EP1670595A2 - Procede et dispositif de revetement d'implants medicaux - Google Patents

Procede et dispositif de revetement d'implants medicaux

Info

Publication number
EP1670595A2
EP1670595A2 EP04770588A EP04770588A EP1670595A2 EP 1670595 A2 EP1670595 A2 EP 1670595A2 EP 04770588 A EP04770588 A EP 04770588A EP 04770588 A EP04770588 A EP 04770588A EP 1670595 A2 EP1670595 A2 EP 1670595A2
Authority
EP
European Patent Office
Prior art keywords
medicament
coat
dispensing element
polymer
motion
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04770588A
Other languages
German (de)
English (en)
Other versions
EP1670595A4 (fr
Inventor
Alexander Dubson
Ori Katz-Oz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nicast Ltd
Original Assignee
Nicast Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nicast Ltd filed Critical Nicast Ltd
Publication of EP1670595A2 publication Critical patent/EP1670595A2/fr
Publication of EP1670595A4 publication Critical patent/EP1670595A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D1/00—Processes for applying liquids or other fluent materials
    • B05D1/007—Processes for applying liquids or other fluent materials using an electrostatic field
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0061—Electro-spinning characterised by the electro-spinning apparatus
    • D01D5/0076—Electro-spinning characterised by the electro-spinning apparatus characterised by the collecting device, e.g. drum, wheel, endless belt, plate or grid
    • D01D5/0084—Coating by electro-spinning, i.e. the electro-spun fibres are not removed from the collecting device but remain integral with it, e.g. coating of prostheses
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/18—Formation of filaments, threads, or the like by means of rotating spinnerets
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B13/00—Machines or plants for applying liquids or other fluent materials to surfaces of objects or other work by spraying, not covered by groups B05B1/00 - B05B11/00
    • B05B13/02—Means for supporting work; Arrangement or mounting of spray heads; Adaptation or arrangement of means for feeding work
    • B05B13/04—Means for supporting work; Arrangement or mounting of spray heads; Adaptation or arrangement of means for feeding work the spray heads being moved during spraying operation
    • B05B13/0421—Means for supporting work; Arrangement or mounting of spray heads; Adaptation or arrangement of means for feeding work the spray heads being moved during spraying operation with rotating spray heads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
    • B05B5/025—Discharge apparatus, e.g. electrostatic spray guns
    • B05B5/0255—Discharge apparatus, e.g. electrostatic spray guns spraying and depositing by electrostatic forces only
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
    • B05B5/08—Plant for applying liquids or other fluent materials to objects

Definitions

  • the present invention relates to a method .and apparatus for coating an object and, more particularly, to a method .and apparatus for coating .an object using electrospinning.
  • the present invention is particularly useful for coating medical implants.
  • Production of fibrous products is described in the literature ter alia using the technique of electrospinning of liquefied polymer, so that products comprising polymer fibers are obtained.
  • Electrospinning is a method for the manufacture of ultra- thin synthetic fibers, which reduces the number of technological operations and increases the stability of properties of the product being m.anufactured.
  • the process of electrospinning creates a fine stre.am or jet of liquid that upon proper evaporation of a solvent to solid transition state yields a nonwoven structure.
  • the fine stre.am of liquid is produced by pulling a small amount of polymer solution through space by using electrical forces. More p.articul.ariy, the electrospinning process involves the subjection of a liquefied subst.ance, such as polymer, into .an electric field, whereby the liquid is caused to produce fibers that are drawn by electric forces to .an electrode, and are, in addition, subjected to a hardening procedure.
  • the hardening procedure may be mere cooling; other procedures such as chemical hardening (polymerization) or evaporation of solvent may also be employed.
  • the produced fibers are collected on a suitably located precipitation device and subsequently stripped from it.
  • the sedimentation device is typically shaped in accordance with the desired geometry of the final product, which may be for example tubular, flat or even an arbitrarily shaped product.
  • tubular fibrous product which can be manufactured via electrospinning are vascular prosthesis, particul.arly a synthetic blood vessel, and tubes through which a wire or other device or structure may pass or lie.
  • Tubular fibrous products may also be used as various kinds of artificial ducts, such as, for example, urinary, air or bile duct.
  • Electrospinning can also be used for coating various objects, such as stents and other medical implants.
  • Stents are widely used to provide coronaries with radial support so as to prevent constriction thereof. Nevertheless, clinical data indicates that stents are usually unable to prevent late restenosis beginning at about three months following an angioplasty procedure.
  • Known in the art are stents having a mechanical barrier thereacross, designed to prevent biological material from the lesion to move through the stent .and into the lumen during placement of the stent.
  • electrospinning permits to obtain durable coating with wide range of fiber thickness (from tens of nanometers to tens of micrometers), achieves exceptional homogeneity, smoothness .and desired porosity distribution along the coating thickness.
  • Stents themselves do not encourage normal cellular invasion and therefore can lead to an undisciplined development of cells in the metal mesh of the stent, giving rise to cellule hyperplasia.
  • the pores of the graft component are invaded by cellular tissues from the region of the artery surrounding the stent graft.
  • diversified polymers with various biochemical and physico-mechanical properties can be used in coating.
  • coated stents having a mechanical barrier can prevent excessive tissue growth from occluding the vessel.
