned above.
  • the non-porous shaped body can be realized in very different forms, about which has not yet been spoken.
  • the shaped body is a sheet material.
  • Sheet materials can be used in a variety of ways as medical substrates in or on the body.
  • the shaped body is a film.
  • films can be readily prepared by casting a solution of a gelatin-containing material, which method can be combined with the two-step crosslinking process described above.
  • plasticizers are selected from glycerol, oligoglycerols, oligoglycols, sorbitol and mannitol.
  • the film preferably has a thickness in the range from about 20 to about 500 ⁇ m, more preferably from about 50 to about 100 ⁇ m.
  • the non-porous shaped body is in the form of particles.
  • the particles may be, for example, beads, granules or powders of a gelatin-containing material.
  • Preferred particles have an average diameter of about 0.1 mm to about 5 mm.
  • the non-porous shaped body comprises one or more non-gelatin-based pharmaceutical active substances. These may be, for example, anti-inflammatory or antibiotic agents.
  • the non-porous shaped body is populated with cells.
  • the substrate according to the invention can be used for cell transplantations in which angiogenesis in the area of the implanted cells is desired.
  • the present invention also relates to the use of a non-porous shaped article formed from a physiologically-insoluble, resorbable, gelatin-containing material for the preparation of an angiogenesis-promoting substrate intended for use in or on the human or animal body.
  • a non-porous shaped article formed from a physiologically-insoluble, resorbable, gelatin-containing material for the preparation of an angiogenesis-promoting substrate intended for use in or on the human or animal body.
  • Advantages and preferred embodiment of this use are apparent in particular from the above description of the angiogenesis-promoting substrate according to the invention.
  • the substrate is used as a wound dressing or cover. By applying the substrate to injuries or burns, especially to the skin, the angiogenic effect can contribute to faster wound healing.
  • the angiogenesis-promoting substrate is intended for implantation in the body.
  • the substrate can be used intracorporally at the most diverse points of the body, wherever targeted promotion of angiogenesis is necessary or desirable.
  • Preferred areas of application of the angiogenesis-promoting substrate according to the invention are e.g. Transplants, the treatment of diabetes or infarction.
  • a non-porous shaped body is provided in the respectively required shape and size or tailored accordingly by the attending physician, and subsequently introduced into or onto the corresponding area of the human or animal body to become.
  • FIG. 1 Photograph of blood vessel formation without an angiogenesis-promoting substrate
  • FIGS. 2a to 2c are photographic representations of blood vessel formation in various angiogenesis-promoting substrates according to the invention.
  • FIG. 3 Photograph of blood vessel formation after resorption of the angiogenesis-promoting substrate.
  • gelatin films having three different degrees of crosslinking were prepared by a two-step crosslinking process.
  • the mixtures were homogenized and knife-coated at about 60 0 C in a thickness of approximately 250 microns onto a polyethylene backing.
  • the films were stripped off from the PE base and after-dried for about 12 hours under the same conditions.
  • the dried films (thickness about 50 microns) were exposed to the equilibrium vapor pressure of a 17 wt .-% aqueous formaldehyde solution at room temperature to perform the second crosslinking step in a desiccator.
  • the exposure time of Formaidehyddampfs 2 h in the case of the film C 17 h.
  • the film A has a total of the lowest and the film C in total the highest degree of crosslinking, the film B is in between. This is reflected in the different degradation behavior of the films, wherein the absorption times of the described Foils under physiological conditions in animal experiments (see below) between about 14 days (slide A) and about 21 days (slide C) are.
  • the films Due to the use of glycerol as plasticizer, the films show sufficient flexibility, in particular in the hydrated state, to ensure good handling in the medical application, without fear of breakage or tearing of the films.
  • the efficacy of the gelatin films A, B and C as angiogenesis promoting substrates in vivo was investigated in animal experiments. Ten weeks old mice of the strain Balb / C from Charles River (Sulzfeld) with a body weight of 20 g were used as test animals.
  • the substrates used were 5 ⁇ 5 mm 2 pieces of the gelatin films described above.
  • the mice were each implanted two pieces of film of a certain degree of crosslinking subcutaneously in the neck area. For this purpose, the animals were anesthetized and shaved the coat in the neck area. With a pair of tweezers, a piece of the neck skin was lifted and an incision of about 1 cm length was made. About this incision, a subcutaneous pocket was created with blunt scissors, in each of which two of the pieces of foil were inserted with tweezers. The wound closure took place by means of two single button booklets.
  • FIG. 1 shows, as a negative control, the corresponding region of the subcutaneous tissue of a mouse in which no implantation of the angiogenesis-promoting substrate was carried out. There is very little blood vessel penetration seen as normal for the subcutaneous skin tissue of the mouse.
  • Figures 2a to 2c show photographs of the subcutaneous skin tissue in the region of the implanted pieces of foil A, B and C, respectively, after the corresponding mice were killed 12 days after implantation. The position of the pieces of film is indicated by black squares (reference numbers A, B and C, respectively, for the corresponding film) because the films themselves are poorly visible in the photograph. The films were partly dyed with Coomassie Brilliant Blue, as is visible in FIG. 2a.
  • FIG. 3 The result is shown in FIG. 3.
  • the relatively thin gelatin films B are already largely absorbed after 21 days and have lost their structural integrity.
  • the photographic representation shows that the newly formed blood vessels, which were observed in the corresponding films after 12 days (see Figure 2b), have regressed again.
  • angiogenesis in the human or animal body can be specifically stimulated both spatially and temporally.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Dermatology (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Materials Engineering (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention a pour objet la mise à disposition d'un substrat favorisant l'angiogenèse, qui peut être réalisé de manière simple et peu coûteuse. A cet effet, le substrat comprend un corps moulé non poreux qui est formé d'un matériau contenant de la gélatine, résorbable et insoluble dans les conditions physiologiques normales.
EP08758535A 2007-05-16 2008-05-15 Substrat favorisant l'angiogenèse Withdrawn EP2155176A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007024239A DE102007024239A1 (de) 2007-05-16 2007-05-16 Angiogenese förderndes Substrat
PCT/EP2008/003895 WO2008138612A2 (fr) 2007-05-16 2008-05-15 Substrat favorisant l'angiogenèse

