ES2366261T3 - SURFACE SHOWER PROCEDURE. - Google Patents

Abstract

Disclosed herein are methods of treating an article surface. The method comprises removing a metal oxide surface from the metal substrate to expose a metal surface; and delivering particles comprising a dopant from at least one fluid jet to the metal surface to impregnate the surface of the article with the dopant. The method also comprises delivering substantially simultaneously a first set of particles comprising a dopant and a second set of particles comprising an abrasive from at least one fluid jet to a surface of an article to impregnate the surface of the article with the dopant.

Description

Field of the Invention

The present invention relates to bombardment of surfaces of objects, such as medical devices, with dopants.

Background of the invention

The bombardment of metal surfaces with abrasive materials, named in this way, is finding an increasing number of technical applications in recent years. Techniques such as blasting blasting blasting, blasting blasting, sandblasting, blasting hammering and microabrasion fall within this category of surface treatment techniques. In each of these techniques, generally, an abrasive material, shot or shot, is mixed with a fluid and fired at high speed to impact the surface to be treated. The technique used to shoot the abrasive material can be classified as wet or dry, depending on the choice of fluid medium used to fire the abrasive to the surface, usually water and air respectively. The generic term "abrasive bombardment" is used to refer to all the techniques mentioned in this specification.

Applications of these technologies include metal cutting, cold work of metal surfaces to induce desirable stress characteristics and pretreatment of surfaces to induce a desirable texture (surface roughness) in order to increase the adhesion of additional coating materials. (See Solomon et al., Welding research, October 2003: p. 278-287; Momber et al., Tribology International, 2002. 35: p. 271281; Arola et al., J. Biomed. Mat. Res., 2000. 53 (5): p. 536-546; and Arola and Hall, Machining science and technology, 2004. 8 (2): p. 171-192.). An example of the latter is in the biomedical sector where titanium implants are cleaned with blasting blast blast with alumina or silica to achieve an optimum level of surface roughness that will maximize the adhesion of hydroxyapatite coatings by plasma spraying . HA coated implants are desirable due to the biomimetic properties of the apatite layer, but a bonding force between the titanium surface and the apatite layer is also necessary.

It has been known for some time that during the bombardment of these surfaces, some of the abrasive material becomes impregnated on the surface of the metal itself, which has generated interest in these techniques as possible candidates to modify the surface chemistry in general (See Arola et al., And Arola and Hall, above). Again, with reference to the biomedical sector, one study has observed the shot blasting as a means of placing a layer of hydroxyapatite directly on a titanium surface in an effort to derivatize the expensive plasma spraying process. Ishikawa, K., et al., Blast coating method: new method of coating titanium surface with Hydroxyapatite at room temperature. J. Biomed. Mat. Res., 1997, 38: p. 129-134. In this study, HA with an unspecified particle size distribution was used as abrasive. However, since the deposited apatite layer could be removed with a gentle washing regime, it seems that a strong bond with the metal surface was not achieved.

Choi et al. (KR20030078480) refer to the use of a single calcium phosphate particle as cleaning means with blasting blasting blast in order to include the shot on the surface of dental implants, but particles of 190 µm in excess are disclosed.

US Patent No. 6,502,442 ([6]) refers to the use of sintered HA as an abrasive using water as a fluid medium. Some impregnation of HA in this example has been achieved as the HA has been thermally processed.

Muller et al. (US2004158330) discloses jet particles comprising calcium phosphate contained in a vitreous matrix. Other disclosures (for example, US Patents Nos. 4,752,457 and 6,210,715) describe processes for the manufacture of calcium phosphate microspheres that normally comprise a polymer component and complex manufacturing processes thereof, but have not been elucidated its effectiveness as a means of jet cleaning.

The RocatecTM system for silicon treatment of metal surfaces and other surfaces also uses individual particles that have multiple components. This technology is widely used in dental sand. In this example, an alumina particle having an external adherent layer of silica is propelled to a pre-corrugated surface and after impact, the local heat generated in the vicinity of the impact causes the shot blasting silica outer layer to merge into the surface in a procedure called ceramization.

Bru-Magniez et al. (United States Patent No. 6,431,958) have disclosed hard abrasive materials with multiple stratified layers for use in blast abrasive blasting techniques to modify surfaces. In this example, the objective of the procedure was to include or otherwise join the stratified layer around the abrasive particles to the surface being treated. The outer layer comprises at least one polymer while the ceramic material of choice of the core is an oxide, carbide, nitride, or carbonitride.

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The use of multiple stratified polymeric layers has been proposed. Lange et al. (United States Patent No. 6,468,658) have disclosed a particle composed of a core base material and an external adhesive layer of titanium dioxide for jet cleaning.

Additional applications of abrasive bombardment for surface modification objectives are found in the biomedical sector such as for example the use of microabrasion to clean rust slag from the struts of laser-machined endovascular prostheses and surfaces of pacemakers and defibrillators with silica for increase adhesion of additional polymeric coatings to the device.

One thing in common among these examples is the use of a single type of solid particle in the fluid stream.

The recent significant interest in surface modification technology with regard to biomedical devices is driven by the successes of the Drug Eluting Endovascular Prosthesis (DES) Due to the introduction of endovascular techniques in the 1990s, the strategies of Revascularization have changed dramatically in recent years. However, in the restenosis of the endovascular prosthesis (ISR) there remains a problem in which the rupture of the lining of the vessel at the site of the endovascular prosthesis can cause platelet activation, secretion of inflammation mediators and, eventually, the Smooth muscle cell formation (CNS), a process analogous to the formation of the scab at the site of a wound In addition, since the endovascular prosthesis comes into contact with blood should not induce a foreign body reaction (FBR) in the tissue or blood cells, that is, should be biocompatible. DES uses surface modification technology to combat these problems in which the surface of the endovascular prosthesis is used to administer active agents (antirestenotic and antithrombotic agents), usually in a polymer matrix locally at the site of the device in the which are more necessary This technology was introduced pioneeringly by Cordis with his Cypher endovascular prosthesis that was approved by the FDA in 2003. Then, because numerous other DESs appeared on the market, all claiming the reduction of ISR and thrombosis in patients who had percutaneous coronary intervention procedures (PCI). All these active devices use a polymer matrix to transport the drug on the surface of the endovascular prosthesis and control its elution characteristics in vivo.

However, problems have arisen with DES attributed to numerous factors, including getting proper control of the elution characteristics of the drug (s). The polymer matrix has been identified (which degrades over time to release the drug and the products of polymer degradation) as a possible culprit in patients with hypersensitivity in this way, continuous efforts have been made to develop new procedures to control administration and drug elution.

A large part of the prior art in the field of endovascular prostheses has been directed towards achieving passive coatings on the surface of endovascular prostheses to mediate ISR. These include the aforementioned procedures such as nitriding and nitriding by carbon the use of carbon and silicon carbide coatings as well as methods for thinning or increasing the natural oxide layer on the surface of endovascular prosthesis materials including oxidation , ionic and electrochemical implant treatments such as electroplating or electroplating with inert metals. All the mentioned procedures have, however, numerous disadvantages and no treatment technique by itself provides the ideal surface for optimal clinical results.

Another field of relevance is the area of biofilm formation on the surfaces of implantable devices in which the bacteria on the surface of the implant surfaces are arranged by themselves in films with three-dimensional macroscopic structure. In this example, the film itself may represent a barrier to standardized antimicrobial treatments such as, for example, the systemic use of antibiotics. It has been reported that the systemic dose of antibiotic required to eliminate the infection of the bacterial biofilm can be up to 1000 times the systemic dose required to eliminate its plantonic equivalent in suspension often inducing serious and unwanted effects in patients. The localized administration of the drug on the surfaces of the implantable devices has been mentioned as a method to direct the antimicrobial agents on the surface of the implant where they are most necessary, avoiding the formation of the biofilm with the added advantage of using dose indices much smaller than those of systemic treatments.

Currently, most bactericidal strategies for localized drug administration use polymeric coatings or polymer microspheres included in other suitable vehicle matrices such as antibacterial agent vehicles. In addition, calcium phosphate salts that include hydroxyapatite have been proposed as suitable vehicles for antibiotics. Biomimetic deposition has been used to deposit nano crystalline apatite layers on the surface of orthopedic metal implants that can be introduced with precipitated drugs onto the inorganic coating of the solution in a separate step (US20040131754). Such strategies may have a double advantage, for example, in the field of orthopedic implants in which calcium phosphate salt provides an osteoconductive benefit on the surface by inducing bone growth in vivo while the antibiotic reduces the risk of biofilm formation. , contributing both factors greatly to the need for review procedures. However, this solution is limited by the surface area available on the implant surface as it determines the amount of antibiotic to be introduced. In addition, the solution is multistage since often, the union of the ceramic layer implies high temperature (as for example in the case of calcium phosphate coatings sprayed by plasma) or the union of the drug requires precise control of pH and other procedure parameters that prevent the simultaneous binding of the inorganic salt and the antibacterial agent. Among the antibiotics that have been attached to metal surfaces by such procedures are gentamicin, tobramycin, vancomycin, ampicillin, and others.

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The range of therapeutic agents that could provide benefit to patients if they are present on the surface of the implants is not limited to antibiotics or immunosuppressants. Some studies have focused on placing other therapeutic agents on the surface of implantable devices to induce desirable responses in vivo. For example, some studies have focused on placing the functional molecules involved in these cascades on implant surfaces. These include, for example, proteins, including hormones, growth factors, structural proteins, immunogens and antigens. As a corollary, this enormous work has focused on the design of peptides and proteins that have structural similarity with the active sites of the proteins involved in the biological pathways. It has been proposed, for example, the use of RGD peptides in orthopedic applications or bactericidal peptides as strategies to combat bacterial infection, for example, in which bacteria have high resistance to conventional antibiotics.

Since more and more medical implants are tailored to the needs of the patient, they can also be seen as means to administer therapeutic agents for the treatment of other more specific diseases of the patient, for example, diabetes, cancers and other diseases not directly related to The main function of the implant. An in vivo device allows for itself multiple functions in which the surface of the device becomes a vehicle for administering therapeutic agents that may be necessary to treat other diseases that the patient may have.

The limiting factors to achieve the ability to administer the therapeutic agent on implant surfaces generally refer to engineering and processing aspects. It is necessary that the procedures for placing these agents on the surface are proportional while maintaining the activity and structural integrity of the agents themselves and controlling surface chemistry, particularly their elution kinetics in vivo. Since many of the desired agents are biological in nature, temperature and dissolution parameters such as pH, etc., can present barriers to realize the benefit of the aforementioned surface modification strategies.

The superficial modification of the implant surfaces is not limited solely to the field of administration of the therapeutic agent. In many cases, the surface modification of the implantable device may be required in order to customize the physical properties of the surface, such as, for example, in titanium-based devices used in coronary intervention procedures, and in the treatment of pathological calcifications such as kidney stones. It may, however, be desirable to have devices with greater radiopacity than those currently associated with these devices in vitro. These would facilitate their radiographic imaging or even by externally magnetic resonance imaging and dispense with the need for invasive procedures or endoscopies currently used with minimally invasive procedures. Examples include doped nitinol alloys with tertiary heavy elements such as platinum, palladium or tungsten between others, to increase the resulting radiopacity of the alloy for biomedical applications and other applications (US Pat. Nos. 7,128,757, 6,776,795, and 6,569,194).

The prior art is also provided in WO 96/16611 A, WO 03/080140 A and US-A-4 950 505.

WO 96/16611 A discloses procedures for improving the surfaces of the devices to be surgically implanted in live bone, and implant devices having improved surfaces. A titanium body that has been exposed to the air has on itself an oxide layer of an oxide or naturally occurring titanium oxides. This layer of natural oxide normally has a thickness in the range of 70 Angstroms to 150 Angstroms. To make the titanium body more suitable for the implant, the outer surface is cleaned by cutting blasting blasting, massively etched with a mordant acid to remove the native oxide layer.

