Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/28—Materials for coating prostheses
  • A61L27/34—Macromolecular materials
• • 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
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/58—Materials at least partially resorbable by the body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/148—Materials at least partially resorbable by the body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/18—Materials at least partially X-ray or laser opaque
• • 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

Definitions

• Self-expandable biodegradable stent made of clad radiopaque fibres covered with biodegradable elastic foil and therapeutic agent and method of preparation thereof
• the invention relates to a stent comprising a skeleton consisting of interlaced biodegradable fibres, said stent being radially self-expanding and coated with a biodegradable foil, said foil and/or said fibres carrying a medicament applied thereon and said fibres being x-ray opaque.
• stents used for various indications such as those involving the vascular system and the gastrointestinal tract.
• the material composition of the "; stents is very diversified; as well. Therefore, diverse stents made of various biodegradable materials' are ! ; fehown in the art.
• the general purpose of the stents is to maintain the patency of tubular organs inside the human body.
• Such tubular organs include the entire digestive tube, in particular the esophagus, the duodenal sections, the small intestine, the colon and the rectum.
• the human body organs treated by means of stents may also include the biliary and urinary tracts or, recently, the pancreatic tract.
• the most suitable area for stenting is the vascular system.
• the present invention is not primarily focused on the aforesaid area, even though it is supposed to be successfully applicable for that purpose.
• the last but not least area of application of the stents is the treatment of the respiratory tract including both 'the : trachea and the bronchi / bronchioles.
• stents are made of the materials which are not harmful for the human body, i.e. of the so called biocompatible ones. This rnearis that the presence of such materials does not invoke any adverse reactions of the surrounding tissues.
• Stents are riormally made of a wide range of biocompatible metal alloys. A significant advantage of such materials consists in their long durability inside the human body.
• Stents may be divided into tw major classes.
• the first class includes so called braided stents, the second one includes stents that are processed by laser trimming. Both of the above classes have their advantages and drawbacks.
• the stents, which are processed by laser trimming, are mostly used in the coronary area, While the domain of the braided stents includes the gastrointestinal and respiratory tracts.
• the braided' stents may be subdivided into self-expanding and balloon expanding ones (U. S. Pat. No. 4,886,062).
• the stents, which are processed by laser trimming need to by expanded by means of balloons in any case.
• One of the most respected self- expanding braided stents 1 is that invented by Wallste (U. S.
• Another major group comprises the stents th&t are processed By laser ' trimming.
• the main area of application of this group of stents is the coronary system and the representatives of this group also include the first stents with controllably releasing medicaments, such as those disclosed in the ,U. S. Pats. Nos. 2008033532 and 2005180919.
• These stents comprise a metallic skeleton coated with at least one polymeric layer containing the medicament do be administered, such layer having a specific degradation period depending on the type, of the polymer used. The degradation period of the polymeric in turn determines the resulting period during which the medicament will be controllably released, ; as disclosed in the patent application MX 9602580 A.
• the above solutions constitute the prior art.
• biodegradatioh means the decomposition into the initial polymerization products due to the interactions with the human body.
• the supporting factors of the decomposition include the presence of enzymes, water, heat etc.
• the process of biodisintegration occurs when a polymeric material decomposes into multiple individual parts, none of such parts being usable as a precursor for the production of polymers. After the lapse of a certain period of time, the implant decomposes into small particles that are eliminated from the human body in a natural way. It should be appreciated that the above two processes do not take place in a clearly separated manner and that the decomposition of an implant inside the human body occurs under the synergy of the above processes. Both the decomposition mechanisms assert themselves simultaneously but their intensities may be different during the individual stages of the process.
• Biodegradable stents are substantially cylindrical formations having various dimensions and geometrical proportions and made of diverse materials that are usable for one of the established braiding or laser trimming methods.
• An example of the available solutions is disclosed in U. S. 5,733,327, wherein the biodegradable stent is primarily intended for vascular applications and may be made, among others, of polydioxanone. In this case, however, no self-expanding solution is concerned since the stent must be dilated by means of a balloon to assume its final shape.
• the use of an x-ray opaque filler is neither specifically described herein and the placement of such a filler inside a fibre is not mentioned, at all.
• the resulting structure of the stent is created by weaving and not by braiding as assumed by the present invention.
• the solution constituting the prior art also anticipates the possibility of using a medicament focused on overcoming the difficulties arising during the application of the same in the coronary pathway, the respective stent is not coated with a biodegradable elastic foil which is contrary to the present invention wherein the application of such foil poses one of the key aspects.
• EP 1721625 A2 discloses a biodegradable implant made of a mixture of a biodegradable material and glass or ceramics.
• the advantages of this solution consist in the increased strength of the implant and fiv th controllable decomposition of the degradable plastic constituents.