  • U.S. Pat. No. 5,916,264 the contents of which .are hereby incorporated by reference, disclose a stent graft including a sheet of PTFE sandwiched between two metal stents. Although this device has been successful at sealing aneurysms .and perforations, it is a bulky device with a significantly larger crossing profile .and reduced flexibility compared to a state- of-the-art stent. Examples of electrospinning methods in stent graft manufacturing are found in U.S. Patent Nos.
  • a stent coat will have good adhesion to the stent metal basis in body liquids, so as not too detached after or during implantation. Further, the elasticity and strength of the stent coat should be compatible with the enormous inflation of the stent metal upon opening (about 300-500 %). Additionally, it is desired that the stent coat will promote better grafting, reduce restenosis risk and optimize medication discharge into implantation-adjacent tissues. With respect to the above requirements, the properties of prior art stent coats are far less th.an satisfactory. For example, in electrospinning systems having elongated electrode system, the electric field becomes critically asymmetrical, and the fibers obtain preferential longitudinal orientation.
  • Such coat structure is known to have high anisotropy of mechanical properties in which axial strength (along fiber orientation) is favored over radial strength. It is recognized that radial strength is a crucial parameter, in particular in stent coat which, as stated, has to comply with significant inflation of the stent metal.
  • electrospinning systems electrostatic repulsion between fibers results in increased opening .angle of the jet, .an exp.anded sedimentation area and low rupture strength.
  • PCI percutaneous coronary intervention
  • the plaques on the wall of the artery cracks and sharp edges thereof cut the surrounding tissue. This causes internal bleeding and a possible local infection, which, if not adequately treated, may spread and adversely affect other parts of the body.
  • Local infections in the region of the defective site in an artery do not lend themselves to treatment by injecting an antibiotic into the blood stream of the patient, for such treatment is not usually effective against localized infections.
  • a more common approach to this problem is to coat the wire mesh of the stent with a therapeutic agent which makes contact with the infected region.
  • such one- shot treatment is not sufficient to diminish infections, .and it is often necessary to administer antibiotic and/or other therapeutic agents for several hours or days, or even months.
  • the risk of vessel damage during stent implantation may be lowered through the use of a soft stent serving to improve the biological interface between the stent and the artery and thereby reduce the risk that the stent will inflict damage during implantation.
  • a soft stent serving to improve the biological interface between the stent and the artery and thereby reduce the risk that the stent will inflict damage during implantation.
  • polymeric stents or stent coatings with biocompatible fibers are found in, for example, U.S. Patent Nos. 6,001,125, 5,376,117 and 5,628,788, all of which are hereby incorporated by reference.
  • U.S. Patent No. 5,948,018 discloses a graft composed of an expensible stent component covered by an elastomeric polymeric graft component which, because of its stretchability, does not inhibit ex ⁇ .ansion of the stent.
  • the graft component is fabricated by electrospinning to achieve porosity hence to facilitate normal cellular growth.
  • U.S. Patent No. 5,948,018 fails to address injuries inflicted by the stent in the course of its implantation on the delicate tissues of the artery. These injuries may result in a local infection at the site of the implantation, or lead to other disorders which, unless treated effectively, can cancel out the benefits of the implant. Additional prior art of interest include: Murphy et al. "Percutaneous Polymeric Stents in Porcine Coronary Arteries", Circulation 86: 1596-1604, 1992; Jeong et al.
  • a method of coating a non-rotary object with an electrospun coat comprising, dispensing a charged liquefied polymer through at least one dispensing element within an electric field to thereby form a jet of polymer fibers, and moving the dispensing element relative to the object so as to coat the object with the electrospun coat.
  • the method further comprises translationally moving the object relative to the jet of the polymer fibers so as to uniformly distribute the polymer fibers onto the object.
  • thetranslational motion is a harmonic motion.
  • the translational motion is a reciprocation motion.
  • the object is an expandable tubular supporting element.
  • the expandable tubul.ar supporting element comprises a deformable mesh of metal wires.
  • the expandable tubul.ar supporting element comprises a deformable mesh of stainless steel wires.
  • the object is a stent.
  • the object is a stent assembly having at least one coat.
  • the object is a stent mounted on a stent delivery system.
  • the object is an impl.antable medical device.
  • the object is .an impl.antable medical device mounted on a stent delivery system.
  • the method further comprises mounting the expandable tubul.ar supporting element onto a mandrel, prior to the dispensation of the ch,arged liquefied polymer.
  • the method further comprises dispensing the charged liquefied polymer through the at least one dispensing element within the electric field, .and moving the dispensing element relative to the mandrel so as to coat the mandrel, hence providing an inner coat to the expandable tubular supporting element.
  • the method further comprises providing at least one adhesion layer onto the expandable tubular supporting element.
  • the at least one adhesion layer is an impervious adhesion layer.
  • an apparatus for coating a non-rotary object with .an electrospun coat comprising at least one dispensing element being at a potential difference relative to the object, the at least one dispensing element being capable of moving relative to the object while dispensing a charged liquefied polymer within .an electric field defined by the potential difference, to thereby form ajet of polymer fibers coating the object.
  • the at least one dispensing element is capable of moving along a circular path. According to still further features in the described preferred embodiments the at least one dispensing element is capable of moving along a helix path. According to still further features in the described preferred embodiments the at least one dispensing element is capable of moving along a zigzag path. According to still further features in the described preferred embodiments the at least one dispensing element is designed and constructed such that the electric field moves synchronically with the motion of the at least one dispensing element.
