EP1699383A1 - Control of the degradation of biodegradable implants using a coating - Google Patents
Control of the degradation of biodegradable implants using a coatingInfo
- Publication number
- EP1699383A1 EP1699383A1 EP04765010A EP04765010A EP1699383A1 EP 1699383 A1 EP1699383 A1 EP 1699383A1 EP 04765010 A EP04765010 A EP 04765010A EP 04765010 A EP04765010 A EP 04765010A EP 1699383 A1 EP1699383 A1 EP 1699383A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- degradation
- coating
- location
- implant
- degradation characteristic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
Definitions
- the invention relates to an at least largely biodegradable endovascular implant whose in vivo degradation can be controlled.
- biodegradable implants A wide variety of materials are available to the medical technician for realizing such biodegradable implants.
- metallic materials In addition to numerous polymers, which are often based on natural origin for better biocompatibility or at least based on natural compounds, metallic materials, with their mechanical properties which are significantly more favorable for the implants, have recently been favored. In this context, particular attention is paid to materials containing magnesium, iron and tungsten.
- One of the problems to be solved in the practical implementation of biodegradable implants is the degradation characteristic of the implant in vivo. On the one hand, this is to ensure that the functionality of the implant is maintained at least for the period of time necessary for the therapeutic purposes.
- the degrada- tion should run as evenly as possible over the entire implant, so that fragments are not released in an uncontrolled manner, which can be the starting point for undesired complications.
- Known biodegradable stents do not show a locally coordinated degradation characteristic.
- the task is to provide a biodegradable implant whose degradation can be optimized depending on the location.
- a tubular basic body made of at least one biodegradable material on its end faces, the basic body having a location-dependent first degradation characteristic D- ⁇ (x) in vivo, and a coating of at least one biodegradable material that completely or possibly only partially covers the base body, the coating having a location-dependent second degradation characteristic D 2 (x) in vivo, and
- a location-dependent cumulative degradation characteristic D (x) results from the sum of the degradation characteristics D- ⁇ (x) and D 2 (x) existing at the location (x) in each case and the location-dependent accumulation the degradation characteristic D (x) is predetermined by varying the second degradation characteristic D 2 (x) in such a way that the degradation takes place at the specified location (x) of the implant in a predeterminable time interval with a predeterminable degradation curve,
- the degradation characteristic of the entire stent can be locally optimized in the desired manner.
- the invention accordingly includes the idea that the degradation of the base body of the implant is adapted by a suitable coating - in extreme cases, however, also by omitting the coating - so that the degradation characteristic existing at one location degrades the implant in a predefinable time interval and with a predeterminable course of degradation enables.
- Biodegradation means hydrolytic, enzymatic and other metabolic degradation processes in the living organism, which lead to a gradual dissolution of at least large parts of the implant.
- biocorrosion is often used synonymously.
- bioresorption also includes the subsequent absorption of the degradation products.
- Materials suitable for the base body can be, for example, polymeric or metallic in nature.
- the base body can also consist of several materials. A common feature of these materials is their biodegradability.
- polysaccharides PSAC
- PHA polylactide
- PLA poly-L-lactide
- PGA polyglycol
- PLLA / PGA polyhydroxybutyric acid
- PHT polyethylene terephthalate
- PML polymalonic acid
- polyanhydrides polyphosphazenes, polyamino acids and their copolymers and hyaluronic acid.
- the polymers can be in pure form, in derivatized form, in the form of blends or as copolymers.
- Metallic biodegradable materials are based on alloys of magnesium, iron or tungsten.
- the biodegradable magnesium alloys in particular show extremely favorable degradation behavior, are easy to process and show little or no toxicity, but rather seem to stimulate the healing process positively.
- the basic body of a stent is generally composed of a large number of support elements arranged in a specific pattern.
- the support elements are loaded with different mechanical forces.
- this can mean, among other things, that the areas of the support elements which are under stress or which are at least temporarily exposed to high mechanical loads are broken down more quickly than areas which are less loaded.
- the present invention allows to counteract this phenomenon.
- the coating can also be formed from the aforementioned biodegradable materials.
- several different materials can also be used in one implant, for example at different locations or as multi-layer systems at a specific location of the implant.
- “Location-dependent degradation characteristic” in the sense of the invention means the time course (degradation course) and the time interval in which this degradation takes place.
- the first point of reference for the time interval is the time of the implantation itself. Of course, other times can also be used.
- An end of the time interval is understood in the sense of the invention as the point in time at which at least 80% by weight of the biodegradable implant mass has been broken down or the mechanical integrity of the implant no longer exists, i.e. the implant can no longer perform its supporting function.
- the degradation curve indicates the speed at which the degradation takes place at specific times in the time interval.
- the degradation of the implant is greatly delayed in the first two weeks after the implantation by means of a suitable coating and only progresses rapidly after the coating has been removed due to the faster degradation of the base body.
- the degradation characteristics of the base body and the coating can be estimated in advance using in vitro tests.
- the degradation characteristic of the coating is preferably determined by - varying its morphological structure, - material modification of the material and / or
- the location-dependent degradation characteristics of the implant can be influenced by adjusting the layer thickness of the coating.
- the focus is on controlling the degradation at a specific location in terms of time and scope.
- “Morphological structures” in the sense of the invention mean the conformation and aggregation of the compounds forming the coating, in particular polymers. This includes the type of molecular order structure, the porosity, the surface quality and other intrinsic properties of the carrier, which influence a degradation behavior of the biodegradable material on which the coating is based.
- Molecular order structures include amorphous, (partially) crystalline or mesomorphic polymer phases, which can be influenced or generated depending on the manufacturing process, coating process and environmental conditions used. The porosity and surface quality of the coating can be influenced by targeted variation of the manufacturing and coating process. In general, the degradation takes place more quickly with increasing porosity of the coating. Amorphous structures show similar effects to (partially) crystalline structures.
- 'Material modification' in the sense of the invention includes both a derivatization of the biodegradable material, in particular the polymers, and the addition of fillers and additives (additives) for the purpose of Understanding of the degradation characteristics understood.
- the derivatization includes, for example, measures such as networking or replacing reactive functionalities in these materials. It is well known, for example, that polymeric materials such as hyaluronic acid are broken down more slowly when increasing the degree of crosslinking. These measures must first be recorded quantitatively by means of established in vitro investigations in order to be able to provide an estimate of the degradation characteristics for the in vivo behavior.
- the location-dependent degradation characteristic of the implant is preferably specified as a function of the pathophysiological and / or rheological conditions to be expected in the application.
- the pathophysiological aspects take into account the fact that the stent is usually placed in the vessel in such a way that it lies in the center of the lesion, ie. H. the adjacent tissue at the ends and in the middle area of the stent is of different nature and therefore the supporting function of the implant needs to be maintained for different times to optimize the healing process.
- the tissue resistances acting on the implant are unequal due to the pathophysiological change, which can lead to an accelerated degradation due to the resulting mechanical stress in places of greater resistance.
- Rheological aspects in turn take into account the fact that the flow conditions, in particular in the area of the ends and in middle sections of the stent, are different. This can lead to accelerated dismantling of the implant at the ends of the stent due to the stronger flow.
- Rheological parameters can vary widely, particularly by specifying the stent design, and must be determined in individual cases. By taking the two parameters mentioned into account, optimal degradation over the entire dimension of the stent can be ensured for the desired therapy.
- the invention is explained in more detail below on the basis of exemplary embodiments and in the associated drawing. Show it:
- FIG. 1 shows a stent with a tubular base body which is open on its end faces and the peripheral wall of which is covered with a coating system
- FIG. 2a, 2b a schematic cross section along a longitudinal axis of a stent to illustrate the coating according to a first variant
- 3a, 3b show a schematic cross section along a longitudinal axis of a stent to illustrate the coating according to a second variant.
- FIG. 1 shows a highly schematic perspective side view of a stent 10 with a tubular base body 14 that is open at its ends 12.1, 12.2.
- a circumferential wall 16 of the base body 14 that extends radially about a longitudinal axis L consists of axially arranged side by side Segments, which in turn are composed of a plurality of support elements arranged in a specific pattern.
- the individual segments are connected to one another via connecting webs and, in summary, result in the base body 14.