• the above document discloses neither the inner structure of the reinforced polymer nor any additional properties of the glass or ceramic admixtures.
• the document does not contain any reference to a filler which would constitute a component of the fibre, thus actually forrfiirig a fibrous composite:
• Most of the- above mentioned solutions are applicable in the vascular area although they also anticipate using the respective stents in other tubular organs of the human body, notwithstanding the fact that any such technological transfer would be very difficult.
• stents with embedded radioactive substances for the treatment of tumors, as shown in U. S. Pat. No. 6,159,142.
• the stent disclosed therein comprises a metallic skeleton provided with a degradable or non-degradable polymeric coating enriched with radionuclides.
• a similar solution may be used for vascular applications, wherein the carrier is a stent processed by laser trimming.
• Polymeric layers do not necessarily constitute the only solution applicable to the metallic coronary stents.
• Another possible approach consists in the use of microparticles for creating protective encapsulations for the medicaments to be administered. Such particles may be then dispersed in a polymeric matter, as described in U. S. Pat. No. 2004052859 A1.
• the subject of the present invention does not comprise a precise definition of particular terms and exact mechanisms of degradation of the materials and so degradation is defined herein as the overall deterioration of the mechanical properties of a biodegradable polymeric stent, particularly with respect to the strength, elastic memory and stiffness of the same. All the mechanisms of degradation mentioned herein involve the decrease of the monitored quantities which directly influences the behaviour of the stent. The term disintegration expresses the loss of integrity of the stent, particularly with respect to the coating and fibrous structure.
• the objective of the present invention neither includes the investigation of the particular causes and mechanisms of degradation, whether they occur under the influence of the environment inside the human or animal body or under the external influence of water, enzymes etc.
• biodegradation and biodisintegration are considered to be equivalent in the present patent application, meaning that the outcome is the decomposition of the biodegradable stent in either case and notwithstanding the different basic definitions.
• biodegradable stent has been selected to constitute the common superior concept. Degradation or disintegration should be both interpreted as the process of decomposition of the coating and of the fibrous mesh of a stent into smalle parts. The resulting parts are then eliminated from the human body (predominantly) in the natural way.
• 2005251248 A1 discloses, an approach that is different from that described in the former patent document where the core is made of a radiopaque matter and the encapsulation is formed from the material of the stent in itself, in contrast to that, the latter solution provides a stent having its core formed from i an unspecified material;; which imparts the desired mechanical properties to the stent and which is covered by a radiopaque coating substance. Nevertheless, the latter document neither .contains the specification of a material, which could be used in the described manner, nor deals with the types of stents foreseen by the respective invention.
• the first main objective of the present invention is to provide a biodegradable self-expanding stent which comprises a skeleton consistihg of degradable fibres and is coated with a biodegradable* elastic foil. *i !
• Another objective of the present invention is to provide a stent which would offer x-ray opaque properties without using conventional markers, such properties being achieved by means of diverse techniques, including co-extrusion, deposition and preparation of mixtures of polymers with radiopaque fillers. Nevertheless, all the mechanical parameters of the stent as well as the period of degradation of the same should be maintained.
• a further objective of the present invention is to provide a stent of the above art which would contain a medicament in its structure.
• the medicament should be either deposited on the surface of the biodegradable foil or embedded in the fibrous structure.
• the second main objective of the present invention is to provide diverse methods of manufacturing stent skeletons.
• One of the methods should comprise the manufacture of radiopaque fibres by means of the extrusion and co-extrusion techniques.
• Another method should comprise the preparation of biodegradable foils by means of casting techniques.
• the overall objective of the invention is to provide a self-expanding biodegradable stent which would enable to be controlled by an x-ray device when being positioned and which would serve as a medicament carrier.
• the polymeric core fibre is provided with a uniformly dispersed x-ray opaque
• the polymeric core fibre is coated with a polymer in which an x-ray opaque matter is uniformly dispersed
• the interlaced fibres forming the ebmplete basic structure of the stent being also coated with a dispersion of a an x-ray opaque filler and with a polymer, said coatings forming a biodegradable foil provided on the basic structure of the stent and encapsulating an active substance, said active substance being selected from the group of substances including medicaments, proteins, enzymes, genes, stem cells or radioactive substances used for the local treatment of tumors.
• Method of manufacturing a self-expanding biodegradable stent having a base structure consisting of interlaced ' biodegradable fibres which method comprises the steps of covering the core polymeric fibre containing an x-ray opaque filler with an additional polymer, or
• the stent is subjected to heat treatment for the second time and recoated; with a further, thinner biodegradable foil containing a second, different medicament.
• Fig. 1 shows the stent according to the invention
• Fig. 2 shows the detail of the stent having distinct blank and coated portions.
