JP2003512098A - Articles that are biocompatible - Google Patents

Abstract

(57) Abstract The present invention relates to articles, particularly implants. The article comprises a substrate which is at least partially coated with at least one layer and on which a substance containing proteins, peptides and / or saccharides is at least partially present, wherein said layer directly adjacent to said substance is , At least one metal selected from titanium, zirconium and hafnium, or a compound of the metal and one or more nonmetals and / or semiconductors, or a compound of the metal and one or more other metals It contains an alloy and is applied by a vacuum coating method. Further provided is a method of making the article, wherein the layer is applied to the substrate under vacuum, and a method of using the article.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION

The present invention relates to a particularly biocompatible article, in particular an implant such as a stent, a method for its production and its use.

[0002]

BACKGROUND OF THE INVENTION

Modern biomedical sciences are characterized in that they bring natural biological fluids and tissues into contact with synthetic products in order to mimic or influence defined physiological processes. Examples include implant insertion, medical devices used externally,
Alternatively, in vitro culture of a specific cell culture in an artificial environment can be mentioned.

The principle applied in these cases is that the higher the compatibility between natural and synthetic substances the better. Thus, biocompatibility refers to the specific use of a technically defined material in a physiologically defined environment for the purpose of supporting or substituting a particular physiological function. Thus, for example, the surface of an orthopedic prosthesis should ideally be designed to be incorporated into the bone as quickly as possible, but at the same time the risk of infection should be low. The biocompatibility of coronary stents is optimal if their thrombogenicity is minimal or absent and has little or no effect on the function of the cells in direct contact. Let's do it. In particular, proliferation of so-called intimal layer cells of the blood vessel wall must be avoided.

Another success of modern medicine is the temporary substitution of organs or their function by medical devices, such as hemodialysis, cardiac bypass, or extracorporeal membrane oxygenation (ECMO). Even in these cases, there is a direct relationship between biocompatibility and the frequency of complications, and some of these complications include iatrogenic anticoagulant-induced hemorrhagic complications and hemolysis. Is a life-threatening thing like.

Many attempts have been made in the past to at least partially solve the aforementioned problems. In fact, Dunn et al., In 1994, attempted to modify the surface of titanium and deposit the antibiotic ciprofloxacin on it (Ciprofloxacin Attachment to Porous-Coated Titanium Surfaces (" Adhesion of ciprofloxacin to coated titanium surface "), DS Dunn, S. Raghava
n, RG Volz, Journal of Applied Biomaterials, Vol. 5, 325-331, 1994).

[0006] In particular, coronary stenosis of the heart is being treated more and more today by the implantation of stents. These stents are made of medical stainless steel, tantalum,
Made of Nitinol or Titanium (DE-A-195 33 682, DE-A-196 53 708; Characte
ristics of metals used in implants, see I. Gotman, J. Endourol., 11 (6): 383-389; and US-A-5,356,433.
However, the use of these metals can result in two significant complications. For one, blood coagulation is activated by metals. This can lead to stent occlusion, especially with thrombus occurring within the first 4 days after implantation. A second problem with the use of coronary stents is the recurrence of stenosis due to intimal hypertrophy. The coronary vessels of the heart consist of three layers of tissue. The intima, media and adventitia. The intima consists of endothelial cells that line the lumen of blood vessels and are in direct contact with the bloodstream. The boundary between this and the media consisting of smooth muscle cells is formed by a so-called inner elastic thin layer. next,
The outer layer, or adventitia, forms the connection between the blood vessel and the surrounding tissue. Histological studies have shown that the introduction of stents results in damage to the endothelial layer of the intima, especially the lamina of the inner elastic layer. The living body responds to this stimulus by proliferation of intimal cells. This is called intimal hypertrophy, but it can be widespread, which can cause reocclusion of the vessel lumen within the stent.