WO 03/080140 A discloses a method for treating a metal surface of a medical implant comprising contacting the metal surface with a bioactive glass using an air abrasion system.

Finally, document US-A-4 950 505 discloses a machine for refining a flange / wheel by first raising the bottom flange / wheel in a washing and degreasing chamber, transfering the flange / wheel into the chamber , transfer the flange / wheel to a cleaning chamber by shot blasting, cleaning the flange / wheel by means of a blasting jet, transfer the flange / wheel to a coating area by spraying, by spraying the flange / wheel with a protective material , and subsequently returning the flange / wheel to its initial elevation for the subsequent application in tire / retreaded of the previous one.

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Summary of the Invention

The present invention is a process for treating a surface of an object as defined in Claim 1 of the appended claims.

The present invention provides a method for treating a surface of an object, wherein the object is a metal substrate, the process comprising:

substantially administering simultaneously a first set of particles comprising a dopant and a second set of particles comprising an abrasive from at least one fluid stream to a surface of the object to impregnate the surface of the object with the dopant;

wherein the method further comprises removing a metal oxide from a surface of the metal substrate to expose a metal surface, abrasively cleaning the metal oxide with the second set of particles substantially simultaneously with the administration of the first set of particles.

The present invention is directed to provide an improved treatment process in order to modify the surfaces of the objects, such as metal objects with desirable materials in order to induce at least desirable chemical, physical and / or biological characteristics on those surfaces.

In the embodiments, the dopants can be polymers, metals, ceramics, therapeutic agents, and combinations thereof. The object may be a medical device, such as an implantable medical device.

Brief description of the drawings

Some embodiments of the invention will be understood from the following description, the appended claims and the accompanying drawings, in which:

FIG. 1 is a schematic representation of the treatment method of the invention;

FIG. 2A is an XPS spectrum of clean cp titanium surfaces with cutting shot blasting only with HA;

FIG. 2B is an XPS spectrum of clean cp titanium surfaces with sharp shot blasting with a mixture of HA: alumina;

FIGS. 3A and 3B show comparative XPS spectra of levels of the Ca 2p (FIG. 3A) and P 2p (FIG. 3B) cores of clean cp titanium (thin line) only with HA and clean cp titanium only with a 50:50 mixture of HA: alumina (thick line);

FIG. 4 shows the spectra of the TI 2p core level in the clean sample with a blasting shot blast with 100% HA (top) and the clean sample with a cutting shot blasting with a 50:50 mix of HA: alumina (part lower);

FIG. 5 shows the XPS maps of cp titanium surfaces of a 0.2 x 0.2 mm square showing (a) the concentration and distribution of Ca in a clean sample with blasting blasting blast with a 50:50 mixture, (b) the concentration and distribution of Ti in a clean sample with a blasting shot blast with a 50:50 mixture; (c) the concentration and distribution of Ca in the clean sample with a blasting shot blast with 100% HA; (d) the concentration and distribution of Ti in the clean sample with a blasting shot blast with 100% HA:

FIGS. 6A and 6B show the comparative XPS spectra of the levels of the Ca 2p and P 2p cores in the case of clean Cp titanium only with HA (thin line) and clean cp titanium with a stream of HA beads: silica (thick line ):

FIG. 7 is a pair of XPS tracking scans of two different clean samples with a 50.50 mixture of HA / silica, which shows the reproducibility of the results;

FIG. 8 shows bacterial tests on surfaces treated with gentamicin / HA for Staphylococcus aureus, (2) Escherichia coli, and (3) Pseudomonas aeruginosa where the sample on the left in each test is a negative control, and “ZI” indicates the zone of inhibition of growth;

FIGS. 9A, 9B, and 9C are schematic diagrams of three different nozzle configurations for administering the dopants and the abrasive on the surface;

FIG. 10, shows three photographs of the zone of inhibition (ZI) on an agar plate inoculated with S. aureus and exposed to a vancomycin cut-out (Plate 1) and inoculated with E coli and exposed to Tobramycin (Plates 2 and 3);

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FIG. 11A shows the FTIR spectra of samples (a) and (b) of 100 µm of alumina beads in duplicate;

FIG. 11B shows the FTIR spectra of samples (a) and (b) of 150 µm of alumina beads in duplicate;

FIG. 12A is an XRD model of surface HA (alumina; 50 µm);

FIG. 12B is an XRD model of surface HA (alumina; 100 µm);

FIG. 13 shows XPS tracking spectra of HA controls in duplicate;

FIG. 14 is an SEM (electron scanning microscopy) image of an adsorbent layer d HA on a stainless steel surface (ASTM F1586);

FIG. 15 is a spectrum of dispersive x-ray energy (EDX) of HA on a stainless steel surface (ASTM F1586);

FIG. 16 is an SEM image of an adsorbent layer on the titanium surface CP (AST F67);

FIG. 17 is an EDX spectrum of HA on a CP titanium surface (ASTM F67);

FIG. 18 is an AFM (Atomic Force Microscope) analysis of the thickness of the HA adsorbent layer on the CP titanium surface, in which FIG. 18A is an AFM image and FIG. 18B is the corresponding AFM graph;

FIG. 19 is an SEM image of nanoporous SIO2 microparticles on the surface of Titanium Quality 5 (Ti6AL4V according to ASTM F136); Y

FIGS. 20A and 20B are SEM images of a nanoporous HA adsorbent layer on the aluminum surface at an increase of x 50 (20A) and x 650 (20B); Y

FIG. 21 is an SEM image of a nanoporous HA adsorbent layer on the nitinol surface.

Detailed description

The present description includes embodiments of procedures that are not part of the invention for the purpose of illustration.

An embodiment provides a method for treatment by impregnating a surface, such as a metal surface, with a dopant. The strength of the bond between the dopant and the surface and the concentration of the dopant achieved on or on the surface can be improved by conventional methods of surface impregnation techniques. The invention relates to dopants that induce desirable chemical, physical and biological properties on the surface of biomedical implants.

Generally, the dopant is a material that is incorporated into the bombarded surface but does not impregnate the surface in extension if it is used as a single solid component in said bombardment technique. If the material is administered to the surface inside a high speed fluid jet by itself, no surface impregnation or minimal surface impregnation will occur. Such circumstances may arise from numerous reasons; the material may not have sufficient particle size or be of sufficient density and hardness to settle on the metal surface and impregnate it. It can also be a consequence of the nature of the surface itself.

In the majority of metallic materials a layer of oxide is formed on the surface, which will be harder than the metal itself

or alloy Metal surfaces (especially those of titanium alloys and titanium derivatives) are naturally contaminated in the air by a variety of contaminants. The detailed physical and chemical properties of any metal surface depend on the conditions under which they are formed. The inherent reactivity of the metal can also attract various environmental / chemical contaminants that oxidize the surface. For example, titanium is a very reactive metal, which is easily oxidized by several different means. This results in a titanium that is already practically coated with an oxide layer. This oxide layer is chemically stable but not always chemically inert, since the oxide layer can continue to react with various reagents in its environment, for example, organic molecules. Traditionally the modification of the surface titanium / oxide layer by which any New material in the oxide layer is produced as a byproduct of this process. In some cases the new material in the oxide layer may be advantageous for the eventual functionality of the affected surfaces; however, in some cases, the new material may constitute an unwanted intrusion. ("Titanium in Medicine," D. M. Brunette; P. Tengvall;

M.

 Textor; P. Thompson, Springer, New York; ISBN 3-540-66936-1.).

The present invention is directed to the intentional addition of a material of choice to the surface. One embodiment takes advantage of the inherent reactivity of metals due to the temporary removal of the oxide layer that overlaps the metal substrate and which treats the newly exposed material below to add a new material (a dopant). Depending on the nature of the added material, the surface properties of the metallic object can be tailored according to its intended functional requirements.

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Titanium and its alloys always form an oxide layer on its surface. This oxide layer is normally inert and non-reactive, while titanium itself is very reactive and will instantly form an oxide layer on exposure to the atmospheric environment. The formation of an oxide layer is often a desired property of an implant device.

Examples of dopants in the biomedical device sector include, for example, hydroxyapatite, drug eluting polymers and other drug delivery systems, and the object to be impregnated comprises a metal such as, for example, titanium, steel. , cobalt, chromium and its alloys.

Accordingly, an embodiment of the present invention provides a method of treating a metal substrate, comprising:

removing a metal oxide from a surface of the metal substrate to expose a metal surface; Y

administer particular comprising a dopant from at least one fluid jet to the metal surface to impregnate the surface of the substrate with the dopant.

In one embodiment, the metal surface is sufficiently reactive in the presence of air such that a new oxide layer can be formed, thus avoiding the addition of a dopant to a metal surface layer. In one embodiment, the present invention involves adding the dopant before reoxidation of the newly formed metal surface. In one embodiment, the step of removing the metal oxide surface is carried out in an inert atmosphere. According to the invention, the removal is carried out substantially simultaneously with the administration, such that the metal surface is not substantially oxidized before administration.

The metal oxide layer can be removed by a variety of techniques. According to the invention, the removal comprises abrasively cleaning the metal oxide surface. The abrasive cleaning step is carried out substantially simultaneously with the step of administering the particles comprising the dopant, for example, two streams of particles can be directed to the metal oxide surface in which a stream abrasively cleans the surface of oxide to expose the new metal surface, and the other current bombards the new metal surface with a dopant.

In another variant, outside the scope of the invention, removal is carried out between at least one stage of drilling, cutting, forming, grinding, micromachining, scraping, grinding, grinding, and abrasion. In another of said variants, the removal is selected from at least one stage acid etching, alkaline etching, and treatment with hydrogen peroxide. In another of these variants, the removal comprises a laser treatment selected from ablation, marking / engraving, welding, cutting and coating. In another of said variants, the removal comprises a plasma treatment selected between etching and cleaning.

As defined above, in some of the embodiments described herein, the oxide removal process can be carried out in an inert environment to expose the new metal surface for a sufficient time to carry out the treatment process. , for example, the addition of a new material to the surface before re-exposing the surface to an oxygen-rich environment. At this time, the oxide layer can be regenerated, but influenced / modified by the added dopant (s) trapped (s).

In one embodiment, equipment can be incorporated to remove the oxide layer before or substantially simultaneously with the surface bombardment with the fluid jet as a stand-alone unit or it can be incorporated into a manufacturing line. The equipment can be used at an established point of use where it would constitute a machine based on aseptic surgery that a surgeon would use in an operating room for custom / prescribed surface modifications before implanting the device into the patient. Disposable dopant / filter vehicle cartridges can be used to prevent therapeutic cross contamination and facilitate cleaning.

If dopant is simultaneously administered simultaneously to the surface with an abrasive impact with sufficient energy (a material with sufficient particle size, density and hardness) to settle the oxide layer, a window of opportunity can be created in which surface can capture the doping material before the oxide layer is re-formed around it. The doping material can become tightly bonded inside the surface oxide layer. In this way, the surface can be impregnated with materials that impart desirable properties to the surface in an economical manner at ordinary temperatures. In addition, the energy dissipated at the site of the impact of the abrasive may be sufficient to ceramize the dopant or otherwise join the surface. Accordingly, one embodiment provides a method of treating a surface of an object, the process comprising substantially simultaneously administering a first set of particles comprising a dopant and a second set of particles comprising an abrasive of at least a fluid jet to a surface of an object, to impregnate the surface of the object with the dopant.

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An embodiment of the present invention relates to the impregnation of metal surfaces with a material of choice (here after the dopant) using conventional abrasive bombardment techniques mixing the dopants with an abrasive material (shot or shot blast) of choice, in the surface. The abrasive, which impacts the surface with sufficient force to settle the oxide layer or otherwise deform the surface to be treated, creates a window of opportunity in which the surface can capture the doping (s) or incorporate it (s) in another way on the surface.