  • the motion of the at least one dispensing element is selected so as to establish a spiral motion of the jet of the polymer fibers about the object, the spiral motion being characterized by a gradually deceasing radius.
  • the at least one dispensing element comprises an arrangement of electrodes.
  • the at least one dispensing element comprises a rotatable ring having at least one capillary.
  • the rotatable ring is made of a dielectric material.
  • the rotatable ring is made of a conductive material.
  • the apparatus further comprises a bath for holding a liquefied polymer, the bath being in fluid communication with the at least one dispensing element.
  • the apparatus further comprises a pump for tr ⁇ ansferring the liquefied polymer from the bath to the at least one dispensing element.
  • the apparatus further comprises a mechanism for tr.anslationally moving the object relative to the jet of the polymer fibers so as to uniformly distribute the polymer fibers onto the object.
  • the apparatus further comprises the charged liquefied polymer .and further wherein a medicament is mixed with the charged liquefied polymer and is co-dispensed therewith through the at least one dispensing element, so as to coat the object with an electrospun medicated coat.
  • the apparatus further comprises a sprayer for distributing compact objects constituting a mendicant therein between the polymer fibers.
  • a method of treating a constricted blood vessel comprising: (a) providing a stent assembly; (b) dispensing a charged liquefied polymer through at least one dispensing element within .an electric field to thereby form ajet of polymer fibers, and moving the dispensing element relative to the stent assembly so as to coat the stent assembly with .an electrospun coat; and (c) placing the stent assembly in the constricted blood vessel.
  • the method further comprises expanding the stent assembly so as to dilate tissues surrounding the stent assembly in a manner such that flow constriction is substantially eradicated.
  • the motion of the at least one dispensing element is selected so as to establish a spiral motion of the jet of the polymer fibers about the stent assembly, the spiral motion being characterized by a gradually deceasing radius.
  • the method further comprises tanslationally moving the stent assembly relative to the jet of the polymer fibers so as to uniformly distribute the polymer fibers onto the stent assembly.
  • a medicament is mixed with the charged liquefied polymer .and is co-dispensed therewith through the at least one dispensing element, so as to coat the object with an electrospun medicated coat.
  • the medicament is dissolved in the ch rged liquefied polymer. According to still further features in the described preferred embodiments the medicament is suspended in the charged liquefied polymer. According to still further features in the described preferred embodiments the medicament is constituted by particles embedded in the polymer fibers. According to still further features in the described preferred embodiments the method further comprises constituting a mendicant into compact objects and distributing the compact objects between the polymer fibers. According to still further features in the described preferred embodiments the medicament is heparin. According to still further features in the described preferred embodiments the medicament is a radioactive compound. According to still further features in the described preferred embodiments the medicament is silver sulfadiazine.
  • the compact objects are capsules. According to still further features in the described preferred embodiments the compact objects are in a powder form. According to still further features in the described preferred embodiments the distributing of the compact objects is by spraying. According to still further features in the described preferred embodiments the method further comprises providing at least one additional coat on the electrospun coat.
  • FIG. 1 is a schematic illustration of a prior art electrospinning apparatus
  • FIG. 2a is a flowchart diagram of a method of coating a non-rotary object with an electrospun coat, according to a preferred embodiment of the present invention
  • FIGs. 2b-e are schematic illustrations of paths along which a dispensing element can move, according to a preferred embodiment of the present invention
  • FIG. 2f is a schematic illustration of a spiral trajectory of a polymer fiber, according to a preferred embodiment of the present invention
  • FIG. 3 is a cross-sectional view of a stent assembly according to a preferred embodiment of the present invention
  • FIG. 4a is an end view the stent assembly, according to a preferred embodiment of the present invention
  • FIG. 4b is an end view of a stent assembly which further comprises at least one adhesion layer, according to a preferred embodiment of the present invention
  • FIG. 5 is a tubule supporting element which is designed .and constructed for dilating a constricted blood vessel in a body vasculature, according to a preferred embodiment of the present invention
  • FIG. 6 is a portion of the tubular supporting element of Figure 5 comprising a deformable mesh of metal wires, according to a preferred embodiment of the present invention
  • FIG. 7 is a stent assembly, manufactured according to the teachings of the present invention, occupying a defective site in an artery;
  • FIG. 8 is a portion of a non- woven web of polymer fibers produced according to a preferred embodiment of the present invention
  • FIG. 9 is a portion of a non- woven web of polymer fibers which comprises a pharmaceutical agent constituted by compact objects and distributed between the electrospun polymer fibers
  • FIG. 10 is a schematic illustration of an apparatus for coating a non-rotary object with .an electrospun coat, according to a preferred embodiment of the present invention
  • FIG. 11 is a flowchart diagram of a method of treating a constricted blood vessel, according to a preferred embodiment of the present invention.
  • the present invention is of a method and apparatus for coating an object which can be implantable medical device.
  • the present invention can be used to provide an electrospun coat to non-rotary objects, such as, but not limited to, stents or other implantable medical devices while being mounted on a delivery system (e.g., a stent delivery system) or a portion thereof.
  • the present invention is further of a method of treating a constricted blood vessel.
  • Figure 1 illustrates a conventional electrospinning apparatus for manufacturing a nonwoven material, generally referred to herein as apparatus 1.