• the polymeric core fibre is provided with a uniformly dispersed x-ray opaque
• the polymeric core fibre is coated with a polymer in which an x-ray opaque matter is uniformly dispersed, 1 s :
• the interlaced fibres forming the complete basic structure of the stent being also' coated with a dispersion of a an x-ray opaque filler arid with a polymer, said coatings forming a biodegradable foil provided on the basic structure of the stent and encapsulating an active substance, said active substance being selected from the group of substances including medicaments proteins, enzymes, genes, stem cells or radioactive substances used for the local treatment of tumors.
• Figs. 1 and 2 show the stent1 comprising the fibres 2 and coatings 3.
• the diameter of the fibres 2 making up the stent1 may range between 0.1 mm and 1 mm. Preferably, the diameter of the fibres ranges between 0.3 mm and 0.6 mm.
• the cross-sectional shape of the fibres is preferably circular. Nevertheless, fibres having oval, ribbon-like or similar cross sections are also conceivable and will fall into the scope of the present invention. However, as mentioned above, the circular cross-sectional shape of the fibres will be preferred. Unless otherwise specified, the term fibre refers to a fibre containing a radiopaque filler when used in connection with the present invention.
• the materials which are suitable for manufacturing self-expanding biodegradable stents, may include polymers on the basis of lactic, sialic, glycolic, butyric or hyaluronic acids and polydioxanone.
• polydioxanone appears to be the most suitable one because of its period of degradation ranging, depending on the environmental effects, from 3 to 4 months.
• dioxanone is well suited owing to its favourable mechanical properties.
• a meshwork having tubular or conical shape is formed from the fibres specified above.
• the stents will have different structural properties.
• the meshwork forming the skeleton of the stent undergoes initial heat treatment.
• the purpose of this processing step is to ensure the structural stability of the meshwork and to eliminate any residual stresses originating prom the preceding knitting stage.
• the stent then undergoes the so called coating stage during which it is covered by the self-expanding biodegradable foil 3.
• the coating process falls into the scope of the present inventiori, as well.
• One of the significant aspects of the above foil is the good adhesion to the rheshwork of the stent which can be further improved by means of conditioning treatment.
• high degrees of elasticity and degradability or disintegrating capability are important aspects of the foil.
• Another important aspect of the foil is its ability to decompose and to detach itself from the stent before the skeleton of the latter begins to disintegrate.
• the coated stent undergoes the second stage of heat treatment in the course of which the solvent, which was used during the preparation of the polymeric matter, is removed and the material is imparted the desirable shape memory.
• the shape memory of the stent has the utmost importance for the clinical application of the same.
• the stent Before being implanted into the gastrointestinal or respiratory tract, the stent is compressed and placed into an introducing device that enables the stent to be exactly positioned in the desired location. After reaching the desired location, the stet is released from the introducing device. Owing to its inherent shape memory, the stent then expands and assumes its nominal dimensions.
• the necessary preconditions of the above procedure are the suitable structure of the stent, adequate elasticity of the foil and appropriate temperature setting during the second heat treatment stage. Owing to the radiopaque properties of the skeleton, the stent is clearly visible inside the introducing device when being positioned and released in the place of application. Furthermore, the radiopaque properties of the material enable to observe the behaviour of the stent during the stage of expansion when the latter assumes its nominal diameter. In this manner, the desired in situ effect of the stent, namely the expansion of a tubular organ affected by stenosis, may. be monitored.
• the stent is the coated with a further, thinner biodegradable foil containing medicaments.
• the medicament encapsulated by the polymeric matter may be deposited directly on the stent or on the foil covering the same.
• the method of coating the stent and applying a medicament onto the same also fall into the scope of the present invention.
• the administration of the medicament should abate the adverse reaction of the tissue induced by the presence of the stent. Such a reaction of the surrounding tissue is an unavoidable side effect of any surgical intervention involving 1 implantatioh of a cases; 'the adverse -reactions-Way be- severe enough to cause restricted - patency >; of ; the stent.
• he medicament administration carried out ( by n eahs 'of ihe stent is to influenc the reaction of the tissue induced by the presence of the implant and, if possible, to prevent the recurrence of the so called stenosis.
• ⁇ ' ⁇ In 1 contrast to other stents coated with a medicinal substance, th& release of the medidamerit from the stent according to the present invention is subject to the presence of the latter inside the human body. The medicament is released and remains effective during the whole life cycle of the respective stent. The depletion of the medicament takes place concurrently with the disintegration or degradation of the stent.
• the stents constituting the prior art i.e.
• the metallic stents with a medicament applied thereon are not able to prevent an adverse reaction of the tissue after the depletion of the medicament.
• the rate of release of the administered medicament depends on the properties of the selected carrying polymer. In case that a polymer having a short period of degradation is used, the medicament is released during a shorter period of time. Accordingly, in case that a polymer having a long period of degradation is used, the medicament is released during a longer period of time.
