US20040091605A1 - Method of coating a stent with a polysaccharide layer and associated stents - Google Patents
Method of coating a stent with a polysaccharide layer and associated stents Download PDFInfo
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- US20040091605A1 US20040091605A1 US10/444,827 US44482703A US2004091605A1 US 20040091605 A1 US20040091605 A1 US 20040091605A1 US 44482703 A US44482703 A US 44482703A US 2004091605 A1 US2004091605 A1 US 2004091605A1
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- layer
- hyaluronic acid
- bonding
- polysaccharide
- crosslinked
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Classifications
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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
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
-
- 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
- A61L2420/00—Materials or methods for coatings medical devices
- A61L2420/02—Methods for coating medical devices
-
- 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
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
- Y10S623/90—Stent for heart valve
-
- 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
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
- Y10S623/901—Method of manufacturing prosthetic device
-
- 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
- Y10T428/31504—Composite [nonstructural laminate]
- Y10T428/31536—Including interfacial reaction product of adjacent layers
Definitions
- the invention concerns methods of coating stents, in particular cardiovascular implants, with a polysaccharide layer or polysaccharide derivative layer, and stents produced in accordance with such methods.
- polysaccharides are known to be biocompatible. Typical representatives in this connection are heparin, chitosan, alginate or hyaluronic acid. The latter have proven on the one hand to be highly body-compatible while on the other hand coatings of hyaluronic acid are hydrophilic and consequently the devices provided therewith can be well implanted.
- Implants coated with polysaccharides in general and hyaluronic acid in particular and methods of coating them with hyaluronic acid are known from the state of the art in many different forms.
- U.S. Pat. No 6,042,876, to Deem discloses a guide wire for implantation purposes, which is coated with such a polysaccharide such as hyaluronic acid or chondroitin sulfate.
- PCT publication WO 8802623 A1 by Guire at Bio-Metric Systems, Inc., relates to biomaterials with a biocompatible surface, wherein among a large number of starting materials and binding mechanisms there is disclosed inter alia the use of hyaluronic acid for the production of a biocompatible contact lens.
- This publication is related to U.S. Pat. Nos. 4,979,959 and 5,263,992.
- the object of the present invention is to provide a method of coating stents with a polysaccharide layer which enjoys improved adhesion on the substrate surface of the implant, and to afford correspondingly fuctionalized stents.
- a fourth variant (IV) provides that the method steps are to be carried out as follows:
- Basic variants I and V of the methods according to the invention by virtue of covalent bonding of the non-crosslinked polysaccharide, provide for a significant increase in the adhesive capability of the polysaccharide layer, which can be demonstrated by experiment.
- the further layer can be applied in the form of a non-crosslinked polysaccharide and can then be crosslinked or it can be applied directly as a crosslinked polysaccharide.
- An especially suitable polysaccharide for use in the method according to the invention is hyaluronic acid, which has already been referred to above, and which can be applied to the most widely varying substrate surfaces of implants.
- Alloplastic vessel wall supports referred to as “stents”—are usually coated with amorphous silicon carbide (a-SiC:H) which involves a particularly intimate and adhesively strong bond to hyaluronic acid.
- a-SiC:H amorphous silicon carbide
- the substrate surface was flushed with water and incubated in a 20 ⁇ 10 ⁇ 6 -molar Fmoc-p-Bz-Phe-OH-solution in N,N′-dimethylformamide (DMF).
- the Fmoc-p-Bz-Phe-OH-solution which is effective as a photoactive spacer substance, can be obtained as a commercial product “Fmoc-p-Bz-Phe-OH”, product number B 2220 from Bachem Biochemica GmbH, of Heidelberg, Germany.
- Reduction of the benzophenone was initiated by irradiation with UV light. After the UV irradiation operation, the reaction solution was poured off and the substrate surface rinsed a plurality of times with distilled water.
- the next step involves cleavage of the Fmoc protective group with 25% piperidine solution in DMF. Bonding of the hyaluronic acid takes place at the amino group which is now exposed and reactive. For that purpose, non-crosslinked hyaluronic acid was firstly covalently bound to the substrate surface treated in that way. The polysaccharide layer formed in that fashion can then be crosslinked.
- polysaccharides and, in particular, hyaluronic acid
- silanized benzophenones epoxysilanes and aminosilanes as spacer substances
- Covalent bonding of the hyaluronic acid to the benzophenone present was effected under the action of UV radiation at a wavelength of 340 nm which initiates the reduction of the benzophenone.
- the photochemical reaction can also be implemented in aqueous hyaluronic acid solution. That photochemical reaction resulted in covalent bonding between the benzophenone and a C—H-group of the polymer chain, in particular of the hyaluronic acid. That polysaccharide layer, which was covalently bound to the substrate surface, was then crosslinked.
- hyaluronic acid can be effected by incubation in a 0.25% hyaluronic acid solution in a 0.1 m HCl at 65° C. for 1 h.
