Patent Application
20220411966
A field of the invention is methods for producing an intraluminal endoprosthesis, in particular in the form of a stent.
Over the past 20 years, the number of interventional vascular (coronary and peripheral) procedures has been steadily increasing. At the same time, on the one hand increasingly more complex and difficult-to-access lesions are being treated, and on the other hand the number of older patients and patients with poor vascular substance (for example calcified and embrittled vessels) is increasing. This has led to an increasing number of patients whose vessels are injured during procedures by the catheters and guide wires used.
Perforations or ruptures of the treated vessels may occur. Perforations or ruptures are generally very serious, life-threatening complications, especially in coronary vessels, and must be treated immediately.
For such a treatment, for example in the coronary area, various so-called stent grafts are available. The coronary implants currently available consist of a permanent main body made of a metal (usually Co-Cr alloys) and a permanent polymer sheath, preferably made of PTFE or a polyurethane, which seals the damage in the vessel wall. This sheath can be a simple polymer tube or a fabric attached to the stent arranged therebeneath or thereabove.
One disadvantage of these implants is that they are only necessary until the vessel wall has healed sufficiently (approximately 2-3 days) to prevent blood from escaping through the perforated or ruptured area (haemostasis), but they then no longer perform any function.
However, permanent polymer sheaths (polymer tubes or spun coverings) in particular pose a major problem subsequently as they allow endothelialisation of the inner side of the vessel only very slowly and incompletely, thereby greatly increasing the risk of thrombosis or the risk of vessel occlusion in general.
In addition, normal vascular peristalsis is prevented by the usually very stiff implants. The main problems or complications are caused by the permanent polymer sheath for the above-mentioned reasons; the permanent support structure underneath (for example stent) poses a much smaller problem.
A method for producing an intraluminal endoprosthesis is disclosed, in particular in the form of a stent, wherein the endoprosthesis includes a support structure and a sheath arranged on the support structure. The method includes providing the support structure, and forming the sheath on the support structure by electrospinning a polymer solution including at least one biodegradable polymer wherein the polymer solution includes at least one biodegradable polymer and at least one additive, wherein the at least one additive is selected from the group consisting of: 1,3-dioxan-2-one, 1,4-dioxan-2-one, triethyl citrate, glycerol triacetate, n-butyryl tri-n-hexyl citrate, polyethylene glycol, L-α phosphatidylcholine.
Embodiments as well as further features and advantages of the invention will be explained hereinafter with reference to the drawings, in which:
In preferred embodiment methods the sheath is spun so tightly that it is able to seal a vascular perforation or rupture against the blood pressure prevailing at the implantation site for at least 48 hours. Support structures (especially stents), as well as the sheaths placed on them, are currently divided into two basic types: the permanent or durable support structures or sheaths and the biodegradable support structures or sheaths. Permanent support structures or sheaths are designed in such a way that they can remain in the vessel or at the implantation site in the human or animal body for an indefinite period of time. Biodegradable support structures or sheaths, on the other hand, are degraded in the vessel or body over a predetermined period of time. Preferably, biodegradable support structures are only broken down once the traumatised tissue of the vessel has healed and the support structure no longer needs to remain in the vessel lumen or body. Furthermore, it is preferable for a biodegradable sheath to be degraded only when it no longer needs to provide a sealing effect.
According to an embodiment of the method according to the invention, the at least one biodegradable polymer is selected from the group consisting of polylactide; poly-L-lactide; poly-D,L-lactide; poly-L-lactide-co-D,L-lactide; polyglycolide; polyanhydride; polyhydroxybutyrate; polyhydroxyvalerate; poly-c-caprolactone; polydioxanones; poly(lactide-co-glycolide); poly(lactide-co-caprolactone); poly(ethylene glycol-co-capro-lactone); poly(glycolide-co-caprolactone); poly (hy droxybutyrate-co-valerate); polytrimethylene carbonate-based polymer; a polypropylene succinate; a polyphosphazene.
According to one embodiment of the method, the at least one biodegradable polymer may be a copolymer including two or more different monomers of the polymers of the above-mentioned group.