  • Apparatus 1 includes a dispenser 2 which can be, for example, a bath provided with one or more capillary apertures 4.
  • Dispenser 2 serves for storing the polymer to be spun in a liquid form (dissolved or melted). Dispenser 2 is positioned at a predetermined distance from a precipitation electrode 6, defining a first axis 5 therebetween. Precipitation electrode 6 serves for forming a structure thereupon. Precipitation electrode 6 is typically manufactured in accordance with the geometrical properties of the final product which is to be fabricated. For example, precipitation electrode 6 can be a mandrel having a longitudinal axis 3 which can be used for manufacturing tubule structures. Dispenser 2 is typically grounded, while precipitation electrode 6 is connected to a source of high voltage (not shown in Figure 1), preferably of negative polarity, thus forming .an electric field between dispenser 2 and precipitation electrode 6.
  • a source of high voltage not shown in Figure 1
  • precipitation electrode 6 can be grounded while dispenser 2 is connected to a source of high voltage with positive pol.arity.
  • the liquefied polymer is extruded, for ex.am.ple under the action of hydrostatic pressure, or using a pump (not shown in Figure 1), through capillary apertures 4 of dispenser 2.
  • a process of solvent evaporation or cooling starts, which is accompanied by the creation of capsules with a semi-rigid envelope or crust.
  • An electric field occasionally accompanied by a unipolar corona discharge in the .area of dispenser 2, is generated by the potential difference between dispenser 2 and precipitation electrode 6.
  • the above-described capsules become charged. Electric forces of repulsion within the capsules lead to a drastic increase in hydrostatic pressure.
  • the semi-rigid envelopes are stretched, .and a number of point micro-ruptures are formed on the surface of each envelope leading to spraying of ultra-thin jets of liquefied polymer from dispenser 2. Under the effect of a Coulomb force, the jets depart from dispenser 2 and travel towards the opposite polarity electrode, i.e., precipitation electrode 6. Moving with high velocity in the inter-electrode space, the jet cools or solvent therein evaporates, thus forming ajet of polymer fibers, collected on the surface of precipitation electrode
  • Tubular non-woven structures are conventionally produced by rotating precipitation electrode 6 about longitudinal axis 3 during the electrospinning process, so as to circularly coat precipitation electrode 6.
  • Typical electrospinning processes e.g., as employed by apparatus 1 suffer from several limitations. First, as will be appreciated by a skilled artisan, when precipitation electrode 6 has a small radius of curvature, the polymer fibers tend to align axially along longitudinal axis 3. In such cases the resulting structure has an axial strength which is favored over the radial strength. Thus, small diameter products, have limited radial strength when manufactured via conventional electrospinning processes.
  • the present embodiment in which the objects .are non-rotary is that there is no need to mount the objects on a rotating electrode prior to the electrospinning process, thus allowing the coating of non-hollow as well as hollow objects.
  • the present embodiment can be used for providing an electrospun coat on stents or other medical implantable devices, either alone or while being mounted on a suitable delivery system, e.g., a stent delivery system, such as, but not limited to, a catheter balloon.
  • a suitable delivery system e.g., a stent delivery system, such as, but not limited to, a catheter balloon.
  • This embodiment is useful when it is desired to improve strength, form a mechanical barrier and/or incorporate medicaments into commercially available medical implantable devices which are typically supplied by the vendor as "one unit products" in which the medical implantable devices are mounted on or integrated with additional members or devices.
  • FIG. 2a is a flowchart diagram of a method of coating a non-rotary object, according to a preferred embodiment of the present invention.
  • a charged liquefied polymer is dispensed through at least one dispensing element within an electric field, to thereby form ajet of polymer fibers.
  • the dispensing element is moved relative to the object so as to coat the object with the electrospun coat. While moving along the predetermined path, the dispensing element(s) can change the direction and/or magnitude of the electric field. These changes can be tailored in accordance with the desired orientation of the polymer fibers on the object.
  • the dispensing element can be moved along a predetermined path.
  • the path is preferably selected so as to coat the entire object or selected portions thereof, as desired.
  • the dispenser can be moved along a helix path (Figure 2b), a circular path ( Figure 2c), a zigzag path ( Figure 2d-e) and the like.
  • the path and the p.arameters characterizing the path are preferably selected according to the desired orientation of fibers on the object.
  • Several sweeps of the dispensing element along the objects can be employed so as to improve the homogeneity of the electrospun coat.
  • the number of seeps is preferably selected according to the desired porosity of the coat, where larger number of sweeps corresponds to lower average pore size.
  • the density of the fibers and/or the type of liquefied polymer can be changes from one sweep to the other thereby to provide a multilayer coat, as further detailed hereinunder.
  • the motion of the dispensing element can be supplemented by a translational motion (e.g., reciprocation motion, harmonic motion, etc.) of the object relative to the jet of polymer fibers.
  • This embodiment is particularly useful when the motion path of the dispensing element is planar (e.g., a circular path), such that upon reciprocal travel of the object relative to the motion plane of the dispensing element the fibers are redistributed along the object and the homogeneity of the coat is improved.
  • the electrical field is generated by a potential difference between the dispensing element and the object.
  • Typical potential difference is from about 20 kN to about 50 kV.
  • Such potential difference can be established, e.g., by grounding the dispensing element and placing the object in a negative potential or in any other electrostatic configuration which ensures the motion of the charged liquefied polymer from the dispensing element to the object.