- Chitosan can be bound by incubation in a 0.2% chitosan solution in a 1-2% acetic acid solution at 65° C. for 1 h.
- the stents were then rinsed with deionized water and thereafter dried.
- the polysaccharide layer which is covalently bound to the substrate surface, was then crosslinked.
- a good adhesive effect can be achieved by a covalently bound chitosan layer (monolayer).
- the glycosaminoglycan chitosan (Mw: 100,000 to 1,000,000 Daltons) was covalently bonded by means of a spacer in a chemical multi-stage reaction to an amorphous silicon carbide layer (a-SiC:H) which covers the basic body of the stent.
- the spacer the photoactive benzophenone component Fmoc-p-Bz-Phe-OH (N-(9-Fmoc)-l-(4-benzoyl)-phenylalanine; 2 ml; 10 mmol/l; available from Bachem)- was covalently bonded to the silicon carbide by photochemical reaction in the solvent N,N′-dimethylformamide (DMF). After rinsing with DMF, cleavage was effected in respect of the Fmoc protective group of the spacer with a 20% piperidine solution in DMF. The amino group of the spacer was then free.
- DMF N,N′-dimethylformamide
- the stent was then incubated in a 0.2% solution of chitosan in 1% acetic acid and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (50 mg/ml) for at least 12 hours in ice-cold water.
- Covalent coupling of the chitosan was effected by linkage of a peptide bond between the activated carboxylic acid of the spacer and the amino group of the chitosan or the formation of an ester bond between the activated carboxylic acid of the spacer and the hydroxyl group of the chitosan.
- the sample was repeatedly rinsed with deionized water and then dried.
- a bonding agent layer which is a few nanometers thick was applied to the cleaned substrate surface.
- the polymer layer served as a bonding agent and had functional groups at the surface, which are suitable for subsequent covalent bonding of a polysaccharide layer.
- Such a bonding agent layer can be produced by plasma polymerization of N-heptylamine and acetaldehyde.
- the plasma polymerization operation was effected with a 40 kHz plasma installation of Piko type from Diener electronics.
- acetaldehyde amyl alcohol, allylamine, acetoacetic acid ester or acrylic acid.
- the plasma-polymerized layers exhibited good wetting with hyaluronic acid solutions by virtue of their hydrophilic nature.
- a thin layer of hyaluronic acid or other polysaccharides can be coupled to the functional surfaces by means of glutaraldehyde, epichlorhydrin or carbodiimides.
- the container was flushed with oxygen for the definitive removal of residual gas, in which case it is continuously evacuated.
- a flushing gas flow of about 40 cm 3 /min was set.
- the sample space was flushed for 10 minutes and the plasma was ignited in the presence of a Teflon block for the surface activation procedure.
- the power of the reactor was about 200 W and an oxygen flow of about 40 cm 3 /min was maintained during the surface treatment. Activation and simultaneous plasma purification lasted for 5-10 min.
- the hyaluronic acid was then covalently bonded by means of a water-soluble carbodiimide to the substrate-bonding agent layer complex.
- Covalent bonding of the hyaluronic acid to the acetaldehyde plasma polymer was effected directly by means of a diimidazole or with bonding of a polyethylene imine intermediate layer which is applied by means of reductive amination.
- Covalent bonding of the hyaluronic acid to that substrate-bonding agent complex was effected by means of a water-soluble carbodiimide.
- the polysaccharide layer which is covalently bonded to the bonding agent layer was then crosslinked.
- the substrate surface was functionalized by derivatized polyhydroxybutyric acid, which exhibits an experimentally demonstrated good layer adhesion to silicon carbide and metals.
- Functionalization of the polyhydroxybutyric acid was effected by amination.
- Covalent bonding of the hyaluronic acid to the amino group of the functionalized polyhydroxybutyric acid (bonding agent layer) was effected by means of a water-soluble carbodiimide, with the formation of a peptide bond.
- a monolayer of chitosan was produced in the following manner.
- the pre-cleaned stent was dried at 75° C. for 30 minutes in a drying oven.
- the stent while still warm, was incubated for 10 minutes in a silane solution of 3 ml of water-free toluene, 20 ⁇ l of 3-[2-(2-aminoethylamino)-ethylamino]-propyl-trimethoxysilane and 70 ⁇ l of Et 3 N at ambient temperature with repeated slight agitation.
- the stents were then dried at 75° C. for 1 hour. Thereafter the stent was rinsed with toluene or chloroform and dried again.
- the next step was covalent coupling of adipinic acid by way of a solution of 10 mg/ml of adipinic acid in water for the production of functional carbonyl functions, to the surface of the implant.
- the adipinic acid had been previously activated in THF or DMF with a carbodiimide or diimidazole. After rinsing in deionized water and drying, the operation of bonding chitosan took place.
- the implant was incubated in a 0.2% solution of chitosan in a 1-2% acetic acid solution at ambient temperature for 1-4 hours. That was followed by rinsing with deionized water and drying.