Furthermore, the at least one biodegradable polymer may be present in a mixture or blend according to an embodiment of the method, the mixture including two or more different polymers of the above-mentioned group. A blend is understood here to be a macroscopically homogeneous mixture of two or more different polymers.
Preferably, the at least one biodegradable polymer is poly-L-lactide (for example Resomer® L210 from Evonik) or poly-D,L-lactide.
Furthermore, according to a preferred embodiment of the method according to the invention, the polymer is a poly-D,L-lactide-co-glycolide with a lactide content of 5 wt. % to 85 wt. %, preferably with a lactide content between 50 wt. % and 85 wt. %.
In addition, according to an embodiment of the method, the at least one biodegradable polymer in the polymer solution is preferably one of the following substances: polyhydroxybutyrate; a copolymer including hydroxybutyrate; polyvalerate; a copolymer including valerate.
Furthermore, according to an embodiment of the method according to the invention, the polymer solution includes at least one additive, wherein the at least one additive is selected from the group of lactones, citrate esters, glycerols or their derivatives as well as mixtures thereof. Preferably, the at least one additive is selected from the group consisting of: 1,3-dioxan-3 2-one or 1,4-dioxan-2-one, triethyl citrate, tributyl citrate, glycerol triacetate, n-butyryl tri-n-hexyl citrate, polyethylene glycol, L-α-phosphatidyl choline.
In general, the additive(s) substantially affect the mechanical properties (ductility) of the polymer fibres to ensure the necessary elongation at break. Here, the additives 1,3-dioxan-2-one, triethyl citrate, glycerol triacetate, n-butyryl tri-n-hexyl citrate and polyethylene glycol each serve as plasticisers. L-α-phosphatidylcholine can be used to lower the surface tension to improve the electrospinning process and the hydrophilicity of the cover.
Intraluminal endoprostheses can assume a compressed state in which they are inserted into the body at the implantation site. At the implantation site, the intraluminal endoprostheses are expanded and thus placed at the implantation site. Accordingly, the polymer fibre sheath must be able to withstand compression and expansion without detriment to the properties of the sheath, particularly in terms of permeability. The additives mentioned above improve the mechanical properties of the fibres of the sheath in a beneficial way. The mechanical properties of the polymer fibre sheath, particularly in terms of permeability, are maintained even in the event of compression and expansion. The elongation at break is increased or the surface tension is reduced so that the fibres are less susceptible to damage during compression or expansion.
If present as a component of the polymer solution, the at least one additive (except L-α-phosphatidylcholine) in the polymer solution preferably has a concentration in the range of 5 wt. % to 25 wt. %, preferably 10 wt. % to 20 wt. %, particularly preferably 10 wt. % to 15 wt. %, based on the total mass of dissolved substances.
If the at least one additive is L-α-phosphatidylcholine, it will preferably have a concentration of 1 wt. % or less in the polymer solution according to an embodiment.
According to a preferred embodiment of the method according to the invention, it is provided that the at least one biodegradable polymer is poly-L-lactide (CAS number 26161-42-2), the polymer solution further containing as additive 1,3-dioxan-2-one, wherein 1,3-dioxan-2-one accounts for a proportion among the substances dissolved in the polymer solution in the range of 5 wt. % to 25 wt. %, preferably 10 wt. % to 20 wt. %, particularly preferably 10 wt. % to 15 wt. %, preferably 12.5 wt. %, the remaining portion of the dissolved substances preferably being formed by poly-L-lactide. Other dissolved substances or substances otherwise present in the polymer solution may also be drugs and/or radiopaque substances.
Furthermore, according to an embodiment of the method, the polymer solution includes a solvent, the solvent being selected from the group consisting of: chloroform (CHCl3), trifluoroethanol (TFE), a mixture including chloroform and trifluoroethanol (TFE), with chloroform and trifluoroethanol preferably being present in a mixing ratio of 1:4 (chloroform:trifluoroethanol).
Furthermore, in accordance with an embodiment of the method, it is provided that the polymer solution has a concentration in the range of 1 wt. % to 10 wt. %, preferably 2 wt. % to 8 wt. %, particularly preferably 3 wt. % to 5 wt. %, preferably 4 wt. %, polymer (based on the mass of solvent(s) used).
