Patent Application
20210388166
The present disclosure relates to suitable materials for use as an insulation material on, for example electrodes or electrode leads of medical implants, which has improved wear resistance and/or sliding/static friction properties.
Silicones or more precisely poly(organo)siloxanes represent one of the most important material classes in the field of medical engineering. Nevertheless, attempts are being made to introduce new materials, since, besides its many advantages, silicone also has disadvantages. A main disadvantage is the relatively low resistance to wearing through. Silicone is a three-dimensionally cross-linked polymer. The desired hardness is determined partially by the network density, but primarily by aggregates, such as quartz flour. These aggregates are partly responsible for the materials having disadvantageous frictional properties of this kind. Furthermore, these aggregates may escape from the matrix under mechanical load and may then act as an abrasive substance.
Known solutions provide, for example, that the silicone is coated with outer sleeves made of a thermoplastic polyurethane (TPU), or that the silicone is replaced entirely by a TPU. The outer or cover sleeves, however, must be manufactured in a separate, demanding process, partly with very thin wall thicknesses, and then must be fitted.
A disadvantage of all thermoplastic polyurethanes (TPUs) is their insufficient hydrolysis stability and biostability, in particular on account of the polyurethane connection being unstable under hydrolysis. In particular, the metal ion oxidation leads to a premature degradation of the insulation material. Furthermore, TPUs based on aromatic isocyanates demonstrate great shortcomings in respect of biocompatibility. In order to minimise the susceptibility to hydrolysis, attempts have been made to use very lipophilic TPU formulations. The water uptake, and accordingly the hydrolysis, should thus be minimised. A further disadvantage is the high sliding friction. Furthermore, soft TPUs exhibit a tacky surface behaviour. In addition, with use of a TPU main body, a coating is essential.
TPU thus has considerable disadvantages as an alternative to silicone, in particular if TPU is used as insulation material for electrodes or electrode leads.
The present disclosure is directed toward overcoming one or more of the above-mentioned problems, though not necessarily limited to embodiments that do.
Based on this background, it is therefore an objective of the present invention to provide a suitable material, for example as an insulation material for electrodes or electrode leads of medical implants, which has a greater wear resistance and/or lower sliding friction or static friction than silicone or TPU, for example.
At least this objective is achieved by a material having the features of claim 1 and by a method having the features of claim 10. Advantageous embodiments are described in the dependent claims and hereinafter.
A material according to claim 1 is therefore provided. The material according to the present invention comprises a silicone, wherein a polymer is arranged on the surface of the silicone, wherein the polymer is characterized by a higher wear resistance than silicone, and the polymer is attached to the surface of the silicone by non-covalent bonds.
In particular, the polymer is attached to the surface of the silicone exclusively by non-covalent bonds.
The term “silicone” in the context of the present invention particularly refers to polysiloxanes with the general formula [R2SiO]n, with R being a carbon bond, in particular an alkyl, such as methyl or ethyl, or an aryl, such as phenyl.
The phrase “wear resistance” in the context of the present invention particularly refers to the capability of a solid surface to resist mechanical loading, in particular friction.
The expression “arranging the polymer on the surface of the silicone” in the sense of the present invention means in particular that the polymer is attached to the silicone surface non-covalently or physically. The polymer is preferably arranged on or physically attached to the silicone surface by non-covalent interactions, such as electrostatic or hydrophobic interactions, hydrogen bridges or Van-der-Waals forces, or by looping of the chains of the silicone with the chains of the polymer.
In particular, the surface of the silicone is coated with the polymer.
This solution according to the present invention provides a silicone which not only has good friction values, but also is extremely resistant to wearing through. Due to the surface coating or the attaching of the polymer to the silicone in a manner achieved by a less complex method, the production of a cover sleeve for example and also the fitting of the cover sleeve on the main body of electrode leads of implantable devices are spared. This, combined with the excellent properties of silicone, makes the material combination or the base material an improved alternative to conventional materials.
In accordance with an embodiment of the material according to the present invention, the polymer is a copolymer formed of two or more monomers.
In accordance with a further embodiment of the material according to the present invention, one or more monomers of the polymer are selected from the group comprising:
In accordance with a further embodiment of the material according to the present invention, the polymer comprises 2-methacryloyloxyethyl phosphorylcholine (CAS no.: 67881-98-5) as monomer, preferably in combination with acrylate, methacrylate and/or methyl methacrylate.
