JP4881728B2 - Biodegradable stent - Google Patents

Description

  The subject of the present invention is a temporary stent made of biodegradable shape memory polymer (SMP) for use in non-vascular and vascular regions. This stent can be implanted in a compressed form with minimal invasive surgery and assumes its desired size at the place of use caused by the shape memory effect. The stent gradually dissipates due to biological degradation, thereby eliminating the need for further surgery to remove the stent. Yet another subject of the present invention is a method of implanting and removing a stent and a method of manufacturing and programming (adjusting) the stent.

Conventional technology

  Tubular tissue supports (stents) are inserted into the tubular organ for the treatment of clogged blood vessels, or narrowed tubular organs, or after surgery. They serve to keep the stenotic area widened, or to act as a substitute for the function of the damaged tubular organ to re-enable normal passage or drainage of bodily fluids. The stent is also inserted into a blood vessel to treat a clogged or stenotic blood vessel, which keeps the stenotic area widened and allows normal blood flow again.

  A stent is usually a cylindrical structure made of a kind of wire mesh (wire coil design) or a tube that may or may not be perforated (slotted tube design). Conventional stents have a length of 1-12 cm and can have a diameter of 1-12 mm.

  The mechanical requirements for stents are contradictory. On the other hand, the stent needs to exert a strong radial force on the supported tubular organ. On the other hand, it is necessary to be able to compress the stent radially so that it can be inserted into a tubular organ without damaging the vessel wall or surrounding tissue.

  This problem was solved by inserting the stent in a compressed form and attaching it only after reaching the correct position. In the compressed state, the diameter is smaller than in the expanded state. Basically, this method can also be used to remove a stent with minimal invasiveness. However, a possible problem is that commonly used metal materials do not necessarily expand completely regularly, cannot be refolded, and have the risk of damaging nearby tissue. .

Two different techniques have been established for minimally invasive insertion (market report “US peripheral and basal stent and AAA stent graft market” (Frost & Sullivan), 2001):
-Balloon expandable stent (system consists of balloon, catheter, stent)
-Self-expanding stent (system consists of insertion sleeve (protective sheath), catheter, stent).

  The self-expanding stent is made of a shape memory material (SM material), and a metal SM material such as nitinol is at the forefront. The shape memory effect is an effect that has been gaining interest in the past few years and is being researched, and it is possible to change the shape of the target by applying an external stimulus (details on this can be found in published literature, See, for example, “Shape Memory Alloys, Scientific American, Vol. 281 (1979), pages 74-82.” These materials can clearly change shape as the temperature increases. When exerted, the diameter of the stent increases “automatically” and the stent is secured in the position where it will be used.

  As already mentioned above, removal of the expanded stent is problematic. If the stent needs to be withdrawn from the tubular gap, the surrounding tissue can be damaged by abrasion because the stent is too large and has sharp edges. Therefore, the shape memory effect is also utilized when reducing the diameter of the stent when removing the stent again. Examples of removable implants (stents) are known in the prior art. U.S. Patent No. 6,413,273 "Method and system for temporary supporting a tubular organ"; U.S. Patent No. 6,348,067, "Method and system training team shaper the shape of the ship" U.S. Pat. No. 5,037,427 “Method of imprinting a tenth with a tubular organ of a living body and of removing same”; U.S. Pat. No. 5,197,978 v “able tissue supporting device”.

  Nitinol cannot be used in the case of nickel allergies. This material is also very expensive and can only be programmed in difficult ways. This programming method requires a relatively high temperature and therefore cannot be programmed in the body. Therefore, this SM material is programmed outside the body, i.e., is made into a temporary shape. When the shape memory effect is exerted after implantation, the stent expands, that is, restores its permanent shape. It is then impossible to remove the stent using the shape memory effect again. A problem that frequently appears on metal stents outside the vascular region is the occurrence of restenosis.

  On the other hand, other metallic stents of SM material, such as those described in US Pat. No. 5,197,978, can utilize the shape memory effect to remove the stent. However, these metallic materials are very difficult to manufacture and the tissue compatibility is not always guaranteed. Inadequate adaptation of the mechanical properties of the stent often results in inflammation and pain.

The temporary stent described in US Pat. No. 5,716,410 “Temporary stent and method of use” is a coil made of shape memory plastic material. This SMP material has an embedded heating wire. The heating wire is connected to the electronic controller via a catheter shaft, and the shaft end is a hollow tube covering the coil end. When the implanted stent in the expanded temporary shape is heated, the diameter of the coil decreases above the temperature T _trans . This facilitates removal of the stent. One disadvantage of this coil structure is that the radial force to expand the tubular void is too small. The radial force of the coil is transmitted with only a small contact surface with the tissue. There is also a risk that the mechanical load is excessively applied locally by pressure such as when incising tissue. Further, since the catheter shaft needs to cover only one end of the coil, it is difficult to attach the catheter shaft (heating element) to the heating wire of the implanted coil.

  U.S. Pat. No. 4,950,258 describes a device for dilating deflated blood vessels. The device is made from a biodegradable polymer based on L-lactide and / or glycolide and exists in the form of a coil or tube. When caused by the shape memory effect, the diameter increases and as a result, the blood vessels can be dilated. The disadvantage of this material used is its brittleness during degradation and the generation of particles that can lead to occlusion of blood vessels released from the device.

  EP 1033145 also describes biodegradable stents made from shape memory polymers for use in blood vessels, lymph vessels, or bile ducts, or ureters. The stent is composed of homopolymer or copolymer yarns or from L-lactide, glycolide, ε-caprolactone, p-dioxanone or mixtures thereof based on trimethylene carbonate. The yarns are woven as monofilaments or multifilaments to form a network structure. The shape memory effect is utilized to expand the diameter of the stent and to secure the stent at the site of use. The switching temperature is a glass temperature not exceeding 70 ° C. Active substances or diagnostic agents can be added to the SMP or applied to the surface.