- FIG. 1 the depiction of a specific stent design was deliberately omitted, since this is not necessary for the purposes of illustrating the invention and, moreover, an individual adaptation for each stent design a coating to the given geometric factors and other parameters is necessary.
- the stent 10 can be formed from a biodegradable magnesium alloy, in particular WE43.
- WE43 a biodegradable magnesium alloy
- the individual support elements are subjected to different mechanical loads, in particular at their articulation points. This can lead to the fact that the metallic structure z. B. changed due to micro-cracking. As a rule, a particularly rapid degradation will take place at points where a particularly high mechanical stress occurs.
- the dimensions of the individual support elements are dimensioned differently depending on the stent design present. It goes without saying that supporting elements with a larger circumference are dismantled more slowly than correspondingly filigree structures in the basic structure. The objective for a satisfactory degradation behavior of the implant should therefore be to counteract a kind of fact formation due to these different degradation characteristics.
- the location-dependent degradation characteristic of the base body is expressed in the following with the abbreviation D ⁇ x).
- the stent 10 of FIG. 1 shows in a highly schematic manner a coating 26 in which a plurality of sections 20.1, 20.2, 22.1, 22.2, 24 of the outer circumferential surface 18 of the peripheral wall 16 are formed from biodegradable materials which differ in their degradation characteristics D 2 (x) ,
- a polymer based on hyaluronic acid is given here as an example of a suitable material for the coating 26.
- Hyaluronic acid not only shows favorable degradation behavior, but is also particularly easy to process and also has positive physiological effects.
- the degradation characteristic D 2 (x) can be influenced, for example, in such a way that a certain degree of crosslinking is predetermined by reaction with glutaraldehyde.
- Numerous processes have been developed for applying a coating to the stent, such as, for example, rotary atomization processes, immersion processes and spray processes.
- the coating at least in regions covers the wall or the individual struts of the stent that form the support structure.
- the degradation characteristic D 2 (x) differs in the individual sections 20.1, 20.1, 20.2, 22.1, 22.2, 24.
- the sections 20.1 and 20.2 at the ends 12.1, 12.2 of the stent 10 show an accelerated degradation characteristic D 2 (x), whereas the sections 22.1 arranged more in the middle , 22.2 and 24 degrade more slowly.
- This in turn has the consequence that, given the same degradation characteristics D ⁇ x) of the base body, degradation at the end of the stent 10 proceeds faster. This makes sense insofar as the lesion to be treated should be centered opposite sections 22.1, 22.2 and 24 if the stent 10 is applied correctly. Accordingly, the degeneration characteristics D -] (x) and D 2 (x) add up to a cumulative location-dependent degeneration characteristic for the implant.
- 2a, 2b, 3a, 3b, 4 and 5 show - in each case in a highly schematic manner - a section along the longitudinal axis L of the stent 10 and in each case only one of the two sections resulting therefrom through the peripheral wall 16 however, the principles underlying the design of the coating are briefly discussed.
- a degradation characteristic D 2 (x) of a coating at a specific location (x) essentially depends on factors such as
- the local degradation characteristic D 2 (x) depends on the morphological structure and material modifications of the coating.
- the porosity of the coating can be varied, an increased porosity leading to accelerated degradation.
- the material modification it can be provided, for example, to add additives to the carriers which delay the enzymatic degradation.
- the degradation of coatings based on polysaccharide can also be delayed by increasing the degree of crosslinking.
- the cumulative degradation characteristic D (x) of the coating 26 can be predetermined by suitable specification of the degradation characteristic D 2 (x) of the coating 26, provided the degradation characteristic D- ⁇ (x) of the base body is known.
- the individual sections of the coating of the stent are also adapted depending on the pathophysiological and theological conditions to be expected in the application.
- the pathophysiological conditions here mean the tissue structure changed by disease in the stented vascular area.
- the stent is placed in such a way that the lesion, ie the fibroatheromatous plaque in coronary applications, is approximately in the central area of the stent.
- the adjoining tissue structures diverge in the axial direction over the length of the stent, and another therapy may also be indicated locally under certain circumstances.
- the theological conditions are understood to mean the flow conditions as they occur in the individual longitudinal sections of the stent after implantation of the stent. Experience has shown that there is a greater flow around the ends of the stent than the central regions of the stent. This can result in increased degradation of the carrier in the end regions.
- Biodegradable materials for the coating can include all polymeric matrices of synthetic nature or of natural origin are used in the sense of the invention, which are degraded in the living organism due to enzymatic or hydrolytic processes.
- pharmacologically active substances which are used in particular to treat the consequences of percutaneous coronary interventions, can be added to the coating.
- FIG. 2a shows a highly schematic and simplified sectional view of the peripheral wall 16, with its coating 26 applied to the outer lateral surface 18.
- the coating 26 consists of two end sections 28.1 and 28.2 and a middle section 30.
- the entire coating 26 is formed from a biodegradable material applied in a uniform layer thickness.
- Sections 28.1, 28.2, 30 differ in that the final soapy sections 28.1, 28.2 degrade more slowly than the middle section 30. In the present exemplary case, this is used to compensate for logically induced accelerations of the digestion process at the stent ends used, d. H.
- the schematic stent shown in FIG. 2a will show a largely homogeneous degradation behavior over the entire length of the stent.
- FIG. 2b discloses a second variant of the coating 26.
- the sections 28.1, 28.2 correspond to those in FIG. 2a.
- the section 30, however, is significantly reduced in its layer thickness. The result of this is that section 30 is broken down much more quickly than sections 28.1 and 28.2.
- Such degradation behavior of the implant can be useful if the artificial structure in the area of the lesion is to be removed as quickly as possible in order to eliminate any starting point for possible complications in this area as early as possible.
- FIG. 3a shows a coating system 26, in which two different materials with a different degradation behavior are applied to the sections 28.1, 28.2, 30 of the stent 10. The same applies to the variation of the system according to FIG. 3b.
- sections 28.1, 28.2 are covered by a material with a delayed degradation behavior compared to the material used in the middle section 30. Accordingly, the location-dependent degradation characteristic D (x) is influenced, ie generally delayed at the end.
- D (x) is influenced, ie generally delayed at the end.
- 3b shows in sections 28.1 and 28.2 a multilayer structure of the coating 26 in the radial direction.
- the material with the delayed degradation behavior is again applied in a first section 32, while a section 34 with the more rapidly degradable material is located radially outward.
- FIGS. 2a, 2b and 3a, 3b, 4 and 5 represent only highly schematic exemplary embodiments of the invention. They can be combined with one another in a variety of ways. For example, it is conceivable to design a complex coating consisting of several materials in individual sections. The primary goal is always to optimize the local degradation of the implant.
Abstract
The invention relates to an endovascular implant, which is at least largely biodegradable and whose in vivo degradation can be controlled. To achieve this, the implant comprises a tubular base body, open on its end faces and consisting of at least one biodegradable material, said base body having an in vivo, location-dependent first degradation characteristic D1(x), in addition to a coating that covers the base body completely or in sections and consists of a biodegradable material, said coating having an in vivo, location-dependent second degradation characteristic D2(x). According to the invention, a location-dependent cumulative degradation characteristic D(x) in one location (x) is made up of the sum of the respective degradation characteristics D1(x) and D2(x) in said location (x) and the location-dependent cumulative degradation characteristic D(x) is predetermined by a variation of the second degradation characteristic D2(x) in such a way that the degradation in the given location (x) of the implant takes place over a predeterminable time period at a predeterminable degradation rate.
Description
Degradationssteuerung biodegradierbarer Implantate durch Beschichtung Degradation control of biodegradable implants by coating
Die Erfindung betrifft ein zumindest weitestgehend biodegradierbares endo- vaskuläres Implantat, dessen in vivo Degradation steuerbar ist.The invention relates to an at least largely biodegradable endovascular implant whose in vivo degradation can be controlled.