All additives, drugs and/or radiopaque substances are added (polymer+additive(s)=100% total mass of dissolved substances), the percentage being related to the total mass of dissolved substances and may lie between 0 and 20%. The amount of polymer in the solution remains constant.
The intraluminal endoprosthesis is a stent according to one embodiment, in particular a coronary stent or a peripheral stent.
The support structure, especially in the case of a stent, may be a self-expanding support structure or a balloon-expandable support structure. A balloon-expandable support structure may be produced in particular from a tube that is cut with a laser, for example. In the case of a self-expanding support structure, it may also be cut from a tube by laser cutting or, for example, may be formed from a suitable wire.
The support structure is preferably lattice-like and is formed by interconnected bars that define openings in the support structure. The bars or openings may be formed from a tube, for example, by laser cutting. A support structure made of a wire can also have a grid-like structure.
Furthermore, a support structure of interconnected bars defining openings can be formed from a non-metallic material (for example from a polymer, see also below).
Furthermore, according to an embodiment of the method, the support structure is a permanent support structure.
Such a permanent support structure may, for example, consist of one of the following materials or may include at least one of the following materials: a Co—Cr-based alloy, an Ni-based alloy, a corrosion-resistant stainless steel, an Ni—Ti alloy (with approximately equal atomic ratios of Ni and Ti, for example nitinol), optionally still containing less than 5% of one or more of the elements Co, Fe, Mn, a Ti-based alloy, an Nb-based alloy, a Ta-based alloy.
Furthermore, according to an alternative embodiment of the method, the support structure is a biodegradable metallic support structure.
Such a biodegradable metallic support structure may, for example consist of one of the following materials or may contain at least one of the following materials: an Mg alloy; an Mg—Al—Zn alloy; an Mg—Al—Mn alloy; an Mg—Al—Zn—Mn alloy; an Mg—RE alloy, wherein RE is selected from the rare earth group; an Mg—Y—RE alloy, wherein RE is selected from the rare earth group; an Mg—RE—Zn alloy, wherein RE is selected from the rare earth group; an Mg—Al—Y alloy; an Mg—Al—RE alloy, wherein RE is selected from the rare earth group; an is Mg—Zn—Zr alloy, an Mg—Ca—Zn alloy; an Mg—Al alloy with an Al content of 3 wt. % to 11 wt. %; an Mg—Ca—Zn alloy with a Zn content of 0.01 wt. % to 12 wt. %, preferably from 0.1 wt. % to 5 wt. %, and a Ca content of 0.01 wt. % to 5 wt. %, preferably from 0.1 wt. % to 1 wt. %; an Mg—Y—RE alloy, wherein RE stands for other rare earths (not Y), with a Y content of 0.1 wt. % to 5 wt. %, an Nd content of 0.01 wt. % to 5 wt. %, a Gd content of 0.01 wt. % to 3 wt. %, a Dy content of 0.01 wt. % to 3 wt. %, and wherein the alloy optionally includes 0.1 wt. % to 1 wt. % Zr and other rare earths.
According to an alternative embodiment of the method according to the invention, the support structure is a biodegradable polymeric support structure. Here, balloon-expandable biodegradable polymeric stent scaffolds or support structures, which according to the present invention are provided with a biodegradable sheath, may have the stent designs described in DE 10 2016 117 398.
Furthermore, according to one embodiment of the method, it is provided that said polymeric support structure includes one of the following materials or consists of one of the following materials: a biodegradable polymer; a poly-L-lactide; a poly-D,L-lactide; a poly-L-lactide-co-D,L-lactide; a polyglycolide; a polyanhydride; a polyhydroxybutyrate; a polyhydroxyvalerate; a poly-c-caprolactone; a polydioxanone; a poly(lactide-co-glycolide); a poly (lactide-co-caprolactone); a poly (ethyleneglycol-co-caprolactone); a poly (glycolide-co-caprolactone); a poly(hydroxybutyrate-co-valerate); a polytrimethylene carbonate-based polymer; a polypropylene succinate; a polyphosphazene; a poly-D,L-lactide-co-glycolide having a lactide content of 5 wt. % to 85 wt. %, preferably from 50 wt. % to 85 wt. %
According to an embodiment of the method, the material from which the support structure is formed or which the support structure may also be a copolymer comprising two or more different monomers of the polymers of the above-mentioned group of materials.
