WO2016059024A1

WO2016059024A1 - Method of growing carbon nanowalls on a substrate

Info

Publication number: WO2016059024A1
Application number: PCT/EP2015/073630
Authority: WO
Inventors: Ita Junkar; Martina MODIC; Alenka Vesel; Miran Mozetic; Gheorghe DINESCU; Sorin Ionut VIZIREANU; Silviu-Daniel STOICA; Karin Stana KLEINSCHEK
Original assignee: Jozef Stefan Institute; National Institute For Laser, Plasma And Radiation Physics; University of Maribor
Priority date: 2014-10-13
Filing date: 2015-10-13
Publication date: 2016-04-21
Also published as: GB201418056D0; EP3206728A1

Abstract

A method for growing carbon nanowalls on a substrate of an implantable medical device by means of a processing chamber is provided, said method comprising: providing said substrate in said processing chamber, evacuating said processing chamber to a processing pressure, entering a gas mixture inside the processing chamber, providing radicals inside said chamber and adsorbing said radicals on said substrate leading to growing of carbon nanowalls on said substrate.

Description

Method of growing carbon nanowalls on a substrate

FIELD OF TECHNOLOGY

The present invention relates to a method for growing carbon nanowalls on a substrate of an implantable device by means of a processing chamber, and furthermore to medical devices comprising a substrate treated by said method.

BACKGROUND OF THE INVENTION

Although new generation of pyrolityc carbon heart valves have significantly decreased undesired thrombotic complications in comparison to the old generation mechanical heart valves the thromboembolism still presents a major drawback.

When artificial materials come into contact with blood, various undesirable host responses such as thrombosis, inflammatory reactions, infections and various other responses occur. Such responses are minimized if the materials are hemocompatible. In fact surface-induced thrombosis is one of the key elements which reduce the life span of the artificial implant in contact with blood. Many attempts to improve hemocompatibility of vascular prosthesis, namely heart valves prosthesis, have been done in the last few decades. However, so far no ideally hemocompatible surface has been developed. Mainly the improvements have been done in scope of coating the surface with various hemocompatible coatings.

In case of biological heart valves the optimization of its functions is done mainly in direction of preventing calcification. In CA 2690539 a polymer coating was applied to the surface of biological heart valves which was shown to reduce calcification, improve hemocompatibility, biocompatibility and bacterial resistance and has higher life span.

Further EP 2491959 discloses a method for coating various biological materials, especially materials used for heart valves, by an inorganic coating which improves its properties. The coating technology is based on pulsed laser deposition of biocompatible inorganic material onto the biological material.

US 5725573 describes a method for coating a titanium-based metal alloy for heart valve with a coating of diamond-like carbon is disclosed. The method is based on ion beam assisted deposition to form a gradient at the surface of the titanium alloy comprising metal alloy/metal-silicide/(silicon or germanium)/silicon- or germanium-carbide/DLC.

Coating of titanium based materials used for heart valves by diamond like carbon is disclosed also in US 5605714. While in US 6761736 diamond like carbon coating is deposited on the heart valves made from polymeric base by ion beam.

In EP 2526977 a method for producing a surface layer on the heart valve made from polyetheretherketon (PEEK) is described. In this method the surface is treated by Ar⁺ ion etching in an atmosphere containing precursors of carbon, nitrogen, and silicon and an argon carrier gas. By such method a gradient surface layer on the implant surface is formed.

Common material used for mechanical heart valves is pyrolytic carbon. Methods of coating pyrolytic carbon to various substrates are known to those skilled in the art. For example US 3298921 , US 3399969 and US 3547676 disclose such methods. Although pyrolytic carbon seems to be compatible with human body over longer period of time and has appropriate mechanical properties, like hardness, wear resistance, friction etc., it still lacks of desired hemocompatible properties. Some morphological modifications of surfaces in order to improve biocompatible properties are known in the art. For instance CN 101496916 describes the surface of steel endovascular stents which are coated with nanometer coating and a microstructure surface. This provides fast endothelization and good hemocompatibility. The method is based on SiOx: H nanometer coating on the surfaces of the micropores of stainless steel implant.

