JP2007160102A - Polymeric stent having modified molecular structures in selected regions of flexible connectors - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To develop materials and the associated processes for manufacturing intraluminal stents that provide device designers with the opportunity to engineer the device to specific applications. <P>SOLUTION: A biocompatible material may be configured into any number of implantable medical devices including the intraluminal stents. Polymeric materials may be utilized to fabricate any of these devices, including stents. The stents may be balloon expandable or self-expanding. By preferential mechanical deformation of the polymer, polymer chains may be oriented to achieve certain desirable performance characteristics. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

Disclosure details

BACKGROUND OF THE INVENTION
[1. (Field of Invention)
The present invention relates to intraluminal polymer stents, and more particularly to intraluminal polymer stents having a modified molecular orientation resulting from the application of stress.

[2. (Explanation of related technology)
Currently manufactured intraluminal stents adequately provide adequate adjustment of the properties of the material forming the stent to the desired mechanical behavior of the device under clinically relevant in vivo loading conditions. I don't mean. Any intraluminal device is preferably used to reconstruct the vessel to its intended lumen diameter to provide sufficient coverage over the entire range of intended expansion diameters. Useful short-term and / or long-term outward force to maintain vascular patency, properties to prevent excessive radial recoil when deployed It is desirable to exhibit several properties, including properties that exhibit sufficient fatigue resistance, as well as properties that exhibit sufficient flexibility.

  Accordingly, there is a need to develop materials and related methods for manufacturing endoluminal stents that provide device designers with an opportunity to design devices for specific applications through engineering techniques. Exists.

[Summary of the Invention]
The limitations of applying commonly available materials to specific endoluminal therapeutic applications as briefly described above are overcome by the present invention.

  The present invention, according to one embodiment, is directed to a substantially tubular intraluminal medical device having a longitudinal axis and a radial axis. The device comprises a plurality of hoops formed of a polymer material having a plurality of radial struts and a plurality of radial arc members; interconnecting the plurality of hoops A plurality of bridges formed of a polymer material, each of said plurality of bridges having a predetermined amount of polymer chain alignment caused by mechanical deformation A plurality of bridges having a member.

  The biocompatible materials for implantable medical devices of the present invention include vessel patency devices (eg, vascular stents, biliary stents, ureteral stents), vascular occlusion devices ( vessel occlusion devices) (eg, atrial septal and ventricular septal occluders, patent foramen ovale occluders), and orthopedic devices (eg, It can be utilized for a number of medical applications, including fixation devices.

  The biocompatible material of the present invention has a unique composition and designed-in properties that can produce stents that can withstand a wider range of loading conditions than currently available stents. Have. More specifically, a molecular structure designed in a biocompatible material designs a stent having a wide range of geometries that can be adapted to various loading conditions. It becomes easy.

  The endoluminal device of the present invention can be formed from a large number of types of biocompatible polymeric materials. In order to obtain the desired mechanical properties, the polymer material, whether it is in the raw state or in the tube or sheet state, is physically deformed to a certain degree of alignment. alignment) polymer chains can be obtained. This alignment can be utilized to improve the physical and / or mechanical properties of one or more parts of the stent.

  The foregoing features and advantages of the invention, as well as other features and advantages, will become apparent from the following more detailed description of the preferred embodiments of the invention, as illustrated in the accompanying drawings.

[Detailed Description of Preferred Embodiments]
Implantable medical devices can be made of any number of suitable biocompatible materials, including polymeric materials. The internal structure of these polymeric materials can be altered utilizing mechanical and / or chemical manipulation of the polymer. Utilizing these internal modification of the internal structure, it has unique overall properties (eg, crystalline and amorphous forms, and crystalline and amorphous arrangements) as described in detail below A device can be created. Although the present invention applies to a large number of implantable medical devices, for ease of explanation, the following detailed description focuses on a typical stent.

  With reference to FIG. 1, a partial plan view of an exemplary stent 100 according to the present invention is illustrated. A typical stent 100 includes a plurality of hoop parts 102 interconnected by a plurality of flexible connectors 104. The hoop component 102 includes a continuous series of substantially longitudinal or axially oriented radial strut members 106 and alternating, substantially circumferentially. The circular arc members 108 arranged in the radial direction are formed. The hoop component 102, shown in plan view, is an essentially annular member that is joined together by a flexible connector 104 to form a substantially tubular stent structure. The combination of radial strut members 106 and alternating radial arc members 108 forms a substantially sinusoidal pattern. The hoop component 102 can be designed with a large number of types of design features and can assume a large number of types of configurations, but a typical example , The radial strut members 106 are wider at their central region 110. This structural feature can be utilized for a number of purposes, including increased surface area for drug delivery.

  The flexible connector 104 is made of flexible strut members 112 and alternating flexible arc members 114. As described above, the flexible connector 104 connects the adjacent hoop parts 102 to each other. In this exemplary embodiment, the flexible connector 104 is substantially N-shaped, with one end connected to a radial arc member on one hoop piece and the other end. The portion is connected to a radial arc member on an adjacent hoop part. Similar to the hoop component 102, the flexible connector 104 can have any number of types of structural features and a number of types of shapes. In a typical embodiment, both ends of the flexible connector 104 are positioned on the radial arc members of adjacent hoop parts to facilitate nesting during stent crimping. It is connected to different parts. For this exemplary shape, the radial arc members on adjacent hoop parts are slightly out of phase, whereas the radial arc members on every other hoop part are substantially different. It is interesting to note that it is in phase. In addition, it is important to note that not all radial arc members on each hoop part need be connected to all radial arc members of adjacent hoop parts. .

  It is important to note that a large number of types of structures can be utilized for the intraluminal scaffold or stent flexible connector or connector. For example, in the structure described above, the connector has two types of elements, a strut member oriented in a substantially longitudinal direction and a flexible arc member. However, in alternative constructions, the connector may have only a substantially longitudinally oriented strut member and no flexible arc member, or may have a flexible arc member. There may be no strut members oriented substantially longitudinally.

