CN1791436A - Medical implants comprising functional carbon coatings - Google Patents

Abstract

The invention relates to a method used for preparing the medical implant with functional surface. The invention comprises the following steps: a layer of medical implant containing a carbon layer is prepared on at least part of surfaces of the implant, the carbon-containing layer is activated through forming porosity, and the activated carbon-containing layer is functioned, thereby obtaining the functional implant.

Description

Implant with carbon surface of functionalization

The present invention relates to the method for medical implant that a kind of preparation has the surface of functionalization, this method a kind ofly has the carbon-containing bed medical implant of one deck at least by preparing to the small part implant surface, this is carbon-containing bed by producing the porosity activation, and functionalization this is activated carbon-containing bed, obtain the implant of functionalization thus.

Medical implant such as surgery or orthopedics's bolt, plate, pseudarthrosis, artificial heart valve, blood vessel prosthesis, support and can be by the various material preparations of selecting by specific biochemistry and mechanical property through active substance reservoir subcutaneous or that intramuscular is implanted.This class material must be suitable for life-time service in vivo, does not discharge toxic materials and has certain machinery and biochemical characteristic.

But, for example be usually used in the metal or metal alloy of support and pseudarthrosis and ceramic material especially when life-time service its biocompatibility or functional aspect have shortcoming.In addition, implant consequently causes objectionable intermingling reaction on the chronic inflammation reaction of prophylactic response and rejection, over-drastic cicatrization or the histolytic meaning to be arranged, cause removing implant and replacement implant or show the treatment intervention that will take additional invasive or Noninvasive under extreme case because of chemistry and/or physical stimulation initiation inflammatory tissue reactions and immunoreation.

There are various prescriptions with appropriate method coating medical implant surface in reason in the prior art thus, with the biocompatibility of raising material therefor or the function effectiveness of implant, and prevents to resist reaction or rejection.

In US 5891507 as described a kind of with silicon, politef and can improve the biomaterial of biocompatibility of this metal rack such as the method for heparin or somatomedin plating rack surface.

Remove plastic layer, the coating of carbon back also shows it is particularly advantageous.

As by known a kind of coronary stent that contains the coating of amorphous carborundum among the DE 19951477, it has improved the biocompatibility of this timbering material.US 6569107 has described a kind of support of carbon coating, and it applies material with carbon element with chemical vapor deposition method or physical vapor deposition (CVD or PVD).Described artificial limb or support in a kind of tubulose of carbon containing coating surface in US5163958, it has the antiprothrombin characteristic.WO 02/09791 describes a kind of intravascular stent that contains coating, and this coating produces by the CVD method of siloxanes.

Except that the CVD method that is used for deposit carbon, the various sputtering methods that are used to prepare the high temperature pyrolysis carbon coating of various structures in fine vacuum have also been described in the prior art, referring to as US 6355350.

But so the implant that modified surface is arranged of preparation has some shortcomings.As biocompatibility is not all to be enough to prevent fully rejection in all cases.In addition, prior art through the implant of surface applied closed pore normally, this is difficult to or hinders and soma's symbiosis on every side or limited that this is functional.Though the implant of prior art is as also applying with antibiotic, but after implant is introduced, the effect of this material only is the short time, because the amount of coated active substance can be limited by the character of implant and its face coat, or its desorbing is uncontrollable, or its effectiveness is because of undermined with interaction physics or chemistry of coating.

See highly significant from the medical science viewpoint in addition and be with desirable, this implant can not only be used as support with its support function, and can provide additional function to discharge medicine as the introducing director phase in implant, with the effect that strengthens implant or produce additional required medicine effect.

Therefore need a kind of method that simple also low being used to of cost prepares the functionalization implant of using.

In addition, also need the preparation of cost lowland to have the medical implant that improves characteristic.

Therefore the object of the present invention is to provide a kind of preparation to have the method for the implant of additional functional.

Another object of the present invention is to provide a kind of medical implant, it can bear additional function as discharging medicine or fixing organization in vivo, and has high biocompatibility or biocompatibility or have stronger function implant effect.

Another object of the present invention is to provide a kind of medical implant, it can discharge the medicinal actives material for a long time or have the improved function by surface modification in the patient body.

A further object of the present invention is to provide a kind of medical implant, and it can discharge coated or bonded pharmaceutically active substance on request and/or controllably in human body after this implant is introduced.