In accordance with a further embodiment of the material according to the present invention, the polymer is a polyvinylidene fluoride, a polyarylsulfone, in particular a polysulfone, a polyacrylate, a polymethyl acrylate, or a polymethyl methacrylate.
In accordance with a further embodiment of the material according to the present invention, the polymer is a polysulfone (CAS no. 25135-51-7), a polyether sulfone (CAS no. 25608-63-3), a polyphenylene sulfone (CAS no. 25608-64-4) or polyphenylene ether sulfone, (PPSP, CAS no. 25608-63-3).
In accordance with a further embodiment of the material according to the present invention, the polymer is a polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene (ETFE), polyamide, or polyether ether ketone (PEEK).
In accordance with a further embodiment of the material according to the present invention, the polymer is attached to the surface of the silicone by an entanglement, looping or intermolecular interlooping of the chains of the silicone and the chains of the polymer.
In the sense of the present invention an entanglement (looping, intermolecular interlooping) is understood to mean in particular a physical/geometrical connection of two or more polymer chains which is created by crossing over the polymer chains. As a result of the entanglement, one polymer chain may be separated from the other polymer chain or the other polymer chains only with difficulty by applying force, or even may not be separated at all.
In accordance with a further embodiment of the material according to the present invention, the silicone is a methyl silicone, in particular a polydimethylsiloxane, a vinyl-methyl silicone, a phenyl-vinyl-methyl silicone, a phenyl-modified silicone, a fluoroalkyl silicone or a fluoro-vinyl-methyl silicone.
In accordance with a further embodiment of the material according to the present invention, the polymer is a copolymer of:
In accordance with a further embodiment of the material according to the present invention, the polymer is a methacrylic acid-methyl methacrylate copolymer, which comprises a residue of a zwitterionic compound, wherein the zwitterionic compound is selected from the group comprising phosphorylcholine, sulfobetaine, carboxybetaine, sulfopyridium betaine, cysteine, phosphatidyl ethanolamine or a sulfobetaine siloxane.
In accordance with a further embodiment of the material according to the present invention, it is provided that in the polymer the methacrylic acid monomer is provided in relation to the methyl methacrylate monomer in a molar ratio in the range of from 1:1 (1 part methacrylic acid monomer to 1 part methyl methacrylate monomer) to 1:3 (1 part methacrylic acid monomer to 3 parts methyl methacrylate monomer), preferably 1:2 (1 part methacrylic acid monomer to 2 parts methyl methacrylate monomer).
In accordance with a further embodiment of the material according to the present invention, the polymer comprises methacrylic acid as monomer with a mole fraction in the range of from 25% to 45%, in particular approximately 33%.
The zwitterionic compound preferably comprises at least one polymerizable molecular group, such as a vinyl group or an acryl group.
In accordance with a further aspect of the present invention a medical implant is provided, wherein the medical implant comprises the material according to the present invention.
In accordance with an embodiment of the medical implant according to the present invention, the medical implant comprises an electrode lead.
In the sense of the present invention, an electrode lead is understood to mean in particular a device which comprises at least one elongate electrically conductive element, in particular a wire, which extends over the length of the electrode lead. In particular the electrode lead comprises an electrical, in particular tubular insulation, wherein the lumen of the insulation surrounds the at least one elongate element with the exception of the two ends. Such an insulation is also referred to as a cover sleeve.
In accordance with a further embodiment of the medical implant, the electrode lead, in particular the elongate conductive element, is sheathed at least in part with the material according to the present invention.
In accordance with a further embodiment of the medical implant, the medical implant comprises a current-generating or current-emitting component (generator component, battery) and/or a current-detecting component (diagnosis component) which is connected to the electrode lead.
In accordance with a further embodiment of the medical implant, it is provided that the medical implant is designed as a cardiac pacemaker, a cardioverter-defibrillator, or a neurostimulator, in particular a spinal cord stimulator.
A cardiac pacemaker is in particular a device which comprises an implantable electronic pulse generator which is connected to a patient's heart by an electrode lead.