- the crosslinking of hyaluronic acid with glutaraldehyde can be implemented.
- the implant was coated with a 0.1-2% hyaluronic acid solution and then subjected to the action of a crosslinker solution for several hours.
- the crosslinker solution comprised 240 ml of acetone, 80 ml of glutaraldehyde in 25% solution in water and 1.6 ml of HCl 3 M. Thereafter the crosslinker solution was replaced by a fresh solution and incubation was again effected at ambient temperature for several hours.
- the hyaluronic acid crosslinked by means of glutaraldehyde was washed several times in distilled water.
- the sample was incubated in a 0.5-3% solution of sodium cyanoborohydride for one hour at ambient temperature.
- the fixer solution was removed and the procedure then involveed a plurality of washing steps in doubly distilled water and isotonic saline solution.
- hyaluronic acid it is also possible to implement crosslinking and covalent bonding of the hyaluronic acid to layer systems comprising amorphous silicon carbide spacer and an amorphous silicon carbide-spacer-polysaccharide monolayer with diimidazole.
- the implant with bound spacer or with a polysaccharide layer was immersed in a diimidazole-bearing acetone solution.
- the substrate-spacer complex or the polysaccharide layer was activated for at least 30 minutes in the diimidazole-bearing acetone solution and then immersed in an aqueous hyaluronic acid solution or sprayed with a hyaluronic acid solution.
- the stent was sprayed for 0.5-1 sec at a pressure in respect of the carrier air of 2-4 bars. Between the spraying steps, the stent was dried for 15-30 sec with a supply of warm air. Repeating the steps makes it possible to produce a desired layer structure on the stent. In order to achieve layer growth, that process was repeated a plurality of times.
- Hyaluronic acid was suspended in dry pyridine in a nitrogen atmosphere in a thermostatizable double-wall reactor with a reflux condenser and an agitator. A sulfur trioxide-pyridine-complex was added to that suspension and heated to the desired reaction temperature. After 3 hours, the reaction was terminated and the suspension, when cooled to ambient temperature, was poured into five times the amount of methanol. The precipitated polymer was filtered off, dissolved in water and dialyzed in relation to de-ionized water.
- the pH-value of the polymer solution after dialysis was adjusted to 11 by the addition of 0.1 N soda lye. Dialysis and titration were repeated three times. At a pH-value of 7.3 the polymer was freeze-dried.
- Active substance loading with suitable drugs was generally effected after crosslinking and fixing of the polysaccharide layer in the swollen condition.
- the active substance can be furnished by means of a spraying or immersion process prior to the coating step or during coating with the polysaccharide.
- Active substance embedding was generally effected by way of diffusion processes.
- the active substance was embedded by way of an immersion process in a hyaluronic acid layer as can be obtained in accordance with one of the preceding examples.
- the implant was immersed in a solution of 15 mg of cyclosporin per ml of a paritetic ethanol-water mixture.
- the ratio of 1:1 of ethanol to water has proven to be surprisingly effective for implementation of the diffusion process.
- Other ratios, especially those with an elevated ethanol content, slow down the embedding effect.
- the implant remained in the solution for at least one hour.
- the implant was then removed and dried. With a coating amount of 0.5 mg of hyaluronic acid, the amount of cyclosporin which can be incorporated in that way was at least 0.2 mg.
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- Heart & Thoracic Surgery (AREA)
- Surgery (AREA)
- Vascular Medicine (AREA)
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Abstract
The invention concerns methods of coating stents and stents produced in accordance therewith. The object of the invention is to provide methods of coating stents with a polysaccharide layer which has improved adhesion capacity on the substrate surface of the implant, and to afford correspondingly functionalized stents. That is achieved inter alia by covalent bonding of a non-crosslinked hyaluronic acid to a substrate surface of the stent with the formation of hyaluronic acid layer and crosslinking of the hyaluronic acid layer.
Description
- The invention concerns methods of coating stents, in particular cardiovascular implants, with a polysaccharide layer or polysaccharide derivative layer, and stents produced in accordance with such methods.
- In regard to the background of the invention it is to be stressed that polysaccharides are known to be biocompatible. Typical representatives in this connection are heparin, chitosan, alginate or hyaluronic acid. The latter have proven on the one hand to be highly body-compatible while on the other hand coatings of hyaluronic acid are hydrophilic and consequently the devices provided therewith can be well implanted.
- Implants coated with polysaccharides in general and hyaluronic acid in particular and methods of coating them with hyaluronic acid are known from the state of the art in many different forms. Thus, U.S. Pat. No 6,042,876, to Deem (Mar. 28, 2000), discloses a guide wire for implantation purposes, which is coated with such a polysaccharide such as hyaluronic acid or chondroitin sulfate.