  • the object comprises conductive parts (e.g., a metal mesh of a stent) the conductive parts can be connected to a voltage source, preferably of negative polarity.
  • the object When the object is non conductive, or if desired, the object can be mounted on a precipitation electrode (e.g., a mandrel), connected to a voltage source.
  • a precipitation electrode e.g., a mandrel
  • the fibers When the fibers moves in space they are subjected to friction forces which result from collisions between molecules of the medium surrounding the object (typically air) and molecules of the fibers. The higher the density of the surrounding medium the larger are the friction forces.
  • the velocity of the dispensing element is selected such that the the polymer fibers acquire a sufficient tansverse velocity relative to the axis defined by the dispensing element and the object (see, e.g., axis 5 in Figure 1).
  • a typical linear velocity of the dispensing element is from about 100 cm/sec to about 3000 cm/sec.
  • a typical rotation frequency is from about 100 rpm to about 1200 rpm.
  • the term "about” refers to ⁇ 10 %.
  • the trajectory of the polymer fibers depends only on the electric force and the transverse velocity.
  • the trajectory of the polymer fiber is curvilinear, while for a process performed in a vacuum, due to the lack of friction, the trajectory is substantially rectilinear. Beside the transverse velocity of the fibers, they also accelerate under the influence of the electric field in the direction of the electric field lines. Thus, the direction of motion of the fibers at a given instant is the (vector) sum of the transverse velocity .and the velocity acquired in the direction of the electric field.
  • the jet of fibers moves along a spiral motion, characterized by a gradually deceasing radius.
  • a representative example of a spiral trajectory is shown in Figure 2f. It was found by the present inventors that although the polymer fibers have relatively low mass per unit length, the momentum acquired by the fibers due to ta. ngent movement becomes sufficient to oppose the electrical field perturbing forces .and to stabilize the movement of the fibers in space. For a tubular object and a circular motion of the dispensing element, it was found that at the aforementioned circular frequencies, the acquired momentum of the fibers is sufficient to provide a coat in which the fibers have a predominant azimuthal spatial orientation.
  • the motion characteristics (e.g., path, linear velocity, frequency) of the dispensing element are selected such that at least 60 % of the polymer fibers, more preferably at least 80 %, most preferably at least 90 % has an azimuthal orientation with respected to the longitudinal axis of the object.
  • the motion characteristics (e.g., path, linear velocity, frequency) of the dispensing element are selected such that the electrospun coat is capable of bearing a radial expansion of at least 300 %, more preferably at least 400 %, most preferably at least 500 % without being ruptured.
  • the motion of the dispensing element substantially narrows the jet spraying angle, thereby producing more concentrated jet resulting in a low average pore size of the final coat.
  • the jet angle can further be n.arrowed by a judicious selection of the geometrical shape of the dispensing element thereby the magnitude and direction of the electric field near the object .and along the trajectory of the fibers.
  • the motion and/or shape of the dispensing element is selected such that the spraying angle is narrowed by at least 10 %, more preferably at least
  • the combination of the electric force, friction force, transverse velocity and preferably the tr.anslational motion of the objects allows controlling the orientation, porosity as well as the density of the final coat.
  • the properties of the coat are suitable for implantation.
  • a predominant azimuthal orientation of the fibers is preferred, which azimuthal orientation can be obtained, as stated, by selecting a circular motion for the dispensing element.
  • the porosity is selected so as to accommodate cells migrating from the surrounding tissues .and to facilitate the proliferation of these cells while, at the same time, preventing undesired chemical materials and plaque debris from entering the blood vessel lumen during placement of the stent or prosthesis.
  • the controllable porosity of the present embodiment allows to design local drug delivery elements, whereby the coat may be incorporated with a mendicant or another pharmaceutical agent.
  • the porosity of the coat is preferably designed both to bear the independent drug load and to serve as a barrier controlling the drug release rate.
  • the embodiments of the present invention can be used for coating expandable tubular supporting elements of stents, as well as stent assemblies which already have a preliminary coat.
  • the above method can be used for providing single as well as multilayer coats, such as the coats disclosed in International Patent Application No. PCT/ILOl/01171, the contents of which .are hereby incorporated by reference.
  • Figure 3 is a schematic illustration of a cross- sectional view of a stent assembly, coated using selected steps of the method of the present invention.
  • the stent assembly comprises an expendable tubular supporting element 10 and at least one coat 12, having a predetermined porosity.
  • Coat 12 comprises an inner coat 14, lining an inner surface of element 10 and an outer coat 16, covering an outer surface of element 10.
  • Figure 4a illustrates an end view of the stent assembly, showing element 10, internally covered by inner coat 14 and externally covered by outer coat 16.
  • coat 12 may further comprise at least one adhesion layer 15, for adhering the components of the stent assembly as further detailed hereinafter.
  • Each of inner 14 and outer 16 coats can be provided using the above method by moving the dispensing element relative to expandable supporting element 10.
  • inner 14 and outer 16 coats are made of different liquefied polymers and have predetermined porosities, which may be different or similar as desired.
  • the liquefied polymer of inner 14 and/or outer 16 coats can be mixed with a mendicant or a pharmaceutical agent prior to the electrospinning process.
  • the mendicant can be either dissolved or suspended in the liquefied polymer.