In WO 2006022887 a morphological modification is done by coating the surface with nanoparticles of less than 500 nm in size. This coating can be used on various materials, also carbon and it reduces protein unfolding, preventing inflammatory and fibrotic cell accumulation and other adverse biological reactions. Hence, one object of the present invention is to enhance hemocompatibility of surfaces, especially surfaces comprising pyrolytic carbon.

SUMMARY OF THE INVENTION

According to the present invention a method for growing carbon nanowalls on a substrate of an implantable medical device by means of a processing chamber is provided, said method comprising: providing a substrate in said processing chamber, evacuating said processing chamber to a processing pressure, entering a gas mixture inside the processing chamber, providing radicals inside said chamber, and adsorbing said radicals on said substrate leading to growing of carbon nanowalls on said substrate.

Further a medical device treatable by means of the method in accordance with the present invention is disclosed. Especially a heart valve addresses the need to improve methods for increasing hemocompatibility of heart valves made from any material, in particular pyrolytic carbon, against the state of the art. According to the present invention deposition of an anti-thrombogenic coating on the surfaces of heart valves that come in contact with human blood is provided. Hence, it provides a method for improved hemocompatibility of heart valves by depositing a stable nanostructured carbon coating, in particular carbon nanowalls. The efficiency of the method according to the invention is confirmed by behavior of blood platelets on modified heart valves, that is heart valves comprising a substrate with a carbon nanowalls structure applied by the present invention. Against the state of the art the methods of the invention prevents adsorption and transformation of platelets from normal state in healthy blood to highly activated states, which would further lead to undesired thrombus reactions. Thus the present invention improves hemocompatibility of heart valve surfaces, as both adhesion and transformation of platelet shape from its normal state to activated states is highly reduced.

When the heart valve is weakened it has to be replaced with an artificial one. The heart valves are divided into two basic types; mechanical heart valves which are more durable and biological heart valves which are more hemocompatible. Patients with mechanical heart valves prosthesis are prone to thromboembolic complications and thus have to be treated with anticoagulant drugs for the rest of their lives. Moreover they should be kept under strict diet and activity constrains. Biological prostheses were developed in order to overcome these complications, as they provide natural anticoagulation. Mainly such grafts are made from human tissue (allograft or homograft) or animal tissue (xenograft). However the main drawback of such graft is in calcification, which causes the graft to lose their functionality. Biological prosthesis cannot withstand such constant mechanical loads and thus have shorter life span in comparison to mechanical ones. Usually another surgical procedure is needed in 10 to 15 years' time due to degeneration of the biological heart valve.

According to the invention the surface properties of implantable medical devices, like for instance mechanical heart valves, in order to reduce thromboembolism was modified. The surface of mechanical heart valve is coated by carbon nanowalls, which highly reduces adhesion and activation of platelets and enables appropriate adsorption of blood proteins. The mechanical heart prosthesis or other implantable medical devices is modified by treatments with carbon containing gaseous radicals which form appropriate nanostructure topography leading to a coated surface of the device.

Implantable medical device means a device, which will have in use direct contact to human blood.

The disease or condition to be treated with implantable medical devices like mechanical heart valve according to this invention is selected from a group of cardiac diseases. By this method of invention the mechanical heart valves have superior biocompatible and hemocompatable properties and longer life span.

Carbon nanowalls are materials composed predominantly of carbon whereas the carbon content in said material is essentially over 50 atomic percent, but typically above 90 atomic percent. The carbon nanowalls are two-dimensional nanostructures containing predominantly carbon atoms. Typically they are standing with their planes almost perpendicular to the substrate surface, or at angles of at most 45 degrees with respect to the normal of the surface. The height of carbon nanowalls, as measured from the substrate, and also the length, are essentially larger than the thickness. The thickness of carbon nanowalls is below one micrometer. A typical thickness of the carbon nanowals is between 1 and 50 nanometers. The carbon nanowalls are often randomly distributed on the surface of substrates with no preferential orientation in the lateral dimensions of the surface. A typical distance between each carbon nanowall is about one micrometer, but in the broadest sense as should be understood in this document the distance between neighboring carbon nanowalls is between 0.01 and 10 micrometers. Carbon nanowalls deposited onto a solid substrate often appear as a network containing separate nanowalls that could be of different thickness, orientation and length providing the dimensions retain above limits stated above. Carbon nanowalls are deposited on substrates by attachment of carbon containing gaseous radicals to the surface of the substrate. The list of suitable said radicals contain but is not limited to C atoms, C₂ dimers, CH_X (0<x<4), C₂H_y (0<y<6), and C_nH_x ⁺ (n=1...8, x=1..3). Said radicals are unstable and thus do not abound in gas at thermal equilibrium. Hence, said radicals are synthesized in non- equilibrium states of gases like non- equilibrium gaseous plasma. The gaseous plasma suitable for synthesis of said radicals is created in gas mixtures containing at least one gas comprising molecules of hydrocarbons (like CH₄, C₂H₂, C₂H₄, C₂H₆, and more complex hydrocarbons).