In der Medizintechnik hat sich in den letzten Jahren die Implantation von endovaskulären Stützsystemen als eine der erfolgversprechenden therapeu- tischen Maßnahmen zur Behandlung von Gefäßerkrankungen etabliert. So hat z.B. in der interventionellen Therapie der stabilen Angina pectoris bei koronarer Herzkrankheit die Einführung der Stents zu einer deutlichen Reduktion der Rate an Restenosen und damit zu besseren Langzeitresultaten geführt. Ursächlich für den Nutzen der Stent-Implantation ist der höhere pri- märe Lumengewinn. Durch den Einsatz von Stents kann zwar ein für den Therapieerfolg primär notwendiger optimaler Gefäßquerschnitt erreicht werden, allerdings initiiert die dauerhafte Anwesenheit eines derartigen Fremdkörpers eine Kaskade von mikrobiologischen Prozessen, die zu einem allmählichen Zuwachsen des Stents führen können. Ein Ansatzpunkt zur Lö-
sung der Problematik besteht daher darin, den Stent aus einem biodegradierbaren Werkstoff zu fertigen.In medical technology, the implantation of endovascular support systems has become one of the most promising therapeutic measures for the treatment of vascular diseases. For example, in interventional therapy for stable angina pectoris in coronary artery disease, the introduction of stents has led to a significant reduction in the rate of restenosis and thus to better long-term results. The reason for the benefit of stent implantation is the higher primary lumen gain. The use of stents can achieve an optimal vascular cross-section that is essential for the success of the therapy, but the permanent presence of such a foreign body initiates a cascade of microbiological processes that can lead to a gradual growth of the stent. A starting point for The solution to the problem is therefore to manufacture the stent from a biodegradable material.
Zur Realisation derartiger biodegradierbarer Implantate stehen dem Medizintechniker verschiedenartigste Werkstoffe zur Verfügung. Neben zahlreichen Polymeren, die häufig zur besseren Biokompatibilität natürlichen Ursprungs oder zumindest an natürliche Verbindungen angelehnt sind, werden in jüngster Zeit metallische Werkstoffe, mit ihren für die Implantate wesentlichen günstigeren mechanischen Eigenschaften favorisiert. Besondere Beachtung finden in diesem Zusammenhang magnesium-, eisen- und wolframhaltige Werkstoffe. Eines der Probleme, die es bei der praktischen Umsetzung biodegradierbarer Implantate zu lösen gilt, ist das Degradationscharakteristik des Implantats in vivo. So soll zum einen sichergestellt sein, dass die Funktionalität des Implantats mindestens über den für die Therapiezwecke notwendigen Zeitraum aufrecht erhalten wird. Zum anderen sollte die Degrada- tion über das gesamte Implantat möglichst gleichmäßig verlaufen, damit nicht unkontrolliert Fragmente freigesetzt werden, die zu Ausgangspunkt ungewünschter Komplikationen sein können. Bekannte biodegradierbare Stents zeigen keine lokal abgestimmte Degradationscharakteristik.A wide variety of materials are available to the medical technician for realizing such biodegradable implants. In addition to numerous polymers, which are often based on natural origin for better biocompatibility or at least based on natural compounds, metallic materials, with their mechanical properties which are significantly more favorable for the implants, have recently been favored. In this context, particular attention is paid to materials containing magnesium, iron and tungsten. One of the problems to be solved in the practical implementation of biodegradable implants is the degradation characteristic of the implant in vivo. On the one hand, this is to ensure that the functionality of the implant is maintained at least for the period of time necessary for the therapeutic purposes. On the other hand, the degrada- tion should run as evenly as possible over the entire implant, so that fragments are not released in an uncontrolled manner, which can be the starting point for undesired complications. Known biodegradable stents do not show a locally coordinated degradation characteristic.
Ausgehend vom Stand der Technik stellt sich damit die Aufgabe, ein biode- gradierbares Implantat bereitzustellen, dessen Degradation ortsabhängig optimiert werden kann.Based on the state of the art, the task is to provide a biodegradable implant whose degradation can be optimized depending on the location.
Diese Aufgabe wird durch das endovaskuläre Implantat mit den in Anspruch 1 genannten Merkmalen gelöst. Dadurch, dass das ImplantatThis object is achieved by the endovascular implant with the features mentioned in claim 1. Because of the implant
- einen rohrförmigen, an seinen Stirnseiten offenen Grundkör- per aus zumindest einem biodegradierbaren Werkstoff, wobei der Grundkörper eine in vivo eine ortsabhängige erste Degradationscharakteristik D-ι(x) besitzt, sowie
- eine den Grundkörper vollständig oder gegebenenfalls nur bereichsweise bedeckenden Beschichtung aus zumindest einem biodegradierbaren Werkstoff, wobei die Beschichtung eine in vivo eine ortsabhängige zweite Degradationscharakteristik D2(x) besitzt, unda tubular basic body made of at least one biodegradable material on its end faces, the basic body having a location-dependent first degradation characteristic D-ι (x) in vivo, and a coating of at least one biodegradable material that completely or possibly only partially covers the base body, the coating having a location-dependent second degradation characteristic D 2 (x) in vivo, and
- wobei sich an einem Ort (x) eine ortsabhängige kumulierte Degradationscharakteristik D(x) aus der Summe der jeweils an dem genannten Ort (x) bestehenden Degradationscharak- teristika D-ι(x) und D2(x) ergibt und die ortsabhängige kumu- lierte Degradationscharakteristik D(x) so durch Variation der zweiten Degradationscharakteristik D2(x) vorgegeben ist, dass die Degradation an dem genannten Ort (x) des Implantats in einem vorgebbaren Zeitintervall mit einem vorgebbaren Degradationsverlauf stattfindet,- Where at a location (x) a location-dependent cumulative degradation characteristic D (x) results from the sum of the degradation characteristics D-ι (x) and D 2 (x) existing at the location (x) in each case and the location-dependent accumulation the degradation characteristic D (x) is predetermined by varying the second degradation characteristic D 2 (x) in such a way that the degradation takes place at the specified location (x) of the implant in a predeterminable time interval with a predeterminable degradation curve,
kann die Degradationscharakteristik des gesamten Stents örtlich in der gewünschten Weise optimiert werden.the degradation characteristic of the entire stent can be locally optimized in the desired manner.
Die Erfindung schließt demnach den Gedanken ein, dass die Degradation der Grundkörper des Implantats durch geeignete Beschichtung - im Extremfall aber auch durch Weglassen der Beschichtung -so angepasst wird, dass die an einem Ort bestehende Degradationscharakteristik einen Abbau des Implantats in einem vorgebbaren Zeitintervall und mit einem vorgebbaren Degradationsverlauf ermöglicht.The invention accordingly includes the idea that the degradation of the base body of the implant is adapted by a suitable coating - in extreme cases, however, also by omitting the coating - so that the degradation characteristic existing at one location degrades the implant in a predefinable time interval and with a predeterminable course of degradation enables.
Unter "Biodegradation" werden hydrolytische, enzymatische und andere stoffwechselbedingte Abbauprozesse im lebendem Organismus verstanden, die zu einer allmählichen Auflösung zumindest großer Teile des Implantats führen. Synonym wird häufig der Begriff Biokorrosion verwendet. Der Begriff Bioresorption umfasst zusätzlich die anschließende Resorption der Abbauprodukte.
Für den Grundkörper geeignete Werkstoffe können beispielsweise polymerer oder metallischer Natur sein. Der Grundkörper kann auch aus mehreren Werkstoffen bestehen. Gemeinsames Merkmal dieser Werkstoffe ist ihre Biodegradierbarkeit. Beispiele für geeignete polymere Verbindungen sind zunächst Polymere aus der Gruppe Cellulose, Kollagen, Albumin, Casein, Polysaccharide (PSAC), Polylactid (PLA) , Poly-L-Iactid (PLLA), Polyglykol (PGA), Poly-D,L-lactid-co-glycolid (PDLLA/PGA), Polyhydroxybuttersäure (PHB), Polyhydroxyvaleriansäure (PHV), Polyalkylcarbonate, Polyorthoester, Polyethylenterephthalat (PET), Polymalonsäure (PML), Polyanhydride, Po- lyphosphazene, Polyaminosäuren und deren Copolymere sowie Hyaluron- säure. Die Polymere können je nach den gewünschten Eigenschaften des Beschichtungssystems in Reinform, in derivatisierter Form, in Form von Blends oder als Copolymere vorliegen."Biodegradation" means hydrolytic, enzymatic and other metabolic degradation processes in the living organism, which lead to a gradual dissolution of at least large parts of the implant. The term biocorrosion is often used synonymously. The term bioresorption also includes the subsequent absorption of the degradation products. Materials suitable for the base body can be, for example, polymeric or metallic in nature. The base body can also consist of several materials. A common feature of these materials is their biodegradability. Examples of suitable polymeric compounds are first of all polymers from the group cellulose, collagen, albumin, casein, polysaccharides (PSAC), polylactide (PLA), poly-L-lactide (PLLA), polyglycol (PGA), poly-D, L-lactide -co-glycolide (PDLLA / PGA), polyhydroxybutyric acid (PHB), polyhydroxyvaleric acid (PHV), polyalkylcarbonates, polyorthoesters, polyethylene terephthalate (PET), polymalonic acid (PML), polyanhydrides, polyphosphazenes, polyamino acids and their copolymers and hyaluronic acid. Depending on the desired properties of the coating system, the polymers can be in pure form, in derivatized form, in the form of blends or as copolymers.
