SI23021A - Method of treatment of biomedical polymeric prostheses for improvement of their antithrombogenous properties - Google Patents

Abstract

The subject of the invention is a method of treatment of biomedical prostheses for improvement of their antithrombogenous properties. The mentioned biomedical prostheses are the cardiovascular ones, particularly artificial veins and stents made of polyethyleneterephtalate (PET) polymer. The method is based on treatment of cardiovascular prosthesis surface with a suitable combination of dose of neutral oxygen atoms and positively charged molecular and atomic oxygen ions. After the dose of said atoms and ions has been received, the surface of cardiovascular prostheses becomes less susceptible to bonding of thrombocytes. The method is characterised in that the exposedness to the mixture of neutral oxygen atoms and positively charged molecular and atomic oxygen ions in pulses is such that in an individual pulse, the achieved dose of neutral oxygen atoms amounts to between 10exp20/m2 and 10exp26/m2 and the dose of charged molecular and atomic oxygen ions to between 10exp16/m2 and 10exp23/m2 with time intervals between individual pulses lasting between 10 s and 300 s, and that the stream of neutral oxygen atoms and positively charged molecular and atomic oxygen ions onto the surface of the prosthesis is approximately uniform.

Description

METHOD OF TREATMENT OF BIO-MEDICAL POLYMER PROSTHESES TO IMPROVE THEIR ANTITROMBOGEN PROPERTIES

The subject of the invention is a method of treating bio-medical prostheses to improve their antithrombogenic properties. These bio-medical prostheses are cardiovascular prostheses, especially artificial veins and vascular supports made of polyethylene terephthalate (PET) polymer. The method is based on treating the surface of cardiovascular prostheses with a suitable combination of a dose of neutral oxygen atoms and positively charged molecular and atomic oxygen ions. Upon receiving the dose of the atoms and ions mentioned, the surface of the cardiovascular prostheses becomes less susceptible to platelet binding. After platelet exposure, the concentration of bound platelets on the surface of cardiovascular prostheses treated by the method of the present invention is reduced by 10-fold or more compared with untreated cardiovascular prostheses. This method can directly affect platelet binding to surfaces of PET polymers or similar polymers.

View the problem

Cardiovascular diseases are the most common cause of morbidity and mortality in the population and represent one of the biggest health problems. First and foremost are atherosclerotic diseases that cause narrowing of the internal diameter of the veins, which makes the blood no longer able to flow freely through the veins and therefore slows its flow.

Treatment of these diseases is possible with the help of a vascular support or by replacement of the diseased vessel with a synthetic one. Both options are widely used, but in the long term, the recovery of patients with vascular support, and especially with vascular prostheses, is still poor as in most cases after 2 to 5 years they need to be replaced.

With the help of a catheter, the vascular support is inserted into the narrowed area of the vessel, which widens the blood vessel and allows blood to flow through it again. The supports are usually made of stainless steel, tantalum or platinum, but in many cases these materials cause thrombosis.

-2in restenosis. Therefore, alternative materials are sought, in particular polymeric materials such as silicone, polyethylene and polyurethane and various biodegradable polymeric materials. However, these are also not suitable for direct blood exposure and usually need to be coated with deposits that prevent atherosclerosis from occurring and are anti-thrombogenic, e.g. heparin.

In the case of severely constricted vascular closures, synthetic vascular prostheses are needed to treat the disease, bypassing and restoring blood flow. The materials used for synthetic vascular dentures must meet the biocompatibility / haemocompatibility requirements and must have adequate mechanical properties, in particular the flexibility and ease of surgical placement. Today, polyethylene terephthalate (PET) or Dacron and polytetrafluoroethylene (ePTFE) polymers are used primarily for these purposes. Both types of veins, both PET and PTFE, have adequate mechanical properties and have been used for synthetic vascular prostheses for many years, but do not offer sufficient hemocompatibility, especially when used for vein replacements smaller than 6 mm in diameter. This is mainly due to the lower blood flow in the narrower vein regions and the likelihood of thrombosis occurring here. Namely, non-specific plasma protein adsorption occurs on the wall of artificial veins, which also affects platelet binding, which is one of the main causes of thrombosis. Vascular prostheses from PET polymers are known to be more susceptible to platelet adhesion and activation than from ePTFE polymers. However, ePTFE is also known to be a more potent stimulator for fibrotic hyperplasia.