An implantable cardioverter-defibrillator (ICD) is in particular a device which comprises a stimulation part (pulse generator) and a diagnostics part (for identifying any threat of arrhythmias), wherein the stimulation/diagnostics part, usually implanted beneath the skin in the vicinity of the left pectoral muscle, is connected to the right ventricle by an electrode lead. The electrode lead is typically guided here into the right ventricle via the upper vena cava.
The spinal cord stimulator is in particular a device for treating chronic neuropathic pain, in which a pulse generator is connected by an electrode lead to the part of the nervous system that is to be treated, for example to the posterior funiculus of the spinal cord.
In accordance with a further embodiment of the medical implant, it is provided that the medical implant comprises a fixing sleeve for fixing an implantable electrode lead (electrode fixing sleeve, EFS), wherein the electrode fixing sleeve comprises or consists substantially of the material according to the present invention.
In the sense of the present invention the electrode fixing sleeve is understood in particular to be a special fixing sleeve which is arranged fixedly on the electrode lead at a defined point and which is then secured in the human body at a suitable position, for example by being sewn in place in the region of a muscle or a vessel.
In accordance with a further aspect of the present invention a method for producing the material according to the present invention is provided. The method comprises the steps:
The silicone and the polymer are a silicone and a polymer according to one of the above-mentioned aspects or embodiments.
The expression “arranging a polymer” in the sense of the present invention means in particular the physical attaching of the polymer to the surface of the silicone by non-covalent bonds. In particular the surface of the silicone is coated at least in part with the polymer.
In accordance with an embodiment of the method according to the present invention, arranging of the polymer on the surface of the silicone comprises the following steps:
In accordance with a further embodiment of the method according to the present invention, arranging of the polymer on the surface of the silicone comprises the following steps:
Alternatively, the arranging of the polymer on the surface of the silicone comprises the following steps:
In the sense of the present invention, “swelling the silicone” means in particular the infiltration of the organic solvent into the silicone, wherein at least the uppermost layers of the silicone experience an increase in volume. The swelling of the silicone in particular causes the silicone chains of the uppermost layers to be movable, and therefore they may entangle or loop with the polymer chains of the polymer, which is advantageous.
The swelling of the silicone also allows the polymer to be formed within the movable chains of the silicone from monomers by polymerisation, whereby an entanglement or looping of the chains of the polymer and of the silicone may also be attained here, advantageously.
A key advantage of the method according to the present invention is that the method may be performed in any step of a manufacturing process for producing a device or an apparatus which is intended to comprise the material according to the present invention. For example, existing electrode leads with customary silicone sheathings already may be processed by the method according to the present invention so as to obtain electrode leads comprising the material according to the present invention.
In the sense of the present invention, “drying the silicone” means in particular the removal of the organic solvent, in particular the technically possible complete removal of the organic solvent, for example by temperature or application of a vacuum.
In order to convert or polymerise the one or more precursors into the polymer, initiators may be used, for example azobis(isobutyronitrile) (AIBN) as initiator of a radical chain reaction, for example during the polymerisation of acrylate, methacrylate (MAA), and/or methyl methacrylate (MMA).
In accordance with a further embodiment of the method according to the present invention, the one or more precursors are monomers which are selected from the following group:
In accordance with a further embodiment of the method according to the present invention, the precursors comprise
Advantageously, antimicrobial surfaces preferably may be produced with the above-described zwitterionic compounds as copolymer.
The precursors preferably comprise methacrylate, ethyl methacrylate and phosphorylcholine or 2-methacryloyloxyethyl phosphorylcholine.
In accordance with a further embodiment of the method according to the present invention, the organic solvent is toluene, xylene, chloroform, dichloromethane, dimethyl acetamide, dim ethyl formamide, dim ethyl sulfoxide, cresol, ortho-dichlorobenzene, sulfolane, tetrahydrofuran, trichlorethylene, N-methyl-2-pyrrolidone, or a methacrylate or methyl methacrylate solution. A preferred solvent for swelling the silicone is N-methyl-2-pyrrolidone, in particular in combination with n-heptane.
Additional features, aspects, objects, advantages, and possible applications of the present disclosure will become apparent from a study of the exemplary embodiments and examples described below, in combination with the Figures and the appended claims.
