WO2021228870A1 - Endoprothèses biodégradables revêtues de laminine - Google Patents

Endoprothèses biodégradables revêtues de laminine Download PDF

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Publication number
WO2021228870A1
WO2021228870A1 PCT/EP2021/062507 EP2021062507W WO2021228870A1 WO 2021228870 A1 WO2021228870 A1 WO 2021228870A1 EP 2021062507 W EP2021062507 W EP 2021062507W WO 2021228870 A1 WO2021228870 A1 WO 2021228870A1
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WIPO (PCT)
Prior art keywords
article
coating
composition
stent
coating according
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PCT/EP2021/062507
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German (de)
English (en)
Inventor
Joachim Storsberg
Anne KRÜGER-GENGE
Jörg BOHRISCH
Jens MEHLHASE
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Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e. V.
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Priority to DE112021002757.3T priority Critical patent/DE112021002757A5/de
Publication of WO2021228870A1 publication Critical patent/WO2021228870A1/fr

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    • 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
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • 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
    • A61L31/041—Mixtures of macromolecular compounds

Definitions

  • the present invention relates to an article which consists of a polymer-based composition and is coated with laminin. This coated object can be used as a stent.
  • stents are used in everyday clinical practice nowadays.
  • Metal-based stents are characterized by high mechanical stability in the vessel.
  • the disadvantage of these stents is that they induce damage after being pressed into the vessel.
  • One possible consequence is intimal hyperproliferation with subsequent vascular occlusion through the formation of a neointima.
  • Another problem is the slow endothelialization of the stent surface, which can take several months.
  • Another disadvantage is the poorer representation of the surrounding tissue in cardio-CT [Lapp, Harald et al., Das Herzkatheterbuch, 2014, pp. 291-308]
  • polymer-based stents with or without drugs in the sheath surrounding the polymer have been developed.
  • the advantage of these stents is that they release substances over time which reduce intimal hyperproliferation after the stent has been pressed in, but at the same time also inhibit the colonization of the stent with endothelial cells.
  • there is no “clogging” of the stent by cells from the vascular intima but at the same time there is delayed endothelialization and thus again an increased risk of thrombus formation on the surface.
  • Endothelialization of the stent surface in view of the hemocompatibility of the materials with regard to minimizing inflammatory processes and thromboses is presented in detail in several current reviews. Furthermore, the specific properties of endothelial cells, their growth conditions and triggers by Krüger-Genge et al. [Int. J. Mol. Sci. 2019, 20, 4411] illuminated. The introduction of a stent into the vessel usually induces inflammation of the surrounding tissue and thus irritation, which in turn is associated with an increased risk for the patient.
  • a more controlled degradation behavior of a degradable stent could be achieved by an improved colonization of the degradable stent with vascular endothelial cells.
  • vascular endothelial cells Before a stent is completely colonized with endothelial cells after implantation in the vascular system, it takes a few weeks. This proliferation time could be shortened by coating the stent with materials that improve the growth of the endothelial cells. During this time, coatings of this type, which are intended to cause accelerated endothelialization of the surface, must remain stable on the surface of the stent. The permanent blood flow in the vascular system creates constant shear stress, which can have a negative effect on the applied coating. In the worst case, the coating will become detached and, subsequently, endothelialization will be delayed.
  • One object of the invention is to provide a stent with an antithrombogenic surface.
  • a further object of the invention is for the stent to degrade in a controlled manner within the vessel wall, thereby preventing fragments of the stent from getting into the interior of the vessel. Furthermore, it is an object of the invention that the coating of the stent withstands the shear stress in the in vivo vascular system.
  • the invention is based on the knowledge that a protein-containing coating on the stent can increase the growth of endothelial cells on the stent surface.
  • a stent consisting of a degradable polymer and a protein-containing coating according to the invention greatly reduces or even completely prevents the risk and the development of inflammation in the vascular system and the formation of thrombi and / or embolisms.
  • the inventors have thus found a hemocompatible stent comprising a biodegradable polymer.
  • the inventors have surprisingly found that the protein-containing coating in combination with a polysaccharide, which in a composition is incorporated, the shear resistance of the coating increases significantly.
  • the invention solves the problem that vascular supports (stents) made of polymers, in contrast to those made of metal, are visible in cardio-CT.
  • the invention relates to an article which is coated by a protein-containing coating.
  • the article comprising Composition A can be in any form, e.g. B. a tube shape,
  • Platelet shape, etc. and is coated with a coating consisting of Composition B.
  • the object preferably consists of a. a composition A comprising i. 85-100% by weight, preferably 85-99% by weight polyester and ii. optionally 1-15% by weight of polysaccharide based in each case on the total weight of the composition A, the surface of the article being at least partially covered with a coating b. consisting of a composition B comprising i. 50.0-100% by weight, preferably 99-100% by weight, laminin based on the total weight of the composition B, is coated.
  • the coating has the surprising effect that it accelerates the endothelialization of the object.
  • the increased endothelialization has the effect that improved hemocompatibility is achieved for the object with the coating, so that the stent degrades in a controlled manner in the vessel wall.
  • the composition B of the article contains a polyester, preferably biodegradable polyester, and a Polysaccharide. This has the additional effect that the polysaccharide is released from the object and gets into the environment.