Another object of the present invention is to prepare cated implantable active substance reservoir, it can be by the bank release of active agent.

A further object of the present invention is to provide a kind of medical implant, and it contains coated or bonded microorganism, viral vector or cell or tissue, so that this implant can produce therapeutical effect on request or improve biocompatibility after introducing in human body.

The realization of above-mentioned purpose of the present invention is to be as defined a kind of method in the independent claims and prepared thus medical implant.The preferred embodiment of method of the present invention or product of the present invention is provided by dependent claims.

Find that within the scope of the present invention available especially simple mode is used carbon-containing bed on the medical implantable device of variety classes, it gives this implant with additional medical science-physiology and treatment function.

Particularly be fixed with the medicine of therapeutical effect amount and can be at human body medium-term and long-term and controllably discharge in the layer that can on implant surface or implant, exist by this invention.

So the method that is used to prepare the medical implant with functionalized surface of the present invention comprises the following steps:

A) prepare a kind of medical implant, have on the part surface at least of this implant that one deck is carbon-containing bed at least;

B) this is carbon-containing bed by forming the porosity activation;

C) this is activated carbon-containing bed for functionalization.

Using the inventive method can suitable modification have the implant of carbon containing face coat, but so that the drug effect material of carrier band treatment effective dose.By forming porosity, adjusting/modification hole size and/or pore structure as required in the carbon surface layer in containing of suitable thickness, and the surface layer that suitable modification discharges when needing is to regulate and to change type and the speed and the biology-physiology surface characteristic of carrier band amount, release as required.Available in this way simple process measure of the present invention realizes being suitable for the various point of applications of various implants and active substance and this medical implant and the customization solution of application purpose.

Implant

But the implant that contains carbon coating with the inventive method functionalization.

Term " medical implantable device " and " implant " are following can be used by synonym, it comprises medical or treatment implant such as blood vessel built-in prothesis, intraluminal prosthesis, support, coronary stent, peripheral bracket, the surgery or orthopedics's implantation piece such as the surgery bolt that are used for temporary transient purpose, plate, nail and other fixture, permanent surgery or orthopedics's implantation piece such as false bone or artificial joint, for example artificial femoral articulation or knee joint, the glenoid fossa insert, bolt, plate, nail, implantable orthopedics fixedly helps part, vertebral body substitutes part, and artificial heart and its parts, artificial heart valve, the heart heartstart shell, electrode, can be through implantation piece subcutaneous and/or that muscle inserts, active substance storage storehouse and microchip etc.

Applied in the methods of the invention implant can be by arbitrarily, the preferred material of temperature stabilization is basically formed, particularly is made up of the typical material for preparing implant.

The example that is suitable for this is unbodied and/or (partly-) crystalline carbon, full material with carbon element, porous carbon, graphite, carbon composite, carbon fiber, pottery as zeolite, silicate, aluminium oxide, aluminosilicate, carborundum, silicon nitride; The metal carbides of transition metal such as titanium, zirconium, hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, manganese, rhenium, ferrum, cobalt, nickel, metal-oxide, metal nitride, carbonitride, metal oxycarbide, metal oxynitrides and metal oxy-carbonitride; Metal and metal alloy, the particularly metal of noble metal gold, silver, ruthenium, rhodium, palladium, osmium, iridium, platinum and metal alloy; The metal of titanium, zirconium, hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, manganese, rhenium, ferrum, cobalt, nickel, copper and metal alloy; Steel, particularly rustless steel, marmem such as nitinol, Nitinol; Glass, rock, glass fibre, mineral, natural or synthetic aggregate, based on the imitated thing of the bone as calcium carbonate, magnesium carbonate, strontium carbonate of alkaline earth metal carbonate, expanded material as polymer foaming body, foamed ceramics etc. and as described in the combination in any of material.

In a preferred embodiment of the invention, this applicable implant is a support, metal rack particularly, preferably by rustless steel, platiniferous radiopaque steel alloy be PERSS (platinum enhancedradiopaque stainless steel alloys), cobalt alloy, titanium alloy, support as making based on niobium, tantalum, tungsten and molybdenic high-melting-point alloy, precious metal alloys, nitinol alloy and magnesium alloy and above-mentioned mixture.