Further features and embodiments of the present invention will be explained hereinafter with reference to the drawings, in which:
The present invention in particular provides an insulation material which displays the known positive properties of silicone, but additionally no longer has the known disadvantages. Here, problems in particular with regard to abrasion and wearing through are reduced or avoided. Both the lead-to-lead abrasion phenomenon and inside-outside wear-through properties may thus be avoided or eliminated. On the whole, the produced materials according to the present invention have a high stability with respect to frictional influences.
By way of the subject matters according to the present invention, two production steps advantageously may be spared in the production of an electrode lead. The production of a correctly sized cover sleeve and the fitting of same are replaced by the method according to the present invention. Customary or established electrode lead designs advantageously may be improved by the method according to the present invention or adapted to market requirements. In particular, the known major problems of the implantable electrode leads, that is to say the fact that they abrade and wear through, are solved, without detriment to the handling properties.
To this end, silicone in particular is coated with suitable materials. The coating is long-lasting and is not abrasive. Apart from the sliding and frictional properties, the mechanical properties advantageously are not influenced by the coating. The surface of the silicone modified in this way makes it possible to use devices or apparatuses produced from this silicone as permanent implants.
In particular, the silicone surface may be modified such that an adhesion to tissue following implantation is reduced. An electrode lead produced from this material may also be removed from the body after a number of years, without difficulty. A further point is the antimicrobial coating. Synergies are present between the two impact directions. This means that a low, unspecific protein adsorption also constitutes an advantage in the case of infections associated with the implant.
Silicone rubber, referred to hereinafter simply as silicone, offers groups that are hardly reactive and which make possible a chemical modification. Silicone swells in some organic solvents, such as toluene or xylene. A monomer is able diffuse into this expanded matrix, which monomer is converted by radical polymerisation to form polymer chains. Following the removal of the swelling agent, these newly formed chains are then mechanically fixed in the matrix. On the other hand, suitable polymers are able to diffuse into the matrix after the swelling. Following the removal of the solvent, these polymers are then also fixed at, and on the surface.
The silicone samples were weighed and kept for 24 h in the solvent to be tested. Following swelling, the sample slices were dabbed at the surface and weighed again.
The swelling factor was calculated in accordance with the following formula Q/100=(a−b)/b): Q is the swelling factor, and a is the weight after expansion, and b is the original weight. The results are shown in the following table.
Test Polymerisation with MMA:
All samples were dried at 80° C. under vacuum.
Coating of the Outer Surface of an Electrode Lead Made of Silicone with PVDF or PSU.
The known biocompatible PVDF, which is stable against wearing through, may be applied by different methods.
On the one hand, a coating method with an annealing process may be used. To this end, PVDF was dissolved, sprayed or immersed in a suitable solvent. The annealing process at temperatures of 240° C. was no problem for the silicone matrix. A pre-treatment of the silicone with a primer or adhesion promoter is feasible, but not absolutely necessary. The cleaning of the silicone before the application of the PVDF is mandatory. The cleaning methods are known to a person skilled in the art.
A further suitable way of fixing PVDF on silicone rubber may be realized with the aid of solvents, which cause the silicone to swell. The silicone was swollen with cyclohexane or cycloheptane, generally a hydrocarbon. PVDF was added to this swollen matrix in a suitable solvent, which resulted in reverse swelling. PVDF was immobilized on the silicone surface in a bristle-like manner by entanglement or looping mechanisms. A pre-treatment of the silicone with a primer or adhesion promoter is possible, but is not absolutely necessary.
Apart from the preferred PVDF, polysulfone or polyether sulfone are also suitable as coating material. Here, the coating was performed from a solvent under usage of hydrocarbons in order to avail of the reversible swelling of silicone. Also utilized, as above, was the fact that the silicone matrix enlarges, and thus the coating polymers may become integrated in the matrix.
Due to the material combination, an “old” electrode design may also be used, which constitutes an attractive selling point due to the surface modification. In contrast to common sleeving methods, a simple immersion process is more cost-effective. Electrode leads having comparable surface properties thus may be produced more cost-effectively. The sliding properties as well as the frictional properties are improved in comparison to silicone. Coatings with PVDF, but also polysulfone or polyether sulfone, are also superior to TPU surfaces. This is thus the case in particular because all TPU materials are subjected to a hydrolytic breakdown.