  The substantially tubular structure of stent 100 provides a temporary or semi-permanent scaffold for maintaining the patency of a substantially tubular organ such as an artery. Stent 100 has a luminal surface and an abluminal surface. The distance between the two surfaces defines the wall thickness. Stent 100 has an unexpanded diameter for delivery and an expanded diameter that approximately matches the normal diameter of the organ into which stent 100 is delivered. Since tubular organs such as arteries can vary in diameter, design different sized stents with different sets of unexpanded and expanded diameters without departing from the spirit of the present invention. be able to. As described herein, the stent 100 can be made of many types of polymeric materials.

Accordingly, in one exemplary embodiment, an intraluminal scaffold element is a non-crosslinked thermoplastic resin, a cross-linked thermoset resin, a non-polymeric material such as a composite material and mixtures thereof. Can be made of metal material. There are typically three forms in which the polymer can exhibit mechanical properties associated with solids: a crystalline structure, a semi-crystalline structure, and / or an amorphous structure. Not all polymers can be fully crystallized because high molecular regularity within the polymer chain is essential for crystallization to occur. Even in polymers that crystallize, the degree of crystallinity is generally less than 100%. Within the continuum between the complete crystal structure and the amorphous structure, there are two thermal transitions: a crystal-liquid transition (ie, melting temperature, T _m ) and a glass-liquid transition (ie, , Glass transition temperature, T _g ). In the temperature range between these two transitions, there may be a mixture of regularly arranged crystals and disordered amorphous polymer regions.

  The Hoffman-Lauritzen theory for the formation of polymer crystals with “folded” chains was based on the discovery in 1957 that thin single crystals of polyethylene could be grown from dilute solutions. Owes. The folded strands should preferably form a substantially crystalline structure. Hoffman and Loritzen have been involved in the crystallization of polymers from "solutions" and "melts" with special recognition of the thermodynamics associated with the formation of chain-folded nuclei. The basis of the theory was established.

  In order to crystallize from a dilute solution, it is necessary to produce a single crystal having a macroscopic perfection (typically a magnification in the range of about 200 times to about 400 times). In this regard, the polymer is not substantially different from low molecular weight compounds such as inorganic salts. Crystallization conditions such as temperature, solvent and solute concentration can affect crystal formation and final morphology. The polymer crystallizes in the form of a plurality of laminae, ie “lamellae”. The thickness of these lamellae is about 10 nanometers (ie, nm). The dimensions of the crystal plates perpendicular to the small dimensions depend on the crystallization conditions but are many times larger than the thickness of the fully grown crystal platelets. The direction of the chain inside the crystal is parallel to the short dimension of the crystal. This means that the molecules fold back and forth (for example, like a folded fire hose), and as a result, a continuous layer of folded molecules forms a lateral growth of the platelets. ). A crystal does not consist of a single molecule, and molecules do not exist exclusively in a single crystal. The loop formed by the chain changes the orientation of the crystal when the chain emerges from the crystal and reintroduces the crystal. The portion connecting the two crystalline sections can be considered an amorphous polymer. In addition, the ends of the polymer chain tend to break and be excluded from the crystal's orderly fold patterns, as described above. Therefore, the end of the polymer chain becomes an amorphous part of the polymer. Thus, any currently known polymeric material is not considered 100% crystalline. The crystal structure is sufficiently affected by the processing conditions for post polymerization.

  Single crystals are not observed in crystallization by bulk processing. Bulk crystallized polymers from melt exhibit domains called “spherulites” that are symmetrical about the nucleation center. If the spherulite growth does not collide by contacting another expanding spherulite, the symmetry is perfectly circular. Chain folding is an essential feature of polymer crystallization from a molten state. Spherulite is composed of aggregates of “lamellar” crystals that radiate from the nucleation site. Thus, there is a relationship between solution and bulk grown crystals.

  Spherical symmetry grows with time. As in the case of dendritic growth, fiber crystals or lathlike crystals begin to branch and spread in all directions. As lamellae spread sterically from the nucleus, the microcrystalline branching continues to produce a spherical morphology. Growth is achieved by adding a continuous layer of chains to the ends of the radially spreading laths. A polymer molecule that a given molecule will be contained in two or more lamellae and thus can link radially extending crystallites from the same or adjacent spherulites. Suggests a chain structure. These interlamellar links cannot occur in the low molecular weight compound spherulite, which results in less mechanical strength.

  Molecular chain folding is the origin of the “Maltese” cross that identifies spherulites under crossed polarizers. The crystal grain size distribution for a given polymer system is affected by the initial nucleation density, the nucleation rate, the rate of crystal growth, and the orientation state. When the polymer is subjected to conditions where nucleation predominates over radial growth, smaller crystals result. Larger crystals are formed when there are relatively few nucleation sites and the growth rate is faster. The diameter of spherulite can range from about a few μm to a few hundred μm, depending on the polymer system and crystallization conditions.

  Thus, the spherulite form in a bulk-crystallized polymer includes an individual molecule that is folded into an organization (ie, a microcrystal that is then oriented into a spherical aggregate). ) Of various levels of ordering. Spherulite has been observed in organic and inorganic systems of synthetic materials, biological agents, and geological origins, including moon rocks, and therefore Not unique to polymers.

  Stress induced crystallinity is important in membrane and fiber technology. When a dilute solution of polymer is rapidly stirred, a unique structure grows, which is said to have a “shish kebab” morphology. These structures consist of large chunks of folded chain crystals that extend along a fibrous central column. In both the “shish” and “kebab” portions of the structure, the polymer chains are parallel to the overall axis of the structure.

  When the polymer melt is sheared and cooled to a thermally stable state, the polymer chains are easily perturbed by their random coils and easily extend parallel to the shear direction. This can result in the formation of small crystal aggregates from deformed spherulites. Transformation from spherulite to fibrils, change of polymorphic crystal formation, reorientation of already formed crystalline lamellae, formation of oriented microcrystals, orientation of amorphous polymer chains, And / or other morphological changes may occur, including combinations thereof.