• the release of the medicament should always be finished at latest simultaneously with the complete decomposition of the stent.
• the stent is very flexible and adaptable to the shape, curvature and translucency of the surrounding tissue.
• the ; method of manufacturing such biodegradable self- expanding stent, which is composed of biodegradable fibres containing a radiopaque filler and coated with a biodegradable elastic foil containing a medicament, may also be considered to involve an inventive step.
• the scope of the present invention also includes multiple unique methods of manufacturing the above mentioned stent.
• the objectives of the present indention also include the possible methods > of preparatio of the radiopaque biodegradable fibres containing a radiopaque filled.
• the methods according to the invention are explained below.
• a radiopaque fibre consists of a radiopaque core, which is made of the mixture of a biodegradable polymer and a radiopaque filler, and a an envelope made of a biodegradable polymer.
• the radiopaque fibre may be composed of a core made of a biodegradable polymer and an envelope made of a biodegradable polymer enriched with a radiopaque filler.
• the method of manufacturing a radiopaque fibre should ensure the homogenous dispersion of the respective radiopaque material across the whole cross section of the fibre.
• biodegradable fibre is covered by a biodegradable coating -- aterial ⁇ eontaWng a radiopaque -filler " dis ' pefsed in it. - s ⁇
• the variable quantity of the radiopaque filler enables different levels of the radiopacity of the fibres to be selected.
• the main purpose is to achieve a certain degree of radiopacity that would enable the stent to be clearly visible against the surrounding tissue.
• the fibres decompose, get absorbed or disintegrate into small atraumatic particles in a natural way inside the human body.
• the stent is present in the gastrointestinal tract, such small particles can be eliminated from the body in a safe natural way.
• the particles can be expectorated by the patient or absorbed by the surrounding tissue.
• the radiopaque filler will be either partly absorbed or partly encapsulated by the surrounding tissue. In both the above mentioned cases, the main proportion of the particles will be eliminated from the human body in a natural way.
• the radiopaque filler is composed of substances having high atomic mass values, such as W, Bi, Ir, Pt, Au or Ba, preferably in the form of particles or in the form salts.
• the surface characteristics of the particles may be altered with suitable surfactants. If it is desirable that the surface of the particles has hydrophobic properties, the respective surface finishing process will involve the application of stearic acid or another similar fatty acid. If the hydrophilic surface finish of the particles is required, the surface will be treated with an agent on the basis of silicones or acrylates. It is apparent that the most suitable surface' finishing process will involve the use of a chained polymeric matter containing dispersed radiopaque particles. After having been finished in the above manner, the radiopaque particles are ready to be used for manufacturing the radiopaque fibres.
• the three types of radiopaque fibres are based on a pre-processed radiopaque filler having a suitable surface finish.
• the radiopaque filler and the granulated polymer have to be intermixed.
• the material is ready to be used for the preparation of the polymer mixture (as described under A and B below).
• the proportion of the radiopaque filler ranges between 10 and 60 percent by weight.
• the resulting mixture will have a granulated form that is well suited for the subsequent extrusion of the fibres.
• the extrusion takes place in a conventional extruder having either a single-screw mechanism or a double-screw arrangement.
• the parameters of extrusion to be selected depend on the type of the polymer and on the proportion of the filler.
• the preparation of the radiopaque fibre comprising a radiopaque core and a biodegradable coating layer involves the extrusion of the core fibre containing a radiopaque filler in a co-extrusion line and the subsequent application of the coating layer, the latter being formed from the co-extruded biodegradable polymer.
• the preparation of the radiopaque fibre comprising a biodegradable core and a biodegradable coating layer composed of a biodegradable polymer containing a radiopaque filler dispersed therein involves the extrusion of the core fibre from the biodegradable polymer and the subsequent application of the coating layer, the latter being formed from the co-extruded biodegradable polymer enriched with the radiopaque filler.
• a fibrous composite is created having at least three constituents: the core of the fibre, the intermediate layer and the coating layer.
• the intermediate layer may be made up of the polymer enriched with the radiopaque filler and the coating layer, which is applied on the former, may be made up of the biodegradable polymer, or vice versa.
• the fibre When prepared in the above described manner, the fibre provides a number of advantages in comparison to that prepared using a conventional technique, each portion of the fibre having a specific purpose.
• the function of the radiopaque filler may be assumed either by the core or by the coating layer of the fibre.
• the properties of the filler must be appropriately balanced. It is necessary to find an optimalized relation between the content of the filler and the mechanical parameters, such as tensile strength and modulus of elasticity, of the resulting mixture.
• One of the advantages provided by the radiopaque core consists in that the mechanical properties and the period of degradation of the resulting co-extruded fibre are not affected by the proportion of the filler.