Typically, other gases such as noble gases (He, Ar, Ne, Xe, Kr) and hydrogen (H₂) are added to said gas mixture. Other gases in small concentrations could be beneficial, too. The said radicals attached to the substrates and carbon atoms self-assemble upon appropriate conditions leading to growth of carbon nanowalls.

Broadly, the invention provides a method for improved hemocompatibility of implantable medical devices like for instance heart valves by deposition of carbon nanowalls on the surfaces that come in contact with human blood. The efficiency of the method which is the subject of this invention is confirmed by behavior of blood platelets on modified heart valves, by the way of example. Other implantable medical devices being in direct contact with human blood may show similar results. Against the state of the art the methods of the invention prevents transformation of platelets from normal state in healthy blood to highly activated states, which would further lead to undesired thrombus reactions. Thus, the present invention improves hemocompatibility of heart valve or implantable medical device surfaces in general, as transformation of platelet shape from its normal state is highly reduced.

The present invention relates to methods for manufacturing of heart valves. In particular the present invention relates to optimization of heart valves surface made from any material, in particularly pyrolityc carbon, by depositing nanostructured hemocompatible material on the wall of implants, which come in contact with human blood. The present invention is described with reference to artificial heart valves comprising at least one entity made of pyrolytic carbon. It should be understood that the present invention might be embodied in other implantable medical devices made of different materials. The invention may work generally for all surfaces which are temperature stable, that is which can be heated to higher temperatures in the processing chamber.

EMBODIMENTS

According to one embodiment said providing of radicals inside the chamber is performed by converting said gas mixture into a state of gaseous plasma comprising radicals.

In one embodiment a heart valve made from pyrolytic carbon is coated with carbon nanowalls in a suitable processing chamber. The processing chamber is evacuated to a pressure below 1 Pa. An electrical discharge is created in the processing chamber in a gas mixture containing acetylene, hydrogen and argon or plasma generated in such mixture is injected in the processing chamber. The gas is converted to the state of gaseous plasma containing radicals such as C atoms, C₂ dimers, CH_X (0<x<4), and C₂H_y (0<y<6). These radicals will adsorb on pyrolytic carbon which is heated to elevated temperature in order to allow for optimal surface mobility of atoms and release of weakly bonded carbon atoms. Thus, self-assembly of carbon arriving from the gas phase will occur leading to formation of carbon nanowalls. The nanowalls will in turn reduce adsorption of fibrinogen and lower adhesion of platelets and their activation. The enzyme thrombin acts on the release of small peptides from fibrinogen, which causes the polymerization of fibrinogen into fibrin. Thus the fibrin structures, if appearing on a surface of heart valves, may cause accumulation of blood proteins, and further activation of blood platelets which will with high probability result in aggregation of platelets and surface induced thrombosis.

In further preferred embodiments the carbon nanowalls are deposited onto heart valves made from pyrolytic carbon in such a way that they form a stable network on the entire surface that comes in contact with human blood after implanting the heart valve. The thickness of separate nanowalls is essentially the same or the distribution of surface carbon nanowalls over the thickness is preferably narrow so that at least 50% of the nanowalls on the surface of a heart valve assume the thickness not deviating for more than 30% from the average thickness. The average thickness of carbon nanowalls in this embodiment is between 1 and 100 nm, and the preferred distance between neighboring nanowalls is between 50 and 5000 nanometers. The preferred height of the nanowalls is between 0.1 and 30 micrometers. Large deviation from preferred embodiments might lead poorer hemocompatible properties of heart valves coated with carbon nanowalls. Preferably the deposition of carbon nanowalls onto the surface of heart valve made from pyrolytic carbon is performed at heart valve temperature above 600 K, or the heart valve is heated to temperature above 600 K for at least 100 seconds and cooled down to room temperature prior to implantation into human body. Such elevated temperatures are beneficial for the durability of the heart valves modified according to the methods of invention since the elevated temperature allows for release of weakly bonded substances prior to implantation. The substances might otherwise release after implantation what could cause serious post-implantation complications. Furthermore, the elevated temperature during deposition and/or heating in oxygen- free atmosphere prior to implantation assures for highly hydrophobic nature of the carbon nanowalls what is also beneficial.

