EP1948143A2 - Substrat favorisant l'angiogenese - Google Patents

Substrat favorisant l'angiogenese

Info

Publication number
EP1948143A2
EP1948143A2 EP06818570A EP06818570A EP1948143A2 EP 1948143 A2 EP1948143 A2 EP 1948143A2 EP 06818570 A EP06818570 A EP 06818570A EP 06818570 A EP06818570 A EP 06818570A EP 1948143 A2 EP1948143 A2 EP 1948143A2
Authority
EP
European Patent Office
Prior art keywords
gelatin
substrate according
shaped body
substrate
angiogenesis
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Withdrawn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
EP06818570A
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 EP1948143A2 publication Critical patent/EP1948143A2/fr
Withdrawn legal-status Critical Current

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
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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
    • 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
    • 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
    • A61L27/58—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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.
  • 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 in reproducible quality and, in particular, remains stable under physiological conditions for a given period of time and is nevertheless biocompatible and resorbable.
  • angiogenesis-promoting substrate which comprises a porous shaped body which is formed from a physiologically insoluble, absorbable, gelatin-containing material.
  • porous shaped bodies which are made of a physiologically insoluble, resorbable, gelatin-containing material have a very pronounced angiogenesis-promoting effect, in the form that angiogenesis in particular the formation of blood vessels within the porous shaped body in causes a significant density, so that targeted angiogenesis by introducing the porous moldings at the desired locations of the body of the patient or animal to be treated is possible.
  • gelatin-containing material prepared as a porous shaped body promotes angiogenesis as such without, as otherwise described in the literature, promoting angiogenesis-promoting factors such as e.g. the aforementioned factors VEGF, FGF, HGF and others would be needed.
  • the gelatin-containing material is a gelatin-based material and consists of gelatin in predominant proportions. This means, that the gelatine 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 types of gelatin are pork rind gelatin, which is preferably of high molecular weight and has a bloom value of about 160 to about 300 g.
  • angiogenesis-stimulating effect is 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 compared to other also less stimulating agents.
  • the gelatin used therefore preferably has an average molecular weight greater than 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).
  • IU / g international units per gram
  • 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 1,200 I.U./g or less, more preferably 200 I.U./g or less. Optimally, the endotoxin content is 50 I.U./g or less, each determined according to the LAL test. In comparison, some commercially available gelatins have endotoxin levels of over 20,000 I.U./g.
  • the gelatin-containing material having a predetermined degree of crosslinking is preferably used.
  • the gelatin can be counteracted by 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 gluatamine 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 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 in solution is subjected to a first cross-linking reaction The material is then foamed and then a porous molded body obtained therefrom is further crosslinked in a second crosslinking step.
  • the porous molding can be brought into contact with a crosslinking solution and thus the degree of crosslinking can be further increased, or especially when the gelatin itself is crosslinked, the porous molding can be exposed to a formaldehyde vapor, so that via the gas phase over the porous Moldings penetrating formaldehyde contribute to further crosslinking.
  • the two-stage cross-linking has the particular advantage that overall a higher degree of cross-linking can be achieved, which then, moreover, can be realized substantially evenly over the entire cross-section of the porous shaped body. This has the consequence that the degradation properties of the porous shaped body in the 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 crosslinking should be such that 20% by weight or less of the gelatin-containing material is degraded during 7 days under the standard physiological conditions mentioned above.
  • the porous molded body can be realized in very different forms, about which has not been spoken yet.
  • the shaped body of the substrate has a fiber structure.
  • This fiber structure may on the one hand have a woven or knitted structure, alternatively, a fibrous structure in the form of a nonwoven may be considered.
  • a completely different structure of the shaped body of the substrate according to the invention is present in the sponge structure, which preferably comprises a proportion of open pores. Further preferred is a sponge structure with a substantially open-pored structure.
  • the porosity gives the endothelial cells an opportunity to migrate into the substrate and penetrate it.
  • the shape of the body through its porosity even the endothelial cells the ability to form capillaries in the substrate into it.
  • the porosity of the other porous shaped bodies should be selected such that there are similar pore structures, since these are optimally suited to receive the endothelial cells and to permit a penetration of the substrate through capillary vessels.
  • the porous shaped body of the angiogenesis-promoting substrates according to the invention additionally has the advantage that one or more non-gelatin-based pharmaceutical active ingredients can be incorporated in the pores of the shaped body.
  • the pores of the shaped body can already be colonized with cells before the substrate is moved to the point to be treated of the human or animal body.
  • the substrate has not been addressed in detail yet, but it will be understood that the substrate can be varied in its outer dimensions.
  • the substrate can also be present in the form of small particles, in particular in powder form, the particles of the powder preferably being produced from a sponge structure, a fleece, a woven fabric or a knitted fabric, in particular by means of grinding.
  • FIG. 1 shows the degradation behavior of various angiogenesis-promoting substrates according to the invention
  • FIGS 2a and b a schematic representation of the experimental arrangement for the investigation of angiogenesis by means of a chorioallantoic membrane (CAM);
  • CAM chorioallantoic membrane
  • FIG. 3 the angiogenesis triggered by a substrate according to the invention promoting angiogenesis on a CAM after 3, 5 and 7 days;
  • Figure 4 is a graph illustrating the formation of blood vessels around the angiogenesis promoting substrate
  • Figure 5 is a diagram illustrating the development of blood vessels in the angiogenesis promoting substrate itself
  • FIG. 6 shows three light microscope images of a collagen sponge reference substrate after 2, 5 and 7 days.
  • Figures 7a and 7b four light micrographs of a substrate according to the invention promoting angiogenesis after 3, 5, 7 and 8 days.