  US Pat. No. 5,964,744 describes implants for urogenital or gastrointestinal tracts, such as tubes and catheters, made from polymeric shape memory materials containing hydrophilic polymers. . In aqueous media, this material absorbs moisture, thereby softening and changing its shape. Alternatively or in addition, the material softens when heated. In urethral stents, this effect is exploited to bend the straight end of the stent at the site of use (eg, kidney or bladder). Thus, the urethral stent is secured at the site of use so that the stent does not slip in the case of peristaltic movement of tissue.

  WO 02/41929 describes a tubular vascular implant with shape memory, which is also suitable, for example, as a biliary stent. This material is an aliphatic polycarbonate-based thermoplastic polyurethane having biostability.

  A disadvantage of the materials used in the prior art is that the materials are not biodegradable. The implant must be removed from the body in a separate operation.

  US Pat. No. 6,245,103 describes a braided filament bioabsorbable self-expanding stent. The stent is compressed by applying an external radial force. This stent is attached to the catheter and is held by the outer sleeve under tension in the compressed state. If the stent is pushed out of this arrangement, its diameter will automatically increase due to the restoring force of the elastic material. This is not a shape memory effect that is activated by an external stimulus (eg, an increase in temperature).

  US Pat. No. 6,569,191 describes a biodegradable interwoven yarn self-expanding stent. Several pieces of elastic biodegradable polymer are adhered to the outside of the stent. This stent has shape memory properties. When heated to body temperature or absorbed moisture, the polymer piece contracts. Therefore, this stent is similarly contracted. At the same time, the stent diameter increases. These elastic pieces force the radial force of the stent outward. These elastic pieces are made, for example, from shape memory polymers based on lactic acid and / or glycolic acid.

  Biodegradable materials used in the prior art (i.e. materials that can be hydrolyzed under normal circumstances), in part, exhibit problematic degradation behavior. Degradation results in the production of small particles that are potentially dangerous. Such particles can clog passageways or ducts (eg, urethra). Moreover, degradation can also change the structure / properties of the implant in a manner that causes incompatibility with blood and / or tissue.

  Yet another frequently occurring problem is the pain caused by poor mechanical adaptation to the surrounding tissue of the stent and the movement of the stent.

Object of the invention

  As stents are increasingly used in medicine, efforts must be made to overcome the above disadvantages. For example, non-vascular or vascular stents need to be capable of minimally invasive implantation while at the same time allowing for unreasonable removal. The stent material should be adaptable at each use location, taking into account, for example, variations in mechanical loads. These materials should preferably allow further functionalization of the stent, such as by further embedding a medically useful substance.

In order to overcome the drawbacks of the prior art, the following is necessary.
A simple procedure that allows for minimally invasive stent implantation and removal;
A stent that degrades without affecting the surrounding tissue (in this case, at the same time sufficient mechanical strength is ensured over the intended period of use and the degradation products do not have any negative effect),
-A method of manufacturing and programming (tuning) such a stent.

BRIEF DESCRIPTION OF THE INVENTION

  This object is solved by the subject matter of the invention as defined by the claims. These stents comprise a shape memory material (SMP material), preferably a biodegradable SMP material, preferably an SMP material that exhibits a shape memory effect induced by heat or light. The SMP material used according to the present invention can store one or two shapes. Preferred embodiments are defined in the dependent claims.

  This type of stent solves all or at least some of the above problems. Thus, the present invention is an SMP material that can be inserted with minimal invasiveness and trauma by using the shape memory effect, and is histocompatible and hemocompatible in its degradation behavior, A stent comprising an SMP material is provided that has stability / strength and as a result exhibits sufficient stability despite the fact that degradation occurs. This type of stent manufactured with the material used according to the present invention exhibits a non-particulate degradation behavior. This is important because the particles produced during degradation can cause various problems such as clogging or injury to the ureter. However, the stent of the present invention does not show such problems because the stent of the present invention is flexible and elastic, and as a result, exists in the form of hydrogel particles that do not cause the above problems.

  Since stents must exist in their temporary shape before being placed in the body, they must also be at a sufficiently low temperature during transport to prevent unintended operation of the shape memory effect, and Must be stored in a manner well protected from radiation.

Detailed Description of the Invention

In a preferred embodiment, the object of the present invention is solved by an SMP stent having the following characteristics.
The stent in a temporary shape is pre-loaded on a temperature-controlled balloon catheter or a catheter with a suitable light source,
The diameter of the temporary shape is smaller than in the permanent shape (see FIG. 1),
The temporary shape functions as a tissue support,
The SMP has a switching temperature of 40 ° C. or higher, or a switching wavelength of 260 nm or higher,
A stent in a compressed temporary shape can be implanted by minimally invasive surgery and takes its desired permanent shape only in the desired manner by the SM effect at the site of use;
Heating of the stent to its switching temperature or above can occur either through a heat source, by irradiation with IR or NIR light, or by applying an oscillating electric field,
-A biodegradable SMP material is used for the stent so that subsequent removal of the stent is not essential.

A possible procedure for minimally invasive insertion of a stent includes the following steps (Figure 2):
1. A stent provided in a temperature-controlled balloon catheter is inserted into a tubular non-vascular organ with minimal invasive surgery.
2. The installed stent is heated by the catheter beyond its T _trans (at least 40 ° C.) (the balloon is filled with warm water (liquid) or gas) or irradiated with light using a light source of less than 260 nm. The The stent expands.
3. The stent will then exist in its permanent shape (expanded shape) and the balloon catheter can be removed.