According to the invention improvement of hemocompatible properties of pyrolytic carbon based materials is achieved by coating the surface with carbon nanowalls. Appropriate hydrophobicity, size and distribution of nanowalls prevent adhesion and activation of platelets which reduces thromboembolic complications on such surfaces.

BRIEF DESCRIPTION OF THE DRAWINGS

Other advantages of the invention will become apparent upon reading the following descriptions and accompanying drawings, said drawing forming part of this application, presenting as follows:

Fig. 1 shows schematic of the contact between a flat surface untreated pyrolytic carbon and same material covered with carbon nanowalls; Fig. 2 shows a scanning electron microscope image of untreated pyrolytic carbon after incubation with human blood at low magnification; shows a scanning electron microscope image of untreated pyrolytic carbon after incubation with human blood at high magnification;

Fig. 4 shows a scanning electron microscope image of pyrolytic carbon coated with carbon nanowalls of hydrophobic character after incubation with human blood at low magnification;

Fig. 5 shows a scanning electron microscope image of an activated blood platelet on the surface of pyrolytic carbon coated with carbon nanowalls of hydrophobic character after incubation with human blood;

Fig. 6 shows a scanning electron microscope image of pyrolytic carbon coated with carbon nanowalls of hydrophilic character after incubation with human blood at low magnification. Fig. 7 shows a scanning electron microscope image of pyrolytic carbon coated with carbon nanowalls of hydrophilic character after incubation with human blood at high magnification; and finally shows the surface density of blood platelets on untreated heart valves and heart valves treated by the method of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The hemocompatibility of standard heart valves is not optimal. The blood platelets often adhere to the surface of pyrolytic graphite, and transform from inactive to active types. The active types release an enzyme called thrombokinase which favors transformation of blood proteins, in particular fibrinogen to fibrin.

Platelets are self-sufficient as they contain all the necessary ingredients needed for adhesion, aggregation and formation of thrombi. In fresh blood platelets have spheroidal form, but have a tendency to extrude hair-like filaments from their membranes and can adhere to each other (Shi et al.; Biomaterials and Tissue Engineering, Springer- Verlag, Berlin; 2004). Their function is to arrest bleeding through the formation of platelet plugs and to stabilize platelet plugs by catalyzing coagulation reactions which lead to the formation of fibrin, as described above.

The basis for understanding platelet function is their structure. In un-stimulated state platelets have a discoid shape, which is maintained by a cytoskeleton of microtubules. The external surface coat of platelets contains membrane-bound receptors (glycoproteins lb and Ilb/IIIa) that mediate contact reactions of adhesion (platelet - surface) and aggregation (platelet - platelet). The membrane also provides a phospholipid surface, which accelerates the coagulation cascade and forms a spongy, canal-like open network that represents an expanded reactive surface to which plasma factors are selectively adsorbed (Ratner et al.; Academic Press, San Diego; 2008).

A possible way to assess the activation degree of adherent platelets is to study their shape and the number of adherent platelets. According to Goodman (Goodman et al.; Platelet responses to silicon-alloyed pyro lytic carbons, Journal of Biomedical Materials Research Part A 83A, 64; 2006), their shape can be categorized on a scale from lower to higher level of activation as: round or discoidic (R); dendritic or early pseudopodial (D); spread- dendritic or intermediate pseudopodial (SD); spreading or late pseudopodial (S) and fully spread (FS). According to the methods of the present invention, the adsorption of blood proteins and transformation to active types is prevented by nanostructuring the surface of the heart valve, preferably by deposition of carbon nanowalls. The presence of nanowalls minimizes the contact area between a blood platelet and the substrate. The schematic of this effect - interaction between a blood platelet and the substrate of different morphology is presented in Fig. 1.