  • a second aspect of the invention is a method for producing an article, preferably a stent, with a coating as described herein, wherein a) the polyester optionally with the polysaccharide in an extruder at 30-100 min 1 , preferably 40-60 min 1 revolutions for a period of 2-10 min, preferably 4-6 min, can be mixed to a composition A, and b) the composition A is formed into an article, and c) the article is coated with composition B.
  • composition A comprising a polyester, preferably biodegradable polyester, and optionally a polysaccharide can be coated with a coating consisting of the composition B, which contains laminin.
  • a third aspect of the invention is the use of the coated article as described herein for the increased growth of endothelial cells.
  • a fourth aspect of the invention is an article with a coating as described herein for use as a stent for blood vessels, preferably coronary vessels.
  • the object with the coating used as a stent has the effect that the stent breaks down in the vessel wall. Consequently, the object with coating used as a stent of blood vessels has the effect of breaking down broken fragments of the Stents cannot get into the bloodstream.
  • the object according to the invention with a coating thus has the surprising effect that the risk of thrombus formation or embolism in humans is reduced.
  • a preferred embodiment of the article according to the invention with a coating as described herein for use as a vascular support (stent) for blood vessels, preferably coronary vessels, has the effect that a polysaccharide can get into the bloodstream and, with an appropriate selection of the polysaccharide, the risk of inflammation can be minimized.
  • the endothelial cells are specialized, flat cells that line the inside of the blood vessels. They form a single-layer squamous epithelium, the endothelium. The most important function of the endothelial cells is the formation of a hemocompatible
  • Endothelialization means the new formation of the inner wall of the vessel.
  • a stent is a tubular stent in the form of a lattice that is made of metal, plastics or synthetic fibers. Stents are inserted into vessels or hollow organs in order to support them or to keep them open. A stent is used, among other things, for circulatory disorders of the coronary arteries, for example coronary heart disease or after an acute heart attack. After a vasodilatation, the stent is used for stabilization. In addition, it smooths the surface of the interior of the vessel because it is pressed against the vessel wall. The severity of the disease determines whether a stent is placed or not.
  • a lifestyle change no smoking, Weight control, a balanced diet and plenty of exercise
  • the use of medication are required for a lifetime.
  • the cardiac stent for coronary arteries is the most frequently used method with 300,000 procedures performed in Germany alone.
  • a stent implantation is performed when a permanent expansion of a closed vessel or hollow organ is no longer possible by simply expanding the vessels (percutaneous transluminal angioplasty, PTA). These cases include:
  • Aneurysm stroke in cases of narrowing of the carotid arteries (carotid stenosis), narrowing of the renal arteries (renal artery stenosis), narrowing of ducts (e.g. bile duct stenosis), narrowing of the coronary vessels in coronary artery disease (CHD), vessels become permanently closed due to arterial calcification, the so-called arteriosclerosis.
  • the following product classes are in use, among others: aliphatic and aliphatic / aromatic polyesters, polyesteramides, polylactides, starch and starch derivatives, as well as blends thereof and cellulose derivatives.
  • the biodegradability of polymers is determined by various factors.
  • the oxygen content, water content, pH value, temperature and pretreatment of the polymer are important [PL Nayak, j. Macromol. Sei., Rev. Macromol. Chem. Phys., 1999, C39 (3), 481]
  • the rate of degradation depends crucially on the crystallinity of the polymer. Due to the larger free volume and the greater mobility of the chain in the amorphous areas, erosion occurs faster there than in the crystalline areas Areas.
  • Biodegradable polymers are divided into biopolymers, which are naturally biodegradable, and synthetic biodegradable polymers.
  • the biopolymers include polypeptides such as proteins and bacterially synthesized polyesters as well as polysaccharides such as starch and cellulose. These natural polymers are mainly broken down enzymatically [T. Hayashi, Prog. Polym. Sci., 1994, 19, 663.]. Synthetic biodegradable polymers, on the other hand, are primarily degraded by chemical hydrolysis. This initially gives low molecular weight oligomers, which are then further hydrolyzed to the monomers and finally to carbon dioxide and water. A necessary property is the resorbability, ie the biological one
  • Polyesters are polymers with ester functions - [- CO-O -] - in their main chain. Aliphatic polyesters are biodegradable, but only partially usable due to their low melting temperature and tensile strength. Aromatic polyesters such as polyethylene terephthalate (PET), on the other hand, are not biodegradable, but have excellent material properties. PET is also very easy to recycle. To ensure biodegradability and good material properties the aliphatic are mixed (copolymerized) with the aromatic. One example is the Ecoflex copolymer.
  • This semi-crystalline material has been used in the manufacture of research medical devices and research tissue engineering solutions such as orthopedic or soft tissue fixation devices. The degradation of this material has been thoroughly studied and has been shown to be safely reabsorbed by the body after implantation. Modification of the molecular weight and the polymer composition enables the degradation rate and the mechanical stability of the polymer to be controlled.
  • PBSA poly (butylene succinate-co-butylene adipate)
  • PBSA poly (butylene succinate-co-butylene adipate)
  • PBSA Activated sludge.
  • PBSA breaks down completely into water and carbon dioxide.
  • PBSA has a low modulus and rapid biodegradability.
  • PBSA is commercially available under the trademark BioPBS TM FD92 by PTT MCC Biochem Co., Ltd., among others. available.