  Molecular orientation is important. This is because molecular orientation primarily affects the properties of the bulk polymer and therefore has a strong impact on the final properties that are essential for various material applications. Some of the properties affected by orientation are permeability, wear resistance, refractive index, absorption, degradation rate, tensile strength, yield stress, tear strength, modulus of elasticity. And physical and mechanical properties such as elongation at break. Because orientation promotes anisotropic behavior, orientation is not always advantageous. Orientation can occur in several directions, such as uniaxial orientation, biaxial orientation, and multiaxial orientation. Orientation can be induced by drawing, rolling, calendaring, spinning, blowing, etc., fibers, membranes, tubes, bottles Present in systems including molded articles, extruded articles, coatings and composite materials. When the polymer material is processed, there will be a preferential orientation in a specific direction. The preferred orientation is usually the direction in which processing takes place and is referred to as the machine direction (MD). Many of the products are intentionally oriented in a specific direction to improve properties. When the product is melt processed, the product has some degree of selective orientation. In the case of solvent-treated materials, for example, while the polymer solution is sheared and then processed by methods such as immediate sedimentation or quenching to the desired geometric conditions to fix the orientation during the shearing process. In some cases, orientation is induced. Alternatively, if the polymer has a chemical structure such as a rigid rod, the rigid rod will be oriented during processing due to its liquid crystal form in the polymer solution. Let's go.

  The orientation state depends on the type of deformation and the type of polymer. Whether the material is significantly deformed or stretched, the polymer chain can return to its original state, so it is not necessary to provide a high level of orientation. This generally occurs with polymers that are very flexible at the stretching temperature. Thus, several factors can affect the orientation state of a given polymer system. These factors include the rate of deformation (eg, strain rate, shear rate, frequency, etc.); amount of deformation (eg, stretch ratio); temperature; molecular weight and molecular weight distribution; chain configuration (eg, steric Regularity, geometric isomers, etc.); chain structure (straight chain, branched chain, bridged, dendritic chain, etc.); chain stiffness (flexible, rigid, semi-rigid, etc.); (Random copolymer, block copolymer, alternating copolymer, etc.); and presence of additives (plasticizer, hard filler, soft filler, long fiber, short fiber, therapeutic agent, mixture, etc.) Are included.

  Since the polymer consists of two phases (ie, a crystalline phase and an amorphous phase), the effect of orientation on these phases is different. Thus, the final orientation for these two phases in the semicrystalline polymer system may not be identical. This is because the flexible amorphous chain reacts differently to deformation and loading conditions than the hard crystalline phase.

  After inducing orientation, various phases can be formed, the behavior of which depends on the chemical nature of the polymer backbone. A homogeneous state, such as a completely amorphous material, will have a single orientation behavior. However, the orientation behavior of polymers that are semicrystalline, block copolymers or composites (fiber reinforced, filled systems, liquid crystals) needs to be described by two or more parameters. The orientation behavior is generally directly proportional to the material structure and orientation state. Some common levels of structure present in polymer systems (eg, crystal unit cells, lamellar thickness, domain size, spherulite structure, oriented superstructures, There are phase separated domains in the polymer mixture, etc.).

  For example, the structure of extruded polyethylene is a laminated folded chain lamellar structure. The orientation of the lamellae inside the structure is parallel to the longitudinal direction, but the platelets are oriented perpendicular to the longitudinal direction. The amorphous structure between the lamellas is generally not oriented. The mechanical properties of the materials are different when tested in various directions (0 ° for the longitudinal direction, 45 ° for the longitudinal direction and 90 ° for the longitudinal direction). The elongation value is usually minimal when the material is pulled in the machine direction. When pulled in the machine direction at 45 °, lamella shear deformation occurs, giving higher elongation values. When pulled in the longitudinal direction at 90 °, the material exhibits maximum elongation when the chain axis is widened.

  When a polymer chain is related to a given deformation axis and oriented at an angle, the orientation of the chain can be defined by a Hermans orientation function f. The Hermans orientation function f is 0, 1 and −1/2, and varies from values representing random orientation, complete orientation and vertical orientation parallel to the axis, respectively. This applies mainly to uniaxially oriented systems. Several techniques used to measure orientation [eg birefringence technique, linear dichroism technique, wide angle X-ray scattering technique, polarized Raman scattering technique, polarized fluorescence technique and NMR (nuclear magnetic resonance analysis)] Exists.

  The stent of the present invention can be prepared by various methods such as a melting method and a dissolving method. Typical melt processes include injection molding, extrusion molding, spinning, compression molding, blow molding, continuous pultrusion, and the like. Typical solution processes include solvent cast tubes and films, electrostatic fiber spinning, dry and wet spinning, hollow Included are fiber and membrane spinning methods, spinning disk methods. Pure polymers, blends and composites can be used to prepare the stent. The precursor material may be a tube or film prepared by any of the methods described above and then laser cut. The precursor material can be used as prepared or can be modified by annealing, orienting or relaxing it under various conditions. Alternatively, a laser cut stent can be used as prepared or can be modified by annealing, orienting or relaxing it under various conditions. .

  The effects of polymer orientation in a stent or device can improve device performance, including radial strength, recoil, and flexibility. The orientation can further change the degradation time of the stent, so that different sections of the stent can be oriented differently as desired. Orientation improves the performance of the stent in each of those directions, not only in the axial and circumferential or radial directions, but in parallel with any other direction in the unit cell and flexible connector Can do. The orientation may be limited to only one direction (uniaxial) or may be two directions (biaxial) and / or multiple directions (multiaxial). Orientation can be induced in a given material by various procedures (eg, first, axial orientation and then induce radial orientation, and vice versa). Alternatively, the material can be oriented in both directions simultaneously. Axial orientation can be induced by stretching along the axial or longitudinal direction of a given material (eg, a tube or film), usually at a temperature above the glass transition temperature of the polymer. The radial or circumferential orientation can be blown into the material in several different ways [eg, by a heated gas (eg, nitrogen) or by using a balloon inside the mold. To do]. Alternatively, composite materials or sandwich structures can be formed by stacking multiple layers of materials oriented in various directions to provide anisotropic properties. Blow molding can also be used to induce biaxial and / or multiaxial orientation.