Pyrolityc graphite does not have a rich surface morphology so the contact area between the platelet and the substrate is large (Fig. 1 (a)). Such an effect is not observed after treatment of the substrate by the method of the present invention. Namely, the presence of carbon nanowalls on the surface of the substrate minimizes the contact area (Fig. 1 (b)). A blood platelet touching the surface will find the substrate a foreign material and will start activating. The first step in activation is adoption to the surface morphology. For the case of flat surface of the substrate the blood platelet will lay over the surface so the contact area will be about the lateral dimension of a platelet, i.e. about 1 μιη². Such a large contact area will allow for quick activation of the blood platelet. More activated blood platelets exhibit even larger lateral dimension (they flatten) so the contact area is increasing with increasing activation stage as shown in Fig. 1 (c). Finally the blood platelet will assume a flake-like morphology of lateral dimension of about 10 μηι, thus the contact area of 100 μιη² - Fig. 1 (e). Such a development of the platelet morphology is not possible for the case when the substrate is covered with carbon nanowalls of right dimensions. Fig. 1 (b) reveals that spreading of a blood platelet is very difficult to occur providing the distance between neighboring carbon nanowalls is smaller than the dimension of inactivated platelet. Another required condition is also that the depth between neighboring nanowalls is large enough, preferably larger than the distance between neighboring carbon nanowalls. In such a case as shown schematically in Fig. 1 (a) the platelet will not detect the surface of the substrate so it will just desorb from the surface as shown schematically in Fig. 1 (d). Another option is that the blood platelet will remain on the surface without activation long after the incubation of the substrate with human blood has been performed - Fig. 1 (f).

Presence of carbon walls on the surface of a material a heart valve is made from thus prevents accumulation as well as activation of blood platelets. Taking into account schematics presented in Fig. 1 one can benefit from the nanowalls only providing the following conditions are satisfied: i) the nanowalls are dense on the surface and cover the entire surface of a heart valve that comes into contact with human blood; ii) the majority of nanowalls are perpendicular to the surface; iii) the lateral distance between the neighboring nanowalls is smaller than the lateral dimension of inactivated blood platelet; iv) the gaps between neighboring nanowalls are deep enough so that blood platelets cannot adopt to the morphology of the material coated with carbon nanowalls; v) carbon nanowalls have almost uniform thickness versus the depth.

In the preferred embodiment the nanowalls deposited onto heart valves satisfy all above stated conditions. A subject of this invention is also a heart valve product made of or containing pyrolytic carbon since the adhesion of carbon nanowalls is best for this type of substrate. Said heart valve products are used when the original valves fail. In such cases the natural heart valve has to be replaced by an artificial one. In therapeutic treatment said heart valve products may be used for replacement of natural ones. Example 1 In the example disclosed here a heart valve made from pyrolytic carbon has not been treated according to the methods of invention. The incubation with human blood has been performed as follows. Whole blood was drawn from healthy volunteers via vein puncture. The blood was drawn into 9 ml tubes with tri sodium citrate anticoagulant (Sigma), and the number of platelets in whole blood was counted (Cell-DY 3200, Abbott). Afterwards the fresh blood was incubated with pyrolytic graphite surfaces in 24 well plates for 1 hour at room temperature and at gentle shaking at 300 RPM. Each sample was incubated with 1 ml of whole blood. After 1 h of incubation, 1 ml of PBS (phosphate-buffered saline) was added to the whole blood. The blood with PBS was then removed and the PET surface was rinsed 5 times with 2 ml PBS in order to remove weakly adherent platelets.

Preparation of pyrolytic carbon samples for SEM analysis was done in the following manner. After incubation of whole blood weakly adherent cells were removed from the surface by rising with PBS. Adherent cells were subsequently fixed with 400 μΐ of 1 % PFA (paraformaldehyde) solution for 15 min at room temperature. Afterwards the surfaces were rinsed with PBS and then dehydrated using a graded ethanol series (50, 70, 80, 90, 100 and again 100 vol. % ethanol) for 5 min and in the last stage in the series (100 vol. % ethanol) for 15 min. Afterwards the samples were placed in a Critical Point Dryer and dried samples were subsequently coated with gold and examined by means of SEM at accelerating voltage of 5kV.