The embodiments of the invention are encompassed, but not limited to the schematic representation of the invention in FIG. 1. FIG. 1 (left) schematically shows a fluid jet (nozzle) 2 simultaneously administering a stream 3 comprising a set of abrasive particles 4 and a set of doping particles 6. The sets of particles 4 and 6 bombard a surface 10 of a substrate 8 In one embodiment, the substrate 8 is a metal substrate and the surface 10 is an oxide layer. As a result of the bombardment of the abrasive particles 4, the surface oxide layer is interrupted, and cracks in the oxide layer 10 result in exposure to a new surface 10a of the substrate 8 (center). In the case of a metal substrate, the recently exposed surface is a metal surface. As the stream of particles 3 continues to impact the substrate 8, the doping particles 6 (right) are integrated into the surface 10 of the substrate 8. When the substrate is a metallic substrate, a new oxide layer 10 is formed again around the doping particles 6.

In some embodiments, the doping materials include, but are not limited to the desired materials on a surface of the implant in order to control and improve the body-implant tissue interaction. The dopant may comprise materials such as polymers, metals, ceramics (for example, metal oxides, metal nitrides), and combinations thereof, for example, mixtures of two or more thereof.

Exemplary dopants include modified calcium phosphates, including Ca5 (PO4) 3OH, CaHPO4 · 2H2O, CaHPO4, Ca8H2 (PO4) 6 · 5H2O, α-Ca3 (PO4) 2, β-Ca3 (PO4) 2 or any modified calcium phosphate containing carbonate, chloride, fluoride, silicate or aluminate anions, protons, potassium, sodium, magnesium, barium or strontium cations.

Other exemplary dopants include titanium (TiO2), zirconium, hydroxyapatite, silica, carbon, and chitosan / chitin.

In one embodiment, the dopant is a combination of agent transport media and at least one therapeutic agent (including biomolecules and biological agents). Potential vehicles of therapeutic agents that include antibiotics, immunosuppressants, antigenic peptides, bactericidal peptides, structural and functional proteins have been disclosed in U.S. Patent No. 6,702,850. Calcium phosphate coatings may also be used as the drug vehicle (see US Pat. Nos. 6,426,114, 6,730,324, and U.S. Provisional Application No. 60 / 410,307, disclosures of which are incorporated in this document by reference). Dopants that can act as agent transport media include nanoporous, mesoporous, nanotubes, microparticles of various materials including hydroxyapatite, silica, carbon, and titanium (TiO2) capable of transporting therapeutic agents, biomolecules and biological agents. Particulate agents and powders (for example, titanium powder) can be both adhesively bonded and covalently bound (bound) to therapeutic agents, biomolecules and biological agents.

Composite materials from media and vehicles (eg, sintered together), and combinations of vehicles can transport drugs and biological agents and can control elution profiles.

Other exemplary dopants include barium titanate, zeolites (aluminosilicates) that include silica zeolite and zeolites that contain at least one component selected from phosphorus, silica, alumina, zirconium, calcium carbonate, biocompatible glass, calcium phosphate glass. The dopant can also be a growth factor consisting of epidermal growth factors, transforming growth factor α, transforming growth factor β, vaccinia growth factors, fibroblast growth factors, insulin-like growth factors, growth factors platelet derivatives, cartilage derived growth factors, interleukin 2, nerve cell growth factors, hemopoietic cell growth factors lymphocyte growth factors, bone morphogenic proteins, osteogenic factors or chondrogenic factors.

In one embodiment, the dopant is hydroxyapatite deposited on a titanium surface. HA and TiO2 constitute biocompatible biointerphases, both being biostable and safe in the body. Both can be called bioreactive agents because they can induce specific responses in some tissues, particularly bone tissue. The surface resulting from the deposition of HA on titanium as administered by the micro-cube technique combines the benefits of both materials. TiO2 is not completely covered by the dopant (HA) and therefore, is still present in the biological tissue, while the HA prefixed on and on the surface is not denatured by the deposition process and thus conveys its full benefit to the surrounding tissue. In this way, the different benefits of both biomaterials can lead them to be present in the biointerphase and when they are additionally combined with the surface texture / morphology better adapt to the intended functionality of the implant, and also, the availability of a drug delivery mechanism It can provide various procedures to tailor the therapeutic, compositional and morphological profile available to the end user patient.

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In one embodiment, the dopant is a therapeutic agent. The therapeutic agent can be administered as a particle by itself, or immobilized on a carrier material. Exemplary carrier materials include any of the different dopants related herein (those dopants that are not a therapeutic agent) such as polymers, calcium phosphate, titanium dioxide, silica, biopolymers, biocompatible glasses, zeolite, bone demineralized, deproteinized bone, allografted bone, and their combinations of composite materials.

Exemplary therapeutic agent types include anti-cancer drugs, anti-inflammatory drugs, immunosuppressants, an antibiotic, heparin, a functional protein, a regulatory protein, structural proteins, oligopeptides, antigenic peptides, nucleic acids, immunogens, and combinations thereof.

In one embodiment, the therapeutic agent is chosen from antithrombotic agents, anticoagulants, antiplatelet agents, antiproliferative thrombolytics, anti-inflammatory, antimitotic, antimicrobial agents, agents that inhibit restenosis, smooth muscle cell inhibitors, antibiotics, fibrinolytic agents, immunosuppressive agents, and antiantrompressive agents. .

Exemplary anticancer drugs include acivicin, aclarubicin, acodazole, acronicin, adozelesin, alanosine, aldesleucine, sodium allopurinol, altretamine, aminoglutethimide, amonaphide, amplify, amsacrine, androgens, anguidine, glycinate, afidinalea, afidic acid, acyccharine, 5-acyccharine azacitidine, azathioprine, bacillus calmette-guerin (BCG), Baker's antifol (soluble), beta-2'-deoxythioguanosine, bisantrene hydrochloride, bleomycin sulfate, busulfan, butionin sulfoximin, BWA 773U82, BW 502U83.HCl, BW7 mesylate, ceracemide, carbetimer, carboplatin, carmustine, chlorambucil, chloroquinoxaline-sulphonamide, chlorozotocin, cromomycin A3, cisplatin, cladribine, corticosteroids, Corynebacterium parvum, CPT-11, chrysolol, cyclocitidinine, cyclophthiazine, dachlodynabis, cyclophthiabamine, cyclophthiazine dacdabenazine, cyclophthiazine, dacdabenacidine, cyclophthysaccharin, cyclophthiazine, dachodotinazine, cyclophthiazine, dachodotinin, cyclophthiazine, dachnobine, dachnobine, dachnobine, dachodotin , daunorubicin hydrochloride, deazauridine, dexrazoxane, dianhydrogalactitol, diazicuone, dibromodulcitol, didemnin B, diethyldithiocarbamate, digl icoaldehído, dihydro-5-azacytidine, doxorubicin, echinomycin, edatrexate, edelfosine, eflornithine, solution Elliott, elsamitrucin, epirubicin, esorubicin, estramustine phosphate, estrogens, etanidazole, ethiofos, etoposide, fadrazole, fazarabine, fenretinide, filgrastim, finasteride, acetic acid flavone, floxuridine, fludarabine phosphate, 5-fluorouracil, Fluosol.RTM., flutamide, gallium nitrate, gemcitabine, goserelin acetate, hepsulfame, hexamethylene bisacetamide, homoharringtonin, hydrazine sulfate, 4-hydroxyacerostenedione of idarubicin, ifosfamide, alpha interferon, beta interferon, gamma interferon, interleukin-1 alpha and beta, interleukin-3, interleukin-4, interleukin-6, 4-ipomeanol, iproplatin, isotretinoin, calcium leucovorin, leuprolide acetate, levamisole , liposomal daunorubicin, liposome encapsulated doxorubicin, lomustine, lonidamine, maitansin, mechlorethamine hydrochloride, melphalan, menogaril, merbarone, 6-mercaptopurine, mesna, rest with methanol extraction from Bacillus de calmette-guerin, methotrexate, N-methylformamide, mifepristone, mitoguazone, mitomycin-C, mitotane, mitoxantrone hydrochloride, monocyte / macrophage colony stimulating factor, nabilophage , nafoxidine, neocarzinostatin, octreotide acetate, ormaplatin, oxaliplatin, paclitaxel, shovel, pentostatin, piperazinodione, pipobroman, pyrarubicin, piritrexim, pyroxantrone hydrochloride, PIXY-321, plicamycin, porphyrimine, pronimatin, pronimatin, pronimatin, prognostin, prognostin, prognostin, prognostin, prognostin, prognostin, prognostin, prognostin, prognostin , sargramostima, semustine, spirogermanium, spiromustine, streptonigrin, streptozocin, sulofenur, sodium suramine, tamoxifen, taxotere, tegafur, teniposide, terephthalamidine, teroxirone, thioguanine, thiotepa, thymidine injection, thiachoprine thiamineurine, thiazopyrine, thiazopherate, thiozoprurine, thiazopherate, thiazopherate, thiazopherate, thiazopherate, thiazopherate, thiazopherate, thiazopherate, thiazopherate, thiazopherate, thiazopherate, thiazopherate, thiazopherate, thiazopherazine , trifluridine, trimetrexate, tumor necrosis factor, uracil mustard, vinblast sulfate ina, vincristine sulfate, vindesine, vinorelbine, vinzolidine, Yoshi 864, zorubicin, and mixtures thereof.

Exemplary therapeutic agents include immunogens such as a viral antigen, a bacterial antigen, a fungal antigen, a parasitic antigen, tumor antigens, a peptide fragment of a tumor antigen, specific metastatic antigens a passive or active vaccine, a synthetic vaccine or a vaccine subunit.

The dopant can be a protein such as an enzyme, antigen, growth factor, hormone, cytokine or cell surface protein.

The dopant can be a pharmaceutical compound such as an antineoplastic agent, an antibacterial agent, an antiparasitic agent, an antifungal agent, an analgesic agent, an anti-inflammatory agent, a chemotherapeutic agent, an antibiotic or combinations thereof.

The dopants could also be growth factors, hormones, immunogens, proteins or pharmaceutical compounds that are part of a drug delivery system such as those immobilized on zeolite or polymeric matrices, biocompatible glass, natural porous apical molds such as coral HA, demineralized bone , deproteinized bone, allograft bone, collagen or chitin.

image8

In one embodiment, the dopant is an anti-inflammatory drug selected from non-steroidal anti-inflammatory drugs, COX-2 inhibitors, glucocorticoids, and mixtures. Non-steroidal anti-inflammatory drugs by way of example include aspirin, diclofenac, indomethacin, sulindac, ketoprofen, flurbiprofen. , ibuprofen, naproxen, piroxicam, tenoxicam, tolmetin, ketorolac, oxaprozin, mefenamic acid, phenorofenne, nabumetone, acetaminophen, and mixtures thereof. Exemplary COX-2 inhibitors include nimesulide, NS-398, flosulid, L-745337, celecoxib, rofecoxib, SC-57666, DuP-697, parecoxib sodium, JTE-522, valdecoxib, SC-58125, etoricoxib, RS-57067, L-748780, L761066, APHS, etodolac, meloxicam, S-2474, and mixtures thereof. Exemplary glucocorticoids include hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, triamcinolone, parametasone, fluprednisolone, betamethasone, dexamethasone, fludrocortisone, deoxycorticosterone, and mixtures thereof.