  • element 10 is mounted on a precipitation electrode (e.g., a mandrel), prior to the electrospinning process.
  • the precipitation electrode function both as a carrier for element 10 and as a conductive element to which a high voltage is applied to establish the electric field.
  • inner coat 14 is provided as follows. First, the electrospinning process is employed so as to directly coat the nrandrel, so as to form inner coat 14 thereon.
  • the elecfrospinning process is tempor-arily ceased and element 10 is slipped onto the mandrel and drawn over inner coat 14.
  • Outer coat 16 is then provided by resuming the elecfrospinning process onto element 10. Since the operation for providing inner coat 14 demands a process cessation for a certain period, a majority of solvent contained in inner coat 14 may be evaporated. This may lead to a poor adhesion between the components of the stent assembly, once the process is resumed, .and might result in the coating stratification following stent graft opening.
  • the present invention successfully addresses the above-indicated limitation by two optimized techniques.
  • the outer sub-layer of inner coat 14 and the inner sub-layer of outer coat 16 are each made by elecfrospinning with upgraded capacity.
  • a typical upgrading can may range from about 50 % to about 100 %.
  • This procedure produce a dense adhesion layer made of thicker fibers with markedly increased solvent content.
  • a typical thickness of the adhesion layer ranges between about 20 ⁇ m and about 30 ⁇ m, which is small compared to the overall diameter of the stent assembly hence does not produce considerable effect on the coats general parameters.
  • the adhesion layer comprises an alternative polymer with lower molecular weight than the major polymer, possessing high elastic properties and reactivity.
  • the elecfrospinning method has the advantage of allowing the incorporation of various chemical components, such as pharmaceutical agents, to be incorporated in the fibers by mixing the pharmaceutical agents in the liquefied polymers prior to electrospinning.
  • Figure 5 is a schematic illustration of tubule supporting element 10 designed .and constructed for dilating a constricted blood vessel in the body vasculature.
  • Element 10 expands radially thereby dilates a constricted blood vessel.
  • the exp-ansibility of the stent assembly may be optimized by a suitable construction of element 10 and coat 12. The construction of element 10 will be described first, with reference to Figure 6, and the construction of coat 12 will be described thereafter.
  • Figure 6 illustrates a portion of element 10 comprising a deformable mesh of metal wires 18, which can be, for example, a deformable mesh of stainless steel wires.
  • element 10 When the stent assembly is placed in the desired location in an artery, element 10 may be expanded radially, to substantially dilate the arterial tissues surrounding the stent assembly to eradicate a flow constriction in the artery.
  • the expansion may be performed by any method known in the art, for example by using a balloon catheter or by forming element 10 from a material exhibiting temperature- activated shape, memory properties, such as Nitinol.
  • the polymer fibers forming coat 12 are elastomeric polymer fibers which stretch as element 10 is radially expanded.
  • inner coat 14 and outer coat 16 are coextensive with element 10, i.e., tubul.ar supporting element 10 is substantially coated.
  • inner coat 14 and/or outer coat 16 may be shorter in length than element 10, in which case at least one end of element 10 is exposed.
  • Figure 7 illustrates the stent assembly occupying a defective site 20 in an artery.
  • the outer diameter of the stent assembly in its unexpended state, including outer coat 16, is such that it ensures transporting of the stent assembly through the .artery to defective site 20, for example by a catheter.
  • the expending range of the stent assembly is such that when in place at defective site 20, the expanded assembly then has a maximum diameter causing the arterial tissues surrounding the stent assembly to be dilated to a degree eradicating the flow constriction at the site.
  • Impl.antation of the stent assembly in a blood vessel may result in disorders in the blood vessel, for example an injury inflicted on tissues of the blood vessel upon the implantation, restenosis, in-stent stenosis and hyper cell proliferation.
  • coat 12 may comprise a medicament for delivery of the medicament into a body vasculature.
  • coat 12 not only serves to graft the assembly to the artery but also functions as a reservoir for storing the medicament to be delivered over a prolonged time period.
  • Figure 8 illustrates a portion of a non- oven web of polymer fibers produced according to a preferred embodiment of the present invention. Fibers 22, 24 and 26 intersect and are joined together at the intersections, the resultant interstices rendering the web highly porous. Since electrospun fibers are ultra-thin, they have .an exceptionally large surface area, which allows a high quantity of pharmaceutical agents and medicaments to be incorporated thereon.
  • the surface area of the electrospun polymer fibers approaches that of activated carbon, thereby making the non- woven web of polymer fibers .an efficient local drug delivery system.
  • the preferred mechanism of medicament release from the coat is by diffusion, regardless of the technique employed to embed the medicament therein.
  • the duration of therapeutic drug release in a predetermined concentration depends on several variants, which may be controlled during the manufacturing process.
  • One variant is the chemical nature of the carrier polymer and the chemical means binding the medicament to it. This variant may be controlled by a suitable choice of the polymer(s) used in the elecfrospinning process.
  • Another variant is the area of contact between the body and the medicament, which can be controlled by varying the free surface of the electrospun polymer fibers.
  • the coat comprises a number of sub-layers.
  • the sub-layers can be differentiated by fiber orientation, polymer type, medicament incorporated therein and desired release rate thereof.
  • medicament release during the first hours .and days following implantation may be achieved by incorporating a solid solution, containing a medicament such as anticoagulants and antithrombogenic agents, in a sub-layer of readily soluble biodegradable polymer fibers.