Method for programming (adjusting) a stent according to the invention (FIG. 3)
1. The stent according to the present invention is made smaller than the initial diameter when programmed. For this purpose, a suitable tool is used as shown in FIG. This programming tool is made from a temperature self-adjustable block composed of tubes with _two different diameters (ID ₁ and ID ₂ ), where ID ₁ > ID ₂ applies.
2. The stent is placed in the left part of the tool in its non-programming (permanent) shape. The outer diameter DS1 of the stent to be programmed must be only slightly smaller than the inner diameter ID1 of the tool.
3. The tool according to FIG. 3 is heated to a temperature above Ttrans.
4). A stent heated to a temperature above Ttrans is drawn into the right region of the tool by a guide wire or guide thread. In the meantime, the outer diameter of the stent is reduced to DS2, and the stent gets its temporary shape.
5. The tool according to FIG. 3 is cooled to a temperature below Ttrans. Thereby, the temporary shape of the stent is fixed.
6). The stent cooled to a temperature below Ttrans is withdrawn from the tool by a guidewire or guide sled. The stent can be attached to a suitable catheter.

  The invention will now be further described.

  The stent of the present invention includes an SMP material. Thermoplastic materials, blends and networks are preferred. A composite material of biodegradable SMP and inorganic degradable nanoparticles is also suitable. It is preferred that the heating element is not incorporated into the SMP material. The shape memory effect can be exerted thermally by a heatable medium, by application of IR or NIR radiation, by applying an oscillating electric field, or by UV irradiation.

  In the definition that the stent according to the invention comprises an SMP material, it is defined that the stent, on the one hand, consists essentially of SMP material, on the other hand, the stent is also made from a biodegradable plastic material, It is defined that it can have a basic frame that is embedded or coated with SMP material. These two essential configurations provide the following advantages.

  If the stent consists essentially of SMP material, the stent uses SMP material to determine the mechanical properties of the stent. The fact that the materials described here are used for this purpose ensures favorable tissue compatibility. Further, as described above, such stents can be implanted and removed by minimally invasive surgery. SMP materials can also be processed relatively easily and are therefore easy to manufacture. Finally, SMP materials can be mixed or layered with other materials, so that further functionalization is possible. In this connection, reference is made to the following description.

  A second embodiment that is possible in principle is a stent that includes a basic frame such as a “wire mesh structure” or deformable tube. These basic frames are coated with SMP material or embedded in SMP material. In particular, it has been found that wire mesh structures can exert a sufficiently large force for the SMP material to deform such a basic frame if the shape memory effect is exerted. This embodiment thus makes it possible to combine the favorable properties of the conventional stent with the above-mentioned favorable effects of the SMP material. In particular, such a basic frame contributes to this, so that a stent with very high mechanical resistance can be obtained thereby. This embodiment is therefore particularly suitable for stents that are subject to high mechanical loads. Furthermore, the use of such a basic frame allows for a reduction in the amount of SMP material, which can help to save costs.

  If such a basic structure consists of a metallic material, the basic structure should preferably be a biodegradable metal such as magnesium or a magnesium alloy.

  This type of stent according to the present invention allows for safe placement of the stent and compatible degradation behavior. In the alternative, the stent according to the invention usually shows post-installation behavior according to a three-phase model.

  The intended use of the stent determines its design (eg, surface composition (microstructuring) or presence of coating).

  The following embodiments are possible in principle.

  The surface of the stent is compatible in terms of the physiological environment at the point of use by a suitable coating (eg, hydrogel coating) or surface microstructure. In designing a stent, basic conditions (eg pH value or number of bacteria, etc.) must be taken into account depending on the location of use.

  Thereafter, colonization of the surface by endothelial cells occurs, which can possibly be a supported body due to the respective modification (eg, coating) of the surface. Thereby, the stent is covered with the endothelial cells, and the endothelial cells grow slowly.

  In the case of a vascular stent, the surface of the stent is formed in a blood compatible manner by a suitable coating (eg, hydrogel coating) or by microstructuring of the surface, so that the stent affects living organisms. Rather, it allows a relatively short period of time after installation in full contact with blood. Thereafter, as mentioned above, anchoring to the surface occurs, so that the stent is slowly absorbed by the vessel wall.

  Finally, hydrolytic degradation usually occurs and the stent degrades in contact with soft tissue, but the stent still exhibits the desired support effect due to the degradation behavior described above (degradation of non-particles) ( Mechanical stability is not affected by degradation over a long period of time).

  Another alternative is that the stent after installation will remain outside the endothelial layer, which is achieved by suitable treatment (eg, surface selection, segment selection for SMP material, etc.). obtain.

  Suitable materials for the stent of the present invention will now be described.

  The SMP material in the present invention is a material that enables an intended shape change depending on a chemical / physical structure. In addition to their actual permanent shape, these materials have yet another shape that can be temporarily formed as a material. Such materials have two structural features: network points (physical or covalent) and switching segments.

An SMP having a shape memory effect induced by heat has at least one switching segment with one transition temperature as the switching temperature. The switching segment temporarily forms a bridging portion, decomposes when heated to a temperature above the transition temperature, and reforms when cooled. The transition temperature, sometimes a glass temperature T _g of the amorphous range, also be a melting temperature T _m of a crystal range. Hereinafter, it is generally described as T _trans .

_Beyond T _trans , the material becomes amorphous and elastic. When the sample is heated above the transition temperature T _trans , it deforms into a flexible state, and then cools below the transition temperature, the chain segments are fixed by freezing the deformation state freedom. (programming). Once the temporary cross-linked portion (non-covalent) is formed, the sample cannot return to its original shape unless an external load is applied. Upon reheating above the transition temperature, these temporary cross-linked moieties decompose and the sample returns to its original shape. The temporary shape can be reshaped by programming again. The accuracy with which the original shape is obtained again is called the reset ratio.

  In SMP that can switch light, photoreactive groups that can be reversibly bonded to each other by irradiating light have the function of a switching segment. In this case, the programming of the temporary shape and the regeneration of the permanent shape are performed by irradiation, and no temperature change is required.