Furthermore, the material from which the support structure is formed or which the support structure includes may be, according to an embodiment, a copolymer or a blend of the above-mentioned polymers, the blend including two or more different polymers of the above-mentioned group of support structure materials.
Furthermore, the support structure may also include one of the following materials or may be formed from one of the following materials: a copolymer including hydroxybutyrate; a copolymer including valerate.
Furthermore, according to an embodiment of the method, it is provided that, during electrospinning, the polymer solution is applied from a nozzle to the support structure in fibre form.
The polymer solution is dispensed from the nozzle in accordance with an embodiment of the method, preferably with a volume flow in the range from 0.1 ml/h [millilitres per hour] to 2 ml/h, preferably 0.5 ml/h to 0.9 ml/h, preferably 0.7 ml/h.
According to an embodiment of the method, the nozzle preferably has a distance to the support structure which is in the range of 50 mm to 200 mm, preferably 70 mm to 110 mm, and preferably 90 mm.
Furthermore, according to an embodiment of the method, it is preferably provided that, between the nozzle (emitter) and a collector (mandrel), on which the support structure is arranged, there is applied an electrical voltage in the range of at least 1 kV, preferably 1 kV to 20 kV, particularly preferably 2 kV to 10 kV, preferably 4 kV.
It is expedient to place the intraluminal endoprosthesis on a mandrel during the electrospinning and to weave the sheath beyond the actual ends of the support structure consisting of individual connected bars. The longitudinal extent of the sheath spun from polymer fibres thus exceeds the longitudinal extent (length) of the support structure. The endoprosthesis with the excessively long polymer fibre sheath is then transferred to a suitable mandrel and trimmed by laser. In doing so, at most half the width of the outer ring segment of the support structure is no longer covered by the polymer fibre sheath. Such laser trimming of the polymer sheath prevents the removal of individual fibres or fibre flaps from the endoprosthesis.
Furthermore, in accordance with an embodiment of the method, it is provided that the electrospun sheath is exposed to a predefined temperature over a predefined period of time after the electrospinning, the period of time preferably being in the range of 10 h to 15 h, and the period of time preferably being 13.5 h, and the temperature preferably being in the range of 70° C. to 90° C., preferably 80° C.
According to one embodiment of the method, the polymer solution may contain at least one drug, so that the electrospun sheath includes and can release the at least one drug.
According to one embodiment of the method, the support structure, in particular a coating of the support structure, may include or contain a drug so that the drug can be released from the support structure/coating.
Such a drug incorporated into the polymer sheath or a support structure can be eluted from the polymer or a carrier material (for example coating of the support structure) preferably over a period of 7 days to 4 years and serves to achieve supportive effects for the therapy; such effects can be, among others:
The at least one drug of the sheath and/or the support structure may be one of the following drugs according to an embodiment of the invention: a drug with antiproliferative activity, a drug with anti-inflammatory activity, a drug with antithrombotic activity, paclitaxel, everolimus, mycophenolic acid, angiopeptin, enoxaparin, hirudin, acetylsalicylic acid, dexamethasone, rifampicin, minocycline, budesonide, desonide, corticosterone, cortisone, hydrocortisone, prednisolone, heparin, heparin derivatives, urokinase, PPACK.
Furthermore, according to one embodiment of the method, the polymer solution includes a substance visible under X-ray.
A further aspect of the invention relates to an intraluminal endoprosthesis, in particular in the form of a stent (for example coronary or peripheral stent), produced by the method according to the invention.
In electrospinning the polymer solution 10 is dispensed from a nozzle (for example at the end of a capillary), which is fluidically connected to a (for example syringe-like) reservoir 100, in which the polymer solution 10 is stored.
Here, an electrical voltage is applied between the nozzle 101, also known as an emitter, and a collector 200, which voltage may be in the range of 4 kV to 8 kV, for example. The support structure 2 is arranged on the collector 200 and can be rotated (for example by the collector 200) about a longitudinal axis z and, in particular, may be moved along the longitudinal axis z in order to distribute the polymer solution 10 in fibre form on the outside of the support structure 2.