- Della Valle, in U.S. Pat. No. 4,957,744 (Sep. 18, 1990), teaches the crosslinking of esters of hyaluronic acid which are used for the most widely varying medical and cosmetic articles, as well as pharmaceutical compositions. The crosslinked esters result from the esterification of polyvalent alcohols with two or more carboxy groups of hyaluronic acid. Such crosslinked esters can be used in particular in the field of bioresorbable plastic materials for medical and surgical articles.
- Finally, PCT publication WO 8802623 A1, by Guire at Bio-Metric Systems, Inc., relates to biomaterials with a biocompatible surface, wherein among a large number of starting materials and binding mechanisms there is disclosed inter alia the use of hyaluronic acid for the production of a biocompatible contact lens. This publication is related to U.S. Pat. Nos. 4,979,959 and 5,263,992.
- Insofar as the above-mentioned publications concern coating methods for medical equipment and in particular stents, they suffer from the disadvantage that the polysaccharide layers produced do not achieve adequate levels of adhesive strength on the substrate surface.
- Accordingly the object of the present invention is to provide a method of coating stents with a polysaccharide layer which enjoys improved adhesion on the substrate surface of the implant, and to afford correspondingly fuctionalized stents.
- That object is attained by the alternative methods having the features of the appended claims as well as the associated stent. Specifically, the object is attained by the following characterizing method steps:
- covalent bonding of a non-crosslinked hyaluronic acid to the substrate surface of the stent forming the polysaccharide layer, and
- crosslinking of the hyaluronic acid layer (variant I).
- In an alternative configuration of the method of the invention, instead of crosslinking of the applied non-crosslinked hyaluronic acid layer, a further layer of a crosslinked hyaluronic acid is applied to the first non-crosslinked hyaluronic acid layer (variant II).
- In accordance with a third variant (III) according to the invention the method is carried out as follows:
- covalent bonding of a non-crosslinked hyaluronic acid to a substrate surface of the stent forming a first hyaluronic acid layer,
- covalent bonding of a second non-crosslinked layer of hyaluronic acid, and
- crosslinking of the second hyaluronic acid layer.
- A fourth variant (IV) provides that the method steps are to be carried out as follows:
- bonding of a bonding agent layer to a substrate surface of the stent,
- covalent bonding of a non-crosslinked hyaluronic acid to the bonding agent layer forming a hyaluronic acid layer, and
- crosslinking of the hyaluronic acid layer.
- Finally in accordance with a fifth variant (V) the coating operation is effected in the following manner:
- bonding a bonding agent layer to a substrate surface of the stent,
- covalent bonding of a non-crosslinked first layer of chitosan to the bonding agent layer forming a chitosan layer, and
- applying a second layer of crosslinked or non-crosslinked hyaluronic acid.
- Basic variants I and V of the methods according to the invention, by virtue of covalent bonding of the non-crosslinked polysaccharide, provide for a significant increase in the adhesive capability of the polysaccharide layer, which can be demonstrated by experiment. In that respect the further layer can be applied in the form of a non-crosslinked polysaccharide and can then be crosslinked or it can be applied directly as a crosslinked polysaccharide.
- Further advantages in particular of variant II lie in the primary application of a uniform polysaccharide layer and coupling thereto of a secondary, preferably thicker layer which, in contrast to other hydrogel films of comparable thickness, has a low swelling capacity. By virtue of their physical and chemical properties polysaccharide layers such as hydrogel films or polymer matrices are suitable for embedding active substances in order to enhance the biocompatible action by means of local active substance liberation or locally to achieve a pharmacological action. In comparison with conventional hydrogel films or polymer matrices, polysaccharide layers of glycosaminoglycans, in particular, hyaluronic acid, additionally have their own pharmacological action.
- An especially suitable polysaccharide for use in the method according to the invention is hyaluronic acid, which has already been referred to above, and which can be applied to the most widely varying substrate surfaces of implants. Alloplastic vessel wall supports—referred to as “stents”—are usually coated with amorphous silicon carbide (a-SiC:H) which involves a particularly intimate and adhesively strong bond to hyaluronic acid.
- Finally, functional coating can be achieved by the alternate application of a respective plurality of layers of non-crosslinked and crosslinked polysaccharides.
- Further features, details and advantages of the invention will be apparent from the embodiments hereinafter.
- The method according to the invention is described by reference to the coating of a substrate surface of amorphous silicon carbide which is applied for example to a stent with a basic structure consisting of a tantalum alloy. The essential features of activation of the silicon carbide substrate surface can be found in that respect from the present applicants' German patent application DE 195 33 682 A1, which discloses the application and immobilization of heparin on a silicon carbide coating.
- I. Bonding of Polysaccharides
- In accordance therewith the substrate surface was flushed with water and incubated in a 20×10−6-molar Fmoc-p-Bz-Phe-OH-solution in N,N′-dimethylformamide (DMF). The Fmoc-p-Bz-Phe-OH-solution, which is effective as a photoactive spacer substance, can be obtained as a commercial product “Fmoc-p-Bz-Phe-OH”, product number B 2220 from Bachem Biochemica GmbH, of Heidelberg, Germany. Reduction of the benzophenone was initiated by irradiation with UV light. After the UV irradiation operation, the reaction solution was poured off and the substrate surface rinsed a plurality of times with distilled water.