  • Laminin is a glycoprotein of the extracellular matrix contained in the basal lamina. It consists of a large complex (molecular weight 850-1,000 kDa) of three long asymmetrically cross-shaped peptide chains (A, B1 and B2) that are cross-linked by disulfide bridges. The polypeptide chains contain more than 1,500 Amino acid building blocks. Three types of A and B1 chains and two different forms of B2 chains are known, so that at least 18 different isoforms of L. can occur, seven of which have already been detected. Laminins are found in all basal laminae, and they have binding sites for cell surface receptors.
  • the laminins form the basement membranes mentioned.
  • Other important components of the basal lamina are fibronectin and a number of other proteoglycans [Timpl, R. et al., European Journal of Biochemistry 1978, 84, 43-52]
  • Polysaccharides also known as polysaccharides, glycans / glycans or polyoses
  • polysaccharides are carbohydrates in which a large number (at least eleven) monosaccharides (simple sugars) are linked via a glycosidic bond. They are biopolymers made up of at least eleven monosaccharide units or with a statistical distribution of molecular sizes.
  • a non-exhaustive list of polysaccharides includes: chondroitin 4 sulfate, chondroitin 6 sulfate, keratan sulfate, dermatan sulfate, heparan sulfate, heparin, alginic acid, chitosan, and hyaluronic acid.
  • Chitosan also known as poliglusam or poly-D-glucosamine or polyglucosamine, is a biopolymer, a naturally occurring polyaminosaccharide or a polysaccharide that is derived from chitin. Like this, it consists of ß-1,4-glycosidically linked N-acetylglucosamine residues (precisely 2-acetamido-2-deoxy-ß-D-glucopyranose residues). If there are more deacetylated 2-amino-2-deoxy-ß-D-glucopyranose units in the entire molecule, it is called chitosan. This results in linear molecules that consist of up to 2000 monomer units.
  • Chitosan is a colorless, amorphous, tough substance. Due to the free amino groups formed by the deacetylation, it is a polycation in non-alkaline solution with a high charge density. It's non-toxic, antibacterial, antiviral, and anti-allergenic.
  • the LD50 of chitosan is 16 g / kg body mass.
  • Hyaluronic acid is a macromolecular chain of disaccharides, which in turn consist of two glucose derivatives: D-glucuronic acid and N-acetyl-D-glucosamine. A chain typically consists of 250 to 50,000 disaccharide units. Accordingly, hyaluronic acid is a polysaccharide.
  • Hyaluronic acid (according to the more recent nomenclature hyaluronan, abbreviation HA) is a glycosaminoglycan that is an important component of connective tissue and also plays a role in cell proliferation, cell migration and metastasis in some cancers [Robert Stern: Hyaluronan in cancer biology. 1st edition. Academic Press / Elsevier, San Diego 2009; D. Vigetti, et al. Biochimica et Biophysica Acta, 2014, 1840, pp. 2452-2459]
  • Heparins are the body's own multiple sugars (polysaccharides) that have an inhibitory effect on the coagulation cascade and are therefore also used therapeutically for anticoagulation (blood coagulation inhibition). From a chemical point of view, these polyelectrolytes are glycosaminoglycans, consisting of a variable number of amino sugars with a molar mass between 4,000 and 40,000 (peak frequency around 15,000).
  • the injection molding process is a primary molding process in which a material
  • Plastic is liquefied (plasticized) in an injection molding machine and injected into a mold, the injection molding tool, under pressure. In the tool, the plastic returns to its solid state through cooling or a crosslinking reaction and is removed as a finished part after the tool is opened.
  • the cavity, the cavity, of the tool determines the shape and the surface structure of the finished part.
  • CAD milling process CAD stands for "Computer Aided Design” and refers to software programs that enable the computer-based construction of components. In doing so, detailed 3D models of the desired component are created with special CAD programs.
  • CNC milling belongs to the group of cutting processes and is based on computer-aided machine control. In contrast to turning, the main movement of the tool is carried out in rotational movements and the feed is perpendicular in the direction of the axis of rotation. Milling is an optimal manufacturing solution for more demanding 3-D contours and, according to DIN 8589, is one of the cutting processes with geometrically defined cutting edges.
  • the processing is carried out with special tools on automated milling machines, which, in addition to plastic and wood, safely mill almost all metals. Characteristic of this machining process is the circular chip removal with mostly multi-tooth tools and the recurring chip breaks.
  • FIG 1 Internal controls: HUVEC on TCP without further treatment (left) and after the addition of Triton (right) 48 hours after the cells had been seeded on the material.
  • FIG 2 Photo of HUVEC on CE PB SA (left) after 48 h after cell seeding and on IE PB SA after 72 h after cell seeding.
  • FIG 3 Photo of HUVEC on CE PB SA CI (left) after 48 h after cell seeding and on IE PB SA CI after 72 h after cell seeding.
  • FIG 4 Photo of HUVEC on CE PB SA C5 (left) after 48 h after cell seeding and on IE PB SA C5 after 72 h after cell seeding.
  • FIG 5 Photo of HUVEC on CE PB SA Hy5 (left) after 48 h after cell seeding and on IE PB SA Hy5 after 72 h after cell seeding.
  • FIG 6 Photo of HUVEC on CE PB SA He5 (left) after 48 h after cell seeding and on IE PB SA He5 after 72 h after cell seeding.
  • FIG 7 Photo of HUVEC on CE LC 703 (left) after 48 h after cell seeding and on IE LC 703 after 72 h after cell seeding.