  • the medicament that releases includes anticoagulants and antithrombogenic agents.
  • the medicament may be constituted by particles 28 embedded in the electrospun polymer fibers forming a sub-layer of at least one coat 12.
  • This method is useful for medicament release during the first postoperative days and weeks.
  • the medicament can include antimicrobials or antibiotics, thrombolytics, vasodilators, and the like.
  • the duration of the delivery process is effected by the type of polymer used for fabricating the corresponding sublayer. Specifically, optimal release rate is ensured by using moderately stable biodegradable polymers.
  • Figure 9 illustrating an alternative method for incorporating the medicament in the coat, ensuring medicament release during the first post-operative days and weeks.
  • the medicament is constituted by compact objects 30 distributed between the elecfrospun polymer fibers of the coat.
  • Compact objects 30 may be in any known form, such as, but not limited to, moderately stable biodegradable polymer capsules.
  • the present invention is also provides a method of releasing medicament, which may last from several months to several years.
  • the medicament is dissolved or encapsulated in a sub-layer made of biosatable fibers. The rate diffusion from within a biostable sub- layer is substantially slower, thereby ensuring a prolonged effect of medicament release.
  • Medicaments suitable for such prolonged release include, without limitation, antiplatelets, growth-factor antagonists and free radical scavengers.
  • App.aratus 50 comprises at least one dispensing element 37 being at a potential difference relative to object 52, dispensing element 53 is capable of moving relative to object 52 while dispensing the charged liquefied polymer as further detailed hereinabove.
  • Dispensing element 37 may be for example, an arrangement of electrodes or a rotatable ring 45 having at least one capillary 46, preferably radially oriented.
  • Ring 45 can be made of a dielectric or conductive material as desired.
  • Capillaries 46 are made of conductive material and in electrical communication thereamongst.
  • the number of capillaries is from 1 capillary to more than 10 capillaries, more preferably 2-4 capillaries, most preferably
  • the diameter of ring 45 .and the length of capillaries 46 are preferably selected such that the distance between object 52 .and tip 51 of capillary 46 is from about 100 mm to about 250 mm, more preferably from about 120 mm to about
  • dispensing element 37 is connected to a shaft 47 having at least one arm 48. Arms 48 and shaft 47 are preferably hollow elements to allow flow of the liquefied polymer therethrough. Alternatively a system of flexible tubes can be used to establish fluid communication between dispensing element 37 .and a bath 41 which holds the liquefied polymer. Shaft 47 is preferably positioned between one or more bearings 58 and serves for mechanically connecting dispensing element 37 with an electric drive 54.
  • Apparatus 50 may further comprise a mandrel 42 which may be connected to a power supply 43 in embodiments in which mandrel 42 serves as conductive electrodes.
  • Mandrel 42 or object 52 is preferably operatively associated with a mechanism 56 for franslationally moving object 52 as further detailed hereinabove.
  • apparatus 50 further comprises a pump 40, connected to bath 41 for drawing the liquid polymer stored in bath 41 into dispensing element 37.
  • Apparatus 50 may further comprise one or more filters 49, through which the liquefied is transferred via shaft 47 and arm 48 into element 37.
  • apparatus 50 comprises a sprayer 57 for distributing compact objects (e.g., objects 30) constituting a mendicant therein between the polymer fibers, as further detailed hereinabove.
  • FIG 11 is a flowchart diagram of a method of treating a constricted blood vessel, according to a preferred embodiment of the present invention.
  • a first step on the method designated in Figure 11 by Block 60
  • a stent assembly is provided in a first step on the method, designated in Figure 11 by Block 60
  • a charged liquefied polymer is dispensed through a moving dispensing element as further detailed hereinabove.
  • the stent assembly is placed in the constricted blood vessel, for example, using a catheter balloon or other stent delivery system.
  • the stent assembly is preferably expanded so as to dilate the arterial tissues surrounding the stent assembly to a degree eradicating the flow constriction of the blood vessel.
  • the invention has been described in conjunction with medical implants, other medical implants, not necessarily of tubular structure, may be coated using the techniques of the present invention.
  • grafts and patches which may be coated prior to procedure of implantation or application can be drug-loaded and enjoy the advantages as described herein.
  • the coat may be made from any known biocompatible polymer.
  • the polymer fibers are preferably a combination of a biodegradable polymer and a biostable polymer.
  • biostable polymers with a relatively low chronic tissue response include, without limitation, polycarbonate based aliphatic polyurethanes, siloxane based aromatic polyurethanes, polydimethylsiloxane and other silicone rubbers, polyester, polyolefins, polymethyl- methacrylate, vinyl halide polymer and copolymers, polyvinyl aromatics, polyvinyl esters, polyamides, polyimides, polyethers .and many others that can be dissolved in appropriate solvents and electrically spun on the stent.
  • Biodegradable fiber-forming polymers that can be used include poly (L-lactic acid), poly (lactide-co-glycolide), polycaprolactone, polyphosphate ester, poly (hydroxy- butyrate), poly (glycolic acid), poly (DL-lactic acid), poly (amino acid), cyanocrylate, some copolymers and biomolecules such as DNA, silk, chitozan .and cellulose.
  • These hydrophilic .and hydrophobic polymers which .are readily degraded by microorganisms and enzymes .are suitable for encapsulating material for drugs.