In principle, any SMP material can be used to produce a stent. As an example, reference may be made to the materials and manufacturing methods described in the following applications, the contents of which are incorporated herein.
German Patent Application Publication Nos. 10208211.1, 102158558.4, 102217351.4, 102173050.8, 10228120.3, 10253391.1 Description, No. 10300271.5, No. 10316573.8.
European Patent Application Nos. 999342944.2 and 99908402.3.

  An SMP material that stores two shapes is described in US Pat. No. 6,388,043, the contents of which are incorporated herein.

Thermoplastic elastomers can be used to manufacture the stent according to the present invention. Suitable thermoplastic elastomers are characterized by at least two transition temperatures. The higher temperature transition temperature can correspond to a physical network point that determines the permanent shape of the stent. The transition temperature on the low temperature side that can exert the shape memory effect can be related to the switching segment (switching temperature, T _trans ). In the case of suitable thermoplastic elastomers, the switching temperature is typically about 3-20 ° C. above body temperature.

An example of a thermoplastic elastomer is a multi-block copolymer. Preferred multi-block copolymers are α, ω diol polymers of poly (e-caprolactone) (PCL), poly (ethylene glycol) (PEG), poly (penta) having a molecular weight range M _n of 250-500,000 g / mol. Decalactone) (poly (pentadecalacton)), poly (ethylene oxide), poly (propylene oxide), poly (propylene glycol), poly (tetrahydrofuran), poly (dioxanone), poly (lactide), poly (glycolide), poly (lactide) -Ran glycolide), polycarbonate, and polyether, or a block (macrodiol) composed of an α, ω diol copolymer of a monomer mainly composed of the above compound. Two different macrodiols are combined by a suitable bifunctional coupling reagent (especially an aliphatic or aromatic diisocyanate, or diacid chloride, or phosgene) to give a molecular weight M _n of 500-50,000. A thermoplastic elastomer in the range of 1,000 g / mol is formed. In the case of polymers that undergo phase separation, a phase having at least one temperature transition (glass transition or melt transition) can be combined with each of the aforementioned blocks of the polymer independently of the other block.

  Particularly preferred is a multi-block copolymer of a diisocyanate with a macrodiol based on pentadeclalactone (PDL) and -caprolactone (PCL). The switching temperature (in this case, the melting temperature) can be set in a range between about 30-55 ° C. depending on the block length of the PCL. The physical network point for anchoring the stent in a permanent shape is formed by a second crystalline phase having a melting point in the range of 87-95 ° C. Blends of multiblock copolymers are also suitable. The transition temperature can be set as intended by the mixing ratio.

  A polymer network can also be used to produce the stent according to the invention. Suitable polymer networks are characterized by covalent network points and at least one switching element having at least one transition temperature. The covalent network point determines the permanent shape of the stent. In the case of a suitable polymer network, the switching temperature at which the shape memory effect can be exerted is typically about 3-20 ° C. above body temperature.

  In order to form a covalent polymer network, one of the macrodiols described in the previous section is cross-linked by a multifunctional coupling reagent. The coupling reagent may be at least a trifunctional low molecular compound or a polyfunctional polymer. In the case of a polymer, it may be a star polymer having at least three arms, a graft polymer having at least two side chains, a hyperbranched polymer, or a dendritic structure. In the case of low molecular compounds and polymer compounds, the end group must be able to react with the diol. For this purpose, in particular isocyanate groups can be used (polyurethane network).

  An amorphous polyurethane network of triol and / or tetraol and diisocyanate is particularly preferred. Star prepolymers such as oligo [(rac lactate) -co-glycolato] triol or -tetraol can be obtained by adding catalytic dibutyltin (IV) oxide (DBTO) to rac-dilactide and diglycolide in the monomer melt. It is obtained by ring-opening copolymerization of with a hydroxy-functional initiator. As an initiator for ring-opening polymerization, ethylene glycol, 1,1,1-tris (hydroxy-methyl) ethane or pentaerythritol is used. Similarly, oligo (lactato-co-hydroxycaproato) tetraol, and (lactate-hydroxyethoxyacetate), and [oligo (propylene glycol) -block-oligo (rac lactate) -co-glycolato] triol are also produced. The The network according to the invention comprises a prepolymer and an isomer mixture of diisocyanates, such as 2,2,4- and 2,4,4-trimethylhexane-1,6-diisocyanate (TMDI), in solution, for example in dichloromethane. And can be easily obtained by conversion followed by drying.

  Furthermore, the macrodiols described in the preceding section can be functionalized to the corresponding α, ω-divinyl compounds that can be crosslinked thermally or photochemically. This functionalization is preferably capable of covalently attaching the macromonomer by a reaction that does not produce a byproduct. This functionalization is preferably imparted by ethylenically unsaturated units, particularly preferably acrylate and methacrylate groups, the latter being particularly preferred. In this case, the conversion to α, ω-macrodimethacrylate or macrodiacrylate can be carried out in particular by reaction with the respective acid chloride in the presence of a suitable base. The network is obtained by crosslinking of end group functionalized macromonomers. This crosslinking can be achieved by irradiating the melt containing the end group functionalized macromonomer component and, optionally, the low molecular weight comonomer, and will be described in more detail below. A suitable process condition for this is to irradiate the molten mixture with light, preferably at a temperature in the range of 40-100 ° C., preferably with a wavelength of 308 nm. Alternatively, thermal crosslinking is possible if the respective initiator system is used.

  When cross-linking the aforementioned macromonomer, if only one type of macromonomer is used, a network having a uniform structure is formed. When two types of monomers are used, an AB type network is obtained. Such AB type networks can also be obtained when the functionalized macromonomer is copolymerized with a suitable low molecular or oligomeric compound. When the macromonomer is functionalized with acrylate or methacrylate groups, suitable copolymerizable compounds are low molecular acrylates, methacrylates, diacrylates, or dimethacrylates. Preferred compounds of these types are acrylates such as butyl acrylate or hexyl acrylate, and methacrylates such as methyl methacrylate and hydroxyethyl methacrylate.