Publications (1)

Publication Number Publication Date
EP2155176A2 true EP2155176A2 (fr) 2010-02-24

Family

ID=39811808

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08758535A Withdrawn EP2155176A2 (fr) 2007-05-16 2008-05-15 Substrat favorisant l'angiogenèse

Country Status (8)

Country Link
US (1) US20100056452A1 (fr)
EP (1) EP2155176A2 (fr)
AU (1) AU2008250580A1 (fr)
BR (1) BRPI0811861A2 (fr)
DE (1) DE102007024239A1 (fr)
IL (1) IL201831A0 (fr)
MX (1) MX2009012324A (fr)
WO (1) WO2008138612A2 (fr)

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Publication number Priority date Publication date Assignee Title
CA2071137A1 (fr) * 1991-07-10 1993-01-11 Clarence C. Lee Composition et methode pour la revitalisation du tissu cicatriciel
DE4201179A1 (de) * 1992-01-17 1993-07-22 Alfatec Pharma Gmbh Wirkstoff(e) enthaltendes granulat oder pellet mit einem geruest aus hydrophilen makromolekuelen und verfahren zu seiner herstellung
US6231881B1 (en) * 1992-02-24 2001-05-15 Anton-Lewis Usala Medium and matrix for long-term proliferation of cells
DE69830166T2 (de) * 1997-06-03 2006-01-26 Innogenetics N.V. Neue arzneimittel auf der basis von polymeren aus mit methacrylamid modifizierter gelatine
JP2003525703A (ja) * 2000-03-09 2003-09-02 シンタコール アーゲー 人および獣の医薬に使用するための改良された性質を備えた新規な天然ポリマーを基材とする材料およびその製造方法
US6893812B2 (en) * 2000-05-30 2005-05-17 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Three-dimensional ex vivo angiogenesis system
JP4878730B2 (ja) 2001-07-18 2012-02-15 株式会社メドジェル Ｈｇｆヒドロゲル徐放性製剤
EP1452182B1 (fr) * 2001-10-02 2017-03-29 Kiyoshi Nokihara Medicaments d'angiogenese
TWI245634B (en) * 2001-12-28 2005-12-21 Ind Tech Res Inst Preparation of a biodegradable thermal-sensitive gel system
JP2004115413A (ja) 2002-09-25 2004-04-15 Yasuhiko Tabata 冠状動脈狭窄または閉塞治療用徐放性製剤
US7718556B2 (en) * 2002-12-16 2010-05-18 Gunze Limited Medical film
US20050064521A1 (en) * 2003-09-24 2005-03-24 Tunghai University In vitro assay for evaluation of angiogenic effects
DE102004024635A1 (de) 2004-05-12 2005-12-08 Deutsche Gelatine-Fabriken Stoess Ag Verfahren zur Herstellung von Formkörpern auf Basis von vernetzter Gelatine
DE102005054941A1 (de) * 2005-11-17 2007-05-31 Gelita Ag Nervenleitschiene
DE102005054937A1 (de) * 2005-11-17 2007-05-24 Gelita Ag Angiogenese förderndes Substrat

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008138612A2 *

Also Published As

Publication number Publication date
DE102007024239A1 (de) 2008-11-20
MX2009012324A (es) 2009-12-01
AU2008250580A1 (en) 2008-11-20
US20100056452A1 (en) 2010-03-04
IL201831A0 (en) 2010-06-16
WO2008138612A3 (fr) 2009-01-08
WO2008138612A2 (fr) 2008-11-20
BRPI0811861A2 (pt) 2014-11-18

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