[0007] Technical attempts have been made to reduce the tendency to thrombosis and / or intimal hypertrophy by applying various coatings to stents. In fact
EP-A-0 836 839 discloses a gold coating layer applied to a stent. Antithrombogenic
Coating of Stents Using a Biodegradable Drug Delivery Technology ("Stent Antithrombogenic Coating Method by Biodegradable Drug Delivery Technology"), R. Herr
man, G. Schmidmaier, B. Maerkl, A. Resch, I. Haehnel, A. Stemberger, E.
Alt, Thromb. Haemost., 82, 51-57, 1999 discloses a stent with a steel or gold surface coated with biodegradable polylactic acid. "Local drug delive
ry of argatroban from a polymeric-metallic composite stent reduces plate
let deposition in a swine coronary model, "(" Local drug delivery of argatroban from a polymer-metal composite stent reduces platelet deposition in the porcine coronary model ") KR Kruse, JJ Crowley, JF Tanguay, RM Santos, DS
Millare, HR Phillips, JP Zidar, RS Stack, Catheter Cardiovasc. I
nterv., 46 (4), 503-7, 1999 is a polymer containing argatroban /
Regarding metal stents. In addition to the anticoagulant heparin (DE-A-195 33 682), the anti-cell proliferative agent Taxol and the anti-inflammatory substance dexamethasone have been applied to the stents. Antiproliferative stent coatings: Taxol and related compounds ((
Anti-Cell Proliferative Stent Coating-Taxol and Related Compounds "), C. Herdeg
, M. Oberhoff, KR Karsch, Semin. Interv. Cardiol., 3, (3-4), 179-9, 19
98; Anti-inflammatory Stent Coatings. Dexamethasone and Relates Compoun
ds ("Anti-inflammatory stent coating-dexamethasone and related substances"), SH
See Park, AM Lincoff, Semin. Interv. Cardiol., 3 (3-4): 191-5, 1998.
It was also investigated in a clinical study that a stent provided with a silicon carbide coating also reduced its endothelial proliferation and platelet activation. Silicon ca
rbide-coated stents: clinical experience in coronary lesions with increa
sed thrombotic risk ("Silicon Carbide Coated Stent-Clinical Experience in Coronary Injury with High Thrombosis Crisis"), B. Heublein, C. Ozbek, K. Pethig, J. En
dovasc. Surg., 5 (1), 32-6, 1998; Silicon-carbide coated coronary stents
have low platelet and leukocyte adhesion during platelet ativation.
Tigchelaar, PJ deKam, HJ Crijns, W. van Oeveren, J. Investig. Med.,
See 47 (6), 304-10, 1999.

Coated stents include: Coated stents: local pharamacology (“Coated Stents—Local Pharmacology”), VK Raman, ER Edelman, Semin. Interv. Cardio
l., 3 (3-4), 133-7, 1998; In vivo evaluation of a fluorine-acryl-stylene-u
rethane-silicone antithrombogenic coating material copolymer for intrava
scular stents ("In-vivo evaluation of fluorine-acrylic-styrene-urethane-silicone copolymer as an antithrombotic coating material copolymer for endovascular stents"), T. Matsuhashi, H. Miyachi, T. Ishibashi, K. Sakamoto. , A. Yama
dera, Acad. Radiol., 3 (7), 531-8, 1996; Antithrombogenic coating of stent
s using a biodegradable drug delivery technology, R. Herrmann, G. Schmidmaier, B.
Markl, A. Resch, I. Hahnel, A. Stemberger, E. Alt. Thromb. Haemost., 82 (
1), 51-7, 1999.

In addition to these methods, attempts have been made to coat the surface with albumin modified to be covalently bonded. The Potent Platelet Inhibitory Effects of S-
Nitrosated Albumin Coating of Artificial Surfaces, N. Maalej, R.
Albrecht, J. Loscalzo, JD Folts, JACC, 33 (5), 1408-1414, 1999;
Adherence and Proliferation of Endothelial Cells on Surface-Immobilized
Alubumin-Heparin Conjugate ("Endothelial cell attachment and proliferation in surface-immobilized albumin-heparin conjugate"), GW Bos, NM Scharenborg, AA Poot, GH
M. Engbers, JGA Terlingen, T. Beugerling, WG Van Aken, J. Feijen, T
See issue Engineering, 4 (3), 267-279, 1998. Hydration and preferentia
l molecular adsorption on titanium in vitro, KE Healy and P. Bucheyne, Biomaterials
In 1992, Vol. 13, No. 8, 553-561, the behavior of titanium in human serum was investigated by surface spectrophotometry.