  These compounds capable of copolymerization with the macromonomer can be present in an amount of 5 to 70% by weight, preferably 15 to 60% by weight, based on the network of macromonomer and low molecular weight compound. . By adding the respective amount of compound to the mixture to be crosslinked, it is possible to introduce low molecular weight compounds in various amounts. The low molecular weight compound is introduced into the network in an amount corresponding to the amount of the crosslinking mixture.

  The macromonomer used in the present invention will now be described in detail.

  By varying the molecular weight of the macrodiol, it is possible to obtain networks having various crosslink densities (or segment lengths) and mechanical properties. The macromonomer crosslinked by covalent bond preferably has a number average molecular weight measured by GPC analysis of 2000 to 30000 g / mol, preferably 500 to 20000 g / mol, and particularly preferably 7500 to 15000 g / mol. Macromonomers that crosslink by covalent bonds preferably have methacrylate groups at both ends of the macromonomer chain. In such functionalization, the macromonomer can be crosslinked by simple photoinitiation (radiation).

  The macromonomer is preferably a polyester macromonomer, and particularly preferably a polyester macromonomer having ε-carprolactone as a main component. Other possible polyester macromonomers are lactide units, glycolide units, p-dioxane units, and mixtures thereof, and mixtures with ε-caprolactone units, with polyester macromonomers having caprolactone units being particularly preferred. Further preferred polyester macromonomers are poly (caprocacton-co-glycolide) and poly (caprolactone-co-lactide). The transition temperature can be set by the ratio of the amount of comonomer along with the decomposition rate.

Particularly preferred for use according to the invention are macromonomer polyesters containing crosslinkable end groups. The polyesters according to the invention which are particularly preferred to use are polyesters based on ε-caprolactone or pentadecalactone as mentioned above with respect to the molecular weight. The preparation of such polyester macromonomers, preferably end-functionalized with methacrylate groups, can be made by simple synthesis well known to those skilled in the art. These networks show semi-crystalline properties, depending on the type of polyester component used, and can be controlled by it, without taking into account the further essential polymer component of the present invention (DSC measurement). Can be measured). As is well known, this temperature (T _m 1) of a segment based on caprolactone units is between 30-60 ° C. and depends on the molecular weight of the macromonomer.

  A preferred network having a melting temperature as the switching temperature is based on the macromonomer poly (caprolactone-co-glycolide) -dimethacrylate. This macromonomer can be converted as it is or can be copolymerized with n-butyl acrylate to form an AB network. The permanent shape of the stent is determined by the covalent network points. This network is characterized by a crystalline phase and the melting temperature can be set as intended in the range of 20-57 ° C. depending on the comonomer ratio of caprolactone to glycolide. N-Butyl acrylate as a comonomer can be used, for example, to optimize the mechanical properties of the stent.

  Yet another preferred network with glass temperature as the switching temperature is obtained from the macromonomer ABA triblock dimethacrylate, which consists of the polyblockene oxide central block B and the end of poly (rac-lactide). Block A. This amorphous network has a very wide switching temperature range.

To produce a stent that stores two shapes, a network having two transition temperatures, such as an interpenetrating network (IPN), is preferred. The covalent bond network is composed mainly of poly (caprolactone) -dimethacrylate, and the interpenetrating component is a multi-block copolymer of macrodiols composed mainly of pentadecalactone (PDL) and ε-caprolactone (PCL) and diisocyanate. It is. The permanent shape of the material is determined by the covalent network points. Two transition temperatures, which are the melting temperatures of the crystalline phases, can be used as transient shape switching temperatures. The lower switching temperature T _trans can be set in a range between about 30 and 5 ° C. depending on the block length of the PCL. The higher switching temperature T _trans 2 is in the range of 87-95 ° C.

  In order to produce the stent according to the invention, a photosensitive mesh can also be used. A suitable photosensitive network is amorphous and is characterized by covalent network points that determine the permanent shape of the stent. Yet another feature is a photoreactive component, or a unit reversibly switchable by light, that determines the temporary shape of the stent.

  In the case of photosensitive polymers, a suitable network is used that includes photosensitive substituents along the amorphous chain segment. When irradiated with UV light, these groups can form a covalent bond with each other. When this material is deformed and irradiated with light having a suitable wavelength λ1, the original network is further crosslinked. Cross-linking temporarily fixes the material in a deformed state (programming). Since this optical coupling is reversible, it can be released from the cross-linking by further irradiation with light of different wavelengths λ2, thereby reproducing the original shape of the material (restoration). Such a photo-mechanical cycle can be repeated arbitrarily. The main component of the photosensitive material is a large mesh polymer network which, as mentioned above, is transparent to the radiation intended to activate the shape change, ie preferably UV transmissive. Forming a sex matrix. The network of the present invention based on low molecular weight acrylates and methacrylates capable of radical polymerization is preferred according to the present invention, particularly C1-C6-meta (acrylate) and hydroxy derivatives, hydroxyethyl acrylate, hydroxyporpymethacrylate. (Hydroxypolymethacrylate), poly (ethylene glycol) methacrylate, and n-butyl acrylate are preferred, and n-butyl acrylate and hydroxyethyl methacrylate are preferred.

  As a comonomer for forming the polymer network of the present invention, a component involved in segment crosslinking is used. The chemical nature of this component naturally depends on the nature of the monomer.

  In the case of preferred networks based on the acrylate monomers mentioned above as preferred, suitable crosslinking agents are difunctional acrylate compounds, which can react appropriately with the starting material of the chain segments and thereby be converted into each other. it can. This type of crosslinker is a short bifunctional crosslinker such as ethylene diacrylate, low molecular bifunctional or polyfunctional crosslinker, oligomer, linear diacrylate crosslinker such as poly (oxyethylene) diacrylate or poly (Oxypropylene) diacrylate, and branched oligomers or polymers having acrylate end groups.