Polysulfone (PSU) is used as separating membrane for dialysis membranes. The polymer also demonstrates only a low tendency to protein adsorption. It is also used as membrane material in biotechnology, in particular if protein-containing solutions are to be filtered, but should not remain on the filter.
In experiments, PSU was tested with great success in animal testing. Here, no protein adhesion or cell adhesion could be observed, even after 4 months.
The following polymers from the class of polysulfones are particularly suitable for the surface-penetrating coating according to the solution according to the present invention: polysulfone (CAS no. 25135-51-7), polyether sulfone (CAS no. 25608-63-3), polyphenylene sulfone (CAS no. 25608-64-4) or polyphenylene ether sulfone, (PPSP, CAS no. 25608-63-3). The trade names of BASF are used in
Potential solvents are: chloroform, dichloromethane, dimethylacetamide and N-methyl-2-pyrrolidone, wherein N-methyl-2-pyrrolidone is preferred. N-methyl-2-pyrrolidone may be combined well with solvents such as n-heptane in order to achieve the desired expansion of the silicone.
Further suitable solvents are toluene, dichloromethane, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, cresol, ortho-dichlorobenzene, sulfolane, tetrahydrofuran, trichlorethylene.
Coating of a Silicone Electrode Lead with PSU or PPSP
The coating differs from conventional coatings in that there is no cohesion layer provided, and instead the coating material also penetrates the surface and reaches into the silicone.
The silicone material was made to swell using n-heptane. This was performed at room temperature for 1 min to 24 h. The extent of the swelling, and thus also the depth to which the polysulfone penetrates into the carrier material (silicone rubber) may be influenced over time. Only a swelling time of from 15 to 45 min was preferably used. The swollen material was then passed through a 5% polysulfone solution in N-methyl-2-pyrrolidone. In order to produce the polysulfone solution, the polysulfone was weighed in, and the solvent added. The solution is then stirred for 24 h at 80° C. The reaction time of the solution as the carrier material was 1 to 120 min. The silicone was preferably left in the polymer solution for 2 to 20 min. The solvent was removed by evaporation at room temperature over 3 to 4 days. Solvent residues were then removed fully by a vacuum treatment at 80° C. for 7 days.
The PSU coating was repeated with dimethylacetamide (DMAC) as solvent, wherein the silicone material was expanded for 2 days in a dimethylacetamide solution with 0.5 wt % PSU (CAS no. 25135-51-7) and was then dried at 85° C. for 1 day.
The PPSP (polyphenylene ether sulfone) coating was repeated with dimethyl acetamide (DMAC) as solvent, wherein the silicone material was expanded for 2 days in a dimethyl acetamide solution with 0.5 wt % PPSP (CAS no. 25608-63-3) and was then dried at 85° C. for 1 day.
Production of Silicone Rubber with MMA/MAA/PC Modification:
The following exemplary embodiment describes the surface modification of a silicone rubber matrix with methyl methacrylate (MMA)/methacrylic acid (MAA) and a zwitterionic molecule.
The silicone matrix was swollen using a solvent. As a result of the swelling, a volume was provided in which monomers could be converted to form prepolymers and polymers. The schema shown at the top of
A series of compounds may be used as zwitterion. A number of zwitterions will be shown in the following schema.
Phosphorylcholine (PC) is particularly preferred here.
In order to couple the PC to the MMA/MAA, the PC was used with a vinyl group, which was attached to the MMA/MAA prepolymer by radical polymerisation.
For surface modification the synthesis schema shown at the bottom in
Substrates made of the silicone Nusil® Med 45xx were added to a solution of MMA/MAA (2:1). 100 ml MMA were mixed with 50 ml MAA and the substrates were stored for 24 h at room temperature and swollen. Following the introduction of the samples, the solution was gassed for 2 min with nitrogen so as to remove oxygen from the solution. For the further treatment, 10 mg/ml of 2,2′-azobis(2-methylpropionamidine)dihydrochloride (AIBN) were dissolved in water, and 10 mg/ml of 2-methacryoxyethyl PC were added and also dissolved at room temperature. The solution was degassed for 5 min with nitrogen. The swollen silicone samples were added to this aqueous solution and washed for 1 to 3 min. The samples were removed and incubated for 24 h at 80° C.