[0010] None of the above development methods have yet brought to market the inspiring product. The occurrence of stent thrombosis is currently called a platelet aggregation inhibitor,
Although systemically administered drugs can be sufficiently treated, there is still no satisfactory treatment for recurrence of stenosis due to intimal hypertrophy.

The aforementioned problem comprises a substrate that is at least partially coated with at least one layer, and is at least partially protein, peptide and / or saccharine.
A solution containing a charide) is solved according to the invention by means of an article present on a substrate. Here, the coating layer directly adjacent to the substance is at least one metal selected from titanium, zirconium and hafnium, or a compound of the metal and one or more non-metals and / or semiconductors, or the metal. It contains an alloy with one or more other metals and is applied by a vacuum coating method. The invention further relates to a method of making the article. In the method, a substrate is at least partially coated with at least one layer and then a substance containing proteins, peptides and / or saccharides is at least partially applied to the coated substrate. Here, the coating layer directly adjacent to the substrate is at least one metal selected from titanium, zirconium and hafnium, or a compound of the metal and one or more non-metals and / or semiconductors, or the metal. Alloy with one or more other metals under vacuum
It is applied at a temperature of 0 to 500 ° C. The present invention further relates to the use of the article for implanting, inserting or adhering in or on an animal or human body, or for contacting animal or human blood or tissue, or animal or human cells. Regarding The invention further comprises the use of substances containing proteins, peptides and / or saccharides which are applied to one layer as defined above. Preferred embodiments of the invention are described in the following description, drawings, examples and dependent claims.

[0012]

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, an article is in contact with human or animal blood or tissue for a very short time, or with human or animal cells, or for a long or short period, a human or animal body. It is intended to mean any device or any device that can be embedded in or inserted or attached to. Examples are catheter tubes, sensors, stents, artificial heart valves, endotracheal tubes or cardiac pacemakers.

[0013]   The metal in the coat layer is preferably titanium. Besides this, titanium compounds
Or alloys are also preferred. Preferred compounds, especially ceramic compounds, have the formula MC_xN_yO _z Have. Where M is Ti, Zr and / or Hf and x, y and z are respectively
0 to 2.1, x + y + z = 0.01 to 4, especially x + y + z = 0.01 to
2, particularly preferably x + y + z = 0.05 to 1.5. Further metal vs. nitrogen vs. acid
The element-to-carbon ratio is 1: (0-2.1) :( 0-2.1) :( 0-2.1), preferably.
Or 1: (0 to 1.0) :( 0 to 2.0) :( 0 to 1.0), particularly preferably
It is 1: (0-0.8) :( 0-1.5) :( 0-0.3). The ratio is grain
Refers to the number or molar ratio of offspring. M is preferably titanium or zirconium / titanium alloy.
It's money. In addition to titanium, zirconium and / or hafnium, the coating layer
As an additional metal, it has a beneficial effect on the resistance of the coating layer to corrosion.
Including niobium, tantalum, tungsten, molybdenum or alloys thereof
Good. Such alloys may additionally have advantageous mechanical properties. Preferred case
Gold is titanium / aluminum / vanadium alloy, titanium / aluminum / niobium
Alloys, titanium / aluminum / iron alloys, and titanium / niobium / zirconium alloys
Is. The coating layer can also contain hydrogen (dissolved or preferred).
What is combined). DE-C-4 3 44 258 and DE-A-196 06 as coating layer materials
 Materials such as those described in 188 are also suitable. TiN preferably about 0.5 μm thick
The layer is titanium suboxide, especially TiO 2._1.7Coated on a conductive intermediate layer consisting of
It is also possible to use a layered system. This layer system is especially resistant to corrosion
high.

The thickness of the coat layer is preferably in the range of 0 to 5 μm, more preferably 50 to 3
000 nm, very preferably 100-1000 nm. The thickness of such layers ensures that when a particular article is bent it can withstand damage.