  Another component of the network according to the present invention includes a photoreactive component (group), which is also involved in activating the shape change that can be controlled as intended. This photoreactive group is a unit capable of undergoing a reversible reaction caused by stimulation of suitable light irradiation, preferably UV radiation (together with a second photoreactive group), whereby the formation or separation of covalent bonds is prevented. Occur. Preferred photoreactive groups are those capable of causing reversible photodimerization. As the photoreactive component of the photosensitive network according to the invention, different cinnamic acid esters (cinnamate, CA) and cinnamyl acrylate esters (cinnamyl acrylate, CAA) can preferably be used.

  Cinnamic acid and its derivatives are known to dimerize under about 300 nm UV light by forming cyclobutane. The dimer can be separated again by irradiation with a smaller wavelength of about 240 nm. The absorption maximum can be shifted by substituents on the phenyl ring, but is always in the UV region. Still other derivatives capable of photodimerization include 1,3-diphenyl-2-propen-1-one (chalcon), cinnamyl Acrylic acid, 4-methylcoumarin, various ortho-substituted cinnamic acids, cinammolyxysilane (silyl ether of cinnamon alcohol).

  Photodimerization of cinnamic acid and similar derivatives is a [2 + 2] cycloaddition to double bond cyclobutane derivatives. The E-isomer and Z-isomer can drive this reaction. When irradiated, E / Z-isomerization proceeds in competition with cycloaddition. However, E / Z-isomerization is suppressed in the crystalline state. Eleven different stereoisomers (truxill acid, truxin acid) are theoretically possible due to the different isomer arrangement possibilities. The distance between the two double bonds of the cinnamic acid group necessary for the reaction with each other is about 4 mm.

  These meshes have the following characteristics.

  Overall, the mesh is a desirable SMP material and has a high reset value, for example the original shape is obtained even if several cycles of shape change are carried out at a high rate, typically exceeding 90%. There is no adverse reduction in the mechanical property values.

  Since the materials mentioned above are based on aliphatic polyesters, the SMP materials used can be hydrolyzed and are biodegradable. Surprisingly, these materials degrade on the one hand in a biocompatible manner (ie the degradation products are not toxic) and at the same time the mechanical integrity of the stent is maintained during the degradation process. Turned out to be. This ensures a sufficiently long functionality of the stent.

  In order to enhance blood compatibility, the chemical structure of the SMP material used according to the present invention can be altered by introducing the aforementioned polyether or oligoether units.

(Processing of polymers into stents)
Any conventional polymer technology methods known to those skilled in the art, such as injection molding, extrusion, rapid prototyping, etc., can be used to process the thermoplastic elastomer into a stent in the form of a hollow tube or the like (FIG. 1). . Further, a manufacturing method such as laser cutting can be used. In the case of thermoplastic elastomers, different designs are possible by spinning single and multifilament yarns and subsequently knitting into a cylindrical mesh with a mesh structure.

In the manufacture of polymer mesh stents, the form in which the macromonomer cross-linking reaction takes place must correspond to the permanent shape of the stent (curing after the casting process). In particular, the network material according to the present invention requires special grinding and cutting methods for further processing. A perforation or cutting of the tube with a laser beam of suitable wavelength is proposed. By using this technique, especially in the case of a combination of CAD and pulsed CO ₂ or YAG lasers, up to 20 μm without exposing the material to high heat loads (and no undesirable side reactions at the surface) Can be processed. Alternatively, it is proposed to perform a debris removal process to obtain a ready-to-use stent.

  The second embodiment is obtained by coating or embedding conventional materials (described above) on the SMP material by a suitable method.

  The mechanical properties required for a stent depend on the location of use and require a suitable design. When an implanted stent is subjected to strong mechanical deformation, it must be very flexible so that it does not break during movement. Basically, “wire coil design” is more suitable. In other regions of the deeper organ, the mechanical load due to the deformation of the stent is reduced, but it is subject to a relatively high external pressure. A suitable stent for this purpose should be characterized by a strong radial force on the surrounding tissue. In this case, the “slotted tube design” seems more suitable. In a tube having a perforation, liquid can flow (drain) from the surrounding tissue into the stent.

  In the case of stents to be used in non-vascular areas, drainage is important, so such stents are particularly designed with embedded basic frames, or SMP materials (perforated tubes or mesh) Basic designs are preferred because the permeation of the liquid required for drainage is very simple and at the same time exhibits sufficient mechanical strength.

  The prior art has shown various problems, especially with small diameter vessels. This is because known stents are not flexible and cannot be adequately adapted for such vessels. However, the stent of the present invention also protects blood vessels in the case of pulsatile movement of arteries, for example, due to the excellent elastic properties of SMP material (ie, high elasticity at small excursions and high strength at large expansions). As such, it allows safe use in such blood vessels.

(Functionalization of stent)
To make stent insertion easier, in some cases the stent can be provided with a coating (eg silicone or hydrogel) that increases slip.

  Further methods for improving blood compatibility include methods of providing a coating (materials necessary for this purpose are well known to those skilled in the art) or forming a microstructure on the surface. Suitable methods for surface modification are, for example, plasma polymerization and graft polymerization.

In order to more easily locate the stent by visual diagnostic procedures, the shape memory plastic material can be viewed with a suitable x-ray contrast agent (eg, BaSO ₄ ). Yet another method can be obtained by introducing a metal thread (eg, stainless steel) into the stent. These metal threads do not serve the purpose of stabilization (used for location purposes) and are only intended to increase the X-ray contrast. The third method is observation using a metal, which has virus growth inhibitory property, fungicidal property, or bactericidal property (for example, nano silver) in addition to enhancing X-ray contrast. Yet another method of this aspect is to introduce a chromophore that is opaque to X-rays, such as a triiodobenzene derivative, into the SMP material itself.