In electrospinning, the polymer solution forms a so-called Taylor cone T due to said voltage at the nozzle 101 or capillary opening (see
Due to the special morphology of the fibre nonwoven structures, an increased elongation at break of polymeric materials is achieved, so that the spectrum of usable polymers is advantageously increased. In this regard,
As a further example of an endoprosthesis produced in accordance with the invention,
The covering of the support structure 2 with polymer solution 10 is carried out in the non-expanded state of the support structure 2. The achievable layer thickness can again be advantageously low (see above).
Furthermore, the invention also advantageously allows the use of polymers which allow a high diffusion of water into the polymer material, so that small layer thicknesses of the sheath with sufficient sealing effect can be achieved.
With these endoprostheses 1, the electrospinning process takes about 10 minutes per sheath 3. The support structures are each placed centrally on a mandrel of about 10 cm length, which forms the collector 200, with the collector having a travel of about 6 cm. The distance A between nozzle 101 and support structure 2 is 90 mm, wherein the polymer solution 10 is dispensed via the nozzle 101 with a volume flow of 0.7 ml/h [millilitres per hour] and is accelerated onto the support structure by an electrical voltage (for example the nozzle/emitter 101 can be at an electrical potential of 8 kV and the collector 200 at an electrical potential of 4 kV). During electrospinning, the temperature, air humidity, exhaust air, mass and layer thickness (for example by means of REM) are documented for comparison purposes. As a post-treatment, each prosthesis 1 is subjected to a tempering (for example for 13.5 h at 80° C.). The produced sheaths 3 were trimmed using a CO2 laser. The cut edges (see
Finally, a measurement report of an endoprosthesis 1 manufactured as described above is given as an example. The support structure 2 (stent) made of a Co—Cr alloy (L605) was weighed in the clean room before spinning (according to
The covered stent 2 was widened (expanded) by placing it on a catheter, crimping it, then holding it in tempered water (37° C.) for 30 seconds according to the test instructions, widening it to 3.0 mm within 30 seconds and leaving it in water for another 30 seconds (holding time). The expanded, covered stent was then removed from the catheter and dried once more at 80° C. for 13.5 h in a vacuum drying oven. Finally, the covered stent 2 was sputtered onto a SEM slide and the fibre diameter was determined (see
mass of the cover 3 (mCover): mStent, uncovered=10.28 mg, mStent, covered=11.63 mg, mCover=(11.63−10.28) mg=1.35 mg layer thickness of the cover 3: DStent, covered-DStent, uncovered=(1.88−1.74) mm=0.14 mm, layer thickness=(0.14 mm/2)=0.07 mm.
The method according to the invention allows the production of a completely or partially biodegradable implant with an electrospun sheath for the treatment of vascular perforations and vascular ruptures.
The use of biodegradable polymers minimises potential late effects when using the implant through its degradation. The use of fibre nonwoven structures, which are created by using electrospinning, also offers the advantage that the spectrum of usable polymers is increased by the increased elongation at break.
The invention further allows the use of a sheath of reduced layer thickness with sufficient sealing by using polymer materials which allow a high diffusion of water into the polymer. Optionally, the polymer sheath can be supported by a rapidly swellable hydrogel.
It will be apparent to those skilled in the art that numerous modifications and variations of the described examples and embodiments are possible in light of the above teaching. The disclosed examples and embodiments are presented for purposes of illustration only. Therefore, it is the intent to cover all such modifications and alternate embodiments as may come within the true scope of this invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2019 132 938.8 | Dec 2019 | DE | national |
This application is a 35 U.S.C. 371 US National Phase and claims priority under 35 U.S.C. § 119, 35 U.S.C. 365(b) and all applicable statutes and treaties from prior PCT Application PCT/EP2020/082351, which was filed Nov. 17, 2020, which application claimed priority from German Application Serial Number 10 2019 132 938.8, which was filed Dec. 4, 2019.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/082351 | 11/17/2020 | WO |