  • Polycaprolacton has a slower degradation rate than most other polymers
  • Suitable pharmaceutical agents that can be incorporated in at least one coat 12 include heparin, tridodecylme yl-ammonium-heparin, epothilone A, epothilone B, rotomycine, ticlopidine, dexamethasone, caumadin, and other pharmaceuticals falling generally into the categories of antithrombotic drugs, estrogens, corticosteroids, cytostatics, anticoagulant drugs, vasodilators, and antiplatelet drugs, frombolytics, antimicrobials or antibiotics, antimitotics, antiproliferatives, antisecretory agents, non- sterodial antiflammentory drugs, grow factor antagonists, free radical scavengers, antioxidants, radiopaque agents, immunosuppressive agents and radio-labeled agents. It is expected that during the life of this patent many relevant implantable medical devices will be
  • Three capillaries 25 mm in length and 0.5 mm in internal diameter, were symmetrically disposed the internal surface of a ring.
  • the flow-rate at each capillary was between 1 ml/min and 5 ml/min.
  • the dispensing element was connected to the pump with flexible polytetrafluorethylene tubes .and was grounded.
  • a rod of polished stainless steel, 1.05 mm in diameter and 60 mm in length, was used as a mandrel and was kept at a potential of 30 kV.
  • the mandrel was positioned in the geometrical center of the ring, about 175 mm from the capillaries ends.
  • the ring was rotated at a frequency of 60-1000 rpm and the mandrel was actuated to a longitudinal reciprocation motion, 30 - 40 mm in amplitude and 12-15 motions/min in frequency.
  • EXAMPLE 1 A stent assembly, 16 mm in length was manufactured using a stainless-steel stent, 3.4 mm in diameter in its expanded state and 1.1 mm in diameter in its non- expanded state, as the tubular supporting element.
  • the used stainless-steel stent is typically intended for catheter and balloon angioplasty.
  • the stent was exposed to 160-180 kJ/m 2 corona discharge, rinsed by ethyl alcohol and deionized water, and dried in a nitrogen flow.
  • the solution parameters were: concentration of 8 %, viscosity of 560 cP .and conductivity of 0.8 mS.
  • heparin in tefrahydrofurane solution was used, at a concentration of 250 U/ml.
  • the polymer to heparin-solution ratio was 100:1.
  • the dispensing element rotating frequency was 60 rpm.
  • a two step coating process was employed. First, the m.andrel was coated by electrospinning with polymer fiber layer the thickness of which was about 20 ⁇ m. Once the first step was accomplished, the tubular supporting element was put over the first coat hence an inner coating for the tubul.ar supporting element was obtained. Second, an outer coating was applied to the outer surface of the tubular supporting element. The thickness of the outer coat was about 40 ⁇ m.
  • the stent assembly was removed from the mandrel, and was placed for about 30 seconds into the saturated dimethylformamide (DMF) vapor atmosphere at 45 °C, so as to ensure upgrading the adhesion strength between the inner coat and the outer coat.
  • DMF dimethylformamide
  • the stent was exposed to partial vacuum processing for about 24 hours.
  • the coated stent was subjected to elasticity tests by radial inflation.
  • the fibers of the resultant coat had a random orientation.
  • the coat was capable of bearing a 320 % radial expansion without being ruptured.
  • EXAMPLE 2 A stent assembly was manufactured as described in Example 1, with an increased rotation frequency of 600 rpm. About 80 % of the fibers of the result.ant coat had an azimuthal orientation. The coat was capable of bearing a 410 % radial expansion without being ruptured.
  • EXAMPLE 3 A stent assembly was manufactured as described in Example 1, with an increased rotation frequency of 1000 rpm. The resultant coat was more uniform and the fibers were mostly azimuthally oriented: about 95 % of the fibers had an azimuthal orientation, and the coat was capable of bearing a 550 % radial expansion without being ruptured.
  • EXAMPLE 4 A stent assembly was manufactured as described in Example 2, with a heparin solution at a concentration of 380 U/ml mixed with 15 % poly (DL-Lactide-CD- Glycolide) solution in chloroform. The change in the pharmaceutical agent did not affect the quality of the coat.
  • EXAMPLE 5 A stent assembly was manufactured from the materials described in Example 1, with 60 ⁇ m inner coat of biodegradable heparin-loaded polymer, and an outer coat of polyurethane fibers completing an overall coat thickness of 100 ⁇ m. The rotation frequencies of 60 rpm and 1000 rpm were used for providing the inner and outer coats, respectively.
  • the resulting inner coat had a predominant axial (longitudinal) orientation, whereas the outer coat had a predominant azimuthal orientation, thus verifying that fiber orientation can be controlled by the dispensing element rotation frequency. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which .are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

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Abstract

L'invention concerne un procédé destiné à revêtir un objet non rotatif d'un revêtement électrofilé. Ce procédé consiste à distribuer un polymère chargé liquéfié à travers au moins un élément de distribution à l'intérieur d'un champ électrique de manière à former un jet de fibres polymères, puis à déplacer l'élément de distribution par rapport à l'objet de sorte à revêtir ledit objet de ce revêtement électrofilé.
EP04770588A 2003-10-06 2004-10-05 Procede et dispositif de revetement d'implants medicaux Withdrawn EP1670595A4 (fr)

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CA2541520A1 (fr) 2005-04-14

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