  In yet another embodiment, SMP can be mixed with biodegradable inorganic particles. Examples include particles made of magnesium or a magnesium alloy or magnetite. Also suitable are particles made of carbon. SMP functionalized in this way can be heated in an oscillating electric field in order to exert a shape memory effect.

A stent according to the present invention can also be loaded with a number of therapeutically active substances that support the healing process, inhibit stent restenosis, or prevent later disease. In particular, the following can be used.
-Anti-inflammatory actives (eg ethacridine lactate)
An analgesic substance (eg acetylsalicylic acid)
-Effective antibiotics (eg enoxacin, nitrofurantoin)
-Effective substances against viruses and fungi (eg elemental silver)
Anti-thrombin active substances (eg AAS, clopidogrel, hirudin, lepirudin, decyldin)
A cytostatic active substance (eg sirolimus, rapamycin or rapamune)
An immunosuppressive active substance (eg ABT-578)
-An active substance that reduces restenosis (eg taxol, paclitaxel, sirolimus, actinomycin D).

The stent according to the invention can be filled with the active substance in various ways.

  The active substance can be directly covered with plastic or can be mounted on the stent as a coating.

  This type of stent can also be used in the field of gene therapy.

  If active materials are introduced into the hydrophilic coating, these active materials are released while the stent allows diffusion controlled release. Note that the diffusion rate of the active material from the hydrophilic coating must be greater than the degradation rate of the stent material.

  If an active substance is introduced into the material of the stent according to the present invention, the release of the active substance probably occurs upon degradation after the endothelial cells have grown over the stent and the stent has come into contact with the soft tissue. . The release of the active substance is accompanied by the degradation of the stent. Therefore, it should be noted that the diffusion rate of the active substance from the stent must be less than the degradation rate of the stent material.

  For vascular stents, the following applies:

:
If active materials are introduced into the hydrophilic coating, these active materials are released while the stent is in contact with the flowing blood. Note that the diffusion rate of the active material from the hydrophilic coating must be greater than the degradation rate of the stent material.

  This is particularly effective in the following applications.

(Iliac stent)
These stents have a length of 10 to 120 mm, usually 40 to 60 mm. These are used in the abdomen. Since the use of long stents is difficult, usually two stents are used. However, because the stent of the present invention has the desired flexibility and is characterized by its very gentle minimally invasive application and removal, it has a length that would not have been possible with the prior art. The stent of the present invention can also be used.

(Kidney stent)
In this case, since a high elastic load is applied in the renal artery, a high strength in the radial direction is required, and in some cases, mechanical reinforcement of the stent is required. In this case, “slotted tube design” is preferred. This embodiment may use a marker that is opaque to radiation. In this case, the accuracy of the safe attachment and insertion of the stent on the balloon of the catheter is important. Because all organisms are anatomically different, adapted variable lengths and diameters are required. Furthermore, the combined use of a tip protector and a plaque filter is desirable.

(Carotid artery stent)
-In order to avoid the prior art of using two stents together, a long stent can be used in this case-it can also be used at vascular bifurcations-an optimal fit is possible even in the case of various diameters- Because of the filter function that may be necessary to prevent the blood clot from flowing into the cerebrum (plaque filter function), a fine mesh is desirable and can be achieved (as described above).
-The stent needs to be pressure stable and the pressure may increase externally so that the stent must not collapse.

(Thigh-popliteal stent (hip joint-knee))
Increased mechanical reinforcement may be required for high radial strength against high elastic loads in blood vessels. In this case, a “slotted tube design” is preferred, especially the use of two long stents.

(Coronal stent)
-Wire coil design-Introduction without frictional action and without trauma is a prerequisite and is possible with the stent of the present invention.

(Design of non-vascular stent)
Important sites for use are the digestive tract, trachea, and esophagus, bile duct, ureter, urethra, and oviduct. Therefore, various sizes of stents are used. The various pH values of body fluids and the presence of microorganisms need to be considered individually in the stent design.

  Individually, depending on the location of use, non-vascular stents are substantially used to drain bodily fluids such as bile, pancreatic juice, or urine. Therefore, a perforated hose design is desirable, while the liquid to be drained from the gap can be safely drained, and on the other hand, it absorbs the liquid as a whole. Furthermore, the polymer material used must be highly flexible so that it can be worn comfortably. For ease of identification by X-ray examination, the starting material can be observed with an X-ray contrast agent such as barium sulfate, or a chromophore that is opaque to X-rays can be produced by SMP, for example by polymerization of suitable monomers. Incorporated into the material. When stents are used in areas where microorganisms are present, it can be advisable to incorporate effective antibiotics into the material.

  Stent deposits that are particularly frequent in the urethral region can be suitably mitigated by coating or surface modification.

  The fixation of the stent depends substantially on the location of use. In the case of a urethral stent, the proximal end is placed in the renal pelvis and the distal end is placed in the bladder or outside the body. The proximal end forms a loop in the renal pelvis after the end of dilation and is therefore held safely.

  Another method of securing the stent is to include a securing element that serves to force or anchor the stent against the surrounding tissue by a radial force directed outward.

  In the case of biliary or kidney stents, it is essential to place and remove intact. In particular, during placement, it is necessary to prevent the tissue from being damaged and inflamed by frictional action. Stents used in this area do not have any retention elements that can damage tissue.

  Thus, for example, suitable materials that are suitable for use in the present invention will be described as examples.

(Example of multi-block copolymer)
The multi-block copolymer was produced from a macrodiol based on pentadecalactone (PDL) and ε-caprolactone (PCL) and diisocyanate. PDL represents the molecular weight of the pentadecalactone moiety (not considering diisocyanate crosslinking) and the polypentadecalactone segment in the multi-block copolymer. PCL represents each data of caprolactone unit.