FIG. 2 illustrates a section 200 of a hoop component 102 formed of a polymer material described herein with reference to FIG. As shown, the section 200 of the hoop component 102 is designed to have two first bands t ₂ and one second band t ₁ . The two zones t ₂ are designed or configured to have a higher degree of polymer chain orientation than the _one second zone t ₁ . A greater degree of polymer chain orientation in zone t ₂ can be achieved by stretching the precursor material in a direction parallel to or along the longitudinal axis of the stent. In addition, orientation can also be achieved by the methods described above. In the exemplary embodiment illustrated in FIG. 2, the t ₂ region is intentionally thinner than the t ₁ region, so that the t ₂ region has a strain compared to the t ₁ region. It is a large band. The performance characteristics of the device can be improved by optimizing the type and degree of orientation of the polymer chain and the feature characteristics. Performance characteristics for a stent hoop component typically include radial strength, radial stiffness, and radial recoil. In addition, it is preferable to consider dynamic loads such as pulsatile motion.

FIG. 3 illustrates a section 300 of a hoop component 102 formed of a polymer material described herein with reference to FIG. As shown, the section 300 of the hoop component 102 is designed to have one _first zone t ₁ and two second zones t ₂ . One first zone t ₁ is designed or configured to have a greater degree of polymer chain orientation than the _two zones t ₂ . A greater degree of polymer chain orientation in zone t ₁ can be achieved by stretching the precursor material in a direction parallel to the radial or circumferential axis of the stent. In addition, orientation can also be achieved by the methods described above. In the exemplary embodiment illustrated in FIG. 3, the t ₁ region is intentionally thinner than the t ₂ region, so that the t ₁ region is in a band where the distortion is greater than the t ₂ region. is there. The performance characteristics of the device can be improved by optimizing the type and degree of orientation of the polymer chain and the functional properties. Performance characteristics for the hoop part of a stent typically include radial strength, radial stiffness, and radial bounce. In addition, it is preferable to consider a dynamic load such as pulsation.

In addition, with reference to FIG. 4, a section 400 of a hoop component 102 formed of a polymeric material described herein is illustrated. This figure shows the combination of polymer chain orientations illustrated in FIGS. In other words, the degrees of alignment in the bands t ₁ and t ₂ may be substantially equal.

FIG. 6 illustrates a section 500 of a flexible connector 104 formed of a polymer material described herein with reference to FIG. As shown, the section 500 of the flexible connector 104 is designed to have two first zones t ₂ and one second zone t ₁ . The two zones t ₂ are designed or configured to have a higher degree of polymer chain orientation than the _one second zone t ₁ . A greater degree of polymer chain orientation in zone t ₂ can be achieved by stretching the precursor material in a direction parallel to the radial or circumferential axis of the stent. In addition, orientation can also be achieved by the methods described above. In the exemplary embodiment illustrated in FIG. 5, the t ₂ region is intentionally thinner than the t ₁ region, so that the t ₂ region is in a band where the distortion is greater than the t ₁ region. is there. The performance characteristics of the device can be improved by optimizing the type and degree of orientation of the polymer chain and the functional properties. The performance characteristics for the flexible connector parts of the stent are multiaxial and torsional flexibility, considering the dynamic load situation, and also considering deployment. Foreshortening.

FIG. 6 illustrates a section 600 of a flexible connector 104 formed of a polymer material described herein with reference to FIG. As shown, the section 600 of the flexible connector 104 is designed to have one _first zone t ₁ and two second zones t ₂ . One first zone t ₁ is designed or configured to have a greater degree of polymer chain orientation than the _two zones t ₂ . A greater degree of polymer chain orientation in zone t ₁ can be achieved by stretching the precursor material in a direction parallel to the longitudinal axis of the stent. In addition, orientation can also be achieved by the methods described above. In the typical example illustrated in FIG. 6, the t ₁ region is a band having a larger strain than the t ₂ region. The performance characteristics of the device can be improved by optimizing the type and degree of orientation of the polymer chain and the functional properties. The performance characteristics for the flexible connector part of the stent are multi-axis and torsional flexibility when considering dynamic load conditions and shortening when considering deployment.

FIG. 7 illustrates a section 700 of a flexible connector 104 formed of a polymer material described herein with reference to FIG. This figure shows the combination of polymer chain orientations illustrated in FIGS. In other words, the degrees of alignment in the bands t ₁ and t ₂ may be substantially equal.

  There are a number of design considerations in the art to determine which configuration is preferred to achieve optimal stent performance. The above figures merely illustrate some possibilities. In order to optimize the combination of design and material, it is appropriate to consider short-term and long-term performance attributes. One of these factors includes the design of the flexible connector element. For example, if the flexible connector is joined to a radial hoop at the apex of a radial arc member, the designer may use the radial direction to include a high strain region. You may choose the longitudinal part of the hoop. Thus, optimization of materials and design will result in selective longitudinal orientation of the polymer chains. Alternatively, if the flexible connector joins the radial hoop at the end of the radial arc member or at the section of the radial strut, the designer may include a high strain region. In addition, the apex of the radial arc member may be selected. Therefore, design optimization between material and design will result in selective circumferential orientation of polymer chains.

  In addition, if the load on the flexible connector is aligned with the longitudinally oriented elements of the flexible connector, material and design optimization results in the longitudinal direction of the polymer chain. Orientation will occur selectively. Similarly, if the load on the flexible connector is aligned with the circumferentially oriented elements of the flexible connector, material and design optimization will result in polymer chain Circumferential orientation will selectively occur.

  The above description is merely exemplary and should not be construed as capturing all considerations for making decisions regarding optimization of design and material orientation.

  It should be noted that although specific configurations are illustrated and described, the described principles can be equally applied to any shape related to the design of the hoop and flexible connector. ,is important. In addition, the alignment axis does not coincide with a single direction (eg, longitudinal or radial), but coincides with a combination of the two directions.