- The next step involves cleavage of the Fmoc protective group with 25% piperidine solution in DMF. Bonding of the hyaluronic acid takes place at the amino group which is now exposed and reactive. For that purpose, non-crosslinked hyaluronic acid was firstly covalently bound to the substrate surface treated in that way. The polysaccharide layer formed in that fashion can then be crosslinked.
- As an alternative to the above-described photochemical reaction, it is possible for polysaccharides, and, in particular, hyaluronic acid, to be covalently bound in a wet-chemical process to silanized benzophenones, epoxysilanes and aminosilanes as spacer substances to the substrate surface, in particular to the silicon carbide substrate surface.
- Wet-chemical covalent bonding of a silanized benzophenone, in particular 4-(3′-chlorodimethylsilyl)propyloxybenzophenone, was effected by a wet-chemical procedure in an organic solvent such as toluene at ambient temperature overnight in the presence of Et3N as a catalyst. After the incubation time, the substrates were rinsed in chloroform and then in methanol. Thereafter the layer system of substrate spacer was wetted with a 0.1% -2% aqueous hyaluronic acid solution and then dried. Covalent bonding of the hyaluronic acid to the benzophenone present was effected under the action of UV radiation at a wavelength of 340 nm which initiates the reduction of the benzophenone. Alternatively the photochemical reaction can also be implemented in aqueous hyaluronic acid solution. That photochemical reaction resulted in covalent bonding between the benzophenone and a C—H-group of the polymer chain, in particular of the hyaluronic acid. That polysaccharide layer, which was covalently bound to the substrate surface, was then crosslinked.
- For wet-chemical coating of silicon carbide substrates with epoxysilanes, the substrates were firstly cleaned and then dried for an hour at a temperature of 75° C. Silanization of the warm substrate was effected with (3-(2,3-epoxypropoxy)-propyl)-trimethoxysilane with immersion in organic solvent. The silanized substrates were then dried and washed in the organic solvent. Subsequent covalent bonding of the hyaluronic acid was effected in an aqueous solvent overnight with agitation at ambient temperature. Alternatively bonding of hyaluronic acid can be effected by incubation in a 0.25% hyaluronic acid solution in a 0.1 m HCl at 65° C. for 1 h. Chitosan can be bound by incubation in a 0.2% chitosan solution in a 1-2% acetic acid solution at 65° C. for 1 h. The stents were then rinsed with deionized water and thereafter dried. The polysaccharide layer, which is covalently bound to the substrate surface, was then crosslinked.
- A good adhesive effect can be achieved by a covalently bound chitosan layer (monolayer). The glycosaminoglycan chitosan (Mw: 100,000 to 1,000,000 Daltons) was covalently bonded by means of a spacer in a chemical multi-stage reaction to an amorphous silicon carbide layer (a-SiC:H) which covers the basic body of the stent.
- In the first step of the coating process the spacer—the photoactive benzophenone component Fmoc-p-Bz-Phe-OH (N-(9-Fmoc)-l-(4-benzoyl)-phenylalanine; 2 ml; 10 mmol/l; available from Bachem)- was covalently bonded to the silicon carbide by photochemical reaction in the solvent N,N′-dimethylformamide (DMF). After rinsing with DMF, cleavage was effected in respect of the Fmoc protective group of the spacer with a 20% piperidine solution in DMF. The amino group of the spacer was then free.
- The stent was then incubated in a 0.2% solution of chitosan in 1% acetic acid and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (50 mg/ml) for at least 12 hours in ice-cold water. Covalent coupling of the chitosan was effected by linkage of a peptide bond between the activated carboxylic acid of the spacer and the amino group of the chitosan or the formation of an ester bond between the activated carboxylic acid of the spacer and the hydroxyl group of the chitosan. After the end of the reaction the sample was repeatedly rinsed with deionized water and then dried.
- An example of use for the application of a bonding agent layer is described in greater detail hereinafter. A polymer layer which is a few nanometers thick was applied to the cleaned substrate surface. The polymer layer served as a bonding agent and had functional groups at the surface, which are suitable for subsequent covalent bonding of a polysaccharide layer. Such a bonding agent layer can be produced by plasma polymerization of N-heptylamine and acetaldehyde.
- The plasma polymerization operation was effected with a 40 kHz plasma installation of Piko type from Diener electronics. As an alternative to the above-mentioned precursor it is possible to use acetaldehyde, amyl alcohol, allylamine, acetoacetic acid ester or acrylic acid. The plasma-polymerized layers exhibited good wetting with hyaluronic acid solutions by virtue of their hydrophilic nature. In addition a thin layer of hyaluronic acid or other polysaccharides can be coupled to the functional surfaces by means of glutaraldehyde, epichlorhydrin or carbodiimides.