This layer is preferably in the range 10 to 10 ⁷ μΩcm, preferably 50 to 100,
It has a specific resistance of 000 μΩcm, particularly preferably 50 to 10,000 μΩcm.
This specific resistance can be easily adjusted by a person skilled in the art within the scope of experimentation customary in the art by changing the oxygen, nitrogen and / or carbon content. Traditionally, measurements have shown that platelet adhesion has a maximum at 1000-10,000 μΩcm. The article can be adapted to electrophysiological conditions by changing the electrical conductivity. The article can be adapted to physicochemical conditions by supplementing the coat layer with substances containing proteins, peptides and / or sugars provided according to the invention. Furthermore, these substances
If necessary, it is assisted by a drug having antibiotic or pharmacological activity.

The coat layer is present as a thin layer on the substrate. Suitable substrates include metals such as molybdenum, silver, gold, copper, aluminum, tungsten, nickel, chromium, zirconium, titanium, hafnium, tantalum, niobium, vanadium, iron or mixtures or alloys thereof, especially stainless steel or nitinol. (Nitinol) or a mixture or alloy with a polymer such as polyester, polyamide, polyurethane (PU), polyethylene (PE), polytetrafluoroethylene (PTFE) or Dacron (registered trade name). The substrate preferably consists of stainless steel, especially medical grade stainless steel, tantalum, nitinol, titanium, gold or polymers. The coat layer is preferably applied to the rough substrate surface. Surface roughness is characterized by a random distribution of deviations from the mean level. The standard deviation of this distribution lies in the range 0.5 to 50,000 nm, preferably in the range 40 to 1200 nm.
The substrate is at least partially, preferably completely covered by the coating layer.

For the purposes of the present invention, the layer which is directly adjacent to the substance and which is applied by the vacuum coating method is preferably released in air or under normal conditions by releasing the vacuum after application by the vacuum coating method. It is intended to mean the layer stored at and exposed to the natural aging process.

In a preferred embodiment, an intermediate layer with greater adhesive strength is provided between the substrate and the coat layer. This intermediate layer consists of a metal, preferably chromium, copper, nickel, molybdenum, tantalum, niobium, silver, or alloys of these metals, or semiconductors such as silicon.

Suitable proteins, peptides and saccharide-containing substances are albumin; fibrinogen; heparin; collagen; blood proteins such as alpha-2 globulin; IgG, IgM, IgE, IgA and proteins of the complement system, cytokines. , Immunoglobulins such as interleukins and interferons; glycoproteins such as ferritin and lactoferrin; salivary gland proteins such as lysozyme, IgA2, mucin and grandulin, and / or alpha-1 proteinase inhibitors. These substances may be present either alone or as a mixture with one another. Preferred substances are albumin, fibrinogen, heparin or mixtures thereof. Albumin is most preferred, in particular a mixture of albumin with fibrinogen, heparin and / or one or more of the other substances mentioned above, in particular a mixture of albumin with fibrinogen. Albumin dissolves very well in water, has high hydration properties, is difficult to salt out, has an oval shape, and is approximately 660,000.
It is a protein having a molecular weight of, including a sulfur-containing amino acid, an isoelectric point of 4.6, and behaving like an ampholyte. Particularly suitable albumin is human albumin,
Bovine albumin, porcine albumin, chicken albumin, dog albumin, or albumin derived from cat, monkey, guinea pig, mouse, turkey, hamster, red-headed monkey, or sheep. Human albumin is most preferred.

[0020]   This material is preferably present in at least part of the coat layer, preferably in its entirety.

The article according to the invention reduces foreign body-biological reactions and allows a wide range of favorable properties to be produced. For example, combining albumin, preferably human albumin, with a TiN _x O _y layer on a medical stainless steel stent matrix reduces the stenosis recurrence rate to 53%. Where x and y are as defined above
(See Example 3 below). Other proteins, such as fibrinogen, reduce the attachment of certain bacterial species (see Example 2 below). This is especially relevant for example in various catheters in the genitourinary tract or in the hematological field or implants in the respiratory tract.