Both concentration and morphological shape of blood platelets after incubation were monitored by scanning electron microscopy (SEM). Fig. 2 reveals a typical SEM image of a heart valve made from pyrolytic carbon at rather low magnification of 2000 times. The scale bar in Fig. 2 is 10 micrometers. There are numerous small flakes of irregular shape on the surface. These flakes are well-activated blood platelets and correspond to the situation (e) in Fig. 1. The flakes are so dense on the surface that they cover almost entire area and overlap in some cases, too. Such a high concentration of fully activated blood platelets reveals rather poor hemocompatibility of untreated pyrolytic carbon. The density of flakes in Fig. 2 is difficult to determine since they overlap but one can determine the lowest possible value which is estimated to about 200 platelets on the entire surface or about 20,000 fully activated platelets per mm². Apart from the flakes which dominate there are also platelets in less activated states. They are recognized as spherical or dendritic features in Fig. 2. There more than about 50 such platelets in the image, so the density of such rather poorly activated platelets is about 5,000 mm^" . The density of platelets is graphically presented in Fig. 8.

A closer view to the surface of untreated pyro lytic carbon is shown in Fig. 3. Here, the magnification is 10,000 times so the scale bar is 1 micrometer. In this figure one can observe lots of fully activated blood platelets which are recognized as thin flakes of irregular shape and typical lateral dimension of several micrometers. There are also few platelets in dendritic form, one right in the center of the image.

Example 2

In the example disclosed here a heart valve made from pyrolytic carbon has been treated according to the methods of invention. The incubation protocol was the same as described in Example 1. Fig. 4 represents a typical SEM image of the sample incubated with human blood. The network of carbon nanowalls is recognized easily but blood platelets are hardly distinguished. The image therefore indicates absence of blood platelets in inactivated state of early activated state (such as the one in the centre of Fig. 3). Blood platelets in fully spread form are difficult to observe at this magnification since they are of the form of semi-transparent membranes. Three of them are pointed with arrows. The fully spread blood platelets on carbon nanowalls are better observed at higher magnification. Fig. 5 represents a corresponding SEM image. The platelet is in the centre of the image and resembles a membrane. Such images are difficult to obtain since very few platelets were observed. In order to estimate the density of platelets on such samples systematic imaging over larger area was performed. The concentration of platelets for the sample covered with hydrophobic carbon nanowalls was then estimated to about 300 fully spread ones per mm² and 50 inactivated per mm². The density of platelets is graphically presented in Fig. 8. These numbers confirm the schematic presented in Fig. 1. The majority of blood platelets touching the surface of samples coated with hydrophobic carbon nanowalls does not stick to the surface but leave it as shown schematically in Fig. 1 (d). Only a few of them stay on the surface and activate there. This Example (Example 2) is a preferred embodiment according to the methods of invention.

Example 3

In the example disclosed here a heart valve made from pyrolytic carbon has been treated according to the methods of invention, but were allowed to lose the hydrophobic character. Carbon nanowalls were deposited as in Example 2 but then briefly treated with oxygen plasma in order to assume hydrophilic character. Then, they were incubated according to standard protocol as described for Example 1.

A SEM image for this Example is shown in Figure 6 (low magnification) and another one in Fig. 7 (high magnification). The network of carbon nanowalls observed in Fig. 6 is same as in Fig. 4 since the oxygen plasma treatment did not cause morphological changes but only functionalization with polar functional groups so that the surface properties changed from hydrophobic to hydrophilic. The blood platelets in Figure 6 are denser than in Fig. 4 but scarcer than in Fig. 2. The number of non-activated blood platelets as deduced from the image presented in Fig. 6 is about 25 in the image, so the density of such rather poorly activated platelets is about 2,500 mm^"2. This value is comparable to the Example 1 (substrates without carbon nanowalls). The value is much larger than for hydrophobic carbon nanowalls (Example 2) just confirming well-known fact that hydrophilic surfaces favor adhesion. The number of fully spread is very difficult to evaluate from images shown in Fig. 6 or 7 but it visually appears that it is much smaller than the number of inactivated blood platelets. The number of fully spread platelets in Fig. 6 is about 10 in the image, so the density of such highly activated platelets is about 1,000 mm^"2. The density of platelets is graphically presented in Fig. 8. The comparison of images 2 and 6 indicate that blood platelets do adhere on the surface of hydrophilic carbon nanowalls but do not activate much.