- The container was flushed with oxygen for the definitive removal of residual gas, in which case it is continuously evacuated. A flushing gas flow of about 40 cm3/min was set. The sample space was flushed for 10 minutes and the plasma was ignited in the presence of a Teflon block for the surface activation procedure. The power of the reactor was about 200 W and an oxygen flow of about 40 cm3/min was maintained during the surface treatment. Activation and simultaneous plasma purification lasted for 5-10 min.
- After activation and cleaning were effected, the power was reduced to 80 W and the precursor is introduced into the container. The polymerization period was 5 min with the aerometer open. After it was been switched off, further surface activation was effected with oxygen, but then the power was only 80 W with a duration of about 30 sec. This short surface activation operation resulted in a still further improvement in wettability of the surfaces.
- Taking the deposited bonding agent layer comprising the N-heptylamine plasma polymer, the hyaluronic acid was then covalently bonded by means of a water-soluble carbodiimide to the substrate-bonding agent layer complex. Covalent bonding of the hyaluronic acid to the acetaldehyde plasma polymer was effected directly by means of a diimidazole or with bonding of a polyethylene imine intermediate layer which is applied by means of reductive amination. Covalent bonding of the hyaluronic acid to that substrate-bonding agent complex was effected by means of a water-soluble carbodiimide. The polysaccharide layer which is covalently bonded to the bonding agent layer was then crosslinked.
- As an alternative to the method of plasma polymerization, the substrate surface was functionalized by derivatized polyhydroxybutyric acid, which exhibits an experimentally demonstrated good layer adhesion to silicon carbide and metals. Functionalization of the polyhydroxybutyric acid was effected by amination. Covalent bonding of the hyaluronic acid to the amino group of the functionalized polyhydroxybutyric acid (bonding agent layer) was effected by means of a water-soluble carbodiimide, with the formation of a peptide bond.
- A monolayer of chitosan was produced in the following manner. The pre-cleaned stent was dried at 75° C. for 30 minutes in a drying oven. Then, the stent, while still warm, was incubated for 10 minutes in a silane solution of 3 ml of water-free toluene, 20 μl of 3-[2-(2-aminoethylamino)-ethylamino]-propyl-trimethoxysilane and 70 μl of Et3N at ambient temperature with repeated slight agitation. The stents were then dried at 75° C. for 1 hour. Thereafter the stent was rinsed with toluene or chloroform and dried again. The next step was covalent coupling of adipinic acid by way of a solution of 10 mg/ml of adipinic acid in water for the production of functional carbonyl functions, to the surface of the implant. The adipinic acid had been previously activated in THF or DMF with a carbodiimide or diimidazole. After rinsing in deionized water and drying, the operation of bonding chitosan took place. For that purpose the implant was incubated in a 0.2% solution of chitosan in a 1-2% acetic acid solution at ambient temperature for 1-4 hours. That was followed by rinsing with deionized water and drying.
- II. Crosslinking and Coating Methods
- Crosslinking and coating methods of hyaluronic acid on implant surfaces will now be described in greater detail. The described methods are suitable in this respect for:
- crosslinking a non-crosslinked polysaccharide layer which is covalently bonded to the substrate,
- covalently bonding a non-crosslinked polysaccharide to a crosslinked or non-crosslinked polysaccharide layer, or
- covalently bonding a crosslinked polysaccharide to a crosslinked or non-crosslinked polysaccharide layer.
- The crosslinking of hyaluronic acid with glutaraldehyde can be implemented. The implant was coated with a 0.1-2% hyaluronic acid solution and then subjected to the action of a crosslinker solution for several hours. The crosslinker solution comprised 240 ml of acetone, 80 ml of glutaraldehyde in 25% solution in water and 1.6 ml of HCl 3 M. Thereafter the crosslinker solution was replaced by a fresh solution and incubation was again effected at ambient temperature for several hours. The hyaluronic acid crosslinked by means of glutaraldehyde was washed several times in distilled water. The sample was incubated in a 0.5-3% solution of sodium cyanoborohydride for one hour at ambient temperature. The fixer solution was removed and the procedure then involveed a plurality of washing steps in doubly distilled water and isotonic saline solution.
- Crosslinking of the hyaluronic acid with bifunctional aldehydes and formaldehyde was effected in a method similarly to crosslinking of the hyaluronic acid with glutaraldehyde.
- 0.38 g of hyaluronic acid was dissolved in 90 ml of water for the crosslinking of hyaluronic acid by epichlorhydrin. 10 g of NaOH and 6.8 ml of aqueous ammonia solution (25%) were added to the solution. The temperature of the reaction solution was set at 20° C. After that temperature was reached, 19.6 ml of epichlorhydrin was added thereto. The solution was stirred at 20° C. for 24 hours. The crosslinked hyaluronic acid was then dialyzed in relation to doubly distilled water. The dialysis hoses used have an exclusion limit of 120,000 DA.