To produce the article, the coat layer is applied to the substrate by a vacuum coating method. This is preferably carried out by PVD (Physical Vapor Deposition), CVD (Chemical Vapor Deposition), PECVD (Plasma Enhanced Chemical Vapor Deposition), or ion plating methods, but especially PVD methods such as reactive vapor deposition, sputtering, reaction. Plasma method or DE-A-195
By the method described in 06 188. The following method is particularly suitable for applying the coating layer to the substrate. The substrate is placed in a vacuum chamber, 20-500 ° C,
It is preferably heated to 100 to 400 ° C, particularly preferably 200 to 350 ° C.
For coating, the metal or alloy as defined above is in the chamber 10 ^-5 to 10 ^-2 mbar, preferably 10 ^-4 to 10 ^-2 mbar, particularly preferably 10 ^{-4 to} 5 x 10 ^-3. It is evaporated by evaporation, preferably by electron beam evaporation, under a vacuum of mbar. When applying multiple compounds, the corresponding gas, a gas containing oxygen, nitrogen and / or carbon, such as ethyne or carbon dioxide, is introduced into the vacuum chamber. The process for producing the required chemical composition of the compound in this case is preferably as follows.

The chemical composition is generally determined by the following parameters. That is, r _M : vaporization rate of metal M a _GM : affinity of gas type G for metal M U _pi I _p : voltage and current of ignited plasma T _s : substrate temperature I: distance between vaporizer and substrate P _tot : total gas pressure, and P _G : partial pressure of gas type G where the last variable is determined by: f _G : mass flux of gas type G L _G : pumping capacity of the vacuum pump for gas type G

Those of ordinary skill in the art will now appreciate the functional “process composition” for each vacuum chamber and each use.
Can be determined experimentally. If the metal M and the gas G (for example, titanium and oxygen) are included, the multidimensional parameter space can be simplified into a linear two-dimensional problem. For example, in the case of titanium / oxygen system in the following parameter range, r _titan = 0.1 to 10 mm / s T _s = 20 ° C to 500 ° C I = 20 to 120 cm P _tot = 10 ^-5 to 10 ^-2 mbar , A linear function of the oxygen flux f ₀₂ controlled by the flow control device. This relationship can be described by the following set of curves that are parameterized. That is, v = 0.0245 × (f ₀₂ + t) −0.879 where v means the ratio of oxygen to titanium particles in the coating layer, and f ₀₂ is a dimensionless oxygen flux (dimensionless oxygen). Flux), and t means a group of curves representing the pumping capacity and the coupling structure of the chamber. In this system, the resistivity (dimensionless) p of the coat layer can also be expressed as a function of chemical composition as follows. That is, v = 0.357ln (p) -2.1987 When the second gas is added, the different affinities (a _GM1 , a _GM2 ) between the metal M and the two gas types G1 and G2 are considered. It The ratio of a _GM1 to a _GM2 defines a linear parameter space between the chemical composition of the coating layer and the flux of the two gas types. When more than 2 gas types and / or more than 1 metal types are used, the parameter space is experimentally investigated by stochastic optimization algorithms, eg genetic algorithms, to derive the desired properties. It is possible to find an area. In this case, the adjustment of the required quantity ratio of the plurality of gases is preferably performed by a flow control device, for example, a so-called mass flow controller. In some cases, it may be advantageous to ignite the plasma. Deposition of the coat layer on the substrate is carried out in conventional vacuum deposition equipment well known to those skilled in the art.

The layers applied to the substrate are still chemically unstable and may have to undergo an aging process shortly after being applied and removed from the vacuum chamber. Thus, for example, titanium can be converted to titanium oxide or TiO ₂ via passivation, which process can take hours or even days.

Next, a substance containing a protein, peptide and / or saccharide is applied to this coated substrate. In a preferred embodiment, the material is applied immediately or promptly after application of the coat layer. This is for 1 minute to 1 week, particularly preferably 1 minute to 5 after coating the coating layer or after removing the coated substrate from the vacuum chamber.
Done in time. The preferred process for contacting the substance with the solution is infiltration and spraying. The substance is suitably applied by introducing the coated substrate into a solution containing the substance. Suitable solutions contain 1 to 70% by weight, preferably 1 to 40% by weight and in particular 1 to 35% by weight of the substance, based on 100% by weight of the solution. Solution 10
A solution containing 1 to 30% by weight of human albumin, particularly 1 to 15% by weight of human albumin relative to 0% by weight is preferably used. In addition to the substances mentioned above, the solution contains water and, if appropriate, salts, electrolytes and / or buffers. Albumin may not only be in the form of a solution for application, but also in the form of a powder, for example produced by heat shock or crystallization (by salt). In the latter case, the powder is distributed in the coat layer and then the article is stored in the wet chamber. It is also possible to modify parts of the material, which extends its range of application. In fact, denatured fibrinogen may suppress platelet aggregation on the surface. The material can also be applied by contacting the coated substrate with a gas mixture of the required material. It is also possible to add a depot drug, such as an anticoagulant or antibiotic, to the substance such that it is subsequently released.