Other exemplary therapeutic agents include cell cycle inhibitors in general, apoptosis inducing agents, antiproliferative / antimitotic agents that include natural products such as vinca alkaloids (eg, vinblastine, vincristine, and vinorelbine), paclitaxel, colchicine , epidipodophyllolotoxins (e.g., etoposide, teniposide), enzymes (e.g., L-asparaginase, which systemically metabolizes L-asparagine and needs cells that do not have the ability to synthesize their own asparagine); antiplatelet agents such as G (GP) IIb / IIIa inhibitors, GP-IIa inhibitors and vitronectin receptor antagonists; antiproliferative / antimitotic alkylating agents such as nitrogen mustards (mechlorethamine, cyclophosphamide and the like, melphalan, chlorambucil), ethylenimines such as methylmelamines (hexamethylmelamine and thiotepa), alkyl sulphonates-busulfan, nitrosureas (carmustine), BCN streptozymetes (BCN streptograms (BCN streptozymetes) —Dacarbazine (DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine, purine analogs and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxydenosine platinum complexes) , carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (for example, estrogen); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab, antimigratives; antisecretories (breveldine); anti-inflammatories; such as adrenocortical steroids (cortisol, cortisone, fluorocortisone, prednisone, prednisolone, 6α-methylprednisolone, triamcinolone, triamcinolone, triamcinolonea, triamcinolonea, triamcinonea beta, triamcinolonea, triamcinolonea, steroid agents (derivatives of salic acid licos, for example, aspirin; para-aminophenol derivatives, for example, acetominophen; indole acetic and indenoacetic acids (indomethacin, sulindaco, and etodalac), heteroarylacetic acids (tolmetine, diclofenac, and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam, tenoxxicam , phenylbutazone, and oxifentatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold sodium thiomalate); immunosuppressants: (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil); antigenic agents: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF); angiotensin receptor blockers; nitric oxide donors; opposite sense oligonucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, and inhibitors of the growth factor receptor kinase transduction signal; retinoid; cyclin / CDK inhibitors; HMG co-enzyme reductase inhibitors (statins); and protease inhibitors (protease matrix inhibitors).

In one embodiment, the dopant is an antibiotic chosen from tobramycin, vancomycin, gentamicin, ampicillin, penicillin, cephalosporin C, cephalexin, cefaclor, cephamandol and ciprofloxacin, dactinomycin, actinomycin D, daunorubicin, doxorubicin, penicillin, penicillin, penicillin, penicillin quinolones, anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramycin), mitomycin, and mixtures thereof.

In one embodiment, the dopant is a protein chosen from albumin, casein, gelatin, lysozyme, fibronectin, fibrin, chitosan, polylysine, polyalanine, polycysteine, Bone Morphogenetic Protein (BMP), Epidermal Growth Factor (EGF), Fibroblast Growth (bFGF), Nerve Growth Factor (NGF), Bone-Derived Growth Factor (BDGF), Transforming Growth Factor-.beta.1 (TGF-.beta.1), Factor-.beta. Transforming Growth (TGF-.beta.), arginine-glycine-aspartic acid tripeptide (RGD), vitamin D3, dexamethasone, and Human Growth Hormone (hGH), epidermal growth factors, transforming growth factor α, factor transforming growth β, vaccinia growth factors, fibroblast growth factors, insulin-like growth factors, platelet-derived growth factors, cartilage-derived growth factors, interleukin-2, nerve cell growth factors, factors of hemopoietic cell growth, lymphocyte growth factors, bone morphogenic proteins, osteogenic factors, chondrogenic factors, or / and mixtures thereof.

In one embodiment, the dopant is a heparin selected from recombinant heparin, heparin derivatives, and heparin analogs or combinations thereof.

In one embodiment, the dopant is an oligopeptide, such as a bactericidal oligopeptide.

In one embodiment, the dopant is an osteoconductive or stereointegrating agent.

In one embodiment, the dopant is an immunosuppressant, such as cyclosporine, rapamycin and tracrolimus (FK-506), ZoMxx, everolimus, etoposide, mitoxantrone, azathioprine, basiliximab, daclizumab, leflunomide, lymphocyte, cycloocyte, murocyte, lymphocyte immunoglobulin , mycophenolate, and thalidomide.

image9

In one embodiment, the carrier material is a polymer such as polyurethanes, polyethylene terephthalate, PLLA-polyglycolic acid (PGA) copolymer (PLGA), polycaprolactone, poly (hydroxybutyrate / hydroxivalerate) copolymer, poly (vinyl pyrrolidone), polytetrafluoroethylene, polytetrafluoro poly (2-hydroxyethyl methacrylate), poly (ether urethane), silicones, acrylics, epoxides, polyesters, urethanes, parlenes, polyphosphazene polymers, fluoropolymers, polyamides, polyolefins and mixtures and copolymers.

In one embodiment, the dopant is a radiopaque material, such as those chosen from alkaline earth metals, transition metals, rare earth metals, and oxides, sulfates, phosphates, polymers and combinations thereof.

In one embodiment, the carrier material is a biopolymer selected from polysaccharides, gelatin, collagen, alginates, hyaluronic acid, alginic acid, carrageenan, chondroitin, pectin, chitosan, and their derivatives, mixtures and copolymers.

In one embodiment, the dopant is administered in a gaseous carrier fluid, such as nitrogen, hydrogen, argon, helium, air, ethylene oxide, and combinations thereof. In another embodiment, the dopant is administered in a liquid carrier fluid. In one embodiment, the liquid is also a liquid mordant (basic or acidic). In one embodiment, the dopant is administered in an inert environment.

Another embodiment relates to the chemical treatment of metal surfaces for adhesion. Good adhesion of paints and polymeric coatings to metal surfaces is an area of increasing technical importance. This technology can be used to pretreat a surface by impregnating it with compounds that have desired chemical functionality. These include, but are not limited to polymers or silica materials that have siloxane groups.

Pretreatment can be used to spread a very tightly bonded layer of polymeric planting material over the surface. The additional polymeric coatings could then be attached to this sowing layer rather than trying to bond directly to the metal surface.

The dopant is not limited to one compound but it could be any combination of any of the related materials or even some material (s) that does not have the mechanical properties necessary to impregnate the surface if administered individually at high speed to the surface.

In one embodiment, the dopant can be any material as long as it is passive, that is, not reactive with the surface. This simply has to be on the surface when the oxide layer settles due to the abrasive so that the oxide around it is re-formed.

In one embodiment, the dopant is nanocrystalline.

In one embodiment the dopant is nanocrystalline hydroxyapatite.

In one embodiment, the abrasive has a suitable property chosen from one of at least size, shape, hardness and density to break the oxide layer. In one embodiment it has a hardness module that varies from 0.1 to 10, such that the hardness module varies from 1 to 10, or a hardness module that varies from 5 to 10. In another embodiment , the abrasive has a particle size ranging from 0.1 µm to 10000 µm, such as a particle size ranging from 1 µm to 5000 µm, or particle size ranging from 10 µm to 1000 µm.

The abrasive materials to be used in this invention include, but are not limited to shot or shot blasting prepared from silica, alumina, zirconium, barium titanate, calcium titanate, titanium oxide, glass, biocompatible glass, diamond. , silicon carbide, calcium phosphate, calcium carbonate, metal powders, carbon fiber composites, polymeric composites, titanium, stainless steel, hardened steel, chromed carbon steel alloys, or any combination thereof.

The fluid jet pressure will also be a factor in determining the impact energy of the abrasive. The abrasive and the dopant (s) must not be administered to the surface through the same jet. They could be on any number of separate jets as long as they administer the solid components to the surface at substantially the same time, for example, before reforming the oxide layer if the surface is a metal. This allows a great deal of flexibility in optimizing the invention towards a specific need. In one embodiment, the fluid jet is selected from wet blasting equipment, abrasive water blasting machines, and wet grenade blasting machines. In one embodiment, the at least one fluid jet operates at a pressure that varies between 0.5 and 100 bar (50 and 10,000 kPa), such as a pressure that varies between 1 and 30 bar (100 and 3000 kPa), or a pressure that varies between 1 and 10 bars (100 and 1000 kPa).

In another embodiment. The at least one fluid jet is selected from wet grenade blasting machines, wet blasting cleaning equipment, abrasive discs, blasting blasting blasting equipment), sandblasting cleaning equipment (s) ( s), and micro cleaning equipment by means of blasting in. In one embodiment, the at least one fluid jet operates at a pressure ranging from 0.5 and 100 bar (50 and 10,000 kPa), such as a pressure ranging from 1 to 30 bar (100 and 3000 kPa), or a pressure that varies between 1 and 10 bars (100 and 1000 kPa).

image10

In other ways, the jet cleaning equipment can be used together with controlled movement such as CNC or robotic control. Jet cleaning can be carried out in an inert environment.

In one embodiment, the dopants and abrasives are contained in the same reservoir and are administered to a surface from the same fluid stream (nozzle). In another embodiment, the dopant is contained in a reservoir and the abrasive contained in a separate reservoir, and multiple nozzles administer the dopants and abrasives. The multiple nozzles can take the form of a jet inside a jet, that is, the particles of each jet bombard the surface at the same angle of incidence. In another embodiment, the multiple nozzles are spatially separated such that they bombard the surface at different angles of incidence but affecting the same point of the surface at the same time.

FIGS. 9A, 9B, and 9C are schematic diagrams of three different nozzle configurations for administering dopants to a surface; single nozzle (9A); multiple co-doping and abrasive nozzles administered from separate tanks in which one nozzle is located inside another nozzle (9B); and multiple separate nozzles with dopants and abrasives administered from separate tanks (9C). More specifically, FIG. 9A shows a single nozzle 20 for administering a single stream 23 of abrasive particles 24 and doping particles 26 to a substrate 28. FIG. 9B shows that multiple nozzles with dopants and abrasives administered from separate tanks can be used, where FIG. 9B illustrates a nozzle 30 for the administration of a stream 33 of particles 24 located inside another nozzle 40 for administering a stream 43 of doping particles 26, in which streams 33 and 43 of abrasive particles 24 and doping particles 26, respectively.

It can easily be seen that when more than one type of dopant is used, dopants of a single nozzle, or separate nozzles, can be administered. For example, when the doping combination is a therapeutic agent combined with another particle (e.g., hydroxyapatite), a two-nozzle design can be used to administer the doping combination from a nozzle and the abrasive from the second nozzle. In another embodiment, a three nozzle configuration can be used when administered in therapeutic agent from a first nozzle, the second set of doping particles is administered from a second nozzle, and the abrasive is administered from a third nozzle. .

In one embodiment, the object is an implantable medical device. Exemplary medical devices include catheters, guided wires, and baskets used in the elimination of pathological calcifications. In the case of biomedical devices, it is desirable that the level of impregnation of the abrasive itself on the surface is minimal. The abrasive should also be biocompatible since some impregnation is likely to occur.

In one embodiment, the object is a metal, such as those metals chosen from pure metals, metal alloys, intermetals comprising individual or multiple phases. Exemplary metals include titanium, titanium alloys (eg, NiTi or nitinol), ferrous alloys, stainless steel and stainless steel alloys, carbon steel, carbon steel alloys, aluminum, aluminum alloys, nickel, nickel alloys, nickel titanium alloys, tantalum, tantalum alloys, niobium, niobium alloys, chromium, chromium alloys, cobalt, cobalt alloys, precious metals, and precious metal alloys. In one embodiment, the metal is titanium.

In one embodiment, the abrasive material is alumina (Mesh 10) while the dopant is HA with a particle size range of 0.1 to 3 µm. Mixed media are achieved by mixing the dopant and the abrasive between the ratio of 5:95 and 95: 5 of HA to silica in volume percent, but more preferably between the ratio of 80:20 to 20:80 and most preferably in the ratio of 60:40 to 40:60. The silica pearl has a Mosh hardness in the range of 0.1 to 10, but more preferably in the range of 2 to 10 and most preferably in the range of 5 to 10. These mixed media are administered to a titanium surface. using a standard cutting shot blasting machine operating in the pressure range of 0.5 bar to 20 bar (50 to 2000 kPa), such as a pressure range of 2 to 10 bar (200 to 100 kPa), or a range from 4 bars to 6 bars (400 to 600 kPa). The distance between the nozzle and the surface may be in the range of 0.1 mm to 100 mm, such as a range of 0.1 mm to 50 mm, or a range of 0.1 to 20 mm. The angle of the nozzle to the surface may vary from 10 degrees to 90 degrees, such as a range of 30 degrees to 90 degrees, or a range of 70 to 90 degrees.