The biological response to biomaterials is very complex and therefore still poorly understood. Given that the surface of biomaterials is the one that enables interaction with the body, the properties of the surface of biomaterials are crucial for an appropriate biological response, that is, biocompatibility. For many years, the most suitable materials have been considered inert materials that do not react with the body and do not allow the integration of biomaterials with the body. Today, however, it is believed that biocompatible materials are intended to integrate with the body and prevent infections, inflammatory reactions, blood clotting and other related reactions. For biocompatible materials that are in contact with blood, it is especially important that their surface has anti-thrombogenic properties, which prevents the formation of thrombosis. In these cases, thrombosis begins with the adsorption of plasma proteins to the surface • ·

-3biomaterial and is highly dependent on the physical and chemical properties of the biomaterial surface. To improve the properties of blood-contacting materials, various surface treatment methods have been used to allow the binding of bioactive components such as heparin and albumin. The preparation of surfaces by the binding of bioactive components has many disadvantages, in particular the unevenness of the coatings, impurities and the difficulty of preparation in narrower areas such as the inner compartments of the pipes. These and many similar technological problems reduce the quality and increase the cost of making cardiovascular dentures, so we want to prepare the antithrombogenic surface of the prosthesis directly by a simpler procedure.

The state of the art

Several different methods have been used to improve the biocompatible / hemocompatible properties of materials. They are divided into mechanical and chemical. Mechanical methods are not the most suitable because they cause material damage and changes in material properties. More commonly, different chemical methods are used, which are divided into wet and dry ones. Wet chemical methods include treatments with various chemical reagents in aqueous or other liquid media. Dry methods, however, include gas or particle treatment as well as plasma treatments, treatments with ionic beams, electron beams, photon beams - lasers, X-rays and other energy beams. Binding of anti-thrombogenic coatings such as heparin or albumin is often used to improve biocompatible properties.

In addition to such coatings, surface treatment with endothelial cells disclosed in CA 02472031 or platelet treatment with adhesion receptors with specific monoclonal antibodies is used to improve the properties of artificial veins. In order to improve the hemocompatible properties of blood-contacted biomedical materials, procedures for the synthesis of novel materials having suitable properties are also used. The disadvantage of these procedures lies in the unexplored effects of these materials on humans after implantation. All of these processes have a limited success rate.

Many different methods for improving the surface properties of artificial cereals can be found in the literature. Mostly for surface modification of polymeric materials • ·

-4 Wet chemical processes are used to allow the further binding of various bioactive substances, some of which are also patent protected. With wet chemical processes, functional groups are formed on relatively inert surfaces of polymers such as PET or PTFE, and further enable the binding of bio-active substances through these functional groups.

Despite the widespread use of wet chemical processes, these have at least three disadvantages: the first is that they do not allow the best control of the chemical reactions that flow on the inner walls of artificial veins; the second is the uneven processing of the interior walls; third, that some of the reactants remain on the walls, as well as impurities that have formed before, during, or after the reactions that can cause adverse reactions in the body. In addition, despite the application, the surface chemocompatibility is still insufficient and in most cases, another layer of material having antithrombogenic properties must be applied to these applications. The problem of deposits is mainly due to their poor bonding and uneven distribution, as well as instability, since over time they can be washed out quickly from the inner wall of the artificial vessel under flowing conditions inside the vessel, e.g. heparin as early as 4 weeks after implementation.

In addition to the wet chemical method with reagents, the surface can be prepared before application by so-called dry methods, where gases or different particles are used as reagents. These methods allow for the covalent binding of bio-active substances and can be bound directly to the substrate surface or via an intermediate molecule.

Some patents disclose the use of plasma to prepare the surface of bio-materials without further binding different bionanos. Thus, US patent US2005163816 describes plasma treatment of materials for biomedical applications. The patent discloses the treatment of ceramic, metallic and polymeric materials with radio frequency plasma. The surfaces thus prepared are intended to improve the binding and functioning of living cells. Also disclosed in European patent EP0348969 is a method by which endothelial cells can be bound to plasma-treated polymer surfaces, in particular ammonium plasma.