  • FIG 8 Photo of HUVEC on IE LC 703 CI, IE LC 703 C5, IE LC 703 Hel, IE LC 703 He5, IE LC 703 Hyl, IE LC 703 Hy5, IE PBSA CI, IE PBSA C5, IE PBSA Hel, IE PBSA He5, IU PBSA Hyl, IU PBSA Hy5 after 72 h after cell seeding at 10x magnification.
  • FIG. 9 Bar chart showing the total number of HUVEC cells in laminin-treated platelets (IE). LC was included as an internal control.
  • FIG. 10 Bar chart showing the vitality of the HUVEC laminin-treated platelets (IE). LC was included as an internal control.
  • FIG 11 top two rows, photos of HUVEC (from columns left to right): after a shear test (IE PBSA S and IE PBSA C5 S), control test without a shear test (IE PBSA S static and IE PBSA C5 S static), control test without a shear test with fresh laminin (IU PBSA S fresh and IU PBSA C5 S fresh) and comparative example after a shear test (IE PBSA S and IE PBSA C5 S); lower row, photos by HUVEC: HC “high control” and LC “low control”.
  • FIG 12 top two rows, photos of HUVEC (from columns left to right): after a shear test (IE LC 703 S and IE LC 703 C5 S), control test without
  • Shear test (IE LC 703 S static and IE LC703 C5 S static), control test without a shear test with fresh laminin (IE LC703 S fresh and IE LC703 C5 S fresh) and comparative example after a shear test (IE LC703 S and IE LC703 C5 S); lower row, photos by HUVEC: HC “high control” and LC “low control”.
  • FIG 13 is a diagrammatic representation of FIG 13
  • PBSA Bar chart of the number of cells per mm 2 of A) PBSA (left to right: LC, CE PBSA S, IE PBSA S, IE PBSA S static), B) PBSA C5 (left to right: LC, CE PBSA C5 S, IE PBSA C5 S, IE PBSA C5 S static), C) LC 703 (left to right: LC, CE LC 703 S, IE LC 703 S, IE LC 703 S static), D) LC 703 C5 (left to right: LC, CE LC 703 C5 S, IE LC 703 C5 S, IE LC 703 C5 S static)
  • FIG 14 is a diagrammatic representation of FIG 14
  • PBSA Bar chart of the number of cells per mm 2 of A) PBSA (left to right: LC, CE PBSA S, IE PBSA S, IE PBSA S static), B) PBSA C5 (left to right: LC, CE PBSA C5 S, IE PBSA C5 S, IE PBSA C5 S static), C) LC 703 (left to right: LC, CE LC 703 S, IE LC 703 S, IE LC 703 S static), D) LC 703 C5 (left to right: LC, CE LC 703 C5 S, IE LC 703 C5 S, IE LC 703 C5 S static) DETAILED DESCRIPTION OF THE INVENTION
  • the invention relates to an object consisting of a. a composition A comprising i. 85-100% by weight, preferably 85-99% by weight, more preferably 92.5-99% by weight, polyester and ii. optionally 1-15% by weight, preferably 1-7.5% by weight, polysaccharide, each based on the total weight of the composition A, the surface of the article being at least partially covered with a coating b. consisting of a composition B comprising i. 50.0-100% by weight, preferably 99-100% by weight, laminin based on the total weight of the composition B is coated.
  • the composition A consists of 85-100% by weight, preferably 85-99% by weight, more preferably 92.5-99% by weight, polyester based on the total weight of the composition A and optionally 1-15% by weight .%, preferably 1-7.5% by weight, polysaccharide based on the total weight of the composition A.
  • the composition A comprises 85-99% by weight, preferably 92.5-99% by weight, polyester based on the total weight of composition A and 1-15% by weight, preferably 1-7.5% by weight,
  • composition A Polysaccharide based on the total weight of the composition A.
  • the endothelial cell growth is higher in contrast to a composition comprising exclusively polyester.
  • a synergistic effect between the polysaccharide and the coating of the object was surprisingly discovered, which ensures that the coating is more resistant to shear stress.
  • the article consists of 85-99% by weight, preferably 92.5-99% by weight, polyester based on the total weight of the composition A and
  • the composition B can consist of laminin.
  • the coating according to the invention can accordingly be laminin.
  • the object consists of a. a composition A consisting of i. 85-99% by weight, preferably 92.5-99% by weight, polyester and ii. 1-15% by weight, preferably 1-7.5% by weight, polysaccharide, each based on the total weight of the composition A, the article being coated with a coating consisting of laminin.
  • a composition A consisting of i. 85-99% by weight, preferably 92.5-99% by weight, polyester and ii. 1-15% by weight, preferably 1-7.5% by weight, polysaccharide, each based on the total weight of the composition A, the article being coated with a coating consisting of laminin.
  • the coating preferably covers the surface of the article to 90% -100%, preferably 98% -100%, of the area.
  • the effect of the coating is that the surface of the object is covered with endothelial cells to a greater extent and more quickly, i.e. endothelialized, than without a coating. Accordingly, it is preferred that the largest possible surface of the object is coated with the coating, since this results in improved endothelialization. However, inclusions or contamination can occur during the coating process, as a result of which practically not the entire surface of the object can be coated with the coating.
  • Coating means a firmly adhering layer of an informal material, preferably composition B, on the surface.
  • the coating can change the shape of the object, for example by filling holes or depressions in the object. However, it is preferred that the coating does not change the shape of the object, so that the basic pattern of the shape of the object remains recognizable even after the object has been coated.