• the fibre containing a radiopaque filler which is loosely dispersed in the basic polymer, may be formed by means of a simple extrusion device.
• the resulting mixture of the biodegradable polymer and the radiopaque filler is the extruded by means of a conventional extrusion line to form the fibres.
• the extrusion line used may be the same as described with reference to the foregoing method.
• the extruded fibres having the diameter ranging between 0.3 and 1 mm are then stretched by means of a stretching mill in the ratio ranging from 1:2 to 1 :50, preferably from 1 :10 to 1 :20.
• the fibres are thermally stabilized during the period ranging from 2 to 240 minutes, preferably from 10 to 120 minutes, the stabilizing temperature being set within the interval of the characteristic temperatures of polymer composites, mainly from T g to T m - 10 °C.
• the fibre is ready to be used for the immediate fabrication of the stent or for enlacing into the structure of the same.
• the resulting solution is applied onto the biodegradable fibre to forrn a 'Coatirt'g : thereoni Due to adhesive forces, the resulting sblution to the surface of the fibre: Thfe : thickness of the polymeric film 1 deposited on the fibre may be influenced by varying the- rate of -application of the polymeric solution onto the fibre: Finally, the solvent is re ⁇ ' ⁇ -' ⁇ ' ⁇ "; : ⁇ . ⁇ .. ⁇ .. ⁇ o i , .. : ⁇ , ; ; ; :::: ::
• radiopaque fibres which are based on the coextrusion of a radiopaque core and a polymeric coating from a degradab!e polymer and vice versa, are also applicable for manufacturing composite polymer fibres.
• the selection of polymers is not limited The preferred solution is based on the use of polydioxanone cores that are coated with polymeric layers, the respective polymers, such as lactic acid or poly-epsilon-caprolactone, having extended periods of decomposition. Although the latter two polymers appear to be the ideal ones for the particular application, the selection of suitable materials is not limited. Hence, other degradable polymeric materials ' may also be used, such as copolymers, polymer blends or the like.
• the manufacturing process based on the coextrusion method provides a fibre, wherein the core is formed from the first degradable polymer having a specific period of degradation, the core being coated with the second polymer having a different period of degradation.
• the core of the fibre is extruded.
• the core is provided with the so called conditioning layer that will enhance the adhesion between the core and the coating and ensure the transfer of the stresses from the surface of the fibre into the core of the same.
• Another significant aspect of the above surface treatment consists in that the adhesion between two different polymer types is also enhanced, such adhesion being particularly useful as a barrier preventing water and other liquids from penetrating into the space between the core and the coating of the respective composite fibre, thus protecting the latter against deterioration.
• An idea! material for such surface treatment could be a block copolymer that is composed of different polymeric blocks, the individual polymeric constituents corresponding to the polymers the core and the coating of the future core are made of, respectively.
• Such block copolymer may be deposited using the dissolving method, as described with respect to the case B, or using the coextrusion method as described hereinbefore.
• a block copolymer based on the above mentioned two polymers may be used for the surface treatment of the respective fibre.
• the thickness of the surface layer may range between 10 and 100 nm, preferably between 20 and 40 nm.
• the fibre is then guided through a system of heated pulleys in order to be stabilized and stretched.
• the ideal temperature range is considered to be between 60 °C and 100 °C, preferably between 80 °C and 90 °C.
• the stretching parameter which is calculated as the ratio between the stretched and initial lengths of the fibre, may be in the range from 1 :5 to 1:20.
• the ideal stretching ratio is that in the range from 1 :7 to 1 : 2.
• the values of the stretching ratio may vary according to the type of the polymer used for the coextrusion of the fibre and in dependence of the required diameter of the fibre.
• the fibre is conditioned with the aim to assume the required degree of gloss, smooth surface and good slipperiness. For this purpose, e.g., a diluted solution of polyvinyl alcohol may be- used, the preferable concentration thereof being between 5 and 10 percent by weight!
• the finished fibre is reeled up on a coil.
• the above fibre may be created from a polymeric solution.
• the polymer preferably lactic acid or poly-epsilon-caprolactone, may be used either, in the regular form or in the form of a copolymer having a specific degree of cross- linking and a specific chain length.
• the polymer is dissolved in a suitable solvent.
• the solvent is selected in accordance with the characteristics of the polymer to be processed. Ideal solvents for the above mentioned polymers are considered to be, e.g., chlorinated compounds.
• the solution having an eleyated concentration of the polymer and, thus, a higher viscosity value is prepared, (hereinafter referred to as thick solution).
• the concentration of such a thick solution should be in the range from 15 to 35 %.
• the solution has to be properly stirred up.
• a polymer fibre is immersed into the solution, which has been prepared as described above, each polymeric material having a different period of decomposition. Due to adhesive forces, the resulting solution to the surface of the fibre.