For repetition of the above-mentioned synthesis, an expansion solution with 40 ml MMA (methyl methacrylate, CAS: 80-62-6, Sigma Aldrich) and 20 ml methacrylic acid (MAA, CAS:79-41-4, Sigma Aldrich) was produced. Silicone substrates made of Nusil MED4765 were cleaned and incubated for 3 days in the swelling solution. The silicone substrates were then removed from the expansion solution, wherein the expansion solution was then allowed to drain off. The incubated silicone substrate was then transferred into a rinsing solution, which contained 100 ml demineralised water (Millipore), 100 mg AIBN (radical starter) 2,2-azobis(2-methyl-propionamidine)dihydrochloride CAS: 2997-92-4 (Sigma Aldrich) and 1000 mg methacryloyloxyethyl phosphorylcholine (zwitterion) CAS:67881-98-5 (Sigma Aldrich), and was rinsed for 5 min with turning. The silicone substrates were then placed on a glass plate or the like and dried for 2 days at 85° C. in a furnace. The dried samples were then sterilized.
In this exemplary embodiment, one monomer is the swelling agent at the same time. Alternatively, the swelling agent may also be cyclohexane, cycloheptane, N-heptane or generally a hydrocarbon.
The exemplary embodiment produces surfaces which have been found to be antimicrobial (see
In a further exemplary embodiment, the silicone matrix was also swollen. Not only cyclohexane, cyclopentane, n-heptane or generally a hydrocarbon, but also dimethyl acetamide and N-methyl-2-pyrrolidone were used as particularly preferred solvents. In this example, it was not a monomer that was added, but a polymer, so as to produce an IP network by diffusion. PESU and PSU were used as polymers.
To this end, the silicone matrix was swollen for 48 h in the solvent at room temperature. The polymer was added as solid substance and was dissolved in the solvent at room temperature over 24 h in the presence of the silicone samples to be treated. The silicone samples were then incubated in this solution for a further 24 h and were then removed, freed from any adhering solution, and were pre-dried at 40° C. for 8 h and were then freed from residual material at 40° C. and 0.01 bar under vacuum.
An embodiment of the implant according to the present invention is shown in
The electrode lead 1 has an outer (for example tubular) electrical insulation 100, which extends along the longitudinal axis z of the electrode lead 1 and surrounds the conductors 10, 11. The electrical insulation 100 here comprises the material according to the present invention or consists substantially thereof.
The conductors 10, 11 are preferably formed as cables which may comprise a plurality of wires, which for example may comprise silver or tantalum or may consist substantially thereof.
In the detailed view of the region A shown in
The electrode lead 1 in its distal region 1a comprises electrode terminals E1 to E8 for contacting bodily tissue. In its proximal region 1b the electrode lead also has contacts C1 to C8, by which the electrode lead may be connected to an active electrical implant, such as an implantable pulse generator for example an implantable cardiac pacemaker or an implantable neurostimulator or an ICD. The contacts C1 to C8 are connected here to the electrode terminals E1 to E8 by means of electrical conductors 10, 11. For this purpose the electrode lead may have more than two conductors 10, 11, as shown schematically in
Another embodiment of the implant according to the present invention relates to an electrode fixing sleeve 2, as shown by way of example in
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 teachings of the disclosure. The disclosed examples and embodiments are presented for purposes of illustration only. Other alternate embodiments may include some or all of the features disclosed herein. Therefore, it is the intent to cover all such modifications and alternate embodiments as may come within the true scope of this invention, which is to be given the full breadth thereof. Additionally, the disclosure of a range of values is a disclosure of every numerical value within that range, including the end points.
| Number | Date | Country | Kind |
|---|---|---|---|
| 18202647.6 | Oct 2018 | EP | regional |
This application is the United States national phase under 35 U.S.C. § 371 of PCT International Patent Application No. PCT/EP2019/077737, filed on Oct. 14, 2019, which claims the benefit of European Patent Application No. 18202647.6, filed on Oct. 25, 2018, the disclosures of which are hereby incorporated by reference herein in their entireties.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2019/077737 | 10/14/2019 | WO | 00 |