Metallische biodegradierbare Werkstoffe basieren auf Legierungen von Magnesium, Eisen oder Wolfram. Gerade die biodegradierbaren Magnesiumlegierungen zeigen ein ausgesprochen günstiges Degradationsverhalten, lassen sich gut verarbeiten und zeigen keine oder allenfalls geringe Toxizität, sondern scheinen vielmehr sogar den Heilungsprozess positiv zu stimulieren.Metallic biodegradable materials are based on alloys of magnesium, iron or tungsten. The biodegradable magnesium alloys in particular show extremely favorable degradation behavior, are easy to process and show little or no toxicity, but rather seem to stimulate the healing process positively.
Der Grundkörper eines Stents setzt sich in der Regel aus einer Vielzahl von in einem bestimmten Muster angeordneten Stützelementen zusammen. Anwendungsbedingt - sei es z.B. bei der Dilatation oder sei es durch die Obstruktion des umgebenden Gewebes - werden die Stützelemente mit unterschiedlichen mechanischen Kräften belastet. Dies kann bei biodegradierba- ren Materialien unter anderem da zuführen, dass die unter Stress stehenden oder die zumindest zeitweise hohen mechanischen Belastungen ausgesetzten Bereiche der Stützelemente schneller abgebaut werden, als weniger belastete Bereiche. Unter anderem erlaubt es die vorliegende Erfindung diesem Phänomen entgegen zu wirken.
Auch die Beschichtung kann von den vorgenannten biodegradierbaren Werkstoffen gebildet werden. Selbstverständlich können auch mehrere verschiedene Werkstoffe in einem Implantat Einsatz finden, z.B. an unterschiedlichen Orten oder als Mehrschichtsysteme an einem bestimmten Ort des Implantats.The basic body of a stent is generally composed of a large number of support elements arranged in a specific pattern. Depending on the application - be it, for example, during dilatation or due to the obstruction of the surrounding tissue - the support elements are loaded with different mechanical forces. In the case of biodegradable materials, this can mean, among other things, that the areas of the support elements which are under stress or which are at least temporarily exposed to high mechanical loads are broken down more quickly than areas which are less loaded. Among other things, the present invention allows to counteract this phenomenon. The coating can also be formed from the aforementioned biodegradable materials. Of course, several different materials can also be used in one implant, for example at different locations or as multi-layer systems at a specific location of the implant.
Unter "ortsabhängiger Degradationscharakteristik" im erfindungsgemäßen Sinne wird der zeitliche Verlauf (Degradationsverlauf) und das Zeitintervall in dem dieser Abbau stattfindet verstanden. Als erster Bezugspunkt für das Zeitintervall dient der Einfachheit halber der Zeitpunkt der Implantation selbst. Natürlich können auch andere Zeitpunkte herangezogen werden. Ein Ende des Zeitintervalls wird im Sinne der Erfindung als der Zeitpunkt verstanden, in dem mindestens 80 Gew.% der biodegradierbaren Implantatsmasse abgebaut sind oder die mechanische Integrität des Implantats nicht mehr besteht, d.h. das Implantat kann seine Stützfunktion nicht mehr wahr- nehmen. Der Degradationsverlauf gibt an, mit welcher Geschwindigkeit die Degradation zu bestimmten Zeitpunkten im Zeitintervall abläuft. So kann beispielsweise durch entsprechende erfindungsgemäße Modifikationen erreicht werden, dass die Degradation des Implantats in den ersten beiden Wochen nach der Implantation durch geeignete Beschichtung stark verzö- gert wird und erst nach Abbau der Beschichtung durch die schnellere Degradation des Grundkörpers zügig voranschreitet. Um die Abbauprozesse geeignet ablaufen zu lassen, ist es daher notwendig, zum einen die Degradationscharakteristik des Grundkörpers an dem bestimmten Ort des Implantats zu kennen und zum anderen durch Aufbringung einer Beschichtung mit einer zweiten Degradationscharakteristik das Gesamtabbauverhalten des Implantats an diesem Ort zu beeinflussen. Die Degradationscharakteristika des Grundkörpers und der Beschichtung lassen sich mit Hilfe von in vitro Untersuchungen vorab abschätzen."Location-dependent degradation characteristic" in the sense of the invention means the time course (degradation course) and the time interval in which this degradation takes place. For the sake of simplicity, the first point of reference for the time interval is the time of the implantation itself. Of course, other times can also be used. An end of the time interval is understood in the sense of the invention as the point in time at which at least 80% by weight of the biodegradable implant mass has been broken down or the mechanical integrity of the implant no longer exists, i.e. the implant can no longer perform its supporting function. The degradation curve indicates the speed at which the degradation takes place at specific times in the time interval. For example, by means of appropriate modifications according to the invention, the degradation of the implant is greatly delayed in the first two weeks after the implantation by means of a suitable coating and only progresses rapidly after the coating has been removed due to the faster degradation of the base body. In order to allow the degradation processes to take place in a suitable manner, it is therefore necessary on the one hand to know the degradation characteristics of the base body at the specific location of the implant and on the other hand to influence the overall degradation behavior of the implant at this location by applying a coating with a second degradation characteristic. The degradation characteristics of the base body and the coating can be estimated in advance using in vitro tests.
Vorzugsweise wird die Degradationscharakteristik der Beschichtung durch - Variation seiner morphologischen Struktur,
- stoffliche Modifikation des Werkstoffs und/oderThe degradation characteristic of the coating is preferably determined by - varying its morphological structure, - material modification of the material and / or
- Anpassung einer Schichtdicke der Beschichtung- Adjustment of a layer thickness of the coating
erreicht.reached.
Durch Anpassung der Schichtdicke der Beschichtung kann die ortsabhängi- ge Degradationscharakteristik des Implantats beeinflusst werden. Auch hier steht im Vordergrund, die Degradation an einem bestimmten Ort zeitlich und in ihrem Umfang zu steuern. So ist es je nach medizinischer notwendig, die Stützfunktion des Implantats über einen bestimmten Zeitraum, gegebenenfalls auch ortabhängig, aufrecht zu erhalten. Mit einer erhöhten Schichtdicke kann der Abbau des Implantats an einem bestimmten Ort verzögert werden.The location-dependent degradation characteristics of the implant can be influenced by adjusting the layer thickness of the coating. Here too, the focus is on controlling the degradation at a specific location in terms of time and scope. Depending on the medical requirements, it may be necessary to maintain the support function of the implant over a certain period of time, possibly also depending on the location. With an increased layer thickness, the removal of the implant at a certain location can be delayed.
Unter 'morphologischen Strukturen' im erfindungsgemäßem Sinne wird die Konformation und Aggregation der die Beschichtung bildenden Verbindungen, insbesondere Polymere, verstanden. Dies beinhaltet den Typ der molekularen Ordnungsstruktur, die Porosität, die Oberflächenbeschaffenheit und andere intrinsische Eigenschaften des Trägers, die ein Degradationsverhalten des der Beschichtung zugrunde liegenden biodegradierbaren Werkstoffs beeinflussen. Molekulare Ordnungsstrukturen umfassen amorphe, (teil- )kristalline oder mesomorphe Polymerphasen, die in Abhängigkeit von dem jeweils eingesetzten Herstellungsverfahren, Beschichtungsverfahren und Umweltbedingungen beeinflussbar bzw. erzeugbar sind. Durch gezielte Variation des Herstellungs- und Beschichtungsverfahrens kann die Porosität und die Oberflächenbeschaffenheit der Beschichtung beeinflusst werden. Generell gilt, dass mit zunehmender Porosität der Beschichtung die Degradation schneller abläuft. Amorphe Strukturen zeigen gegenüber (teil-)kristallinen Strukturen ähnliche Effekte.“Morphological structures” in the sense of the invention mean the conformation and aggregation of the compounds forming the coating, in particular polymers. This includes the type of molecular order structure, the porosity, the surface quality and other intrinsic properties of the carrier, which influence a degradation behavior of the biodegradable material on which the coating is based. Molecular order structures include amorphous, (partially) crystalline or mesomorphic polymer phases, which can be influenced or generated depending on the manufacturing process, coating process and environmental conditions used. The porosity and surface quality of the coating can be influenced by targeted variation of the manufacturing and coating process. In general, the degradation takes place more quickly with increasing porosity of the coating. Amorphous structures show similar effects to (partially) crystalline structures.