In one embodiment, the abrasive material is silica (Mesh 10) while the dopant is HA with a particle size range of 0.1 to 3 µm. Mixed media are achieved by mixing the dopant and the abrasive between the ratio of 5:95 and 95: 5 HA to alumina in volume percent, but more preferably between the ratio of 80:20 to 20:80 and most preferably in the ratio of 60:40 to 40:60. The alumina cutting shot has a Mosh hardness in the range of 0.1 to 10, such as a range of 2 to 10, a range of 5 to 10. These mixed media are administered to a titanium surface using a blasting machine. of standard shear blasting operating in the pressure range of 0.5 bar to 20 bar (50 to 2000 kPa), such as a pressure range of 2 to 10 bar (200 to 100 kPa), or a range of 4 bar to 6 bars (400 kPa to 600 kPa). The distance between the nozzle and the surface may be in the range of 0.1 mm to 100 mm, such as a range of 0.1 mm to 50 mm, or a range of 0.1 to 20 mm. The angle of the nozzle to the surface may vary from 10 degrees to 90 degrees, such as a range of 30 degrees to 90 degrees, or a range of 70 to 90 degrees.

image11

One skilled in the art can appreciate the influence of machine parameters that include the speed of the jet, the operating pressure, the venturi configuration, the angle of incidence and the distances from the surface to the nozzle, in the extent of the impregnation of dopants on the surface using these mixed media.

One skilled in the art can appreciate the effect of the size, shape, density and hardness of the abrasive material used in the extent of impregnation of the dopant on the surface using these mixed media.

One skilled in the art can appreciate the effect of the fluid flow itself, the shot blasting equipment that uses a gaseous medium (normally air), makes use of inert gases as a carrier fluid, for example, N2 or noble gases such as Ar and He in the extension of the impregnation of the dopant on the surface using these mixed media.

In the case of wet shot blasting, the equipment uses a liquid as carrier fluid (usually water). One skilled in the art can appreciate the effect of acidity and basicity on the extent of impregnation of the dopant on the surface using these mixed media.

As disclosed herein, the communicated procedures may be useful for modifying the surfaces of medical devices. In the context of medical device applications, dopants can be active (stimulating a biological response) or passive (without stimulating a biological response). Passive dopants can be transported to increase lubrication or return a radiopaque substrate, to increase support characteristics

or to increase the adhesion of an adsorbent layer. Active agents can arouse a response from the host tissue in vivo, increasing the functionality of the device or surgery, or administering a benefit as a secondary function of the device.

The procedure is a deposition procedure that allows the addition of material (s) to a surface by a methodology normally used to remove material from a surface. In one embodiment, the process allows impregnation of the surface using:

one.

 an abrasive bombardment to transport additional material on and / or on a surface;

2.

the removal of oxide layers from a surface in an inert environment and the subsequent deposition of additional material on or on the surface before allowing the surface to oxidize again; or

3.

 a combination of 1 and 2 above.

The procedure can be used to modify, augment or treat surfaces such as to change surface characteristics / properties that include one or more of:

Morphology / topography / shape / texture / roughness / microstructure

Surface area

Surface porosity

 structure - order / disorder of molecular assemblies, inclusions, holes, and organization

 crystallinity, size, distribution and orientation of the crystals

Chemistry

Chemical composition

Elementary composition

Chemical state of the elements

Molecular composition

 functional groups  molecular adsorbent layers  contaminants and accidental impurities  porosity of the oxide layer  biochemistry  biological behavior  surface energy - lipophilic / lipophobic properties.  wettability - hydrophilic and hydrophobic properties  adsorption - fisisorption and chemisorption  electrical properties - surface potentials and surface charges, dielectric constant  magnetic properties  optical properties - reflection / optical absorption  surface mechanical properties - elastic / plastic nature of the surface layers, forces

image12

tensile / comprehensive on the surface  surface dynamic properties - mobility of atoms and molecules The effect on the surface is such as to modify the chemistry and topography of the surface material giving as

result an infinite variety of manifestations. The desired result resulting from the treatment is influenced by:  the substrate material and its surface characteristics  the parameters of the treatment procedure and the environmental conditions  the abrasive (s) and their mechanical and chemical properties, size, hardness, morphology , etc.  the doping material (s) and their chemical and mechanical properties, whether it is a carrier medium

additional (for example, therapies), such as an active or passive agent, or a composite or a cocktail mixture.

In one embodiment the procedures described in the present process can provide one or more of the following characteristics  a process at room temperature  No degradation of the doping material (s) due to temperature or process  Ability to transport temperature sensitive agents to the intact surface  A process stage that has a respectful manufacturing  No compliant polymeric film is required to transport the therapeutic agents  No result of laminated layers - they cannot be chipped or peeled  Adaptable to allow implants that are specifically treated for specific applications  Applies to industrial sectors independent of the medical device sector, for example, industries

using titanium, for example, the aerospace sector, the food sector (use of titanium pipes), and the sector of

semiconductors, etc. Examples Example 1 This example describes the modification of a titanium substrate using hydroxyapatite (HA) as a dopant and alumina beads as an abrasive.

Mixed media consisting of 50% by weight alumina (White Saftigrit: mesh size 150, particle size 88 micrometers, Mohs 9 hardness, Guyson international Ltd) and 50 weight percent HA (hydroxyapatite

image13

5

10

fifteen

twenty

25

30

35

40

Fluka Synthetic (Fluka production GmbH, Buchs, Switzerland, part of the Sigma-Aldrich family). A Rocatec ™ cutting blast blasting cleaning equipment was used at a pressure of 5 bar (500 kPa) to clean a 2 cm x 2 cm CP titanium cut (Medical Grade 2 Titanium Laminate) by cutting blasting blasting. ASTM F67 Spec.). The distance from the nozzle to the surface was 1 cm and the nozzle was kept at 90 ° from the surface. The silicon carbide nozzle had a hole with a diameter of 1 mm and crossed the surface at 2 cm per second. He underwent three passes.

Two additional samples of titanium (Medical Grade 2 Titanium Sheet according to ASTM F67 Spec) were subjected to the same treatment but with means consisting only of HA.

The samples were then subjected to a cleaning treatment that involved 20 minutes of ultrasonic cleaning in deionized water to remove any material that was not intimately fixed to the surface. After ultrasonic cleaning the samples were rinsed with deionized water and air dried in an oven at 95 ° C for one hour.

The samples were subjected to XPS analysis (X-ray photoelectronic spectroscopy) to determine the relative concentration of Ca, P, Ti and Al on the surfaces. FIG. 2 shows wide sweeps of both samples, wherein FIG. 2A is a transport scan of XPS of titanium treated with mixed media of HA / alumina 50:50. As can be seen, the concentration of Ca and P (indicative of HA) in the clean shot blasting sample using the mixed media technique was significantly higher than that observed in the clean shot blasting sample only with HA. This was confirmed by the superior resolution of the sweeps of the nearby regions. FIGS. 3 and 4 show the levels of the Ca 2p, P 2p and Ti 2p nuclei over 50% HA: 50% alumina and 100% HA samples. Specifically, FIGS. 3A and 3B show comparative XPS spectra of the levels of the Ca 2p (FIG. 3A) and P 2p (FIG. 3B) cores only with cp titanium blasting jet (fine line) and HA 50:50: clean alumina with cp titanium shot blasting (thick line), and FIG. 4 shows the XPS spectra of the Ti 2p core level on the clean sample with 100% HA shot blasting (upper part) and the clean sample with cutting shot blasting with a 50:50 mixture of HA: alumina ( bottom), which indicates that the titanium is substantially coated by HA. In the case of a clean sample with mixed media shear blasting jet, a significant increase in the concentration of calcium and phosphorus was observed compared to the clean sample only with HA. In addition, the Ca: P ratio was found to be 1.65, confirming that the material on the surface was, in fact, HA.

An additional indication of the presence of a significant surface layer of HA was the very low Ti concentration observed on the clean surface with mixed media shot blasting compared to that observed on the clean surface with 100% shot blasting HA indicating a layer of HA is a substantial thickness (> 10 nm). XPS can be used to calculate the relative concentrations of the species on a surface comprised within a 10% error) by normalizing the areas below the core level with the RSF (Relative Scattering Factor) of each element. The calculated atomic ratio of Ca / Ti on the surface is provided in Table 1. This value best represents the level of cover on the surfaces. In the case of the alumina / HA shot blast clean sample, the relative concentration of Ca to Ti is approximately 30 times that observed in a clean sample with 100% HA shot blast.

Table 1. The atomic ratio of Ca / Ti as determined from nearby XPS scans on the surface of clean Cp Ti surfaces with cutting blasting blasting.

CLEAN MEDIA WITH BULK JET (% BY WEIGHT /% BY WEIGHT)

CA / IT RELATIONSHIP RELATIVE RELATIONSHIP

100% HA

0.45 0.98

100% HA

0.47 1.02

50% HA: 50% Alumina

13.43 29.90

50% HA: 50% silica pearls

1.96 4.26

50% HA: 50% silica pearls

2.01 4.37

image14

In order to evaluate the uniformity of the HA concentration that covers the surface surface maps of the surface XPS (0.2 x 0.2 mm), both samples were advanced, settling on the Ti 2P and Ca 2P peaks, the right and left panels of FIG. 5, respectively. The observed color uniformity is indicative of the distribution uniformity of the HA on the material substrate.

These results indicate that simultaneous bombardment allows the HA to be impregnated on the titanium surface. In addition, more than both samples given were subjected to a rigorous cleaning cycle, it is likely that the hydroxyapatite that remained on the surface was strongly bound on the substrate.

Example 2

This Example describes the modification of a titanium substrate using hydroxyapatite as a dopant and silica beads as an abrasive.

Mixed media consisting of 50 percent silica beads (Honita 14: particle size range of 75-150 microns, Mohs 5 Guyson international Ltd hardness) and 50 percent by weight HA (Fluka Synthetic Hydroxyapatite) were prepared. . A Rocatec ™ cutting blast blasting cleaning equipment was used at a pressure of 5 bar (500 kPa) to clean two 2 cm x 2 cm CP Titanium cuttings (Medical Grade 2 titanium foil) by cutting blasting blasting according to ASTM F67 Spec). The distance from the nozzle to the surface was 1 cm and the nozzle was maintained at 90 ° from the surface. The silicon carbide nozzle had a hole with a diameter of 1 mm and crossed the surface at 2 cm s-1. The surface was subjected to three passes.

The samples were then subjected to a cleaning treatment that involved 20 minutes of ultrasonic cleaning in deionized water to remove any material that was not intimately fixed to the surface. After ultrasonic cleaning, the samples were rinsed with deionized water and air dried in an oven at 95 ° C for one hour.

The samples were subjected to XPS analysis (X-ray photoelectronic spectroscopy) to determine the relative concentration of Ca, P Ti and Si on the surfaces. In the right panel of FIG. 6 shows a comparison of the Ca 2p core level in one of the samples and 100% clean sample with 100% HA shot blasting jet. In the left panel of FIG. 6 P 2p core levels are shown. In the case of the sample of mixed media with blasting blasting blasting, a significant increase in the concentration of calcium and phosphorus was observed compared to the sample with blasting blasting co HA only though not as high as it was in the case with alumina.