• ·

The present invention is based on a method for treating the surface of PET polymers with a combination of neutral oxygen atoms and positively charged molecular and atomic oxygen ions, thereby achieving anti-thrombogenic properties directly on the surface. The method allows uniform modification of the upper atomic layer of the PET polymer without deep damage to the material. To prevent the effects of surface heating during plasma treatment and the related undesirable changes in thermomechanical properties, plasma treatment can be performed pulsed. At doses of neutral oxygen atoms between 10 ² ° m ' ² and 10 ²⁸ m' ² , preferably between 10 ²² m ' ² and 10 ²⁶ m' ² , and ion doses between 10 ¹⁶ m ' ² and 10 ²³ m' ² , preferably between 10 ¹⁷ m ' ² and 10 ²¹ m' ² , on the surface we form suitable species and a suitable relationship between the types of oxygen functional groups, thereby reducing platelet binding. Therefore, we assume that the prepared surfaces of PET polymers reduce the likelihood of thrombosis and can be used for cardiovascular prostheses as well as for other biomedical materials from PET polymers, where the surface chemocompatibility is of great importance.

Description of the pictures

A method for treating the surface of dentures made from PET polymer or bio-medical polymer-like polymers is described by means of figures showing:

Fig. 1. Number of adhered platelets per 10,000 pm ² of PET polymer surface depending on received dose of oxygen atoms

Fig 2. Image obtained by scanning electron microscope showing adhered platelets on untreated PET polymer surfaces

Fig. 3. Image obtained with a scanning electron microscope showing the adhered platelets on the treated surface of a PET polymer with a dose of 1.8 Ί O ²⁵ m ′ ² oxygen atoms.

Fig. 4. Image obtained with a scanning electron microscope showing the adhered platelets on the untreated surface of a PET polymer fiber web.

Fig. 5. Image obtained with a scanning electron microscope showing the adhered platelets on the surface of a machined artificial polymer wire of PET polymer fibers with a dose of 1.8 -10 ²⁵ m ² oxygen atoms.

Fig. 6. Schematic of a device for treating the inner surface of an artificial vessel.

-6Description of problem solution and implementation example

The method of the invention comprises exposing the prosthesis to a mixture of neutral oxygen atoms and positively charged molecular and atomic oxygen ions, which can be generated using the apparatus described in the embodiment. The flow of neutral oxygen atoms and positively charged molecular and atomic oxygen ions to the surface of the product is approximately uniform, which is achieved by uniformly moving the prosthesis during machining and thus the possible inhomogeneity of treatment is less than a factor of 100. The prosthesis is exposed to a mixture of neutral oxygen atoms and positively charged molecular and of atomic oxygen ions in pulses so that in a single pulse a dose of neutral oxygen atoms between 10 ² ° m ' ² and 10 ²⁸ m' ² is reached, and preferably between 10 ²² m ' ² and 10 ²⁶ m ² , and a charge of molecular and atomic charges oxygen ions between 10 ¹⁶ m ' ² and 10 ²³ m ² , and preferably between 10 ¹⁷ m' ² and 10 ²¹ m ' ² , and the interval between individual pulses lasts between 10 s and 300 s, and preferably between 60 s and 150 s . The temperature of the cardiovascular prostheses is lower than 170 ° C during treatment, preferably lower than 75 ° C. Total received dose of neutral oxygen atoms between 1O ²⁰ m ' ² and 10 ²⁸ m' ² , and preferably between 10 ²³ m ' ² and 10 ²⁶ m ² . Received dose of positively charged molecular and atomic oxygen ions between 10 ¹⁶ m ' ² and 10 ²⁵ m' ² , and preferably between 10 ¹⁷ m ' ² and 10 ²² m' ² . Kinetic energy of positively charged molecular and atomic oxygen ions along the surface of dentures between 1 eV and 1000 eV, and preferably between 5 eV and 100 eV.

Modification of the PET polymer surface is achieved by neutral oxygen atoms and by a combination of positively charged molecular and atomic oxygen ions. Thus, new functional groups are formed on the surface, such as C-O, C = O, C-O-O, O = C-O, while also changing the topographic characteristics of the surface, thereby increasing the roughness. Optimized conditions of this type of treatment allow the surface to have an adequate number of new functional groups and a suitable topography. The treatment also results in the surface becoming more hydrophilic, which promotes endothelial cell growth. In addition, this treatment also achieves anti-thrombogenic properties of the surface, thereby reducing platelet binding by 10 times or more. Thus, according to the known solutions so far, this technique enables rapid and efficient surface modification, which leads to antithrombogenic properties of the surfaces.

-7Modification of surfaces of bio-medical polymers such as polyesters, polyamides, polysaccharides, polyurethanes, polyesteramides or combinations thereof, depending on the required dose of atoms and ions, can also be carried out for a period of less than one minute, which according to the techniques used so far The advantage is that the application of various antithrombogenic coatings is extremely time consuming and may take several hours or even days. In addition, the surfaces treated by the method disclosed in this patent do not require any further treatment with the cells, such as the deposition of endothelial cells, which must be applied to the surface of the biomedical material prior to implantation.