When the substance is applied by dipping in a solution, the article is stored in the solution at a temperature of -12 to + 20 ° C, preferably 0 to + 7 ° C for a few seconds to a few days. The article can also be marketed with the solution. In this form the article is stable for at least 1 month. In one preferred embodiment of the invention, the article is designed as an implant, in particular a stent.

The article according to the invention is for implantation, insertion or attachment in or on an animal or human body, or for contact with animal or human blood or tissue, or with animal or human cells, It is possible to use. In particular, the article is used for implantation, insertion or attachment in or on the animal or human body.

The present invention also relates to substances containing proteins, peptides and / or sugars, which are applied, in particular added or deposited, to the layers as defined above. The substance in this case is defined as described above. The substance is preferably selected from albumin, fibrinogen and heparin, with albumin being most preferred.

FIG. 1 schematically shows the structure of a preferred article according to the invention. This item is PV
It has a substrate (3) coated with a layer D (2) on which the substance (1) is located.

[0031]

【Example】

The invention is explained in detail on the basis of the following examples, which represent preferred embodiments of the invention.

Example 1 Medical steel 1440 was attached to a specially made substrate holder and placed in a vacuum chamber. The chamber is evacuated to 10 ^-5 mbar and the substrate is heated to 400 ° C.
Heated to. Titanium was vaporized using an electron gun at a rate of 0.5 nm / s. Using a mass flow controller, 150 sccm (standard cm ³ ) nitrogen flux and 35 s
An oxygen flux of ccm was supplied. The pressure achieved in this process is 10 ^-3 m
It was bar. In this way, a TiN _0.95 O _0.15 layer having a specific resistance of 1000 μΩcm was applied. This layer had a thickness of 1 μm.

The sample was then incubated with a 1% human albumin solution (wt%) for 1 hour at room temperature and then dried. After incubation with albumin, the samples were rinsed with phosphate buffer (PBS) to wash out excess unbound albumin.

Next, the sample is divided into 5 squares (length × width × height = 76 × 38 × 0.2 [mm])
Carved into Of these, four were sampled with filtered human plasma and 1, 2 respectively.
Incubated for 3 and 4 days. Platelet adhesion to these four samples and to a fifth sample incubated with albumin alone (not incubated with human plasma) was measured. This was done by flowing human blood anticoagulated with citric acid over a specific sample in a flow chamber (size 0.6 mm x 38 mm). Flow rate is 39.67 ml
/ Min. In each case, perfusion lasted 5 minutes and was performed at a temperature of 37 ° C. After perfusion, this particular sample was rinsed with Hepes / NaCl. The comparison sample is
Samples contacted with an untreated substrate, human plasma, were incubated with the same size and in the same manner and contained medical steel.

Next, the sample thus treated and the comparative sample were fixed, and the amount of platelets adhering to the sample was quantified by fluorescence microscopy and expressed as% of the covered area to the whole area.

The results are shown in FIG. In the figure, “Platelet adhesion” is expressed in “days” as a function of time.
% ". From FIG. 2 it is clear that the platelet adhesion to the article according to the invention is reduced even after 1 day.

Example 2 The surface of medical steel 1440 was coated in the vacuum chamber in the same manner as in Example 1. However, the amounts of nitrogen and oxygen supplied were as shown in Table 1 below. The pressure achieved in this process was 10 ^-3 mbar. DE-A-195 06 18
By varying the process parameters as specified in 8, it was possible to produce multiple layers with different conductivities. The layer thickness was 10 ^-6 m. Table 1
A coated substrate having a resistance value shown in was obtained in this way.