Table 1 provides the calculated atomic ratio of Ca / Ti on surfaces. In the case of the clean sample with blasting blasting of silica / HA beads, the relative concentration of Ca to Ti is approximately 4 times that observed in the clean samples with 100% HA blasting. Table 1 also demonstrates the reproducibility of the results achievable with this technique facilitates that the Ca / Ti ratio measured on the samples treated with the same mixed media is approximately the same. This is further demonstrated in FIG. 7 which shows the similarity in the follow-up sweeps of the two samples.

Example 3

This Example describes the modification of a titanium substrate that uses hydroxyapatite / gentamicin as a dopant and alumina beads as an abrasive.

Mixed media consisting of 50 percent alumina (White Saftigrit: 150 mesh size, 88 micron particle size, Mohs 9 hardness, Guyson international Ltd), 40 percent HA weight (Fluka Synthetic hydroxyapatite) were prepared. and 10 percent gentamicin weight. RocatecTM cleaning equipment was used by blasting blasting blasting running at a pressure of 5 bar (500 kPa) to cleanse three 0.5 cm x 0.5 cm CP titanium cuttings CP (titanium foil) Medical Quality 2 according to ASTM F67 Spec). The control clippings were cleaned by shot blasting with HA and alumina only. The distance from the nozzle to the surface was 1 cm and the nozzle was maintained at 90 ° from the surface. The silicon carbide nozzle had a hole with a diameter of 1 mm and crossed the surface at 2 cm s-1. The surface was subjected to three passes.

The samples were then subjected to a cleaning treatment that involved 20 minutes ultrasonic cleaning in deionized water to remove any material that was not intimately prefixed to the surface. After ultrasonic cleaning, the samples were rinsed with deionized water and air dried in an oven at 40 ° C for one hour.

Administration and antibacterial activity of antibiotic-filled surfaces against three bacterial species [Staphylococcus aureus (FIG. 8.1), Escherichia coli (FIG. 8.2) and Pseudomonas aeruginosa (FIG. 8.3)], identified as opportunistic pathogens were evaluated. they colonized postoperative periprosthetic tissue, and a major cause of implant corrosion using an agar plate diffusion procedure.

image15

Briefly, bacteria were grown from stem cultures on heart brain infusion agar (BHI) at 37 ° C for 16 h and isolated colonies were used to sow fresh cultures in 10 ml of Luria broth (LB). After incubation at 37 ° C for 12-16 h with stirring (200 rpm), the cultures were diluted in Mueller Hinton Broth (MH) to give an OD 600 of 0.05 Taps of a volume of 350 µl of each suspension were given bacterial using clinical swabs on MH agar plates containing agar at a depth of 4 mm. After this, these cuts of material were placed on the agar. The plates were inverted and incubated under anaerobic conditions (36 h, 37 ° C).

The possibility that the implant material is inhibitory with respect to microbial growth independent of the activity of the gentamicin administered using control samples that were not filled with the antibiotic on the surface marked 1 (negative control) in FIGS. 8.1, 8.2 and 8.3 respectively. Samples filled with the antibiotic were marked as 2 in FIGS. 8.1, 8.2 and 8.3 respectively.

In FIG. 8 results are displayed. In the case of each of the three bacterial species tested, an inhibition zone was observed in which bacterial growth was inhibited (marked ZI in FIGS. 8.1, 8.2 and 8.3 respectively) around the samples treated with HA / Gentamicin . This indicates that gentamicin was incorporated into the surface in the procedure and also that the antibiotic remains active throughout the cleaning process by shot blasting.

Example 4

This Example describes the modification of a titanium substrate that uses hydroxyapatite / vancomycin as a dopant and alumina beads as an abrasive.

Mixed media consisting of 67 percent alumina (Saftigrit White mesh size 150, particle size 88 micrometers, Mohs 9 hardness, Guyson international Ltd), 30 percent by weight HA (Fluka Synthetic hydroxyapatite) and 3 percent by weight vancomycin. A RocatecTM cleaning device was used by shot blasting, operating at a pressure of 5 bar (500 kPa) to clean through 18 shot blasting blasting gun Titanium plates 10 mm diameter Quality 5 (6AL-4V Medical Titanium Sheet according to ASTM F 136 Spec). Shot blast blades were cleaned with HA and alumina only. The distance from the nozzle to the surface was 0.5 cm and the nozzle was maintained at 90 ° from the surface. The silicon carbide nozzle had a hole of a diameter of 1 mm and crossed the surface at 2 cm s-1. The surface was subjected to three passes.

Numerous samples were then subjected to a cleaning treatment that involved 20 minutes of ultrasonic cleaning in deionized water to remove any material that was not intimately prefixed to the surface. After ultrasonic cleaning, the samples were rinsed with deionized water and allowed to air dry in an oven at 40 ° C for one hour.

Administration and antibacterial activity of antibiotic-filled surfaces against the bacterial species Staphylococcus aureus (NCIMB 9518), identified as an opportunistic pathogen that colonized the postoperative periprosthetic tissue, were evaluated using an agar plate diffusion procedure. Plate 1 of FIG. 10 is a photograph of the zone of inhibition (ZI) on an agar plate inoculated with S. aureus and exposed to a cut doped with vancomycin.

Tests were carried out in accordance with the BSAC (British Society for Antimicrobial Chemotherapy) Plate Diffusion procedure to test Antimicrobial Susceptibility (Version 2.1.1, January 2002). A bacterial suspension containing 107 CFU / ml of Staphylococcus aureus NCIMB 9518 was prepared from recent overnight cultures, and 0.5 ml of this suspension was sprayed homogeneously onto iso-sensitest plates. After this, the material clippings were placed on the agar The plates were incubated under anaerobic conditions (20 hours @ 37 ° C).

The possibility that the implant material was inhibitory with respect to microbial growth was eliminated using control samples that did not have the antibiotic filled on the surface (negative control).

In FIG. 10, the results of plaque 1 are shown, as demonstrated by an inhibition zone that pointed to an inhibited bacterial growth around the samples treated with HA / vancomycin. This indicates that vancomycin was incorporated into the surface in the procedure and also that the antibiotic remains active throughout the cleaning process by shot blasting.

Example 5

This Example describes the modification of a titanium substrate that uses hydroxyapatite (tobramycin as a dopant and alumina beads as an abrasive.

Mixed media consisting of 67 percent alumina (Saftigrit White mesh size 150, particle size 88 micrometers, Mohs 9 hardness, Guyson international Ltd), 30 percent by weight HA (Fluka Synthetic hydroxyapatite) and 3 percent by weight of tobramycin. A RocatecTM cleaning device was used by shot blasting, operating at a pressure of 5 bar (500 kPa) to clean through 18 shot blasting blasting gun Titanium plates 10 mm diameter Quality 5 (6AL-4V Medical Titanium Sheet according to ASTM F 136 Spec). Shot blast blades were cleaned with HA and alumina only. The distance from the nozzle to the surface was 0.5 cm and the nozzle was maintained at 90 ° from the surface. The silicon carbide nozzle had a hole of a diameter of 1 mm and crossed the surface at 2 cm s-1. The surface was subjected to three passes.

image16

Numerous samples were then subjected to a cleaning treatment that involved 20 minutes of ultrasonic cleaning in deionized water to remove any material that was not intimately prefixed to the surface. After ultrasonic cleaning, the samples were rinsed with deionized water and allowed to air dry in an oven at 40 ° C for one hour.

Administration and antibacterial activity of antibiotic-filled surfaces against the bacterial species Escherichia coli (NCIMB 12210), identified as an opportunistic pathogen that colonized postoperative periprosthetic tissue, were evaluated using an agar plate diffusion procedure. Plates 2 and 3 of FIG. 10 are photographs of the zone of inhibition (ZI) on an agar plate inoculated with E. coli and exposed to a cut doped with tobramycin.

Tests were carried out in accordance with the BSAC (British Society for Antimicrobial Chemotherapy) Plate Diffusion procedure to test Antimicrobial Susceptibility (Version 2.1.1, January 2002). A bacterial suspension containing 107 CFU / ml of E. coli NCIMB 12210 was prepared from fresh cultures overnight, and 0.5 ml of this suspension was sprayed homogeneously on iso-sensitest plates. After this, the material clippings were placed on the agar The plates were incubated under anaerobic conditions (20 hours @ 37 ° C).

The possibility that the implant material was inhibitory with respect to microbial growth was eliminated using control samples that did not have the antibiotic filled on the surface (negative control).

In FIG. 10, the results of plates 2 and 3 are shown, as demonstrated by an inhibition zone that pointed to an inhibited bacterial growth around the samples treated with HA / tobramycin. This indicates that tobramycin was incorporated into the surface in the procedure and also that the antibiotic remains active throughout the cleaning process by shot blasting.

Example 6

This Example describes the modification of a titanium substrate using hydroxyapatite as a dopant and abrasives of varying size / hardness.

Mixed media consisting of 80 percent abrasive (silica beads with a particle size of 50, 100 microns), Mohs 6 hardness, Comco Inc .; alumina beads with a particle size of 50, 100, 150 micrometers. Mohs 9 hardness, Comco Inc.) and 20 percent HA (Fluka Synthetic hydroxyapatite). A Comco MB1000 microcleaning equipment was used operating at a cleaning pressure using 80 psi shot blasting to clean through blasting blast blasting blades Titanium Plates Quality 5 10 mm in diameter (Medical Titanium Sheet 6AL-4V according to the ASTM F 136 Spec) for each type of abrasive. The distance from the nozzle to the surface was 15 mm and the nozzle was maintained at 90 ° from the surface. The HP (high performance) nozzle used had a hole with a diameter of 0.060 inches (0.1524 cm) and crossed the surface at 3,175 mm s-1. The surface was subjected to a pass along the center of each metal plate.

The samples were then subjected to a cleaning treatment that involved 20 minutes of ultrasonic cleaning in deionized water to remove any material that was not intimately prefixed to the surface. After ultrasonic cleaning, the samples were rinsed with deionized water and air dried in an oven at 40 ° C for one hour.

The samples were subjected to XPS (X-ray photoelectronic spectroscopy); FTIR (Fourier Transform Infrared Spectroscopy); Surface Roughness Analysis - Tip profilometry; (XRD) X-ray diffraction, to determine the relative concentration of Ca, P and Ti on the surface of each sample along with the morphological characteristics of each sample.

Table 2 indicates the results showing the clean titanium by shot blasting with abrasives of variable particle size and hardness, as indicated by the XPS. FIGS 11A and 11B show the graphs of the FTIR spectra in duplicate of 100 µm and 150 µm alumina beads, respectively.

image17

Table 2: Atomic concentrations by XPS of surface elements (and Ca: P ratio) as a function of the hardness and size of clean particles by shot blasting.

Elements

Control 100 µm glass beads 50 µm Alu oxide beads 100 µm Alu oxide beads 150 µm Alu oxide beads

Or 1s

37.78 54.80 53.38 54.71 54.12

C 1s *

44.33 20.73 24.95 23.08 24.02

N 1s

3.37 0.25 0.57 0.84 0.55

Ti 2p

5.00 0.23 1.18 1.32 0.86

Ca 2p

0.28 ** 14.58 12.23 12.36 11.99

P 2p

0.29 ** 9.40 7.69 7.68 8.47

At 2p

8.94 *** - - - -

Ca / P ratio

n / a 1.55 1.61 1.61 1.42

* The normal level of additional carbon in titanium and its alloys - may be higher depending on the training / manufacturing procedures they undergo. ** Additional HA due to cross contamination of treated samples. *** Aluminum in TiAl4V6 alloy (Titanium Quality 5)

FIG. 11A shows the FTIR spectra of duplicate samples of alumina beads (a) and (b), and FIG. 11B shows the FTIR spectra of duplicate samples of alumina beads of 150 µm (a) and (b).

Table 3 indicates the results showing abrasives of varying hardness and particle size, as indicated by the tip profilometry.