An advantage of the method disclosed in this patent is that the modification is platelet-specific, since treatment reduces platelet binding without affecting the proliferative properties of endothelial cells.

That the treatment method achieves the anti-thrombogenic properties of the surface of PET polymers is also evident from the images forming part of this disclosure. The first column in Figure 1 shows the number of adhered platelets per surface of the untreated PET polymer, and all the following shows the number of platelets on the surface of the polymer previously exposed to different doses of neutral oxygen atoms. A large number of adhered platelets, approximately 100 platelets / 10000pm ^2, is observed on the untreated surface of the PET polymer. A decrease in the number of adhered platelets was observed on the surface of a PET polymer that received a dose of neutral oxygen atoms between 1.8 Ί 0 ²⁴ m ′ ² and 5.4 Ί 0 ²⁵ m ′ ² .

Figure 2 is taken with a scanning electron microscope and shows the surface of the untreated PET polymer after one hour incubation with platelets obtained by apheresis procedure. From the picture we can see that the surface is susceptible to platelet binding. However, if the surface of the PET polymer was exposed to a dose of 1.8 Ί0 ²⁵ m ′ ² neutral oxygen atoms before incubation with platelets, a much smaller number of adhered platelets was observed, as can be seen in Figure 3. A similar effect was observed on artificial woven vessels made of PET polymer fibers. In Figure 4, we see a large number of platelets in the active expanded form, with well-visible pseudopodia. However, if artificial veins were exposed to neutral oxygen atoms prior to incubation with platelets, a significant decrease in platelet counts was observed on the surface, as can be seen in Figure 5.

-8Figure 6 is a schematic representation of a device that enables the treatment of the inner surface of artificial veins with neutral oxygen atoms and with a mixture of positively charged molecular and atomic oxygen ions.

The described method of treating the surface of PET polymers with neutral oxygen atoms and with a mixture of positively charged molecular and atomic oxygen ions significantly reduces platelet adhesion. Since platelets are one of the main agents for thrombogenic reactions and related complications after the implementation of artificial blood vessels or other implantable implants, this treatment method is an appropriate alternative to modify the surface on which anti-thrombogenic properties are desired.

An implementation example

To provide a suitable dose of neutral oxygen atoms and positively charged oxygen molecular and atomic oxygen ions, a device is shown schematically in Figure 6. The device consists of a source of neutral oxygen atoms 1, a connecting tube 2, a unit for changing the flow of neutral oxygen atoms 3, tubes for partial ionization of gas molecules and atoms 4, high-frequency generator 5, vacuum vessels 6 and artificial vessel displacement devices 7. An artificial vessel is installed on tube 4. The vacuum system is pumped with a vacuum pump 9 to ensure gas flow from springs the atoms 1 through the flow modifier 3, down the tube 6 and the artificial vessel 8 to the pump 9.

The source of oxygen atoms 1 can be any device that guarantees the production of at least 1O ²⁰ atoms per second. The source of the oxygen atoms may be made of any material heated above 1000 ° C, such as gold, platinum or any other metal that does not form an oxide, but may be ceramics that are resistant to high temperatures in an oxygen-containing atmosphere. The source of oxygen atoms 1 may also be a gas discharge that provides the production of at least 1O ²⁰ atoms per second, such as a high pressure arc or low pressure gas discharge.

The connecting tube 2 between the source of oxygen atoms 1 and the unit for changing the flow of neutral oxygen atoms 3 is made of a material that transmits at least 1% oxygen atoms, which means that the density of atoms at the mouth of tube 2 against the changing unit

-9 flux of atoms 3 at most 100 times lower than in origin 1. Preferably, the connecting tube 2 is such that it allows more than 10% of the atoms from source 1 to change the flow of neutral oxygen atoms 3. In the embodiment, the connecting tube 2 is a quartz tube of length 30 mm and inner diameter 6 mm.

The unit for changing the flow of neutral oxygen atoms 3 is made of any material with a high coefficient for the surface association of oxygen atoms in molecules. In the embodiment, the unit for changing the flow of neutral oxygen atoms 3 is made of OFHC copper. The unit for changing the flow of neutral oxygen atoms 3, in the embodiment, has a length of 50 mm and a diameter of 20 mm.