  Polymeric materials can generally be classified as synthetic, natural, and / or combinations thereof. Polymeric materials can be defined within these general classifications as being biostable or biodegradable. Examples of biologically stable polymers include polyolefins, polyamides, polyesters, fluoropolymers and acrylic resins. Examples of natural polymers include polysaccharides and proteins.

  Bioabsorbable polymers are comprised of bulk erodible materials and surface erodable materials. Surface erosion polymers are typically hydrophobic and have water labile linkages. Hydrolysis tends to occur rapidly on the surface of such surface erodible polymers and does not produce a large amount of water permeation. However, the initial strength of such surface erosion polymers tends to be low and such surface erosion polymers are often not readily available commercially. Nonetheless, examples of such surface erosion polymers include polyanhydrides such as poly (carboxyphenoxyhexane-sebacic acid), poly (fumaric acid-sebacic acid), poly (carboxyphenoxyhexane). -Sebacic acid), poly (imide-sebacic acid) (50-50), poly (imide-carboxyphenoxyhexane-) (33-67) and polyorthoesters (diketone acetal based polymers).

  On the other hand, bulk erosion polymers are typically hydrophilic and have water labile bonds. Hydrolysis of the bulk erodible polymer tends to occur at a more uniform rate across the polymer matrix of the device. Bulk erosion polymers exhibit excellent initial strength and are readily available commercially.

  Examples of bulk erosion polymers include poly (α-hydroxy esters) such as poly (lactic acid), poly (glycolic acid), poly (caprolactone), poly (p-dioxanone), Poly (trimethylene carbonate), poly (oxaesters), poly (oxaamides), and copolymers and mixtures thereof are included. Some types of commercially available bulk erodible polymers and their commonly associated medical applications include poly (dioxanone) [Somerville, NJ, Ethicon, Inc. PDS® sutures available from.), Poly (glycolide) [Dexon (available from United States Surgical Corporation, North Haven, Connecticut) Registered suture), poly (lactide) -PLLA [bone repair], poly (lactide / glycolide) [Vicryl® (10/90) suture available from Ethicon, Somerville, NJ and Panacryl® (95/5) suture, poly ( Glycolide / Caprolactone (75/25)) (Monocryl® suture available from Ethicon, Somerville, NJ) and poly (glycolide / trimethylene carbonate) [North Haven, Connecticut, United States Maxon® sutures available from Surgical Inc.] are included.

  Other bulk erosion polymers include polyamino acids derived from tyrosine [eg, poly (DTH) carbonate, poly (arylates) and poly (iminocarbonate)], phosphorus-containing polymers [eg, poly ( Phosphoesters) and poly (phosphazenes)], poly (ethylene glycol) [PEG] based block copolymers [PEG-PLA, PEG-poly (propylene glycol), PEG-poly (butylene terephthalate)], poly (α-apple) Acid), poly (ester amide), and polyalkanoates [e.g., copolymers of poly (hydroxybutyrate) (HB) and poly (hydroxyvalerate) (HV) ].

  Of course, the device can be made from a combination of surface erodible polymer and bulk erodible polymer to achieve the desired physical properties and control the degradation mechanism. For example, two or more polymers can be mixed to achieve the desired physical properties and device degradation rate. Alternatively, the device can be made of a bulk erosion polymer that is coated with a surface erosion polymer.

  Shape memory polymers can also be used. Shape memory polymers exhibit characteristics as phase segregated linear block co-polymers having hard and soft segments. Hard segments are typically crystals having a defined melting point, and soft segments are typically amorphous having a defined glass transition temperature. In shape memory polymers, the soft segment transition temperature is substantially lower than the hard segment transition temperature. The shape of the shape memory polymer is stored in the hard and soft segments of the shape memory polymer by heating and cooling techniques. Shape memory polymers may be biologically stable and bioabsorbable. Bioabsorbable shape memory polymers are relatively new and contain thermoplastic and thermoset materials. The shape memory thermoset can contain poly (caprolactone) dimethyl acrylate, and the shape memory thermoplastic can contain poly (caprolactone) as a soft segment and poly (glycolide) as a hard segment. Can be contained.

  High ductility and toughness, for example orthopedic implants, sutures, stents, grafts, and other medical applications that include drug delivery devices are often required In order to provide such a flexible and tough material, a plurality of bioabsorbable polymer materials can be modified to form a composite material or mixture thereof. Such composite materials or mixtures can be obtained by altering the chemical structure of the polymer backbone or by creating the composite material by mixing the bioabsorbable polymer materials with different polymers and plasticizers. it can. Any additional material used to modify the underlying bioabsorbable polymer is preferably compatible with the main polymer system. These additional materials tend to reduce the glass transition temperature of the bioabsorbable polymer, which makes the underlying polymer more flexible and less rigid.

  As an example of producing a composite or mixed material, very stiff polymers [eg, poly (lactic acid), poly (glycolide) and poly (lactide-co-glycolide) copolymers] can be converted into soft, flexible polymers [eg, , Poly (caprolactone) and poly (dioxanone)] tend to produce materials with high flexibility and rigidity. Elastic copolymers can be synthesized from various proportions of rigid and soft polymers. For example, poly (glycolide) or poly (lactide) is copolymerized with poly (caprolactone) or poly (dioxanone) to produce a poly (glycolide-co-caprolactone) copolymer or poly (glycolide-co-dioxanone) copolymer. Polymers and poly (lactide-co-caprolactone) copolymers or poly (lactide-co-dioxanone) copolymers can be prepared. These elastic copolymers are then mixed with a rigid material [eg, poly (lactide), poly (glycolide) and poly (lactide-co-glycolide) copolymers] to produce a highly flexible material. be able to. Alternatively, terpolymers can be prepared from various monomers to obtain the desired properties. Macromers and other crosslinkable polymer systems can be used to obtain the desired properties.