• the thickness of the polymeric film deposited on the fibre may be influenced by varying the rate of application of the polymeric solution onto the fibre.
• the adhesion of the deposited layer may be enhanced by means of an additional conditioning treatment.
• the conditioning agent - in this particular case, the copolymer consisting of the block polymers the core and the coating of the fibre are made respectively - is dispersed using the same method and process as described above with respect to the application of the coating layer. Afterwards, the solvent is remove and a continuous film consisting of the block polymer is formed on the surface of the fibre.
• the fibre, which has been prepared in the above manner, may be then coated with the desired polymeric matter: After having beerv deposited in the dissolved form, the polymeric film having a different period of decomposition will assume the thickness ranging from 20 nm to 40 nm, thus being ' thinner in comparison to .hat deposited on a fibre prepared using the co-extrusion method.
• the casting technique may be more convenient for certain types of polymers because, in contrast to co- extrusion, it does not involve any heat treatment of the fibres.
• a self-expanding biodegradable stent may be manufactured using either of the following methods:
• the methods referenced as A) and B) are used for the preparation of the stents from the biodegradable fibres containing a radiopaque filler made using the manufacturing processes A and B described above.
• the method referenced as C) is intended for the preparation of the stents from degradable fibres without a radiopaque filler.
• the meshwork is fabricated on a mandrel.
• the mandrel is provided with the so called guiding grooves that serve for directing the fibre and define the shape of the resulting meshwork.
• the size of the grooves corresponds to the diameter of the fibre used.
• the finished meshwork has a tubular shape.
• the stent will assume a conical shape. If a mandrel having a flared proximal or distal portion is used, such a tulip-like end portion or a slightly conical one, the finished stent will assume an identical shape.
• the sizes of the geometrical shapes created from interlaced fibres may also vary.
• the mandrel is rotatably clamped in a clamping device, the axis of rotation being the longitudinal one.
• the fibre is guided onto the mandrel.
• the fibre may be a single or double one.
• the fibre is attached thereto.
• the fibre is led around a helical circumference towards the other end of the mandrel where the direction of the fibre is reversed by means of a plug and led backwards.
• the fibre may be wound around the plug in one of the following manners: the resulting enlacement angle is less than 90° or the resulting enlacement angle is less greater than 90° but less than 360°. After that, the fibre is led back to the crossing point.
• the backwardly oriented fibre passes under the first fibre, that is to say under the forwardly oriented on, towards the first end where it is reversed by means of the plug again.
• the enlacement of the fibre may be the same as above or different.
• the fibres are alternately interlaced.
• the stent is formed from consecutive helices. When the last helix is enlaced, the process of manufacturing the stent is finished. The ends of each fibre are then enlaced into the central portion of the stent.
• the stents with so called atraumatic ends may be manufactured In this context, the atraumatic ends are such ends that cannot cause and injury or rupture of any tissue inside the human body. s Ref.
• the other method of manufacturing braided stents consists in forming a meshwork from more than two fibres by means of a mandrel and a mechanical braiding device. After having been measured out, the fibres are attached to a mandrel that is placed on a rotational mechanism. In its proximal portion, the mandrel is provided with the plugs that enable a specific number of fibres to be attached.
• the stents may be manufactured from, e.g., 4, 6, 8, 10 or more fibres. The number of the plugs is variable. Nevertheless, it is in direct proportion with that of the fibres the stent is to be composed of.
• Each fibre is attached to the corresponding plug of the mandrel, the point of attachment being in the half of the length of the fibre. Both the ends of the fibre are directed along the mandrel into the mechanism where they ar also attached.
• the formation or the stent is accomplished in that the central mandrel is driven in rotation. In this way, a stent having one traumatic and one atraumatic end portion may be created. Then the stent and the mandrel are removed from the device; Subsequently, the traumatic ends of the fibres must also assume atraumatic properties: This may be accomplished in one of the following manners:
• the ends may be terminated by welding in order to form one of the aforesaid structures.
• the end may be welded means of external heat or a laser that is adjusted according to the parameters of the respective material.
• the alternative method of making the ends of the fibres atraumatic consists in circumfusing them with a molten polymer. In this case, the polymer should form a flexible strip in which all the fibres are embedded.
• the ends of the fibres may be bonded together by means of an adhesive certified for medical application, , ⁇ ,
• the meshwork is stabilized in a furnace, the stabilizing temperature depending on the properties of the material used for manufacturing the stent.
• the most efficient temperature is between T g and T m -10 °C, the corresponding time interval being from 10 to 120 minutes, preferably between 20 and 40 minutes.
• the most appropriate treatment parameters are as follows: 80 - 120 °C, 10 - 50 minutes.
• the material is diluted by adding an ample quantity of solvent, the desired final concentration ranging between 10 and 20 %.