  • the coating on the object can withstand shear forces such as occur, for example, in an in vivo vascular system with liquid blood or in an orbital shaker with medium. In other words, the coating does not completely detach from the article despite the shear forces. This has the effect that the
  • the coating is evenly distributed on the object.
  • a uniformly thin coating is preferred so that less of the
  • Composition B must be used, which is advantageous both economically and in practical application.
  • composition B can also contain other proteins in a weight proportion of 0-50.0% by weight, preferably 0-1.0% by weight, based on the total weight of the composition B.
  • Suitable proteins are those which are known to promote the proliferation of endothelial cells.
  • Composition B preferably does not contain collagen. Accordingly, the coating preferably does not contain any of the known 28 different types of collagen (types I to XXVIII) and the at least ten other proteins with collagen-like domains. However, it is preferred that the composition B contains no proteins other than laminin.
  • the coating consists of laminin.
  • the polyester in composition A is preferably biodegradable, more preferably enzymatically and / or hydrolytically. It is particularly preferred that the polyester in composition A is enzymatically, even more preferably by human enzymes, and / or hydrolytically degradable.
  • the polyester in composition A is preferably selected from a list consisting of polylactic acid (PLA), polyglycolic acid (PGA), poly-e-caprolactone (PCL), polyhydroxybutyrate (PHB) and poly (3-hydroxyvalerate), poly (ethylene succinate) ( PESu), poly (propylene succinate) (PPSu) and poly (butylene succinate) (PBSu), poly-e-carolactone, poly (dioxanone), poly (L-lactide-co-glycolide), poly (L-lactide-co-e -Caprolactone, poly (butylene succinate-co-adipate and / or a mixture thereof, more preferably from a list consisting of
  • the polyester in Composition A is a copolymer.
  • the use of a copolymer has the advantage that the mechanical properties of the polyester and the degradation of the polyester and also of the composition A can be adapted to the respective requirements.
  • the polysaccharide in composition A may preferably comprise chitosan, heparin and / or hyaluronic acid. It is particularly preferred that the polysaccharide in composition A is selected from a list consisting of chitosan, heparin, hyaluronic acid or mixtures thereof.
  • the polysaccharide in composition A can form strong ionic interactions, which can ensure a more stable bond between the coating and the polyester.
  • the strong ionic interactions formed by functional groups such as. B. amino, carboxyl or sulfate / sulfonamide groups ensure a more stable connection of the coating to the polyester.
  • a coating containing the functional group e.g.
  • Amino, carboxyl or sulfate / sulfonamide groups involves more stable bonding to polyester as a coating than a low molecular weight molecule that does not contain any amino, carboxyl or sulfate / sulfonamide groups.
  • the polysaccharide in particular comprising amino, carboxyl or sulfate / sulfonamide groups, has the effect of making the coating according to the invention more shear-resistant.
  • the polyester of composition A preferably has an inherent viscosity of at least 0.5 dl / g.
  • the upper limit of the inherent viscosity is usually 3 dl / g.
  • the inherent viscosity is preferably in a range of 0.5-3 dl / g, more preferably in a range of 1-2 dl / g, especially preferably in a range of 1-1.8 dl / g, particularly preferably in a range of 1.3 - 1.8 dl / g measured as a 0.1% (w / v) solution in CHCh at 25 ° C with an Ubbelohde 0c glass capillary viscometer.
  • the polyester preferably has a melt index (MFI) of at least 2 g / 10 min.
  • the upper limit of the melt index (MFI) is usually 10 g / 10 min.
  • the melt index (MFI) is preferably in a range from 2-10 g / 10 min, more preferably in a range of 2-6 g / 10 min, 3-5 g / 10 min, particularly preferably in a range of 3.5-4.5 g / 10 min according to ISO 1183.
  • the article is preferably sterile without a coating, more preferably sterile with a coating. In order to obtain a sterile article with a coating, a sterile article and a sterile coating are brought together.
  • the object is freed from living microorganisms, including their dormant stages (e.g. spores), preferably in a process.
  • Suitable processes are sterilization processes for thermal sterilization (steam sterilization, hot air sterilization, fractional sterilization), chemical sterilization (wet antiseptics, dry antiseptics, alcohol-containing solvents), physical sterilization (high pressure sterilization, radiation sterilization, plasma sterilization, sterile filtration).
  • the article is preferably in the form of a periodically arranged braid in a tubular shape.
  • a periodically arranged braid can e.g. B. be a grid.
  • a tube is an elongated hollow body, the length of which is generally much greater than its diameter and made of a relatively inflexible material.
  • Another aspect of the invention is a method for producing an article with a coating as described herein, wherein a) the polyester, optionally with the polysaccharide, in an extruder at 30-100 min 1 , preferably 40-60 min 1 revolutions for a period of 2-10 min, preferably 4-6 min, are mixed to a composition A, and / or b) the composition A is formed into an object, and / or c) the object is coated with composition B.
  • the object with the coating preferably has all the properties and technical features described herein.
  • the object is shaped by injection molding processes, CAD milling processes, 3D printing and / or laser cutting.
  • CAD milling process it is meant that a digital model is constructed using a computer-aided design (CAD) software program, this digital CAD model is converted into a Computerized Numerical Control (CNC) program and that the CNC program is a CNC Manually assisted or automatically operated machine, which mills the model into a material.