As the device is implanted in a patient, visualizing the device is important to the physician placing the device, so a radiopaque material may be added to the device. The radiopaque material can be added directly to the matrix of the bioabsorbable material comprising the device during processing, so that the radiopaque material is fairly uniform throughout the device. Be incorporated. Alternatively, the radiopaque material can be added to the device in the form of a layer, coating, band or powder to a predetermined portion of the device, which is the geometry of the device. Depending on the physical conditions and the process used to form the device. Coatings can be made by various methods known in the art (eg, chemical vapor deposition (CVD), physical vapor deposition (PVD), electroplating, high vacuum deposition, microfusion, spray coating, dip coating, It can be applied to the device by electrostatic coating or other surface coating or surface modification techniques. Ideally, the radiopaque material does not add significant stiffness to the device so that the device can easily pass through the anatomy in which the device is placed. The radiopaque material is desirably biocompatible with the tissue in which the device is placed. Such biocompatibility minimizes the possibility of undesirable tissue reactions with the device. Inert noble metals (eg, gold, platinum, iridium, palladium and rhodium) are well recognized as biocompatible radiopaque materials. Other radiopaque materials include barium sulfate (BaSO ₄ ), bismuth hypocarbonate [(BiO) ₂ CO ₃ ], and bismuth oxide. In such a way that peeling or peeling of the radiopaque material from the device is minimized or ideally such that peeling or peeling does not occur. Ideally, the radiopaque material adheres well to the device. If the radiopaque material is applied to the device as a metal band, the metal band can be crimped on a given section of the device. Alternatively, certain sections of the device can be coated with a radiopaque metal powder, while other portions of the device are free of the metal powder.

  The local delivery of therapeutic / therapeutic drug combinations can be used to treat a wide variety of conditions while utilizing a fairly large number of types of medical devices, or the function of medical devices and / or The service life can be increased. For example, intraocular lenses placed to restore vision after cataract surgery are often damaged by the formation of secondary cataract. Secondary cataracts are often a result of cell overgrowth on the lens surface and potentially minimize secondary cataracts by combining one or more drugs with the device. be able to. Other medical devices that often fail due to tissue in-growth or due to the accumulation of protein material in, on or around the device [ For example, hydrocephalus shunts, dialysis grafts, colon fistula bag attachment devices, ear drainage tubes, pacemaker leads, and implantable defibrillators] are also device-drug combinations Benefit from this approach. Devices that help to improve the structure and function of a tissue or organ can also show advantages when combined with one or more appropriate agents. For example, improving the osteointegration of an orthopedic device and increasing the stability of the implanted device can be combined with a drug (eg, a bone morphogenetic protein). Could potentially be achieved. Similarly, other surgical instruments, sutures, staples, anastomosis devices, vertebral disks, bone pins, suture anchors, hemostatic barriers, fasteners Clamps, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds, various types of dressings, bone stock Articles, intraluminal devices, and vascular supports could also increase patient benefit using this drug-device combination approach. Perivascular wraps may be particularly advantageous either alone or in combination with other medical devices. The perivascular wrap can supply additional medication to the treatment site. Essentially any other type of medical device can be coated in some way with a drug, or combination of drugs, so that the treatment is used when the medical device or drug is used in a single use Better than.

In addition to various medical devices, coatings on these devices can be used to carry multiple types of therapeutic agents and drugs. These therapeutic agents and drugs include natural products, including anti-proliferative / anti-proliferative / antimitotic agents [eg, vinca alkaloids (ie, vinblastine, vincristine ( vincristine and vinorelbine), paclitaxel, epidipodophyllotoxins (ie, etoposide, teniposide), antibiotics (dactinomycin) (actinomycin D) (actinomycin D)), daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramycin) )) And mitomycin, enzyme (systemically L-aspa It metabolizes Gin, and eliminates the cells do not have the ability to synthesize asparagine cells themselves L- asparaginase (L-asparaginase))]; anti-platelet aggregation inhibitors [for example, G (GP) II _b / III _a inhibitors and vitronectin receptor antagonists]; antiproliferative alkylating agent / antimitotic alkylating agents [e.g., nitrogen mustards (mechlorethamine (mechlorethamine), cyclophosphamide (cyclophosphamide) and analogs , Melphalan, chlorambucil, ethylenimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas ) (Carmustine (BCNU) and analogues, streptozocin (strep tozocin)), trazenes-dacarbazinine (DTIC)]; antiproliferative antimetabolite / anti-mitotic antimetabolite [eg folic acid analogue (methotrexate), pyrimidine analogue ( Fluorouracil, floxuridine and cytarabine), purine analogues and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine) {Cladribine})]; platinum coordination complex (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormone (Ie, estrogen); anticoagulants (heparin, synthetic heparin salts, And other thrombin inhibitors); fibrinolytic agents [eg tissue plasminogen activator, streptokinase and urokinase], aspirin, dipyridamole, ticlopidine, Clopidogrel, abciximab; antiimigratory; antisecretory (breveldin); anti-inflammatory drugs [eg corticol, cortisone, cortisone, Fludrocortisone (fludrocortisone), prednisone (prednisone), prednisolone (prednisolone), 6α-methylprednisolone (6α-methylprednisolone), triamcinolone (betamethasone) and dexamethasone (dexamethasone), non-steroidal agent (dexamethasone) That is Aspirin)]; paraaminophenol derivatives, ie acetaminophen; indole and indene acetic acid (indomethacin, sulindac and etodalec), heteroaryl acetic acid (tolmetin, diclofenac) ) And ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid and meclofenamic acid), enolic acid (piroxicam), Tenoxicam, phenylbutazone and oxyphenthatrazone), nabumetone, gold compounds (auranofin), aurothioglucose, gold sodium sodium thiomalate thi immunosuppressants [cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil]; Angiogenic agents [vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)]; angiotensin receptor blockers; nitric oxide donors donors), antisense oligonucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and growth factor receptor signal transduction kinase inhibitors Retenoids; cyclin / CDK inhibitors; HMG co-fermentation Elemental reductase inhibitors (statins); and protease inhibitors are included.