- For the crosslinking of hyaluronic acid by divinyl sulfone, 2 g of hyaluronic acid was dissolved in 50 ml of 0.1 m aqueous NaOH solution, giving a 2% solution. The solution was put on ice. When temperature equalization was effected, 2 ml of divinyl sulfone was added. The resulting two-phase mixture was agitated for 15 minutes on ice. After 5 minutes, only one phase was still to be observed. The implants were immersed in that solution and then dried.
- For the crosslinking of hyaluronic acid with ethylene glycol diglycidylether, a 0.1-2% hyaluronic acid solution in a 0.9% isotonic saline solution was produced. The reaction was conducted at 25° C. As the crosslinking agent, up to 10 molar percent of ethylene glycol diglycidylether was added, with respect to the repetition unit of the hyaluronic acid.
- It is also possible to implement crosslinking and covalent bonding of the hyaluronic acid to layer systems comprising amorphous silicon carbide spacer and an amorphous silicon carbide-spacer-polysaccharide monolayer with diimidazole. The implant with bound spacer or with a polysaccharide layer was immersed in a diimidazole-bearing acetone solution. The substrate-spacer complex or the polysaccharide layer was activated for at least 30 minutes in the diimidazole-bearing acetone solution and then immersed in an aqueous hyaluronic acid solution or sprayed with a hyaluronic acid solution. For the spray coating operation, the stent was sprayed for 0.5-1 sec at a pressure in respect of the carrier air of 2-4 bars. Between the spraying steps, the stent was dried for 15-30 sec with a supply of warm air. Repeating the steps makes it possible to produce a desired layer structure on the stent. In order to achieve layer growth, that process was repeated a plurality of times.
- The crosslinking of the OH- and NHR-groups of polysaccharides was effected by means of acid dichlorides or phosphorus oxychloride with the formation of ester or amide groups and with the liberation of HCl in an organic solvent.
- III. Derivatization of the Polysaccharide Layer
- Derivatization of the coated hyaluronic acid hydrogel on the implant can also be implemented.
- By virtue of polymer-analogous transformation of hyaluronic acid, for example, by means of an SO3*pyridine complex, enzymatic decomposition of hyaluronic acid in vivo was delayed or hyaluronic acid was stabilized in the body, as the following example of use shows.
- Hyaluronic acid was suspended in dry pyridine in a nitrogen atmosphere in a thermostatizable double-wall reactor with a reflux condenser and an agitator. A sulfur trioxide-pyridine-complex was added to that suspension and heated to the desired reaction temperature. After 3 hours, the reaction was terminated and the suspension, when cooled to ambient temperature, was poured into five times the amount of methanol. The precipitated polymer was filtered off, dissolved in water and dialyzed in relation to de-ionized water. As the product was partly in the form of pyridinium salt and the polymer chains were intermolecularly esterified with each other, the pH-value of the polymer solution after dialysis was adjusted to 11 by the addition of 0.1 N soda lye. Dialysis and titration were repeated three times. At a pH-value of 7.3 the polymer was freeze-dried.
- A variation in the degree of sulfatization in this polymer-analogous transformation procedure is possible by virtue of the amount of added sulfatization reagent SO3* pyridine, the reaction time and the reaction temperature.
- IV. Embedding Drugs
- Active substance loading with suitable drugs was generally effected after crosslinking and fixing of the polysaccharide layer in the swollen condition. Alternatively the active substance can be furnished by means of a spraying or immersion process prior to the coating step or during coating with the polysaccharide. Active substance embedding was generally effected by way of diffusion processes.
- The active substance was embedded by way of an immersion process in a hyaluronic acid layer as can be obtained in accordance with one of the preceding examples. For that purpose, the implant was immersed in a solution of 15 mg of cyclosporin per ml of a paritetic ethanol-water mixture. The ratio of 1:1 of ethanol to water has proven to be surprisingly effective for implementation of the diffusion process. Other ratios, especially those with an elevated ethanol content, slow down the embedding effect. Depending on the respective layer thickness and degree of crosslinking of the polysaccharide layer the implant remained in the solution for at least one hour. The implant was then removed and dried. With a coating amount of 0.5 mg of hyaluronic acid, the amount of cyclosporin which can be incorporated in that way was at least 0.2 mg.
Claims (9)
1. A method of coating a surface of a stent with a polysaccharide layer, the method comprising the steps of:
providing a stent with a surface prepared for covalent bonding of a polysaccharide thereto; and
bonding a non-crosslinked polysaccharide covalently to the prepared surface, thereby providing a polysaccharide surface layer.
2. The method of claim 1 , comprising the further step of:
forming a cross-linked polysaccharide outer layer.
3. The method of claim 2 , wherein:
the non-crosslinked polysaccharide is hyaluronic acid; and
the crosslinked polysaccharide outer layer is formed by crosslinking the polysaccharide surface layer.