  • Example 1 Production and Properties of Moldings with Cell Structure Based on Crosslinked Gelatin
  • Five batches of a 12% by weight solution of pork rind gelatin (bloom strength 300 g, average molecular weight 140 kDa) in water were prepared by dissolving the gelatin at 60 ° C., degassed by ultrasound, and in each case with the appropriate amount of aqueous Formaldehyde solution (1.0 wt .-%, room temperature) were added so that 1500 ppm of formaldehyde (based on the gelatin) were present.
  • aqueous Formaldehyde solution 1.0 wt .-%, room temperature
  • the homogenized mixtures were heated to 45 ° C. and, after a reaction time of 10 minutes, were mechanically foamed with air.
  • the approximately 30-minute foaming process was carried out for the six batches with a different ratio of air to gelatin solution, resulting in cell structures with different wet densities and pore sizes according to Table 1.
  • the foamed Gelatine momentsen which had a temperature of 26.5 0 C, were poured into molds with a dimension of 40 x 20 x 6 cm and dried for about four days at 26 0 C and a relative humidity of 10%.
  • the dried moldings of all six batches have a sponge-like cell structure (hereinafter referred to as sponges). They were cut into 2 mm thick layers and exposed to the equilibrium vapor pressure of a 17% by weight aqueous formaldehyde solution at room temperature for 17 hours in a desiccator for the second crosslinking step. For the sixth approach, this was the first (and only) cross-linking step. To ensure uniform fumigation of the entire volume of the To reach moldings, the desiccator was evacuated two to three times and ventilated again.
  • the pore structure of the sponges was determined by light microscopy and confirmed by scanning electron microscopy.
  • FIG. 1 shows the dissolution behavior, ie the absorption behavior of the two-stage crosslinked sponges 1-1 to 1-5 and of the singly crosslinked sponge 1-6 (the sequence of the bars shown is in each case: 1-6, 1-1, 1-2 , 1-3, 1-4, 1-5).
  • sponge 1-6 is already completely dissolved after three days, all two-stage cross-linked sponges are still over 80% preserved even after 14 days.
  • further degradation behavior which are due to the different foaming densities of the materials.
  • sponge 1-1 is completely dissolved after 21 days and sponge 1-2 after 28, while sponges 1-4 and 1-5 are still largely preserved even after 35 days. This results in a further possibility to specifically influence the degradation behavior of these sponges or cell structure materials independently of other parameters.
  • the properties of the cell structure materials can also be significantly modified by changing the gelatin concentration in the starting solution.
  • Breaking strength increases steadily as the gelatin concentration of the starting solution increases from 10 to 18% by weight, covering a wide range from about 500 to almost 2,000 Newtons. At the same time, the deformation changes only slightly until it breaks. Surprisingly, the correlation between breaking strength and gelatin concentration is largely independent of the degree of crosslinking.
  • the degree of crosslinking ie the choice of the concentration of the crosslinking agent, can influence the stability of the moldings, in particular with regard to proteolytic degradation.
  • Example 2 the degree of crosslinking, ie the choice of the concentration of the crosslinking agent, can influence the stability of the moldings, in particular with regard to proteolytic degradation.
  • two-crosslinked moldings dry matter 22 mg / ml, average pore size about 250 microns
  • implants 15 x 15 x 2 mm
  • FIG. 2a shows schematically the structure of a chicken egg in cross section.
  • CAM choriallantois membrane
  • FIG. 3 shows the reorientation and new formation of blood vessels in light micrographs after 3, 5 and 7 days.
  • FIG. 4 shows the evaluation according to the number of blood vessels per image section around the substrate and it is shown that a significantly higher number of blood vessels is present in all three samples compared to the zero value (CAM without attached implant) three samples similar effects, especially when compared to the zero value, were achieved.
  • the CAM is a tissue that represents the interface between air and egg fluid. It may be that the mechanical stimulus of applying the substrate to the CAM alone leads to activation of receptors, which could lead to a release of pro-angiogenic factors such as VEGF of the cells. As a result, endothelial cells could be attracted and blood vessel formation directed to the implant would then occur. Another explanation is that due to the placement of the implant, the access of atmospheric oxygen to the epithelial tissue is hindered. Thus, in the region of the implant so-called anoxia, as in the epithelial tissue less oxygen is available. Cells typically respond to anoxia with the release of VEGF, thereby inducing blood vessel rebuilding. This means that the underserved part of the cells is organizing new supply lines. This biological phenomenon probably occurs above a critically underserved (deformed) tissue surface.
  • the area of the blood vessels (in ⁇ m 2 ) within the substrates or implants of the comparison materials and the angiogenesis-promoting substrate of the present invention is applied after 3, 5 and 7 days.
  • the sequence gelatin sample, collagen sample, poly-DL-lactide sample applies.
  • the measurable blood vessels after 5 days show an extreme increase in the angiogenesis-promoting substrates according to the invention, while for the Poly-DL-Lactidprobe and for the collagen sponge still no effect is observed.
  • the regression of the blood vessels in the implant according to the invention after 7 days is expressed in a reduction of the measured area. This could be due to the fact that the blood vessel network is again reduced as much as it actually is needed for the implant areas, because, for example, relatively few other cell types have yet to migrate, which must be supplied. This corresponds to a process that is also found in infections where a blood vessel network regresses as soon as the inflammation goes down.
  • Solutions containing angiogenic factors can also be accommodated in the porous shaped body, thus further enhancing the pro-angiogenic effects, at least in the initial phase. Furthermore, it appears possible to use the porous shaped body as a carrier for pharmaceutical active ingredients without hindering its effect of promoting angiogenesis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Dispersion Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'objectif de l'invention est de produire un substrat favorisant l'angiogenèse de manière simple, présentant une qualité stable et reproductible, en particulier dans des conditions physiologiques sur une période prédéterminée, tout en étant biocompatible et résorbable. A cet effet, le substrat favorisant l'angiogenèse comprend un corps moulé poreux, lequel est fabriqué dans un matériau insoluble dans des conditions physiologiques, résorbable et gélatineux.
EP06818570A 2005-11-17 2006-11-16 Substrat favorisant l'angiogenese Withdrawn EP1948143A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005054937A DE102005054937A1 (de) 2005-11-17 2005-11-17 Angiogenese förderndes Substrat
PCT/EP2006/010977 WO2007057178A2 (fr) 2005-11-17 2006-11-16 Substrat favorisant l'angiogenese