• the resulting material is then deposited onto the fibrous skeleton of the stent as described below in more detail. Due to the pre-selected viscosity of the solution, the polymeric matter will only cover the fibres of the stent and will not penetrate into the interspaces between the individual fibres. Thus/ the stent itself remains exposed, being ready to co be coated with a biodegradable foil as discussed below.
• the further step of the process of manufacturing a biodegradable stent according to the invention consists in coating the same with a degradable foil.
• the most suitable materials for the application of degradable coatings appear to be the biodegradable materials having elastomeric or thermoplastic characteristics.
• such materials should have the Young's module of elasticity under 100 MPa, the rate of tear elongation over 400 %, the zero or negligible yield point and the shape memory between 80 and 90%.
• the rate of degradation depends on the thickness of the material.
• the thickness of the foil coatings according to the present invention ranges from 20 ⁇ to 200 ⁇ , preferably from 80 ⁇ to 120 ⁇ .
• the degradable foil is manufactured using the following method.
• the material is dissolved by means of a suitable solvent.
• the suitable solvent is considered to be an organic one having hydrophilic or hydrophobic characteristics.
• Supercritical solvents are utilizable, as well.
• the following solvents are considered to be the most suitable ones: acetone, toluene, dimethylacetamid, tetrahydrofurane, dimethyl sulfoxide or chlorinated solvents, such as chloroform or trichlorethane. Any combination of at least two solvents is also conceivable.
• the polymer to be deposited onto the biodegradable stent is dissolved the resulting solution with a concentration from 1 to 80 percent by weight.
• the preferred range of concentration of the solution which provides an adequate viscosity and good ability to form a film, is from 10 to 20 percent.
• the solution must be thoroughly stirred during dissolving. For this purpose, a magnetic or centrifugal agitator may be employed. The selected method should lead to an adequate intermixing degree of the polymer and solvent and to the formation of a homogenous solution.
• the solution prepared in the manner described above is then degased by means of a vacuum device. The solution having adequate concentration and viscosity is then ready to be applied onto the surface df the stent.
• the device for applying coatings onto the stents comprises the following components:
• a coating mandrel which is arranged horizontally and ma rotate around its axis. It is 1 made of a heat resistant material, such as of PTFE.
• a storage reservoir for a polymeric solution and a metering device which regulates the input quantity of silicone is provided.
• a rotational device serving for clamping the mandrel with the stent thereon and for driving the same in rotation.
• the aforesaid device should be able to rotate clockwise 1 or counter clockwise around its longitudinal axis.
• a dosing device provided with a thin outlet tube or orifice, such as a thin needle, leading to the horizontally situated stent.
• a tempering furnace that serves for removing the solvent from the polymeric solution deposited on the stent and for stabilizing the cross-linked structure of polymers. The temperature inside the furnace should be selected Jn accordance with the boiling point of the solvent. In case that the heat treatment is also used to form a cross- linked degradable elastomer, the temperature setting should create optimum cross- Sinking conditions. Both for the evaporation of the solvent and for the cross-linking of the polymer, a source of infrared or ultraviolet light may also be used.
• the process of providing the stent with the coating comprises the following consecutive steps:
• the stent is placed o a coating mandrel. t>)
• the bottle of the storage reservoir is filled wit .the.polymeric solution.. :, . , e)
• a discrete -quantity of the polymer' is- selected depending on the desirable thickness of the coating to be applied! '
• the solution is deposited onto the stent through a narrow orifice, preferably by means of a needle which is moving in the horizontal direction at a defined speed.
• the stent may be coated with the foil in a continuous manner or in ⁇ a discontinuous manner.
• the stent After having been formed on the mandrel and coated with said solution, the stent is placed into a furnace where the polymer gets dry and a film is formed on the surface of the stent under the temperature of T m - 10°C.
• the foil may assume one of the following shapes: it may cover the entire surface of the stent, it may cover the intermediate portion of the stent leaving the proximal and distal portion of the same blank or it may form a variable number of transversal or longitudinal strips having different thicknesses and lengths.
• the coating applied on the surface of the stent may project over the structure of the meshwork at the distal end to form a free envelope having hollow cylindrical shape. In this manner, the so called anti-reflux valve max be created.
• the anti-reflux valve forms a long hollow sleeve intended to prevent the food from travelling back from the stomach into the esophagus of the patient.
• the sleeve may me made from the basic foil forming the coating of the stent or from a different foil having a shorter period of decomposition.
• the thickness of the foil forming the anti-reflux valve may be equal to that of the coating applied oh the skeleton. Alternatively, this thickness may range between 10 ⁇ and 250 ⁇ ⁇ ⁇ .
• the application of a medicament onto the stent is the ; final step of the manufacturing method according to the present invention.
• the purpose of the medicament is to prevent the reactions of the tissue induced by the presence of the stent.