  According to another exemplary embodiment, the stents described herein, whether metallic or polymeric, can be utilized as therapeutic or drug delivery devices. Metallic stents can be coated with a biostable or bioabsorbable polymer, or a combination thereof, in which the therapeutic agent is incorporated. Typical material properties for coatings include flexibility, ductility, tackiness, durability, adhesion and cohesion. Biologically stable or bioabsorbable polymers that exhibit these desired properties include methacrylates, polyurethanes, silicones, poly (vinyl acetate), poly (vinyl alcohol), ethylene vinyl alcohol, poly (vinylidene fluoride), Poly (lactic acid), poly (glycolic acid), poly (caprolactone), poly (trimethylene carbonate), poly (dioxanone), polyorthoester, polyanhydride, polyphosphoester, polyamino acid, and copolymers thereof And mixtures.

  In addition to the therapeutic agent being incorporated, the coating may contain other additives [eg, radiopaque components, chemical stabilizers for the coating and / or the therapeutic agent, radiopharmaceuticals, tracing reagents. agents (eg, radioisotopes (eg, tritium or heavy water) and ferromagnetic particles), and mechanical modifiers (eg, ceramic microspheres (described later in more detail) microspheres))]. Alternatively, entrapped gaps can be created between the surface of the device and the coating and / or within the coating itself. Examples of these gaps include not only air but also other gases and the absence of matter (ie, a vacuum environment). These entrapped gaps can be created utilizing any number of known techniques (eg, injection of microencapsulated gaseous matter).

  As described above, various drugs can be used as therapeutic agents. These drugs include not only sirolimus, heparin, everolimus, tacrolimus, paclitaxel, cladribine, but also statins. The These agents and / or agents may be hydrophilic, hydrophobic, lipophilic and / or oleophobic. The type of agent plays a role in determining the type of polymer. The amount of drug in the coating can vary and includes a number of factors including not only the storage capacity of the coating, the drug, the concentration of the drug, the dissolution rate of the drug, but also many additional factors. It depends on the factors. The amount of drug may vary from substantially 0% to substantially 100%. A typical range may be less than about 1% to about 40% or more. The distribution of the drug in the coating can vary. One or more drugs can be distributed in a single layer, multiple layers, a single layer with a diffusion barrier, or any combination thereof.

  Various solvents can be used to dissolve the drug / polymer mixture to prepare the coating formulation. Some of these solvents may be good or poor solvents, which are based on the desired drug elution profile, drug form and drug stability.

  There are several methods for coating stents that are disclosed in the prior art. Some commonly used methods include spray coating, dip coating, electrostatic coating, fluidized bed coating, and supercritical fluid coatings.

  Some of the methods and modifications described herein that can be used will eliminate the need for a polymer to retain the drug on the stent. To increase the drug content and tissue-device interaction, the stent surface can be partially modified to increase the surface area. Nanotechnology can be applied to create self-assembled nanomaterials that can contain nanoparticles containing tissue specific drugs. Microetching, which can incorporate these nanoparticles, can form microstructures on the surface. These microstructures can be formed by methods such as laser micromachining, lithography, chemical vapor deposition and chemical etching. Microstructures have been created on polymers and metals by taking advantage of advances in micro electro-mechanical systems (MEMS) and microfluidics. Examples of nanomaterials include carbon nanotubes and nanoparticles formed by sol-gel technology. The therapeutic agent can be chemically or physically deposited on these surfaces, or can be deposited directly. The combination of these surface modifications can release the drug at the desired rate. A polymer top-coat can be applied to control the initial burst due to direct exposure of the drug in the absence of the polymer coating.

  As described above, the polymeric stent can contain a therapeutic agent as a coating (eg, surface modification). Alternatively, the therapeutic agent can be incorporated into a stent structure (eg, bulk modification) that may not require a coating. Coatings for stents made of biostable polymers and / or bioabsorbable polymers, when used, should be biostable and / or bioabsorbable. However, as mentioned above, the coating may not be necessary because the device itself is made with a delivery depot. This embodiment provides a number of advantages. For example, higher concentrations of one or more therapeutic agents can be obtained. In addition, higher drug concentrations of one or more therapeutic agents can be used to achieve local drug delivery for a longer period of time.

  In yet another alternative embodiment, intentional mixing of ceramic and / or glass into the base material can be utilized to modify the physical properties of the base material. Intentional mixing of ceramic and / or glass will typically occur in polymeric materials used for medical applications. Examples of biologically stable ceramics and / or biologically stable glasses and / or bioabsorbable ceramics and / or bioabsorbable glasses include hydroxyapatite, tricalcium phosphate, magnesia, alumina Zirconia, yttrium tetragonal polycrystalline zirconia, amorphous silicon, amorphous calcium and amorphous phosphate. Although numerous techniques can be used, biologically stable glasses can be formed using industrially suitable sol-gel methods. The sol-gel technique is a melting method for making hybrids of ceramic and glass. The sol-gel process typically involves the transformation of a system from a liquid (sol), which is mostly colloidal, to a gel.

  While what has been illustrated and described are believed to be the most practical and preferred embodiments, variations from the specific designs and methods described and illustrated will occur to those of skill in the art and are contemplated by the present invention. Clearly, it can be used without departing from the spirit or scope. The present invention is not limited to the specific configurations described and illustrated, but is preferably configured to be consistent with any partial modifications that may be included in the claims.