Unter 'stofflicher Modifizierung' im Sinne der Erfindung wird sowohl eine De- rivatisierung des biodegradierbaren Werkstoffs, insbesondere der Polymere, als auch die Zugabe von Füll- und Zusatzstoffen (Additiven) zum Zwecke der
Beeinflussung der Degradationscharakteristik verstanden. Die Derivatisie- rung umfasst beispielsweise Maßnahmen wie eine Vernetzung oder ein Ersetzen von reaktiven Funktionalitäten in diesen Werkstoffen. So ist beispielsweise hinlänglich bekannt, dass mit Erhöhung eines Vernetzungsgra- des polymere Werkstoffe wie Hyaluronsäure langsamer abgebaut werden. Auch diese Maßnahmen müssen durch etablierte in vitro Untersuchungen zunächst quantitativ erfasst werden, um eine Abschätzung der Degradationscharakteristik für das in vivo Verhalten abgeben zu können.'Material modification' in the sense of the invention includes both a derivatization of the biodegradable material, in particular the polymers, and the addition of fillers and additives (additives) for the purpose of Understanding of the degradation characteristics understood. The derivatization includes, for example, measures such as networking or replacing reactive functionalities in these materials. It is well known, for example, that polymeric materials such as hyaluronic acid are broken down more slowly when increasing the degree of crosslinking. These measures must first be recorded quantitatively by means of established in vitro investigations in order to be able to provide an estimate of the degradation characteristics for the in vivo behavior.
Die ortabhängige Degradationscharakteristik des Implantats wird vorzugs- weise in Abhängigkeit von den in der Applikation zu erwartenden pathophy- siologischen und/oder rheologischen Verhältnissen vorgegeben. Die pa- thophysiologischen Aspekte tragen dem Umstand Rechnung, dass in der Regel der Stent derart im Gefäß platziert wird, dass er mittig an der Läsion anliegt, d. h. das anliegende Gewebe an den Enden und im mittleren Bereich des Stents unterschiedlicher Beschaffenheit ist und damit die Stützfunktion des Implantats zur Optimierung des Heilprozesses unterschiedlich lange aufrecht erhalten werden braucht. Weiterhin sind die auf das Implantat wirkenden Gewebswiderstände aufgrund der pathophysiologischen Veränderung ungleich, was dazu führen kann, dass an Orten stärkeren Widerstands eine durch den resultierenden mechanischen Stress beschleunigter Abbau stattfinden würde.The location-dependent degradation characteristic of the implant is preferably specified as a function of the pathophysiological and / or rheological conditions to be expected in the application. The pathophysiological aspects take into account the fact that the stent is usually placed in the vessel in such a way that it lies in the center of the lesion, ie. H. the adjacent tissue at the ends and in the middle area of the stent is of different nature and therefore the supporting function of the implant needs to be maintained for different times to optimize the healing process. Furthermore, the tissue resistances acting on the implant are unequal due to the pathophysiological change, which can lead to an accelerated degradation due to the resulting mechanical stress in places of greater resistance.
Rheologische Aspekte tragen wiederum dem Umstand Rechnung, dass die Strömungsverhältnisse, insbesondere im Bereich der Enden und in mittleren Abschnitten des Stents unterschiedlich sind. So kann es an den Enden des Stents zur einem beschleunigten Abbau des Implantats aufgrund der stärkeren Strömung kommen. Rheologische Parameter können insbesondere durch Vorgabe des Stentdesigns stark variieren und müssen im Einzelfall bestimmt werden. Durch Berücksichtigung der beiden genannten Parameter kann eine für die angestrebte Therapie optimale Degradation über die ge- samte Dimension des Stents sicher gestellt werden.
Die Erfindung wird nachfolgend anhand von Ausführungsbeispielen und in der zugehörigen Zeichnung näher erläutert. Es zeigen:Rheological aspects in turn take into account the fact that the flow conditions, in particular in the area of the ends and in middle sections of the stent, are different. This can lead to accelerated dismantling of the implant at the ends of the stent due to the stronger flow. Rheological parameters can vary widely, particularly by specifying the stent design, and must be determined in individual cases. By taking the two parameters mentioned into account, optimal degradation over the entire dimension of the stent can be ensured for the desired therapy. The invention is explained in more detail below on the basis of exemplary embodiments and in the associated drawing. Show it:
Fig. 1 einen Stent mit einem rohrförmigen, an seinen Stirnseiten offenen Grundkörper, dessen Umlaufswandung mit einem Beschich- tungssystem bedeckt ist;1 shows a stent with a tubular base body which is open on its end faces and the peripheral wall of which is covered with a coating system;
Fig. 2a,2b einen schematischen Querschnitt entlang einer Längsachse eines Stents zur Illustration der Beschichtung nach einer ersten Variante und2a, 2b a schematic cross section along a longitudinal axis of a stent to illustrate the coating according to a first variant and
Fig. 3a,3b einen schematischen Querschnitt entlang einer Längsachse ei- nes Stents zur Illustration de Beschichtung nach einer zweiten Variante.3a, 3b show a schematic cross section along a longitudinal axis of a stent to illustrate the coating according to a second variant.
Die Fig. 1 zeigt stark schematisiert eine perspektivische Seitenansicht auf einen Stent 10 mit einem rohrförmigen, an seinen Enden 12.1 , 12.2 offenen Grundkörper 14. Eine sich radial um eine Längsachse L erstreckende Um- laufswandung 16 des Grundkörpers 14 besteht aus in axialer Richtung nebeneinander angeordneten Segmenten, die sich wiederum aus einer Vielzahl von in einem bestimmten Muster angeordneten Stützelementen zusammensetzen. Die einzelnen Segmente werden über Verbindungsstege miteinander verbunden und ergeben zusammengefasst den Grundkörper 14. In der Fig. 1 wurde bewusst auf die Darstellung eines bestimmten Stentdesigns verzichtet, da dies zu Zwecken der Darstellung der Erfindung nicht notwendig ist und zudem für jedes Stentdesign eine individuelle Anpassung auch einer Beschichtung an die jeweils gegebenen geometrischen Faktoren und anderen Parameter notwendig ist. Stentdesigns unterschiedlichster Ausbildung sind in sehr großer Vielfalt aus dem Stand der Technik bekannt und werden hier nicht näher erläutert. Festzuhalten bleibt lediglich, dass alle gängigen Stents 10 ein wie auch immer geartetes rohrförmiges Grundgerüst 14 aufweisen, das eine umlaufende Umlaufswandung 16 umfasst. Im folgenden wird daher eine äußere Mantelfläche 18 der Umlaufswandung 16 mit der sich
ggf. aus einer Vielzahl von vorhandenen Stützelementen gebildeten äußeren Umlauffläche dieser Stützelemente gleichgesetzt.1 shows a highly schematic perspective side view of a stent 10 with a tubular base body 14 that is open at its ends 12.1, 12.2. A circumferential wall 16 of the base body 14 that extends radially about a longitudinal axis L consists of axially arranged side by side Segments, which in turn are composed of a plurality of support elements arranged in a specific pattern. The individual segments are connected to one another via connecting webs and, in summary, result in the base body 14. In FIG. 1, the depiction of a specific stent design was deliberately omitted, since this is not necessary for the purposes of illustrating the invention and, moreover, an individual adaptation for each stent design a coating to the given geometric factors and other parameters is necessary. A wide variety of stent designs are known from the prior art in a very large variety and are not explained in more detail here. All that remains to be said is that all common stents 10 have a tubular basic structure 14 of whatever kind, which comprises a circumferential peripheral wall 16. In the following, therefore, an outer circumferential surface 18 of the peripheral wall 16 with the possibly made up of a plurality of existing support elements, the outer circumferential surface of these support elements equated.