  • CNC Computerized Numerical Control
  • Objects, in particular stents can be manufactured using 3D printing [Guerra, Antonio J .; Cano, Paula; Rabionet, Marc; Puig, Maria; Ciurana, Joaquim, Materials 2018, 11, 1679], injection molding (WO 002002041929 Al), CAD milling and / or laser cutting (DE 102004043166 Al) can be achieved.
  • the object is preferably placed in a solution which has the composition B in a range of 50-80 pg / mL, preferably 55-70 pg / mL, more preferably 55-65 pg / mL, particularly preferably contains 60-65 pg / mL.
  • the solution is preferably an aqueous solution.
  • the solution can be buffered with conventional buffers used in cell culture, such as, for example, Tris / HCl or Dulbecco's phosphate-buffered saline solution (PBS).
  • PBS Dulbecco's phosphate-buffered saline solution
  • the article is then preferably incubated in the solution and then removed from the solution.
  • the incubation time is preferably 1 to 3 hours.
  • the incubation temperature is preferably 10-40 ° C, more preferably 15-30 ° C.
  • the coated object is usually dried.
  • the drying time is preferably 0.1-1 hour. The soaking of the object in a solution with the composition B has the effect that the composition B can settle on the object, preferably evenly.
  • Taking out of the solution means that the object with / or without a coating is no longer in contact with the solution. Accordingly, the active removal of the object with / or without a coating from the solution is not necessarily meant as an activity, since the object can no longer come into contact with the solution by other methods (e.g. draining, suctioning, evaporation, etc.) Have solution.
  • the object is preferably sterilized before being coated with composition B in process step b).
  • the object according to the invention is sterilized by placing it in an alcoholic solution.
  • the article is preferably coated with Composition B in
  • Process step b) sterilized but not otherwise pretreated.
  • Objects are usually pretreated prior to coating to allow for improved adhesion.
  • Pre-treatment means that the surface of the object is mechanically or chemically changed. It has been found that, in the method according to the invention, such a pretreatment step is not necessary for improved adhesion.
  • Another preferred aspect of the invention is the use of the article with a coating as described herein for improved adherence of the endothelial cells to the article with a coating.
  • the improved adherence of the cells has the consequence that the proliferation of the endothelial cells is increased. Only adherent cells can proliferate.
  • the use of the article with a coating ensures increased growth of endothelial cells, preferably vascular ones Endothelial cells.
  • Increased growth of endothelial cells means that the rate at which the endothelial cell grows increases through cell division.
  • the article according to the invention with a coating shows greater growth of endothelial cells compared with the same article without a coating.
  • the object according to the invention is used as described herein for increased growth of endothelial cells on the surface of the object according to the invention.
  • the increased growth of endothelial cells has the effect that the surface of the object with coating can be occupied more quickly by endothelial cells.
  • the increased growth or faster occupation of a surface can be measured by the area occupied by endothelial cells per time.
  • the object of comparison for the increased endothelial cell growth is the same object made of the same material only without a coating and with the same shape and size.
  • the endothelial cells preferably grow under the influence of shear forces on the object according to the invention with a coating.
  • Another aspect of the invention is an article with a coating as described herein for use as a stent for blood vessels, preferably coronary vessels.
  • the stent can promote the growth of endothelial cells in the blood vessel of a mammal, preferably a human.
  • the surface of the stent vessel with the coating can be occupied more quickly by endothelial cells in the blood vessel of a mammal, preferably a human.
  • the stent used in mammals, preferably humans, can degrade within 6 to 36 months. With dismantling it is meant that the Stent decomposes, i.e. divides into several parts.
  • the stent is preferably broken down enzymatically and / or by chemical hydrolysis. In other words, the stent reacts with the environment in the blood vessel at body temperature, preferably at 36-37.5 ° C., and is hydrolytically and / or enzymatically degraded in the process.
  • the starting time from which the breakdown of the stent is counted is the day on which the stent is inserted into the mammal, preferably humans.
  • the stent can deliver active ingredients, preferably polysaccharides, to the vascular system, preferably over a period of at most 36 months, preferably between 6 and 36 months.
  • active ingredients preferably polysaccharides
  • the starting time from which the release of the active ingredient is counted is the day on which the stent is inserted into the mammal, preferably human.
  • the object with a coating especially the vascular support (stent) of blood vessels, preferably has all the properties and technical features of the object according to the invention with a coating as described herein for all of the uses described above.
  • LC 703 S and PBSA were selected from a large number of biodegradable polyesters.
  • the polyesters were optionally mixed with polysaccharides (chitosan, heparin, hyaluronic acid) in the "Mini Lab HAAKE Rheomex CTW5" from Thermo Electron Corporation to form a compound.
  • polysaccharides chitosan, heparin, hyaluronic acid
  • the optimal Extrusion conditions determined (Table 1).
  • the platelets were transferred to a 12-well plate with sterile forceps. 1 mL of 70% ethanol (in water) was placed on each of the platelets. After 1 hour, the ethanol was removed and the platelets were dried under the sterile bench.
  • Polyester LC 703 poly (L-lactide-co-s-caprolactone) marketed under the name LC 703 S by Evonik, consisting of 70 wt.% L-lactide and 30 wt.% E-caprolactone based on the total weight of the poly ( L-lactide-co-s-caprolactone), biodegradable.