[0038]

[Table 1]

Further, five coated substrates having the resistance values shown in FIG. 3 were separately prepared. The substance was deposited according to the invention on 5 samples and the samples were purified in a solution containing human fibrinogen (grade L, KabiVitrum, 33 g human fibrinogen /
Incubated with potassium phosphate (100 ml) for 30 minutes. Another 5 sample was used as a comparative sample without treatment with the substance (fibrinogen).

Next, the adhesion degree of Staphylococcus epidermidis 11047 (staphylococcus epidermidis) was examined for this sample and the comparative sample in a flow chamber (size: length × width × height = 76 × 38 × 0.6 mm). . For this purpose, the bacterial solution was flown over the sample and the comparative sample at a flow rate of 2 ml / min for 5 hours for quantification.

The results are shown in FIG. In the figure, the total degree of adhesion expressed in "number of bacteria / cm ² " is plotted against the specific resistance of the sample expressed in [μΩcm]. From this it is clear that the samples according to the invention show a clear decrease in the degree of adhesion.

Example 3 A commercially available coronary stent was coated as described in Example 1 to achieve the same resistivity and the same coat layer thickness. After passing nitrogen through the vacuum chamber, the stent was placed in a solution containing 5% by weight human albumin and sealed.

The stent was implanted in the coronary vessels of 20 pig hearts. At the same time, untreated control stents, ie stents without coating and without substance, were implanted in pigs. After 6 weeks, the intimal hypertrophy induced by the stent and the control stent was measured. For this, samples were taken immediately upstream of the implanted stent and from within the implanted stent and histological specimens were prepared. The intima thickness in histological specimens was measured. Comparison of the inventive stent with the control stent showed a 53% reduction in intimal hypertrophy in the inventive stent. This result is p
<0.04 was significant.

[Brief description of drawings]

[Figure 1]   FIG. 1 is a schematic diagram of a preferred article according to the present invention.

[Fig. 2]   FIG. 2 is a graphical representation of the results obtained in Example 1.

[Figure 3]   FIG. 3 is a graphical representation of the results obtained in Example 2.

[Procedure for Amendment] Submission for translation of Article 34 Amendment of Patent Cooperation Treaty

[Submission date] December 18, 2001 (2001.12.18)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

4. An article according to any of claims the thickness of the layer is 5μm smaller prior.

5. The article according to claim resistivity of the layer is previous is between 10 to 10 ⁷ .mu..OMEGA.cm.

6. The article according to claim, wherein the layer which is coated by the adjacent and vacuum coating directly to the material precedes undergo aging in air.

7. The article according to claim wherein said at least one substance is albumin, a preceding selected from fibrinogen and heparin.

8. The article according to claim wherein the substance is a preceding at least albumin.

9. The article according to claim, wherein the substrate is stainless steel, tantalum, nitinol, prior titanium, gold, and / or polymers.

10. Article according to any of the preceding claims, designed as a stent.

11. The substrate is at least partially coated with at least one layer,
A substance containing proteins, peptides and / or sugars is then at least partially applied to the coated substrate, and the layer directly adjacent to the substance is at least one metal selected from titanium, zirconium and hafnium. Or said metal and one or more non-metals and / or
Alternatively, a compound with a semiconductor, or an alloy of the above metal and one or more other metals is applied at a temperature of 20 to 500 ° C. by an electron beam vaporization method at a pressure of 10 ⁻⁴ to 10 ⁻² mbar. A method of manufacturing an article according to any one of claims 1 to 11.

12. The substance The method of claim 11, wherein the coating by introducing coated substrate in a solution containing the substance.

13. The method of claim 12, further comprising a 0.5 to 40% by weight of said material based on said solution a solution of 100% by weight.

14. The substrate, the layer and the method according to any one of claims 11 to 13 wherein the material is as defined in any of claims 2 to 9.

15. implantation into the animal or human body or on, for inserting or attached, or a blood or tissue of a human or animal, or for contact with human or animal cells, claims 1 10. Use of the article according to any one of 10 .