Publications (1)

Publication Number Publication Date
EP1948143A2 true EP1948143A2 (fr) 2008-07-30

Family

ID=37989389

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06818570A Withdrawn EP1948143A2 (fr) 2005-11-17 2006-11-16 Substrat favorisant l'angiogenese

Country Status (9)

Country Link
US (1) US20080267919A1 (fr)
EP (1) EP1948143A2 (fr)
JP (1) JP2009515919A (fr)
KR (1) KR20080071563A (fr)
AU (1) AU2006314769A1 (fr)
BR (1) BRPI0618761A2 (fr)
CA (1) CA2626778A1 (fr)
DE (1) DE102005054937A1 (fr)
WO (1) WO2007057178A2 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007024256A1 (de) 2007-05-16 2008-11-20 Gelita Ag Gefäßstent
DE102007024239A1 (de) 2007-05-16 2008-11-20 Gelita Ag Angiogenese förderndes Substrat

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Also Published As

Publication number Publication date
US20080267919A1 (en) 2008-10-30
AU2006314769A1 (en) 2007-05-24
KR20080071563A (ko) 2008-08-04
BRPI0618761A2 (pt) 2011-09-13
DE102005054937A1 (de) 2007-05-24
CA2626778A1 (fr) 2007-05-24
WO2007057178A3 (fr) 2007-08-02
WO2007057178A2 (fr) 2007-05-24
JP2009515919A (ja) 2009-04-16

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