The inflow of oxygen atoms into the tube for partial ionization of gas molecules and atoms 4 is adjustable by varying the distance between the mouth of the connecting tube 2 and the inlet to the tube for partial ionization of gas molecules and atoms 4. In the case where the tube for partial ionization of gas molecules and of atoms 4 fits tightly into the connecting tube 2, the unit for changing the flow of neutral oxygen atoms 3 allows the permeation of all oxygen atoms. In the extreme extreme case, where the tube for partial ionization of gas molecules and atoms 4 is farthest from the connecting tube 2, the unit for changing the flow of neutral oxygen atoms 3 leaves only a negligible part of the oxygen atoms entering the unit for changing the flow of neutral oxygen atoms 3 through the connecting tube 2.

The tube for partial ionization of gas molecules and atoms 4 is made of a dielectric that transmits neutral oxygen atoms well. In the embodiment, the tube for partial ionization of gas molecules and atoms is 4 quartz tubes with a length of 30 cm and an outer diameter of 5 mm. Part of the tube is located in a high-frequency electromagnetic field, which is generated by a high-frequency generator 5. The high-frequency generator 5 typically operates in pulses. Any generator with a frequency exceeding 10 kHz can be used. In the embodiment, a radio frequency generator with a frequency of 13.56 MHz is used. The high-frequency generator 5 allows the generation of pulsatile discharge in the tube for partial ionization of gas molecules and atoms 4, thereby ensuring a suitable concentration of ions used to process the artificial vessel 8.

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-10At the mouth of the tube for partial ionization of gas molecules and atoms 4, on which the artificial vessel 8 is mounted, a suitable flow of neutral oxygen atoms and molecular and atomic oxygen ions is provided. Suitable flow of neutral oxygen atoms at the mouth of a tube for partial ionization of gas molecules and atoms 4 is achieved by a suitable source of oxygen atoms 1 and a suitable tuning unit for changing the flow of neutral oxygen atoms 3, a suitable flow of molecular and atomic oxygen ions at the mouth of a tube for partial ionization of gas of molecules and atoms 4, however, is achieved by a suitable high frequency generator power and pulse length and period.

The artificial wire 8 is moved along the tube for partial ionization of gas molecules and atoms 4 by means of a guide 7 so that at the selected flow of neutral oxygen atoms and molecular and atomic oxygen ions, the required dose of neutral oxygen atoms and molecular and atomic oxygen ions is achieved for optimum surface treatment artificial veins 8.

Suitable flow of all gas atoms and molecules is achieved by vacuum pump 9. The final pressure of the vacuum pump must be less than 100 mbar and preferably lower than 0.01 mbar, thus ensuring a negligible influence of the residual atmosphere. The pumping speed of the pump must be greater than 3 m ³ / h and preferably greater than 16 m ³ / h.

Claims (5)

A method of treating bio-medical prostheses for improving their antithrombogenic properties, wherein said prostheses are made of PET polymers or similar polymers, characterized in that the prosthesis is exposed to a mixture of neutral oxygen atoms and positively charged molecular and atomic oxygen ions, wherein the exposure to a mixture of neutral oxygen atoms and positively charged molecular and atomic oxygen ions in pulses is such that in a single pulse a dose of neutral oxygen atoms is obtained between 1O ²⁰ m ' ² and 10 ²⁸ m' ² , and preferably between 10 ²² m ² and 10 ²⁶ m ' ² , and a charge of charged molecular and atomic oxygen ions between 10 ¹⁶ m' ² and 10 ²³ m ' ² , and preferably between 10 ¹⁷ m' ² and 10 ²¹ m ' ² , and the interval between individual pulses lasts between 10 s and 300 s, preferably between 60 s and 150 s, and that the flow of neutral oxygen atoms and positively charged molecular and atomic oxygen ions is approximately uniform to the surface of the prosthesis. Method according to claim 1, characterized in that the approximately uniform flow of neutral oxygen atoms and positively charged molecular and atomic oxygen ions onto the surface of the prosthesis is achieved by uniformly moving the prosthesis during the treatment and thus the possible inhomogeneity of treatment is less than a factor of 100. Method according to claim 1, characterized in that the temperature of the cardiovascular prostheses during treatment is lower than 170 ° C, preferably lower than 75 ° C. Method according to claim 1, characterized in that the kinetic energy of the positively charged molecular and atomic oxygen ions at the surface of the prosthesis is between 1 eV and 1000 eV, and preferably between 5 eV and 100 eV. Biomedical prostheses with improved antithrombogenic properties, said prostheses being made of PET polymers or similar polymers, characterized in that they are treated by the method of claims 1 to 4.