16. A method of using a substance containing a protein, peptide and / or saccharide, which is applied to one layer, wherein the layer is at least one metal selected from titanium, zirconium and hafnium, or A compound of a metal and one or more non-metals and / or semiconductors,
Alternatively, a method of use, which comprises an alloy of the above metal and one or more other metals, and is applied by electron beam vaporization at a pressure of 10 ⁻⁴ to 10 ⁻² mbar .

17. Use according to claim 15, wherein the substance as defined in claim 7 or 8 is used.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AU, BR, CA, CN, CZ, ID, IL, IN, JP, KP, KR, L T, LV, MA, MK, MX, NO, NZ, PL, RO , SI, TR, US, VN, ZA F-term (reference) 4C081 AC16 BA02 CD062 CD172                       CD20 CG02 CG08 DA02 DC03                       EA06                 4C167 AA46 AA50 AA52 BB02 BB05                       BB06 BB12 BB13 BB26 CC08                       CC09 DD01 FF05 GG02 GG16                       GG21 GG22 GG23 GG24 GG42                       HH08

Claims (19)

[Claims] 1. An article comprising a substrate which is at least partially coated with at least one layer and on which a substance containing proteins, peptides and / or sugars is at least partially present, said substance comprising: The directly adjacent layer may be at least one metal selected from titanium, zirconium and hafnium, or the metal and one or more non-metals and / or
Alternatively, an article comprising a compound with a semiconductor, or an alloy of the above metal and one or more other metals and coated by a vacuum coating method. 2. The article of claim 1, wherein the metal is titanium. 3. The layer comprises a compound of at least one metal selected from titanium, zirconium and hafnium and at least one element selected from nitrogen, oxygen and carbon, the compound having the formula MC _x N _y O 2. _z , where M is Ti, Zr
And / or Hf, x, y, z are each 0.0 to 2.1, and x +
The article according to claim 1 or 2, wherein y + z = 0.01 to 4. 4. Article according to claim 1, wherein the layer is applied by PVD, PECVD or CVD. 5. Article according to any of the preceding claims, wherein the thickness of the layer is between 0 and 5 μm. 6. Article according to any of the preceding claims, wherein the resistivity of the layer is between 10 and 10 ⁷ μΩcm. 7. Article according to any one of the preceding claims, wherein the layer directly adjacent to the material and applied by a vacuum coating process is aged in air. 8. Article according to any of the preceding claims, wherein the at least one substance is selected from albumin, fibrinogen and heparin. 9. Article according to any of the preceding claims, wherein the substance comprises at least albumin. 10. The substrate is stainless steel, tantalum, nitinol,
An article according to any of the preceding claims consisting of titanium, gold and / or polymers. 11. Article according to any of the preceding claims, designed as a stent. 12. The substrate is at least partially coated with at least one layer,
A substance containing proteins, peptides and / or sugars is then at least partially applied to the coated substrate, and the layer directly adjacent to the substance is at least one metal selected from titanium, zirconium and hafnium. Or said metal and one or more non-metals and / or
Alternatively, a compound with a semiconductor or an alloy of the metal and one or more other metals is applied under vacuum at a temperature of 20 to 500 ° C. Manufacturing method. 13. The method according to claim 12, wherein the substance is applied by introducing a coated substrate into a solution containing the substance. 14. The method according to claim 13, wherein the solution contains 0.5 to 40% by weight of the substance, based on 100% weight of the solution. 15. The method according to claim 12, wherein the substrate is coated under a pressure of 10 ⁻⁵ to 10 ⁻² mbar. 16. A method according to any of claims 12 to 15 wherein the substrate, the layer and the substance are defined in any of claims 2 to 10. 17. A method according to claim 1 for implantation, insertion or attachment in or on an animal or human body, or for contact with human or animal blood or tissue, or human or animal cells. 11. Use of the article according to any one of 11 above. 18. A method of using a substance containing a protein, a peptide and / or a saccharide, which is applied to one layer, wherein the layer is at least one metal selected from titanium, zirconium and hafnium, or A compound of a metal and one or more non-metals and / or semiconductors,
Alternatively, a method of use, which comprises an alloy of the above metal and one or more other metals and is applied by a vacuum coating method. 19. A substance as defined in claim 8 or 9 is used.
Usage as described.