  • the inherent viscosity of the composition A is 1.3-1.8 dl / g (measured as a 0.1% (w / v) solution in CHCb at 25 ° C with a
  • Polyester PBSA poly (butylene succinate-co-adipate) under the trademark BioPBS TM FD92 manufactured by PTT MCC Biochem Co., Ltd., consisting of 75 wt.% Butylene succinate and 25 wt.% Butylene adipate based on the trademark BioPBS TM FD92 manufactured by PTT MCC Biochem Co., Ltd., consisting of 75 wt.% Butylene succinate and 25 wt.% Butylene adipate based on the
  • melt index 4 g / 10 min according to ISO 1183.
  • Polysaccharide chitosan (low-viscosity, ⁇ 200 mPa.s, 1% in acetic acid (20 ° C)), marketed by SIGMA, (product no .: 50494, lot # BCBW4761, CAS no .: 9012- 76- 4) isolated from shrimp cells.
  • Polysaccharide heparin marketed as sodium salt by SIGMA-ALDRICH (Product No .: H4784, Lot # 041M1271V, CAS No .: 9041-08-1, isolated from porcine intestinal mucosa.
  • HUVEC human venous endothelial cells
  • HUVEC was freshly thawed and then cultivated in EGM TM -2 Endothelial Cell Growth Medium-2 + BulletKit TM at 37 ° C. and 5% CO2.
  • the cells were then trypsinized and the number of cells was determined using a cell counter. After the number of cells had been set, 3 ⁇ 10 4 cells / well (24-well plate) in 1 mL of medium were sown on the sterile coated examples or comparative examples, which had previously been placed in 24-well plates.
  • the coated examples or comparative examples were incubated for a maximum period of 72 hours at 37 ° C. and 5% CO2.
  • the comparative examples or after 72 h for the coated examples were colonized with HUVEC and the vitality of the cells with fluorescein diacetate (FDA; Sigma-Aldrich, stock solution: 5mg / mL in acetone) and propidium iodide (PI; Sigma; stock solution: 1.0 mg / mL in ultrapure water) coloration determined.
  • FDA fluorescein diacetate
  • PI propidium iodide
  • Comparative examples transferred with sterile tweezers into a 24-well plate which contained 1 mL staining solution (1 mL EGM TM -2 + 2 m ⁇ FDA + 4 m ⁇ PI). After a 3-minute incubation at 37 ° C. and 5% CO2, images were taken with an inverted microscope with fluorescence excitation. In order to get an overview of the colonization (confluence) of the material and the vitality of the cells, images were recorded in 10x primary magnification. To assess the cell morphology, images were taken at a higher magnification (20x primary magnification).
  • HUVEC which had been colonized on TCP for 48 h, were used as negative controls.
  • HUVEC were used, which were also resettled on TCP for 48 h, but were then lysed by the addition of Triton and thus killed (visible through red coloring of the cells).
  • the internal controls used confirmed the vitality and proliferation ability of the HUVEC used (negative control) and the functionality of the staining method used (negative control and positive control). Vital cells were colored green, dead cells were colored red (Tab. 2) (see FIG. 1)
  • coated examples or comparative examples were tested for their properties in cell culture.
  • HUVEC which could be detected on the material, were vital, but accumulated in cluster-shaped colonies (see, for example, FIG. 2, FIG. 3, FIG. 4, FIG. 5, FIG. 6, FIG. 7). This indicates that the cells could only inadequately adhere to the uncoated comparative example. The spread of cells on the material was minimal. There was therefore no typical HUVEC morphology. A quantification of the number of cells and the resulting vitality was therefore not possible.
  • the comparative examples are accordingly not suitable for the cultivation of HUVEC.
  • the overall rating for all comparative examples is:
  • IE PBSA C5 In the case of IE PBSA C5, after 72 hours of cultivation of the HUVEC, the IE PBSA C5 was very well colonized by the HUVEC. The typical spread of HUVEC on IE PBSA C5 was shown with a vitality of approx. 97%. There was a slight activation of the HUVEC, visible through the migration of the HUVEC and an elongated cell body (FIG. 4). Hence the overall rating is: ++.
  • IE PBSA He5 showed good growth on IE PBSA He5 after 72 hours of cultivation of the HUVEC, but with irregular colonization by the HUVEC. A vitality of approx. 99% on IU PBSA He5 was shown. There was an activation of the HUVEC, visible through the migration of the HUVEC (FIG. 5). So the overall rating is +.
  • IE PBSA Hy5
  • the total number of cells (FIG. 9) and vitality of the cell (FIG. 10) were observed in the same ratio in each case. If vitality is comparable, the total number of adherent HUVEC cells should be prioritized.
  • the shear resistance of the applied coating in vitro was checked over 72 hours. To investigate whether the applied coating was shear-resistant, HUVEC was sown on the samples after 72 hours and then incubated with the samples in the incubator for 48 hours. The number of adherent cells was then determined via a live / dead staining with subsequent cell counting and vitality calculation.
  • the platelets PB SA, PB SA C5, LC 703 and LC 703 C5 were transferred under the sterile bench to a sterile 24-well plate in order to obtain the coated platelets.
  • Table 4 Comparative examples and coated examples
  • the coated examples and comparative examples were each used in one well of a 24-well plate. 1 mL of EGM TM -2 Endothelial Cell Growth Medium-2 BulletKit TM from (Lonza # CC-3162) was added to the well. The 24-well plate was then shaken on a thermal shaker at 145 rpm (rotation of the orbital shaker) and 37 ° C. for 72 h.