The temperature-dependent mechanical properties of Example 8 are shown below.

(Example of polymer network)
A suitable polymer network is obtained by copolymerization of macrodimethacrylates based on glycolide units and ε-caprolactone units and n-butyl acrylate. The weight ratio of glycolide in macrodimethyl acrylate is 9% by weight (or 11% by weight in Example 13). The molecular weight of macrodimethacrylate is about 10,000 to 11000 g / mol.

(Example of amorphous polymer network)
Amorphous networks are prepared from ABA triblock dimethacrylate, where A represents a segment of poly (rac-lactide) and B represents a segment of atactic poly (propylene oxide) (M _n = 4000 g / mol).

Further investigations were made regarding the thermal and mechanical properties of the polymer amorphous network. The results of these tests are summarized in the following table.

(Example of photosensitive mesh)
10 mmol n-butyl acrylate (BA), cinnamic acid ester (0.1-3 mmol), and optionally 2 mmol hydroxyethyl methacrylate (HEMA) are mixed in the flask. 1 mol% AiBN and 0.3 mol% poly (propylene glycol) dimethacrylate (M _n = 560) are added to the mixture. The mixture is filled with a syringe into two silylated object carrier molds with a 0.5 mm thick Teflon seal ring in between. Polymerization of the mixture is carried out at 80 ° C. for 18 hours.

  The type in which crosslinking occurs corresponds to a permanent type. This mixture can also be crosslinked in any other shape.

After polymerization, the mesh is removed from the mold and covered with 150 mL hexane fraction. Next, gradually add chloroform. This solvent mixture is changed several times within 24 hours to dissolve the low molecular components and non-crosslinked components. Subsequently, the mesh is washed with a hexane fraction and vacuum dried at 30 ° C. overnight. The weight of the extracted sample relative to the previously measured weight corresponds to the gel content. The following two tables show the amount of monomer used, as well as the water expansion in chloroform and its gel content G.

In yet another series, 2 mmol of hydroxyethyl methacrylate (HEMA) is further added to the binary polymer system to investigate further possibilities for controlling the mechanical properties of the polymer network with this comonomer.

(Manufacture of interpenetrating network IPN)
As described above, n-butyl acrylate is crosslinked in the presence of 3 wt% (0.6 mol%) poly (propylene glycol) dimethacrylate (molecular weight 560 g / mol) and 0.1 wt% AiBN. Subsequently, the obtained film is put in THF, the unused monomers are eluted and dried again. The film is then placed in a solution of star photoreactive macromonomer (10% by weight) in THF and then dried again. The filling of the network with the photoreactive component is about 30% by weight.

(Production of star-shaped photosensitive macromonomer)
Star poly (ethylene glycol) with 4 arms (molecular weight 2000 g / mol) is dissolved in dry THF and triethylamine. For this purpose, cinnamylidene acetyl chloride slowly dissolved in dry THF is added dropwise. The reaction mixture is stirred at room temperature for 12 hours and then at 50 ° C. for 3 days. The precipitated salt is filtered off, the filtrate is concentrated and the resulting product is washed with diethyl ether. The conversion rate in H-NMR measurement was 85%. From the viewpoint of UV spectroscopy, this macromonomer exhibits an absorption maximum at 310 nm before the photoreaction and has an absorption maximum at 254 nm after the photoreaction.

Further investigations were made regarding the thermal and mechanical properties of the polymer amorphous network. The results of these tests are summarized in the following table.

  The shape memory characteristics were determined by a cylindrical photomechanical test. For this purpose, a barbell-type sheet piece having a thickness of 0.5 mm, a length of 10 mm and a width of 3 mm was punched and used.

  Various examples of shape memory polymers that memorize two shapes are described in US Pat. No. 6,388,043, which is incorporated by reference.

FIG. 4 is a schematic diagram showing the size difference between the permanent and temporary shapes of the stent of the present invention. FIG. 6 is a schematic view of a working step for introducing and removing a stent. The light gray portion indicates the stent, the dark gray portion indicates the catheter balloon, and the black portion indicates the catheter. FIG. 2 is a schematic diagram illustrating a known method of programming a stent (see US Pat. No. 5,591,222).

Claims (10)

A biodegradable stent comprising an SMP material for use in a non-vascular or vascular region, wherein the stent is designed to be a wire coil or slotted tube, wherein the SMP material comprises a thermoplastic elastomer, a polymer network, and a mutual mesh. selected from the group consisting of interpenetrating networks, wherein the SMP material comprises a caprolactone unit and a pair printer decalactone unit, stents.   The stent according to claim 1, comprising a basic structure made of a degradable material or a biodegradable plastic material coated with an SMP material.   The stent according to claim 2, wherein the degradable material is a magnesium alloy, pure magnesium, or a mixed material of magnesium or a magnesium alloy and a biodegradable polymer.   The stent according to any one of claims 1 to 3, further comprising an additional additive selected from an X-ray contrast agent and a medically effective compound.   The SMP material is selected from SMP materials in which the SMP effect is thermally induced and photoinduced and / or the SMP material is biodegradable and / or blood compatible and / or the SMP material The stent according to any one of claims 1 to 4, wherein the material exhibits non-particle-generated degradation behavior.   The stent according to any one of claims 1 to 5, wherein the network is composed of a crosslinked caprolactone macromonomer.   The stent according to any one of claims 1 to 6, further comprising a surface coating.   The stent according to claim 7, wherein the surface coating is selected from coating materials that modify blood compatibility. A method for producing a stent according to any one of claims 1-8,
A method comprising processing the SMP material into a stent by an extrusion method, a coating method, a metal casting method, or a spinning / weaving method.   A kit comprising the stent according to any one of claims 1 to 8, and further, a temperature-controlled balloon catheter and / or a balloon catheter having an optical fiber.

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