Table 3: Tip profilometry of surface topography showing roughness as a function of hardness and clean particle size by shot blasting

100 µM glass beads

50 µM Alu oxide beads 100 µM Alu oxide beads 150 µM Alu oxide beads

Average surface roughness (µM)

0.35 0.37 0.62 0.61

Standard deviation

0.06 0.03 0.05 0.02

10

FIGS 12A and 12B show the XRD models of 50 µm and 100 µm alumina pearl samples, respectively.

The data indicates that varying the size and hardness of the abrasion media will result in a variant surface morphology as expected, but also differences in the amount and coverage of hydroxyapatite in the adsorbent layer.

15 Example 7

This Example describes the modification of a titanium substrate by administering hydroxyapatite as a dopant in a stream of particles and alumina beads as an abrasive in a separate stream of particles using a double nozzle, while varying the parameters of blasting with shot blasting and the Abrasive to dopant ratio.

An experiment was carried out to control the uniformity of the abrasive flow and the doping materials that were

20 were treating on the surface by filling the materials in the tanks of two units of micro-cleaning equipment using a Comco MB 1000 shot blasting jet that fed separate nozzles directed to the same point on the surface, as schematically depicted in the FOG. 9C. The following parameters were varied; nozzle diameters, distances from the nozzles to the surface, cleaning pressure by shot blasting, incidence angle and ratio of abrasive to dopant at the point of contact with the substrate (See Table 4;

25 Variations of the test parameters to study the effect of HA deposition and surface topography). Alumina beads with a particle size of 100 micrometers, (Mohs hardness 9, Comco Inc.) were used in all test steps. The synthetic HA used (Glantreo Ltd, Cork, Ireland) had a particle size range of 20 to 60 micrometers. Nine Quality 5 titanium plates 10 mm in diameter (Medical 6AL-4V titanium sheet according to ASTM F 136 Spec) were treated for each step. The surface was subjected to a pass through the center of each metal plate at a feed rate of 3,175 mm s-1.

image18

Table 4: Variations of the test parameters to study the effect on HA deposition and surface topography

He passed

A: Nozzle Diameter B: Nozzle distance C: Cleaning pressure by shot blasting D: Angle of incidence E: Abrasive to dopant ratio

one

30 12 95 90 70:30

2

30 18 95 Four. Five 90:10

3

60 18 60 90 90:10

4

30 18 95 90 90:10

5

46 fifteen 80 67.5 80:20

6

30 12 95 Four. Five 70:30

7

60 12 60 90 70:30

8

30 12 60 Four. Five 90:10

9

30 18 60 90 70:30

10

60 18 95 Four. Five 70:30

eleven

60 12 60 Four. Five 70:30

12

60 18 60 Four. Five 90:10

13

30 12 60 90 90:10

14

60 12 95 90 90:10

fifteen

60 12 95 Four. Five 90:10

16

30 18 60 Four. Five 70:30

17

60 18 95 90 70:30

The samples were then subjected to a cleaning treatment that involved 20 minutes of ultrasonic cleaning in deionized water to remove any material that was not intimately prefixed to the surface. After ultrasonic cleaning, the samples were rinsed with deionized water and air dried in an oven at 40 ° C for

10 an hour.

The samples were subjected to XPS (X-ray photoelectronic spectroscopy): FTIR (Fourier Transform Infrared Spectroscopy); Surface Roughness Analysis - Profile profilometry; to determine the relative concentration of Ca, P, and Ti on the surface of each sample along with the morphological characteristics of each sample. Table 5 shows the results of the XPS analysis and Table 6 shows the results of the profilometry

15 tip.

image19

Table 5: XPS atomic concentrations of the surface elements (and Ca: P ratio) as a function of the variable cleaning parameters by shot blasting and the ratio of abrasive to dopant

image20

Element

one 2 3 4 5 6 7 8 9 10 eleven 12 13 14 fifteen 16 17

Or 1s

45.7 48.7 49.3 43.9 44.8 44.6 51.1 39.8 48.0 42.9 51.0 50.0 50.8 46.2 48.8 47.8 53.2

C 1s *

32.6 32.9 32.6 36.2 34.2 42.7 30.1 44.7 30.4 40.3 36.5 34.2 27.1 37.3 31.3 31.0 30.1

Na 1s

0.6 0.3 0.0 0.4 0.3 1.1 1.9 0.7 0.2 0.7 1.9 1.8 0.4 3.6 1.3 0.4 2.1

Ti 2p

0.4 2.9 2.0 2.0 1.8 5.7 3.7 6.7 0.2 3.3 6.0 5.2 0.7 2.8 3.7 0.7 4.7

Ca 2p

13.3 10.1 10.3 11.2 12.3 4.0 8.2 5.6 13.5 7.9 3.1 5.7 13.9 6.8 9.3 12.9 6.4

P 2p

7.4 5.0 5.8 6.2 6.5 1.9 4.4 2.6 7.8 4.9 1.4 3.1 7.1 3.3 5.5 7.2 3.5

Ca / p ratio

1.81 2.00 1.77 1.80 1.89 2.01 1.99 2.17 1.73 1.61 2.3 1.83 1.94 2.04 1.72 1.80 1.84

* Normal level of additional carbon in titanium and its alloys - may be higher depending on the training / manufacturing procedures you experience

Table 6: Atomic concentrations by XPS of duplicate HA controls

HA dust control

Atomic concentration (%)

Peak

BE position (eV) Point a B point

Or 1s

532.5 38.2 40.29

Ca 2p

346.5 13.08 13.72

C 1s

285 41.58 38.65

P 2p

133.5 7.31 7.34

Ca: P ratio

1.79 1.87

image21

Table 7: Tip profilometry of surface roughness as a function of variable cleaning parameters by blasting blasting and the abrasive to dopant ratio

one

2 3 4 5 6 7 8 9 10 eleven 12 13 14 fifteen 16 17

Average surface roughness (µM)

0.50 0.46 0.59 0.40 0.55 0.41 0.51 0.46 0.43 0.57 0.53 0.55 0.51 0.53 0.55 0.48 0.54

Standard deviation

0.02 0.03 0.05 0.03 0.02 0.03 0.03 0.02 0.03 0.04 0.01 0.04 0.03 0.02 0.05 0.04 0.04

image22

The data indicate that the variation of the cleaning parameters by shot blasting and the abrasive ratio: dopant, as described in the experiment, results in a variable surface morphology as expected, but also, differences in the amount and coverage of the hydroxyapatite in the adsorbent layer The data from the HA controls indicate that the procedure does not have a detrimental effect on the quality of HA as it has

5 exemplified by the data of the Ca: P ratio (calcium to phosphate), as shown in FIG. 13, XPS Tracking Spectra of duplicate HA controls.

Example 8

This Example describes the modification of a stainless steel substrate and a Quality 2 titanium substrate using hydroxyapatite as a dopant and alumina beads as an abrasive.

10 Mixed media consisting of 80 percent by weight alumina (White Saftigrit: 150 mesh size, 88 micrometer size, Mohs 9 hardness, Guyson international Ltd) and 20 percent HA (synthetic HA, were prepared particle size 20-60 micrometers, Glantreo Ltd, Cork, Ireland). A RocatecTM cleaning equipment was used by cutting blasting jet running at a pressure of 5 bar (500 kPa) to clean a stainless steel tube (medical grade stainless steel according to ASTM 1586 spec) by cutting blasting jet.

15 used to make cardiac endovascular prostheses) and a Quality 2 Titanium sheet (Medical Quality Titanium 2 sheet according to ASTM F67 Spec). The distance from the nozzle to the surface was 0.5 cm and the nozzle was maintained at 90 ° from the surface. The silicon carbide nozzle had a hole with a diameter of 1 mm and crossed the surface at 2 cm s-1. The surface was subjected to three passes.

The sample was then subjected to a cleaning treatment that involved 20 minutes of ultrasonic cleaning in

20 deionized water to remove any material that was not intimately preset to the surface. After ultrasonic cleaning, the samples were rinsed with deionized water and air dried in an oven at 40 ° C for one hour.

Samples were subjected to SEM / EDX analysis (Scanning Electron Microscope / X-ray Measured by Dispersive Energy System) to determine if HA was preset to the surface of both materials. Figures 14 (SEM)

25 and 15 (EDX) show a well preset layer of HA on the surface of the stainless steel sample that provides a good cover as indicated in Table 8, with a thickness of up to 6.5 micrometers (see FIG. 14). As expected, CP titanium showed an adherent layer of HA, see FIG. 16 (SEM) and FIG. 17 (EDX), while table 9 shows the elementary analysis of the surface. FIG. 18 (AFM) shows that the preset HA layer has a thickness of 7 micrometers.

30 Table 8: Elemental analysis of the HA-Stainless Steel interface

Element

Weight % Atomic%

C

33.19 43.85

OR

47.78 47.39

To the

2.12 1.25

Yes

0.58 0.33

P

6.14 3.14

AC

10.19 4.04

Ca / P = 1.28

Table 9: Elemental analysis of the HA-Titanium interface

Element

Weight % Atomic%

OR

33.76 58.38

P

6.41 5.73

AC

11.81 8.15

You

48.02 27.73

Ca / P = 1.42

image23

Example 9

This Example describes the modification of a titanium substrate that uses alumina beads as an abrasive and a nanoporous silica as a dopant. Nanoporous silica is known as a suitable drug elution vehicle.

Mixed media consisting of 50 percent by volume of alumina / particle size of 100 microns, Mohs 9 hardness, Comco Inc.) and 50 percent by volume of mesoporous silica were prepared (the particle size is approximately 1 micrometer; 10 nanometer pore size, Glantreo Ltd, Cork, Ireland). A Comco MB1000 microcleaning equipment was used by shot blasting at a cleaning pressure using 80 psi shot blasting to clean through nine blasting blast blades nine Quality 5 titanium plates of 10 mm diameter (6AL-4V titanium sheet Medical according to ASTM F 136 Spec). The distance from the nozzle to the surface was 15 mm and the nozzle was maintained at 90 ° from the surface. The HP nozzle used (high performance) had a hole with a diameter of 0.060 inches (0.1524 cm) and crossed the surface at 3,175 mm s-1. The surface was subjected to a pass through the center of each metal plate.

The samples were then subjected to a cleaning treatment that involved 20 minutes of ultrasonic cleaning in deionized water to remove any material that was not intimately prefixed to the surface. After cleaning the samples were rinsed with deionized water and dried in the oven in an oven at 40 ° C for one hour.

The samples were subjected to SEM (Scanning Electron Microscope) analysis to determine the presence of silica microparticles on the surface of quality titanium 5. FIG. 19 shows the particles preset to the surface.

Example 10

This Example describes the modification of aluminum and nitinol substrates with nanoporous HA (a drug elution vehicle) as a dopant and alumina beads as an abrasive

Mixed media consisting of 90 percent by weight alumina (White Saftigrit: Mesh size 150 particle size 88 micrometers, Mohs hardness 9, Guyson international Ltd) and 10 percent by weight nanoporous HA (particle size) were prepared average 50 micrometers), irregular non-spherical particles; Pore size 3-4 nanometers, Glantreo Ltd, Cork, Ireland). RocatecTM cleaning equipment was used by cutting blasting blasting at a pressure of 5 bar (500 kPa) to clean by cutting blasting blasting aluminum and nitinol. The distance from the nozzle to the surface was 0.5 cm and the nozzle was maintained at 90 ° from the surface. The silicon carbide nozzle had a hole with a diameter of 1 mm and crossed the surface at 2 cm s-1. The surfaces were subjected to three passes.

The samples were then subjected to a cleaning treatment that involved 20 minutes of ultrasonic cleaning in deionized water to remove any material that was not intimately prefixed to the surface. After ultrasonic cleaning, the samples were rinsed in deionized water and air dried in an oven at 40 ° C for one hour.