  • the coated examples and comparative examples were each used in one well of a 24-well plate. 1 mL of EGM TM -2 Endothelial Cell Growth Medium-2 BulletKit TM from (Lonza # CC-3162) was added to the well. The 24-well plate was then placed in an incubator at 37 ° C. for 72 h.
  • the sterile coated examples or comparative examples from D2a) were each placed in a 24-well plate and a sterile glass ring was placed on each of the plates.
  • coated examples or comparative examples were incubated for a period of 48 hours at 37 ° C. and 5% CO2.
  • the comparative examples and coated examples were colonized with HUVEC and the vitality of the cells with fluorescein diacetate (FDA; Sigma-Aldrich, stock solution: 5mg / mL in acetone, product number: F7378) and propidium iodide (PI; Sigma; stock solution: 1, 0 mg / mL in ultrapure water, product number 81845) coloration determined.
  • FDA fluorescein diacetate
  • PI propidium iodide
  • the respective coated examples or comparative examples were dipped into PBS (- / -) with sterile tweezers and then transferred into the staining solution, which contained 1 mL staining solution (1 mL EGM TM -2 + 2 ml FDA + 4 ml PI). After a 3-minute incubation at 37 ° C. and 5% CO2, images (5x, 10x, 20x magnification) were recorded with an inverted microscope under fluorescence excitation. In order to get an overview of the colonization (confluence) of the material and the vitality of the cells, images in lOx
  • FDA stains vital cells in green (FDA passes through the intact cell membranes and is split into fluorescein by cytosolic esterases, among other things; fluorescein accumulates in the cytosol and fluoresces green when excited with blue light)
  • PI stains dead cells red (storage of the dye in the DNA of dead cells due to the non-intact cell membrane).
  • control test B control test fresh laminin without shear
  • Comparative examples and coated examples which were prepared as in Dl) were seeded without further delay with HUVEC cells as described in D3a).
  • Table 5 Overview of the investigated HUVEC growth with and without shear conditions of the laminine coating (see FIG. 13 and FIG. 14).
  • the shear resistance was evaluated on the basis of the comparative photos in FIG. 11 for platelets made from PBSA or PBSA C5, or in FIG. 12 for platelets made from LC 703 or LC703 C5 and by the cell count or the vitality in FIG. 13 and FIG. Table 6a) Total number of cells per mm 2 (see FIG. 13)
  • the control has a total cell count of 489.6 per mm 2
  • Table 6b Total number of cells per mm 2 (see FIG. 14)
  • the control (TCP) has a vitality of 99.8%.
  • the cell count in FIG. 13 and Table 6a shows, in summary, that especially the polyesters with a polysaccharide, such as. B. C5, provides an improved shear resistance of the coating.
  • the respective low control in the diagram shows the highest number of cells as a control.
  • IE PB SA it was found that IE PB SA S is only minimally better than CE PB SA S, measured in terms of the number of cells per mm 2.
  • IE PBSA S has a significantly smaller cell number than IE PBSA S static (see Table 6a). It can therefore be assumed that the coating is not resistant to the shear conditions.
  • PBSA C5 it can be seen that IE PBSA C5 S is significantly better than CE PBSA C5 S, measured in the number of cells per mm 2.
  • IE PBSA C5 S is comparable to the value from IE PBSA C5 S static (see Table 6a). It can therefore be assumed that the coating is resistant to the shear conditions.
  • IE LC 703 S is only minimally better than CE LC 703 S, measured in terms of the number of cells per mm 2.
  • IE LC 703 S has a smaller number of cells than IE LC 703 S static (see Table 6a). It can therefore be assumed that the coating is not resistant to the shear conditions.
  • IE LC 703 C5 S is more than twice as high compared to CE LC 703 C5 S, measured in the number of cells per mm 2.
  • IE LC 703 C5 S even has a higher cell count than IE LC 703 C5 S static (see Table 6a). It can therefore be assumed that the coating is resistant to the shear conditions.
  • the vitality shown in FIG. 14, no significant difference can be seen and all the systems tested showed a high vitality (see Table 6b) comparable to the low control.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Chemical & Material Sciences (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un produit constitué d'une composition A comprenant du polyester et éventuellement un polysaccharide, le produit étant revêtu d'un revêtement constitué d'une composition B comprenant de la laminine. L'invention concerne en outre un procédé de fabrication dudit produit avec le revêtement, l'utilisation du produit avec le revêtement pour une croissance accrue de cellules endothéliales, et enfin le produit avec le revêtement pour une utilisation en tant qu'endoprothèse pour vaisseaux sanguins, de préférence des vaisseaux sanguins coronaires.
PCT/EP2021/062507 2020-05-14 2021-05-11 Endoprothèses biodégradables revêtues de laminine WO2021228870A1 (fr)

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WO2002041929A1 (fr) 2000-11-21 2002-05-30 Schering Ag Tuteurs intravasculaires tubulaires (stents) et leurs procedes de production
WO2003072748A2 (fr) * 2002-02-22 2003-09-04 University Of Washington Substituts de tissus resultant de manipulations genetiques
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WO2003072748A2 (fr) * 2002-02-22 2003-09-04 University Of Washington Substituts de tissus resultant de manipulations genetiques
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EP1913961A1 (fr) * 2006-10-17 2008-04-23 Cheng Henrich Conduit pour la régénération nerveuse modifié avec de la laminine et sa méthode de préparation.
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