Embodiment
(1) In a substantially tubular intraluminal medical device having a longitudinal axis and a radial axis,
A plurality of hoops formed of a polymer material having a plurality of radial struts and a plurality of radial arc members;
A plurality of bridges formed of a polymer material interconnecting the plurality of hoops, each of the plurality of bridges having a predetermined degree of polymer chain alignment caused by mechanical deformation; Having the plurality of bridges;
Equipped with a device.
(2) In the device according to embodiment 1,
The device, wherein the polymer material contains a bioabsorbable polymer.
(3) In the device according to embodiment 2,
The device, wherein the bioabsorbable polymer contains poly (α-hydroxy esters).
(4) In the device according to embodiment 2,
The device wherein the bioabsorbable polymer contains a tyrosine-derived polyamino acid.
(5) In the device according to embodiment 2,
The device, wherein the bioabsorbable polymer contains a phosphorus-containing material.
(6) In the device according to embodiment 2,
The device, wherein the bioabsorbable polymer contains polyalkanoates.
(7) In the device according to embodiment 2,
The device, wherein the bioabsorbable polymer contains a polyanhydride.
(8) In the device according to embodiment 2,
The device wherein the bioabsorbable polymer contains polyorthoesters.
(9) In the device according to embodiment 1,
The device, wherein the polymeric material contains biostable polymers.
(10) In the device according to embodiment 9,
The device, wherein the biostable polymer contains a polyolefin.
(11) In the device according to embodiment 9,
The device wherein the biologically stable polymer contains polyurethane.
(12) In the device according to embodiment 9,
The device, wherein the biologically stable polymer comprises a fluoropolymer.
(13) In the device according to embodiment 9,
The device, wherein the biostable polymer contains a polyamide.
(14) In the device according to embodiment 9,
The device, wherein the biostable polymer contains a polyester.
(15) In the device according to embodiment 9,
The device, wherein the biologically stable polymer contains an acrylic resin.
(16) In the device according to embodiment 1,
At least one therapeutic agent,
The device further comprising:
(17) In the device according to embodiment 16,
The device, wherein the at least one therapeutic agent comprises an antirestenotic agent.
(18) In the device according to embodiment 17,
The device, wherein the anti-restenosis drug comprises rapamycin.
(19) In the device according to embodiment 17,
The device, wherein the anti-restenosis drug comprises paclitaxel.
(20) In the device of embodiment 16,
The device wherein the therapeutic agent contains an anti-inflammatory agent.
(21) In the device of embodiment 19,
The device, wherein the anti-inflammatory drug contains rapamycin.
(22) In the device of embodiment 19,
The device, wherein the anti-inflammatory agent contains dexamethasone.
(23) In the device of embodiment 16,
The device wherein the therapeutic agent contains an anticoagulant.
(24) In the device of embodiment 23,
The device, wherein the anticoagulant is heparin.
(25) In the device according to embodiment 1,
Radiopaque materials,
The device further comprising:
(26) In the device of embodiment 1,
The device, wherein the stent is self-expanding.
(27) In the device according to embodiment 1,
The stent is balloon expandable, the device

1 is a plan view of an exemplary stent made of a biocompatible material according to the present invention. FIG. FIG. 6 is a diagram of a section of a typical stent hoop component illustrating two high strain zones corresponding to axial orientation. FIG. 5 is a diagram of a section of a typical stent hoop component illustrating one high strain zone corresponding to circumferential orientation. FIG. 3 is a diagram of a typical stent hoop component section illustrating three high strain bands corresponding to biaxial orientation. FIG. 3 is a diagram of a section of a typical stent flexible connector part, illustrating two high strain zones corresponding to circumferential orientation. FIG. 3 is a diagram of a section of a typical stent flexible connector component, illustrating one high strain zone corresponding to axial orientation. FIG. 4 is a diagram of a section of a typical stent flexible connector component illustrating three high strain bands corresponding to biaxial orientation.

Claims (27)

In a substantially tubular intraluminal medical device having a longitudinal axis and a radial axis,
A plurality of hoops formed of a polymer material having a plurality of radial struts and a plurality of radial arc members;
A plurality of bridges formed of a polymer material interconnecting the plurality of hoops, each of the plurality of bridges having a predetermined degree of polymer chain alignment caused by mechanical deformation; Having the plurality of bridges;
Equipped with a device. The device of claim 1, wherein
The device, wherein the polymer material contains a bioabsorbable polymer. The device of claim 2, wherein
The device, wherein the bioabsorbable polymer contains poly (α-hydroxyester). The device of claim 2, wherein
The device wherein the bioabsorbable polymer contains a tyrosine-derived polyamino acid. The device of claim 2, wherein
The device, wherein the bioabsorbable polymer contains a phosphorus-containing material. The device of claim 2, wherein
The device wherein the bioabsorbable polymer contains a polyalkanoate. The device of claim 2, wherein
The device, wherein the bioabsorbable polymer contains a polyanhydride. The device of claim 2, wherein
The device, wherein the bioabsorbable polymer contains a polyorthoester. The device of claim 1, wherein
The device, wherein the polymeric material contains a biologically stable polymer. The device of claim 9, wherein
The device, wherein the biostable polymer contains a polyolefin. The device of claim 9, wherein
The device wherein the biologically stable polymer contains polyurethane. The device of claim 9, wherein
The device, wherein the biologically stable polymer comprises a fluoropolymer. The device of claim 9, wherein
The device, wherein the biostable polymer contains a polyamide. The device of claim 9, wherein
The device, wherein the biostable polymer contains a polyester. The device of claim 9, wherein
The device, wherein the biologically stable polymer contains an acrylic resin. The device of claim 1, wherein
At least one therapeutic agent,
The device further comprising: The device of claim 16, wherein
The device, wherein the at least one therapeutic agent comprises an anti-restenosis agent. The device of claim 17, wherein
The device, wherein the anti-restenosis drug contains rapamycin. The device of claim 17, wherein
The device, wherein the anti-restenosis drug comprises paclitaxel. The device of claim 16, wherein
The device wherein the therapeutic agent contains an anti-inflammatory agent. The device of claim 19, wherein
The device, wherein the anti-inflammatory drug contains rapamycin. The device of claim 19, wherein
The device, wherein the anti-inflammatory drug contains dexamethasone. The device of claim 16, wherein
The device wherein the therapeutic agent contains an anticoagulant. 24. The device of claim 23.
The device, wherein the anticoagulant is heparin. The device of claim 1, wherein
Radiopaque materials,
The device further comprising: The device of claim 1, wherein
The device, wherein the stent is self-expanding. The device of claim 1, wherein
The device, wherein the stent is balloon expandable.

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