Samples were subjected to SEM (Scanning Electron Microscope) analysis to determine the presence of nanoporous HA on aluminum and nitinol surfaces. FIGS 20A and 20B are SEM images of the nanoporous HA adsorbent layer on the nitinol surface.

The scope of the invention is defined by the appended claims.

image24

Claims (23)

1. A method of treating a surface of an object, in which the object is a metallic article, the procedure comprising: substantially simultaneously administering a first set of particles comprising a dopant (6) and a second set of particles comprising an abrasive (4) from at least one fluid jet (2) to a surface (10) of the object, to impregnate the surface of the object with the dopant (6); wherein the process further comprises removing a metal oxide from the surface of the metal substrate to expose a metal surface, abrasively blasting the metal oxide with the second set of particles substantially simultaneously with the administration of the first set of particles . 2. A process as claimed in claim 1, wherein the substrate is selected from titanium, stainless steel, aluminum, and nitinol. 3. A method as claimed in claim 1 or claim 2, wherein at least one fluid jet (2) operates at a pressure ranging from 0.5 to 100 bar; p in which at least one fluid jet operates at a pressure ranging from 1 to 30 bars; or in which at least one fluid jet operates at a pressure ranging from 1 to 10 bars; or in which at least one fluid jet operates at a pressure ranging from 0.5 to 100 bar; or in which at least one fluid jet operates at a pressure ranging from 1 to 30 bars; or in which at least one fluid jet operates at a pressure ranging from 3 to 10 bars; 4. A method such as that claimed in any preceding claim, wherein the metal is selected from titanium, titanium alloys, ferrous alloys, stainless steel, stainless steel alloys, carbon steel, carbon steel alloys , aluminum, aluminum alloys, nickel, nickel alloys, nickel titanium alloys, tantalum, tantalum alloys, niobium, niobium alloys, chromium, chromium alloys, cobalt, cobalt alloys, precious metals, and precious metal alloys ; and preferably wherein the metal is selected from titanium, aluminum, stainless steel, and nitinol. 5. A method as claimed in any preceding claim, wherein the object is an implantable medical device. 6. A method as claimed in any preceding claim, wherein the object is selected from a catheter, guide wires, and baskets used in the elimination of pathological calcifications. 7. A method as claimed in any preceding claim, wherein the administration is carried out in an inert environment. 8. A method as claimed in any preceding claim, wherein the dopant (6) is selected from polymers, metals, ceramics and combinations thereof; or in which the dopant comprises two or more different materials, or in which the dopant is a metal oxide; or wherein the dopant is selected from barium titanate, calcium titanate, sodium titanate, zeolite, siliceous zeolite, zeolites containing phosphorus, silica, alumina, zirconium, calcium carbonate, biocompatible glass, calcium phosphate glass, and titanium dioxide. 9. A method as claimed in any preceding claim, wherein the dopant (6) is an osteoconductive or osteointegrating agent. 10. A method as claimed in claim 9, wherein the osteoconducting agent or osteointegrator is selected from modified calcium phosphates. 11. A method as claimed in claim 9 or claim 10, wherein the osteoconducting or osteointegrating agent is selected from Ca5 (PO4) 3OH, CaHPO42H2O, CaHPO4, Ca8H2 (PO4) 6 · 5H2O, αCa3 (PO4) 2, β-Ca3 (PO4) 2, and combinations thereof. image 1 12. A process as claimed in claim 10 or claim 11, wherein the modified calcium phosphate contains at least one anion selected from carbonate, chloride, fluoride, silicate or aluminate; I wherein the modified calcium phosphate contains at least one cation selected from protons, potassium, sodium, magnesium, barium and strontium. 13. A method as claimed in any preceding claim, wherein the dopant (6) is a therapeutic agent. 14. A method as claimed in claim 13, wherein the therapeutic agent is immobilized on or in a carrier material. 15. A method as claimed in claim 14, wherein the carrier material is selected from polymers calcium phosphate, titanium dioxide, silica, biopolymers, biocompatible glasses, zeolite, demineralized bone, deproteinized bone, allograft bone, and their combinations of composite materials. 16. A process as claimed in claim 15, wherein the polymers are selected from polyurethanes, polyethylene terephthalate, PLLA-polyglycolic acid (PGA) copolymer (PLGA), polycaprolactone, poly (hydroxybutyrate / hydroxivalerate) copolymer. , poly (vinyl pyrrolidone), polytetrafluoroethylene, poly (2-hydroxyethyl methacrylate), poly (etherurethaneurea), silicones, acrylics, epoxides, polyesters, urethanes, parlenes, polyphosphazene polymers, fluoropolymers, polyamides, polyolefin, and mixtures and copolymers thereof; or in which the biopolymers are selected from polysaccharides, gelatin, collagen, alginate, hyaluronic acid, alginic acid, carrageenan, chondroitin, pectin, chitosan, and their derivatives, mixtures and copolymers. 17. A method as claimed in claim 14, wherein the therapeutic agent is selected from anticancer drugs, anti-inflammatory drugs, immunosuppressants, an antibiotic, heparin, a functional protein, a regulatory protein, structural proteins, oligopeptides, peptides. antigens, nucleic acids, immunogens, and combinations thereof. 18. A method as claimed in claim 17 wherein the anticancer drugs are selected acivicin, aclarubicin, acodazol, acronicin, adozelesin, alanosine, aldesleucine, sodium allopurinol, altretamine, aminoglutethimide, amonafide, amplify, amsacrine, androgens anguidine, afidicoline glycinate, asaley, asparaginase, 5-azacitidine, azathioprine, bacillus calmette-guerin (BCG), Baker's antifol (soluble), beta-2'-deoxythioguanosine, bisantrene hydrochloride, bleomycin sulfate, busulfan, butulphine sulfoximine, BWA 773U82, BW 502U83.HCl, BW 7U85 mesylate, ceracemida, carbetimer, carboplatin, carmustine, chlorambucil, chloroquinoxaline-sulfonamide, chlorozotocin, chromomycin A3, cisplatin, cladribine, corticosteroids, Corynebacterium parvum, CPT-11, crisnatol, cyclocytidine, cyclophosphamide, cytarabine, citembena, dabis maleate, dacarbazine, dactinomycin, daunorubicin hydrochloride, deazauridine, dexrazoxane, dianhydrogalactitol, d iazicuone, dibromodulcitol, didemnin B, diethyldithiocarbamate, diglycoaldehyde, dihydro-5-azacitidine, doxorubicin, echinomycin, edatrexate, edelfosine, eflomitin, Elliott's solution, elsamitrucin, etrorphtholotin thiatrohydenedin, ethostrophosphate , fazarabine, fenretinide, filgrastim, finasteride, flavone of acetic acid, floxuridine, fludarabine phosphate, 5-fluorouracil, Fluosol.RTM., flutamide, gallium nitrate, gemcitabine, goserelin acetate, hepsulfame, hexamethylene bisacetatonide, homo bisacetatonide, homo bisacetamine, sulfonate hydrazine, 4-hydroxyandrostenedione, hydroxyurea, idarubicin hydrochloride, ifosfamide, alpha interferon, beta interferon, gamma interferon, interleukin-1 alpha and beta, interleukin-3, interleukin-4, interleukin-6, 4-ipomeanol, iproplatin, isotretinoin, calcium leucovorin, leuprólido acetate, levamisole, liposomal daunorubicin, liposome encapsulated doxorubicin, lomustine, lonidam ina, maitansin, mechlorethamine hydrochloride, melphalan, menogaril, merbarone, 6-mercaptopurine, mesna, rest with methanol extraction of Bacillus from calmette-guerin, methotrexate, N-methylformamide, mifepristone, mitoguazone, mitomycin-C, mitothane, chlorhydrate mitoxantrone, colony stimulating monocytes / macrophages, nabilone, nafoxidine, neocarzinostatin, octreotide acetate, ormaplatin, oxaliplatin, paclitaxel, pala, pentostatin, piperazinedione, pipobroman, pirarubicin, piritrexim, piroxantrone hydrochloride, PIXY-321, plicamycin, porfimer factor sodium, prednimustine, procarbazine, progestins, pyrazofurin, razoxana, sargramostima, semustine, spirogermanium, spiromustine, streptonigrine, streptozocin, sulofenur, sodium suramin, tamoxifen, taxotere, tegafur, teniphoside, thioethamine thiaphoamine injection , thiazofurin, topotecan, toremifene, tretinoin, trifluoperazine hydrochloride, trifluridine, trimetrexate, tumor necrosis factor, uracil mustard, vinblastine sulfate, vincristine sulfate, vindesine, vinorelbine, vinzolidine, Yoshi 864, zorubicin, and mixtures thereof; or in which anti-inflammatory drugs are selected from non-steroidal anti-inflammatory drugs, COX-2 inhibitors, glucocorticoids, and mixtures thereof. 19. A method as claimed in claim 18, wherein the non-steroidal anti-inflammatory drugs are selected from aspirin, diclofenac, indomethacin, sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen, piroxicam, tenoxicam, tolmetine, ketorolac, oxaprozin , mefenamic acid, fenoprofen, nabumetone, acetaminophen, and mixtures thereof, or in which COX-2 inhibitors are selected from nimesulide, NS-398, flosulid, L745337, celecoxib, rofecoxib, SC-57666, DuP-697, parecoxib de sodium, JTE-522, valdecoxib, SC-58125, etoricoxib, RS57067, L-748780, L-761066, APHS, etodolac, meloxicam, S-2474, and mixtures thereof; or image2 wherein glucocorticoids are selected from among such as hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, meprednisone, triamcinolone, parametasone, fluprednisolone, betamethasone, dexamethasone, fludrocortisone, deoxycorticosterone, and mixtures thereof. 20. A method as claimed in claim 17, wherein the antibiotics are chosen from tobramycin, vancomycin, gentamicin, ampicillin, penicillin, cephalosporin C, cephalexin, cefaclor, cephamandol and ciprofloxacin, and mixtures thereof, or in the that proteins are chosen from albumin, casein, gelatin, lysozyme, fibronectin, fibrin, chitosan, polylysine, polyalanine, polycysteine, Bone Morphogenetic Protein (BMP), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (bFGF) , Nerve Growth Factor (NGF), Bone Derived Growth Factor (BDGF), Transformant Growth Factor-1 beta (TGF-1 beta), Beta Factor. Transforming Growth (TGF-.beta.), arginine-glycine-aspartic acid tripeptide (RGD), vitamin D3, dexamethasone, and Human Growth Hormone (hGH), epidermal growth factors, transforming growth factor α, factor transforming growth β, vaccinia growth factors, fibroblast growth factors, insulin-like growth factors, platelet-derived growth factors, cartilage-derived growth factors, interleukin-2, nerve cell growth factors, factors of hemopoietic cell growth, lymphocyte growth factors, bone morphogenic proteins, osteogenic factors, chondrogenic factors, or / and mixtures thereof. wherein heparin is selected from recombinant heparin, heparin derivatives, and heparin analogues or combinations thereof; or wherein the oligopeptide is a bactericidal oligopeptide; or wherein the immunogen is a viral antigen, a bacterial antigen, a fungal antigen, a parasitic antigen, tumor antigens, a peptide fragment of a tumor antigen, specific metastatic antigens, a passive or active vaccine, a synthetic vaccine or a subunit of vaccine. 21. A method as claimed in any one of claims 1 to 14, wherein the dopant (6) is a radiopaque material, and preferably, in which the radiopaque material is chosen from alkaline earth metals, transition metals, rare earth metals, and oxides, sulfates, phosphates and combinations thereof; or in which the radiopaque material is a polymer. 22. A method as claimed in any preceding claim, wherein the first and second set of particles are administered to the surface from the same fluid jet. 23. A method as claimed in any one of claims 1 to 21, wherein the first and second set of particles are administered to the surface from separate fluid jets.