4. The method of claim 3 , wherein:
the step of providing the stent with a surface prepared for covalent bonding comprises bonding a bonding agent layer to the substrate surface.
5. The method of claim 2 , wherein:
the non-crosslinked polysaccharide is hyaluronic acid; and
the crosslinked polysaccharide outer layer is formed by covalently bonding a layer of a crosslinked hyaluronic acid to the polysaccharide surface layer.
6. The method of claim 2 , wherein:
the non-crosslinked polysaccharide is hyaluronic acid; and
the crosslinked polysaccharide outer layer is formed by the steps of covalently bonding a layer of a non-crosslinked hyaluronic acid to the polysaccharide surface layer and crosslinking the non-crosslinked hyaluronic acid layer.
7. The method of claim 1 , wherein:
the step of providing the stent with a surface prepared for covalent bonding comprises bonding a bonding agent layer to the substrate surface; and
the step of bonding a non-crosslinked polysaccharide covalently to the prepared surface is accomplished by the steps of:
bonding a non-crosslinked chitosan covalently to the bonding agent; and
bonding a layer of crosslinked hyaluronic acid covalently to the chitosan.
8. The method of claim 1 , wherein:
the step of providing the stent with a surface prepared for covalent bonding comprises bonding a bonding agent layer to the substrate surface; and
the step of bonding a non-crosslinked polysaccharide covalently to the prepared surface is accomplished by the steps of:
bonding a non-crosslinked chitosan covalently to the bonding agent; and
bonding a layer of non-crosslinked hyaluronic acid covalently to the chitosan.
9. A stent, comprising a polysaccharide surface layer applied by the method of claim 1.
Priority Applications (1)
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US11/531,512 US8173196B2 (en) | 2002-05-24 | 2006-09-13 | Method of coating a stent with a polysaccharide layer and associated stents |
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DE2002123310 DE10223310A1 (en) | 2002-05-24 | 2002-05-24 | Process for coating implants with a polysaccharide layer |
DE10223310.1 | 2002-05-24 |
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US11/531,512 Division US8173196B2 (en) | 2002-05-24 | 2006-09-13 | Method of coating a stent with a polysaccharide layer and associated stents |
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US10/444,827 Abandoned US20040091605A1 (en) | 2002-05-24 | 2003-05-23 | Method of coating a stent with a polysaccharide layer and associated stents |
US11/531,512 Expired - Fee Related US8173196B2 (en) | 2002-05-24 | 2006-09-13 | Method of coating a stent with a polysaccharide layer and associated stents |
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US (2) | US20040091605A1 (en) |
EP (1) | EP1364664A1 (en) |
AU (1) | AU2003240641A1 (en) |
DE (1) | DE10223310A1 (en) |
WO (1) | WO2003099348A1 (en) |
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US11058802B2 (en) | 2010-10-08 | 2021-07-13 | Board Of Regents, The University Of Texas System | Anti-adhesive barrier membrane using alginate and hyaluronic acid for biomedical applications |
US11246937B2 (en) | 2010-10-08 | 2022-02-15 | Board Of Regents, The University Of Texas System | One-step processing of hydrogels for mechanically robust and chemically desired features |
US11744926B2 (en) | 2010-10-08 | 2023-09-05 | Board Of Regents, The University Of Texas System | Anti-adhesive barrier membrane using alginate and hyaluronic acid for biomedical applications |
US11857701B2 (en) | 2010-10-08 | 2024-01-02 | Board Of Regents, The University Of Texas System | Anti-adhesive barrier membrane using alginate and hyaluronic acid for biomedical applications |
US11890344B2 (en) | 2010-10-08 | 2024-02-06 | Board Of Regents, The University Of Texas System | One-step processing of hydrogels for mechanically robust and chemically desired features |
EP2649101B1 (en) | 2010-12-06 | 2021-06-02 | Teoxane | Process of preparing a cross linked gel |
US8901092B2 (en) | 2010-12-29 | 2014-12-02 | Surmodics, Inc. | Functionalized polysaccharides for active agent delivery |
US11565027B2 (en) | 2012-12-11 | 2023-01-31 | Board Of Regents, The University Of Texas System | Hydrogel membrane for adhesion prevention |
US10232090B2 (en) | 2013-08-23 | 2019-03-19 | Southwest Research Institute | Electrophoretically deposited strontium fluoride nanoparticle/polymer coatings for medical implants |
US11980700B2 (en) | 2017-03-08 | 2024-05-14 | Alafair Biosciences, Inc. | Hydrogel medium for the storage and preservation of tissue |
Also Published As
Publication number | Publication date |
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US8173196B2 (en) | 2012-05-08 |
DE10223310A1 (en) | 2003-12-11 |
US20070026038A1 (en) | 2007-02-01 |
WO2003099348A1 (en) | 2003-12-04 |
AU2003240641A1 (en) | 2003-12-12 |
EP1364664A1 (en) | 2003-11-26 |
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