• the medicament is embedded in the biodegradable polymeric coating, the parameters 1 of the latter being selected with respect to the desired rate of release of the particular medicament. If a rapid release of the medicament from the stent is required, a polymer having a short period of degradation should be selected, otherwise a polymer with prolonged period of degradation should be used.
• the period of degradation must not be longer than that of the polymer the skeleton of the stent is made of: in this respect, the ideal polymer should have a period of degradation which is equal to or slightly shorter than that of the coated stent.
• a medicament is not the only substance to which the above mentioned process is applicable. This means that there is a number of other substances that could be deposited onto biodegradable coated stents. Such substances may include proteins, enzymes, genes, stem cells, radioactive substances used for the local treatment of tumors etc. : 1 '
• the medicament may be applied onto the stent using either of the following methods:
• the medicament is encapsulated in a degradable polymeric envelope that protects the therapeutic effect of the active substance, controls the respective releasing mechanism and enables the deposition onto a prepared stent.
• a degradable polymeric envelope that protects the therapeutic effect of the active substance, controls the respective releasing mechanism and enables the deposition onto a prepared stent.
• the surface treatment consists in the application of a polymer solution with a concentration between 5 and 60%, preferably between 10 and 15%. Such solution may be prepared from any of the suitable biodegradable polymers known in the art.
• the stent When undergoing the above surface treatment, the stent is attached to a mandrel. Afterwards, the stent undergoes heat treatment.
• the treatment temperature is selected from the range of 20 to 80 °C.
• the stent ' ⁇ ' ⁇ may ⁇ be coated with a biodegradable elastic foil in the subsequent step.
• the medicament is deposited on the coating of the stent.
• the coated biodegradable stent is placed on a coating mandrel again.
• the stent undergoes the surface treatment process consisting ip the application of a polymeric solution with the aim to enhance the adhesive properties of the stent.
• the polymeric solution may have a concentration between 5 and 60%, preferably between 10 and 15%.
• Such solution may be prepared from any of the soluble biodegradable polymers known in the art.
• the stent undergoes heat treatment.
• the treatment temperature is selected from the range of 20 to 80 °C.
• the stent After having been prepared in the foregoing steps, the stent, while still attached to the coating mandrel, is provided with a layer consisting of the polymeric solution containing the medicament.
• the content of the medicament in this polymeric bath may be between 1 and 20%, preferably between 1 and 5%. It is desirable that the basic polymeric material used for the surface treatment of the stent and that containing the medicament are of the same type in order to ensure good adhesion properties of the materials.
• the deposited layer of the polymer containing the medicament also undergoes a heat treatment stage.
• the biodegradable stent according to the invention is manufactured from
• biodegradable fibres in particular:
• the core being encased in another polymeric material forming the coating of the final fibre (the polymeric materials of the core and coating may be different, thus controllably influencing the biodegradability of the final fibre), or
• the respective polymeric materials may also be different, thus controllably influencing the biodegradability of the final fibre.
• the interlaced fibres of the finished stent may be coated with a polymeric dispersion containing a radiopaque substance (again, the respective polymeric materials may be different).
• the finished stent may either remain uncoated or be provided with a coat formed from a "neutral" biodegradable foil.
• the content of the polymer in the above foil may range between 1 and 80 percent by weight, preferably between 10 and 20 percent by weight.
• the further step is:
• the stent having a coat formed by a "neutral” biodegradable foil with another biodegradable foil in which an active substance is encapsulated.
• the active substance may be selected from the group of substances including medicaments, proteins, enzymes, genes, stem cells or radioactive substances used for the local treatment of tumors.
• the main area of application of the biodegradable stent coated with a biodegradable elastic foil is the gastrointestinal tract.
• the application of the stent may be particularly desirable in the esophagus, in the transitional section between the stomach and the duodenum, in the duodenum or anywhere in the small intestine, the colon and the rectum.
• the stent according to the invention may also be applied in the biliary and pancreatic pathways.
• the stent may also be applied in the respiratory tract, whether in the trachea or in the bronchi / bronchioles.
• the present invention may also be applicable in the lacrimal pathways or in the gynecology.
• the present invention is not primarily intended to be applied in the vascular system even though such application would be definitely possible. The latter application, however, does not fall into the scope of the present invention.
• the main fields of application also includes the provision of patency of the above mentioned tubular organs inside the human body when such organs are obstructed, e.g. due to a surgical intervention.
• Such obstruction may also be caused by diverse malignant or benign structures! fistulae, anastomoses and hemorrhagic leaks.
• biodegradable self-expanding stents according to the invention may serve as carriers of stem cells and as scaffolds for the direct regenerative treatment of tissues.
• the stent supports and ensures the patency of a tubular organ until the wall thereof gets recovered by means of stem cells.
• the stents according to the invention may also serve as carriers of genes and proteins.

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