Beispielhaft kann der Stent 10 aus einer biodegradierbaren Magnesiumlegierung, insbesondere WE43, geformt sein. Infolge des Übergangs und seinem nicht expandierte Zustand in seinen expandierten Zustand während der Dilatation des Stents 10 im Körper werden die einzelnen Stützelemente, insbesondere an ihren Gelenkpunkten unterschiedlich stark mechanisch beansprucht. Dies kann dazu führen, dass sich das metallische Gefüge z. B. aufgrund von Mikrorissbildungen verändert. In der Regel wird an Punkten, an denen ein besonders hoher mechanischer Stress auftritt, eine besonders rasche Degradation erfolgen. Weiterhin sind die einzelnen Stützelemente in ihren Abmessungen je nach vorliegendem Stentdesign unterschiedlich dimensioniert. Es versteht sich von selbst, das Stützelemente mit einem größeren Umfang langsamer abgebaut werden, als entsprechend filigrane Strukturen im Grundgerüst. Zielsetzung für ein zufriedenstellendes Abbauverhalten des Implantats sollte daher sein, eine Art Faktbildung aufgrund dieser unterschiedlichen Degradationscharakteristik entgegen zu wirken. Die ortsabhängige Degradationscharakteristik des Grundkörpers wird im folgenden mit dem Kürzel D^x) ausgedrückt.For example, the stent 10 can be formed from a biodegradable magnesium alloy, in particular WE43. As a result of the transition and its unexpanded state into its expanded state during the dilation of the stent 10 in the body, the individual support elements are subjected to different mechanical loads, in particular at their articulation points. This can lead to the fact that the metallic structure z. B. changed due to micro-cracking. As a rule, a particularly rapid degradation will take place at points where a particularly high mechanical stress occurs. Furthermore, the dimensions of the individual support elements are dimensioned differently depending on the stent design present. It goes without saying that supporting elements with a larger circumference are dismantled more slowly than correspondingly filigree structures in the basic structure. The objective for a satisfactory degradation behavior of the implant should therefore be to counteract a kind of fact formation due to these different degradation characteristics. The location-dependent degradation characteristic of the base body is expressed in the following with the abbreviation D ^ x).
Der Stent 10 der Fig. 1 zeigt in stark schematisierter Weise ein Beschichtung 26, bei der mehrere Abschnitte 20.1, 20.2, 22.1 , 22.2, 24 der äußeren Mantelfläche 18 der Umlaufswandung 16 aus in ihrer Degradationscharakteristik D2(x) divergierenden biodegradierbaren Werkstoffen geformt sind. Beispielhaft für einen geeigneten Werkstoff für die Beschichtung 26 wird hier ein Polymer auf Basis von Hyaluronsäure angegeben. Hyaluronsäure zeigt nicht nur ein günstiges Abbauverhalten, sondern lässt sich auch besonders einfach verarbeiten und besitzt zusätzlich positive physiologische Effekte. Die Degradationscharakteristik D2(x) lässt sich beispielsweise derart beeinflussen, dass ein bestimmter Vernetzungsgrad durch Umsetzung mit Glutaral- dehyd vorgegeben wird. Je höher der Vernetzungsgrad ist, umso langsamer wird sich die Hyaluronsäure zersetzen.
Zur Aufbringung einer Beschichtung auf den Stent sind zahlreiche Verfahren entwickelt worden, wie beispielsweise Rotationszerstäubungsverfahren, Tauchverfahren und Sprühverfahren. Die Beschichtung bedeckt zumindest bereichsweise die Wandung bzw. die einzelnen die Stützstruktur ausbilden- den Streben des Stents.The stent 10 of FIG. 1 shows in a highly schematic manner a coating 26 in which a plurality of sections 20.1, 20.2, 22.1, 22.2, 24 of the outer circumferential surface 18 of the peripheral wall 16 are formed from biodegradable materials which differ in their degradation characteristics D 2 (x) , A polymer based on hyaluronic acid is given here as an example of a suitable material for the coating 26. Hyaluronic acid not only shows favorable degradation behavior, but is also particularly easy to process and also has positive physiological effects. The degradation characteristic D 2 (x) can be influenced, for example, in such a way that a certain degree of crosslinking is predetermined by reaction with glutaraldehyde. The higher the degree of crosslinking, the slower the hyaluronic acid will decompose. Numerous processes have been developed for applying a coating to the stent, such as, for example, rotary atomization processes, immersion processes and spray processes. The coating at least in regions covers the wall or the individual struts of the stent that form the support structure.
In den einzelnen Abschnitten 20.1 , 20.1 , 20.2, 22.1 , 22.2, 24 unterscheidet sich die Degradationscharakteristik D2(x). So kann - wie im einzelnen noch näher erläutert wird - vorgesehen sein, dass die Abschnitte 20.1 und 20.2 an den Enden 12.1 , 12.2 des Stents 10 eine beschleunigte Degradationscharak- teristik D2(x) zeigen, wohingegen die mehr in der Mitte angeordneten Abschnitten 22.1 , 22.2 und 24 langsamer degradieren. Dies hat wiederum zur Folge, dass bei vorausgesetzter gleicher Degradationscharakteristik D^x) des Grundkörpers ein Abbau an den Ende des Stents 10 schneller abläuft. Dies ist insofern sinnvoll, als dass die zu behandelnde Läsion bei richtiger Applikation des Stents 10 mittig gegenüber von den Abschnitten 22.1 , 22.2 und 24 liegen sollte. Demnach addieren sich die Degenerationscharakteristi- ka D-](x) und D2(x) zu einer kumulierten ortsabhängigen Degenerationscharakteristik für das Implantat.The degradation characteristic D 2 (x) differs in the individual sections 20.1, 20.1, 20.2, 22.1, 22.2, 24. Thus, as will be explained in more detail below, it can be provided that the sections 20.1 and 20.2 at the ends 12.1, 12.2 of the stent 10 show an accelerated degradation characteristic D 2 (x), whereas the sections 22.1 arranged more in the middle , 22.2 and 24 degrade more slowly. This in turn has the consequence that, given the same degradation characteristics D ^ x) of the base body, degradation at the end of the stent 10 proceeds faster. This makes sense insofar as the lesion to be treated should be centered opposite sections 22.1, 22.2 and 24 if the stent 10 is applied correctly. Accordingly, the degeneration characteristics D -] (x) and D 2 (x) add up to a cumulative location-dependent degeneration characteristic for the implant.
Die Fig. 2a, 2b, 3a, 3b, 4 und 5 zeigen - in jeweils stark schematisierter Wei- se - einen Schnitt entlang der Längsachse L des Stents 10 und zwar jeweils nur einen der sich dabei ergebenen zwei Schnitte durch die Umlaufswandung 16. Zuvor wird jedoch kurz auf die zugrundeliegenden Prinzipien bei der Ausgestaltung der Beschichtung eingegangen.2a, 2b, 3a, 3b, 4 and 5 show - in each case in a highly schematic manner - a section along the longitudinal axis L of the stent 10 and in each case only one of the two sections resulting therefrom through the peripheral wall 16 however, the principles underlying the design of the coating are briefly discussed.
Eine Degradationscharakteristik D2(x) einer Beschichtung an einem be- stimmten Ort (x) hängt im wesentlichen von Faktoren wieA degradation characteristic D 2 (x) of a coating at a specific location (x) essentially depends on factors such as
- einer Schichtdicke der Beschichtung,a layer thickness of the coating,
- einer morphologischen Struktur der Beschichtung und
einer stofflichen Modifizierung der Beschichtung.- a morphological structure of the coating and a material modification of the coating.
Eine Erhöhung der Schichtdicke des Beschichtung verlängert die Dauer der Degradation. Es bestehen fundierte theoretische als auch praktische Modellsysteme, die eine Abschätzung des späteren in vivo Verhaltens ermöglichen.Increasing the layer thickness of the coating extends the duration of the degradation. There are well-founded theoretical as well as practical model systems that allow an assessment of the later in vivo behavior.