Heart valves according to the invention show increased hemocompatibility of artificial heart valves, in particular those made from or containing pyrolytic carbon. Against the state of the art it represents a method for minimization of blood platelet adhesion on the surfaces of an artificial heart valve likely to be exposed to human blood after implantation. The present invention does not involve deposition or grafting of any known biological anti-thrombogenic coating on the surface of a heart valve. Hence, it provides a method for improved hemocompatibility of heart valves by deposition of carbon nanowalls on surfaces exposed to human blood. The efficiency of the innovative method for coating heart valves, which is the subject of this invention, is confirmed by behavior of blood platelets. Against the state of the art the methods of the invention prevent adhesion of blood platelets due to minimization of the contact area (appropriate distribution and size of carbon nanowalls) as well as proper surface hydrophobicity. The methods of invention minimize transformation of platelets from normal state in healthy blood to highly activated states, which would further lead to undesired thrombus reactions. Thus the present invention improves hemocompatibility of artificial heart valve surfaces, as adhesion and transformation of platelet shape is highly reduced.

Many modifications and other embodiments of the inventions set forth herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the inventions are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Moreover, although the foregoing descriptions and the associated drawings describe example embodiments in the context of certain example combinations of elements and/or functions, it should be appreciated that different combinations of elements and/or functions may be provided by alternative embodiments without departing from the scope of the appended claims. In this regard, for example, different combinations of elements and/or functions than those explicitly described above are also contemplated as may be set forth in some of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. A method for growing carbon nanowalls on a substrate of an implantable medical device by means of a processing chamber, comprising:

providing said substrate in said processing chamber;

evacuating said processing chamber to a processing pressure;

entering a gas mixture inside the processing chamber;

- providing radicals inside said chamber; and

adsorbing said radicals on said substrate leading to growing of carbon nanowalls on said substrate.

2. Method according to claim 1 , wherein said substrate comprises pyro lytic carbon.

3. Method according to claim 1 or 2, wherein said processing pressure is below 1 Pa.

4. Method according to any of the preceding claims, further comprising heating, especially above 600 K, said substrate directly and/or indirectly, thereby increasing adsorption of said radicals on said substrate.

5. Method according to any of the preceding claims, said gas mixture containing acetylene, hydrogen and argon in a non- equilibrium state of gas or plasma.

6. Method according to any of the preceding claims, said gas mixture further comprising gases such as noble gases (i.e. He, Ar, Ne, Xe, Kr) and/or hydrogen (¾).

7. Method according to any of the preceding claims, said radicals comprising carbon radicals such as C atoms, C₂ dimers, CH_X (0<x<4), C₂H_y (0<y<6) and/or C_nH_x ⁺ (n=1...8, x=1..3). Implantable medical device with at least one entity, said at least one entity having at least one surface treated according to a method of any of the preceding claims.

Medical device according to claim 8, said at least one entity comprising pyrolytic carbon, said pyrolytic carbon entity having a surface treated according to a method of any of the preceding claims 1 to 8.

Medical device according to claim 8, said medical device being an artificial heart valve having at least one entity made of pyrolytic carbon to be contacted with human blood.

Medical device according to claims 8 or 9, said surface comprising a carbon nanowall structure, wherein a lateral distance between the grown neighboring carbon nanowalls is smaller than the dimension of a blood platelet in inactivated form, preferably three times smaller, most preferably ten times smaller.

Medical device according any of the claims 8 to 10, wherein said lateral distance between the neighboring carbon nanowalls is between 30 nm and 3000 nm, preferably between 200 nm and 2000 nm.

Medical device according any of the claims 8 to 12, wherein a thickness of said grown carbon nanowalls is below 100 nm, preferably below 30 nm, and larger than 5 nm.

Medical device according any of the claims 8 to 13, wherein the height of said grown carbon nanowalls is over 100 nm, preferably over 1000 nm.

Use of medical devices of any of the preceding claims 8 to 14 in therapeutic treatment of disease or condition.