Schließlich hängt die lokale Degradationscharakteristik D2(x) von der morphologischen Struktur und stofflichen Modifikationen der Beschichtung ab. So kann insbesondere die Porosität der Beschichtung variiert werden, wobei eine erhöhte Porosität zu einer beschleunigten Degradation führt. Zur stofflichen Modifikation kann beispielsweise vorgesehen sein, Additive den Trä- gern beizumengen, die den enzymatischen Abbau verzögern. Ebenso kann eine Verzögerung des Abbaus bei Beschichtungen auf Polysaccharidbasis durch Erhöhung eines Vernetzungsgrades erfolgen.Finally, the local degradation characteristic D 2 (x) depends on the morphological structure and material modifications of the coating. In particular, the porosity of the coating can be varied, an increased porosity leading to accelerated degradation. For the material modification, it can be provided, for example, to add additives to the carriers which delay the enzymatic degradation. The degradation of coatings based on polysaccharide can also be delayed by increasing the degree of crosslinking.
Zusammenfassend ist daher festzuhalten, dass durch geeignete Vorgabe der Degradationscharakteristik D2(x) der Beschichtung 26 die kumulierte Degradationscharakteristik D(x) vorgebbar ist, sofern die Degradationscharakteristik D-ι(x) des Grundkörpers bekannt ist.To summarize, it should therefore be stated that the cumulative degradation characteristic D (x) of the coating 26 can be predetermined by suitable specification of the degradation characteristic D 2 (x) of the coating 26, provided the degradation characteristic D-ι (x) of the base body is known.
Eine Anpassung der einzelnen Abschnitte der Beschichtung des Stents wird dabei auch in Abhängigkeit von den in der Applikation zu erwartenden pathophysiologischen und Theologischen Verhältnissen durchgeführt.The individual sections of the coating of the stent are also adapted depending on the pathophysiological and theological conditions to be expected in the application.
Unter den pathophysiologischen Verhältnissen wird hier die durch Krankheit in dem gestenteten Gefäßbereich veränderte Gewebsstruktur verstanden. In der Regel wird der Stent so platziert, dass die Läsion, d. h. bei koronaren Applikationen in der Regel die fibroatheromatöse Plaque, etwa im mittleren Bereich des Stents liegt. Mit anderen Worten, die anliegenden Gewebsstruk- turen divergieren in axialer Richtung über die Länge des Stents und damit ist auch unter Umständen lokal eine andere Therapie indiziert.
Unter den Theologischen Verhältnissen werden die Strömungsverhältnisse verstanden, wie sie sich nach Implantation des Stents in den einzelnen Längsabschnitten des Stents einstellen. Erfahrungsgemäß hat sich gezeigt, dass die Enden des Stents stärker als die mittleren Bereiche des Stents um- strömt werden. Dies kann zur Folge haben, dass eine Degradation des Trägers in den Endbereichen erhöht ist.The pathophysiological conditions here mean the tissue structure changed by disease in the stented vascular area. As a rule, the stent is placed in such a way that the lesion, ie the fibroatheromatous plaque in coronary applications, is approximately in the central area of the stent. In other words, the adjoining tissue structures diverge in the axial direction over the length of the stent, and another therapy may also be indicated locally under certain circumstances. The theological conditions are understood to mean the flow conditions as they occur in the individual longitudinal sections of the stent after implantation of the stent. Experience has shown that there is a greater flow around the ends of the stent than the central regions of the stent. This can result in increased degradation of the carrier in the end regions.
Eine zu schnelle Degradation kann den Heilungsprozess nicht unterstützen. Durch gezielte Vorgabe des Zeitintervalls, in dem an einem bestimmten Ort (x) der Abbau erfolgen soll, kann einer solchen Fehlentwicklung vorgebeugt werden.Degradation that is too fast cannot support the healing process. Such an undesirable development can be prevented by specifically specifying the time interval in which mining is to take place at a specific location (x).
Als biodegradierbare Werkstoffe für die Beschichtung können u.a. alle poly- meren Matrizes synthetischer Natur oder natürlichem Ursprungs im erfindungsgemäßen Sinne eingesetzt werden, die aufgrund enzymatischer oder hydrolytischer Prozesse im lebenden Organismus abgebaut werden. Insbe- sondere können dazu Polymere aus der Gruppe Cellulose, Kollagen, Albumin, Casein, Polysaccharide (PSAC), Polylactid (PLA) , Poly-L-Iactid (PLLA), Polyglykol (PGA), Poly-D,L-lactid-co-glycolid (PDLLA/PGA), Polyhydroxybut- tersäure (PHB), Polyhydroxyvaleriansäure (PHV), Polyalkylcarbonate, Poly- orthoester, Polyethylenterephthalat (PET), Polymalonsäure (PML), Polyan- hydride, Polyphosphazene, Polyaminosäuren und deren Copolymere sowie Hyaluronsäure eingesetzt werden. Die Polymere können je nach den gewünschten Eigenschaften des Beschichtungssystems in Reinform, in deriva- tisierter Form, in Form von Blends oder als Copolymere aufgebracht werden.Biodegradable materials for the coating can include all polymeric matrices of synthetic nature or of natural origin are used in the sense of the invention, which are degraded in the living organism due to enzymatic or hydrolytic processes. In particular, polymers from the group cellulose, collagen, albumin, casein, polysaccharides (PSAC), polylactide (PLA), poly-L-lactide (PLLA), polyglycol (PGA), poly-D, L-lactide-co -glycolide (PDLLA / PGA), polyhydroxybutyric acid (PHB), polyhydroxyvaleric acid (PHV), polyalkylcarbonates, polyorthoesters, polyethylene terephthalate (PET), polymalonic acid (PML), polyanhydrides, polyphosphazenes, polyamino acids and their copolymers and hyaluronic acid are used , Depending on the desired properties of the coating system, the polymers can be applied in pure form, in derivatized form, in the form of blends or as copolymers.
Sofern gewünscht können pharmakologisch wirksame Substanzen, die ins- besondere zur Behandlung der Folgen perkutaner koronarer Interventionen dienen, der Beschichtung beigemengt sein.If desired, pharmacologically active substances, which are used in particular to treat the consequences of percutaneous coronary interventions, can be added to the coating.
Die Fig. 2a zeigt in einer stark schematisierten und vereinfachten Schnittansicht die Umlaufswandung 16, mit ihrer auf der äußeren Mantelfläche 18 aufgebrachten Beschichtung 26. Die Beschichtung 26 besteht aus zwei End-
abschnitten 28.1 und 28.2 sowie einem mittleren Abschnitt 30. Im vorliegenden Falle wird die gesamte Beschichtung 26 von einem in gleichmäßiger Schichtdicke aufgetragenen biodegradierbaren Werkstoff gebildet.2a shows a highly schematic and simplified sectional view of the peripheral wall 16, with its coating 26 applied to the outer lateral surface 18. The coating 26 consists of two end sections 28.1 and 28.2 and a middle section 30. In the present case, the entire coating 26 is formed from a biodegradable material applied in a uniform layer thickness.
Die Abschnitte 28.1 , 28.2, 30 unterscheiden sich dadurch, dass sich die end- seifigen Abschnitte 28.1 , 28.2 langsamer abbauen als der mittlere Abschnitt 30. Dies wird in dem vorliegende beispielhaften Fall zur Kompensation reo- logisch bedingter Beschleunigungen des Abbauprozesses an den Stenten- den genutzt, d. h. der in Fig. 2a dargestellte schematische Stent wird ein weitesgehend homogenes Abbauverhalten über die gesamte Länge des Stents zeigen.Sections 28.1, 28.2, 30 differ in that the final soapy sections 28.1, 28.2 degrade more slowly than the middle section 30. In the present exemplary case, this is used to compensate for logically induced accelerations of the digestion process at the stent ends used, d. H. The schematic stent shown in FIG. 2a will show a largely homogeneous degradation behavior over the entire length of the stent.
Die Fig. 2b offenbart eine zweite Variante der Beschichtung 26. Die Abschnitte 28.1 , 28.2 entsprechen denen der Fig. 2a. Der Abschnitt 30 ist dagegen in seiner Schichtdicke deutlich reduziert. Dies hat zur Folge, dass der Abschnitt 30 sehr viel schneller abgebaut wird als die Abschnitte 28.1 und 28.2. Ein solches Abbauverhalten des Implantats kann dann sinnvoll sein, wenn möglichst schnell ein Abbau der künstlichen Struktur in dem Bereich der Läsion stattfinden soll, um jeden Ausgangspunkt für mögliche Komplikationen möglichst frühzeitig in diesem Bereich zu beseitigen.FIG. 2b discloses a second variant of the coating 26. The sections 28.1, 28.2 correspond to those in FIG. 2a. The section 30, however, is significantly reduced in its layer thickness. The result of this is that section 30 is broken down much more quickly than sections 28.1 and 28.2. Such degradation behavior of the implant can be useful if the artificial structure in the area of the lesion is to be removed as quickly as possible in order to eliminate any starting point for possible complications in this area as early as possible.
Der Fig. 3a ist ein Beschichtungssystem 26 zu entnehmen, bei der zwei ver- schiedene Werkstoffe, mit einem unterschiedlichen Degradationsverhalten in den Abschnitten 28.1 , 28.2, 30 des Stents 10 aufgebracht sind. Ebenso verhält es sich bei der Variation des Systems nach Fig. 3b.3a shows a coating system 26, in which two different materials with a different degradation behavior are applied to the sections 28.1, 28.2, 30 of the stent 10. The same applies to the variation of the system according to FIG. 3b.
Gemäß der Ausführung nach Fig. 3a werden die Abschnitte 28.1 , 28.2 von einem Werkstoff mit einem verzögerten Degradationsverhalten gegenüber dem Werkstoff, der im mittleren Abschnitt 30 Einsatz findet, bedeckt. Dementsprechend wird die ortabhängige Degradationscharakteristik D(x) beeinflusst, d. h. in der Regel endseitig verzögert. Eine solche Ausführung ist immer dann sinnvoll, wenn die Stützstruktur an den Enden über einen längeren
Zeitraum aufrecht erhalten werden soll und die rheologischen Verhältnisse ansonsten einen beschleunigten Abbau erwarten lassen.According to the embodiment according to FIG. 3a, sections 28.1, 28.2 are covered by a material with a delayed degradation behavior compared to the material used in the middle section 30. Accordingly, the location-dependent degradation characteristic D (x) is influenced, ie generally delayed at the end. Such a design is always useful if the support structure has a longer end Period should be maintained and the rheological conditions otherwise lead to accelerated degradation.
Fig. 3b zeigt in den Abschnitten 28.1 und 28.2 ein in radialer Richtung mehrschichtigen Aufbau der Beschichtung 26. In einem ersten Teilabschnitt 32 ist wiederum der Werkstoff mit dem verzögerten Degradationsverhalten aufgetragen, während sich radial nach außen ein Teilabschnitt 34 mit dem schneller degradierbaren Werkstoff befindet.3b shows in sections 28.1 and 28.2 a multilayer structure of the coating 26 in the radial direction. The material with the delayed degradation behavior is again applied in a first section 32, while a section 34 with the more rapidly degradable material is located radially outward.
Die vorgenannten Beispiele der Fig. 2a, 2b und 3a, 3b, 4 und 5 stellen nur stark schematisierte Ausführungsbeispiele der Erfindung dar. Sie können in vielfältiger Weise untereinander kombiniert werden. So ist es beispielsweise denkbar ein komplexe Beschichtung zu entwerfen, die in einzelnen Abschnitten aus jeweils mehreren Werkstoffen besteht. Primäres Ziel ist es dabei immer die lokale Degradation des Implantats zu optimieren.
The above-mentioned examples of FIGS. 2a, 2b and 3a, 3b, 4 and 5 represent only highly schematic exemplary embodiments of the invention. They can be combined with one another in a variety of ways. For example, it is conceivable to design a complex coating consisting of several materials in individual sections. The primary goal is always to optimize the local degradation of the implant.
Claims
1. Endovaskuläres Implantat mit1. Endovascular implant with
- einem rohrförmigen, an seinen Stirnseiten offenen Grundkörper aus zumindest einem biodegradierbaren Werkstoff, wobei der Grundkörper eine in vivo eine ortsabhängige erste Degradationscharakteristik D-t(x) besitzt, sowiea tubular base body, open on its end faces, made of at least one biodegradable material, the base body having a location-dependent first degradation characteristic D-t (x) in vivo, and
- einer den Grundkörper vollständig oder gegebenenfalls nur bereichsweise bedeckenden Beschichtung aus zumindest einem biodegradierbaren Werkstoff, wobei die Beschichtung ei- ne in vivo eine ortsabhängige zweite Degradationscharakteristik D2(x) besitzt, unda coating of at least one biodegradable material that completely or possibly only partially covers the base body, the coating having a location-dependent second degradation characteristic D 2 (x) in vivo, and
- wobei sich an einem Ort (x) eine ortsabhängige kumulierte Degradationscharakteristik D(x) aus der Summe der jeweils an dem genannten Ort (x) bestehenden Degradationscharak- teristika D^x) und D2(x) ergibt und die ortsabhängige kumulierte Degradationscharakteristik D(x) so durch Variation der zweiten Degradationscharakteristik D2(x) vorgegeben ist, dass die Degradation an dem genannten Ort (x) des Implantats in einem vorgebbaren Zeitintervall mit einem vorgebbaren De- gradationsverlauf stattfindet.- Where at a location (x) a location-dependent cumulative degradation characteristic D (x) results from the sum of the degradation characteristics D ^ x) and D 2 (x) existing at the location (x) and the location-dependent cumulative degradation characteristic D (x) is predetermined by varying the second degradation characteristic D 2 (x) in such a way that the degradation takes place at said location (x) of the implant in a predefinable time interval with a predeterminable degradation curve.
2. Implantat nach Anspruch 1 , dadurch gekennzeichnet, dass die Degradationscharakteristik D2(x) der Beschichtung durch2. Implant according to claim 1, characterized in that the degradation characteristic D 2 (x) of the coating
- Variation seiner morphologischen Struktur, stoffliche Modifikation des Werkstoffs und/oder - Anpassung einer Schichtdicke der Beschichtung gegeben ist.- Variation of its morphological structure, material modification of the material and / or - adjustment of a layer thickness of the coating given is.
3. Implantat nach den Ansprüchen 1 oder 2, dadurch gekennzeichnet, dass die Degradationscharakteristik D2(x) der Beschichtung in Abhängigkeit von den in der Applikation zu erwartenden pathophysiologischen Verhältnissen vorgegeben ist.3. Implant according to claims 1 or 2, characterized in that the degradation characteristic D 2 (x) of the coating is predetermined as a function of the pathophysiological conditions to be expected in the application.
4. Implantat nach den Ansprüchen 1 oder 2, dadurch gekennzeichnet, dass die Degradationscharakteristik D2(x) der Beschichtung in Abhängigkeit von den in der Applikation zu erwartenden rheologischen Verhältnissen vorgegeben ist. 4. Implant according to claims 1 or 2, characterized in that the degradation characteristic D 2 (x) of the coating is predetermined as a function of the rheological conditions to be expected in the application.
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DE10361940A DE10361940A1 (en) | 2003-12-24 | 2003-12-24 | Degradation control of biodegradable implants by coating |
PCT/EP2004/010077 WO2005065576A1 (en) | 2003-12-24 | 2004-09-07 | Control of the degradation of biodegradable implants using a coating |
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2003
- 2003-12-24 DE DE10361940A patent/DE10361940A1/en not_active Withdrawn
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2004
- 2004-09-07 EP EP04765010A patent/EP1699383A1/en not_active Withdrawn
- 2004-09-07 JP JP2006545930A patent/JP4861827B2/en not_active Expired - Fee Related
- 2004-09-07 US US10/596,791 patent/US20090208555A1/en not_active Abandoned
- 2004-09-07 WO PCT/EP2004/010077 patent/WO2005065576A1/en active Application Filing
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DE10125999A1 (en) * | 2001-05-18 | 2002-11-21 | Biotronik Mess & Therapieg | Implantable bio-resorbable vessel-wall-support consists of a framework of interconnected arms with different cross-sections, thicknesses and widths |
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DE10361940A1 (en) | 2005-07-28 |
JP4861827B2 (en) | 2012-01-25 |
WO2005065576A1 (en) | 2005-07-21 |
JP2007518473A (en) | 2007-07-12 |
US20090208555A1 (en) | 2009-08-20 |
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