Particularly preferred implant is the support of being made by rustless steel in the scope of the invention, particularly the support of being made by Fe-18Gr-14Ni-2.5Mo (" 316LVM " ASTM F 138), Fe-21Cr-10Ni-3.5Mn-2.5Mo (ASTM F1586), Fe-22Cr-13Ni-5Mn (ASTM F1314), Fe-23Mn-21Cr-1Mo-1N (nickelles stainless steel); The support of making by cobalt alloy such as Co-20Cr-15W-10Ni (" L605 " ASTM F 90), Co-20Cr-35Ni-10Mo (" MP35N " ASTM F 562), Co-20Cr-16Ni-16Fe-7Mo (" Phynox " ASTM F 1058); For example preferred titanium alloy is CP titanium (ASTM F 67, grade 1), Ti-6Al-4V (α/β ASTM F136), Ti-6Al-7Nb (α/β ASTM F 1295), Ti-15Mo (β grade ASTM F 2066); The support of being made by precious metal alloys is particularly by containing iridium alloy such as Pt-10Ir; Nitinol alloy such as martensite nitinol alloy, super-elasticity nitinol alloy and cold working (preferred 40%) nitinol alloy; And the support made of magnesium alloy such as Mg-3Al-1Z.

The applicable medical implantable device of the present invention can have almost external shape arbitrarily; The inventive method is not limited to some structure.

This implant must have on the part surface carbon-containing bed at it at least.Carbon, graphitic carbon, metal carbides, carbonitride, metal oxynitrides or the metal oxycarbide of the carbon of the carbon that this layer can be produced by high temperature pyrolysis, category of glass amorphous carbon, evaporation, the carbon that applies with CVD method, PVD method or sputtering method, diamond class, with and combination in any constitute.This is carbon-containing bed to be amorphous, part crystal form or crystallization shape, and preferred this layer is made up of unbodied high temperature pyrolysis carbon, in some embodiments, also can be made of the carbon such as the evaporate carbon of diamond class.

Special preferably by producing the material and/or the polymeric film of carbon in coating on the implant and following the implant that contains carbon coating that has that this material of carbonization prepares under anaerobic and hot conditions.As disclosed in DE10322187 or PCT/EP2004/005277, DE 10324415 or PCT/EP2004/004987 or DE10333098 or PCT/EP2004/004985.Its content is drawn this as a reference.

Other carbon-containing bed implant that is suitable for is the commercially available carbon implant that is coated with, as Radix Carbostent  type (Sorin Biomedica company) metal rack etc., it is most of by physical vapor deposition method or spray method, carbon coating that also can the sputtering method preparation.

One or more layers carbon-containing bed thickness can be 1nm-1mm usually, also can be several millimeters when needing, and as 10mm at the most, preferably reaches 6mm, especially preferably reaches 2mm, particularly 10nm-200 μ m.

In a preferred embodiment of the invention, the implantable device of this medical science also can have the carbon-containing bed of multilamellar same thickness or different-thickness and/or identical porosity or different aperture degree.As can the porous layer of underlying and the pore layer above it is combined, it can delay the release of the active substance that stores suitably in the layer of thick hole.

Activation

By the inventive method, the physics of this carbon-base coating and chemical characteristic can be by the further modifications of suitable activation step, and adapt to each required application purpose.The common carbon implant that is coated with has the surface that major part is closure substantially, and it has limited as the effectiveness of carrier band active substance and durability greatly or has been confined to considerably less amount.Activatory purpose is to form porosity or form porous on implant carbon-containing bed in carbon-containing bed, with functionalization preferably such as available active substance, cell, protein, microorganism, and improves the absorbability of carbon-containing bed per surface.

Activation step of the present invention mainly is to produce porosity in the carbon-coating on implant.Multiple use probability is arranged for this reason.

A kind of possible activation of this carbon-coating comprises as reduction or oxidation treatment step, in this step this layer through appropriate reductant and/or oxidant such as hydrogen, carbon dioxide, water vapour, oxygen, air, nitrous oxide or oxidizing acid such as nitric acid etc. and in case of necessity its mixture carry out the one or many processing.

Preferred this activation is to use air, particularly preferably in carrying out under the high temperature.

Can be when this activation step needs for example 40---1000 ℃ of high temperature, preferred 70--900 ℃, preferred 100--850 ℃ especially, carry out under more preferred 200--800 ℃ and particularly about 700 ℃.In particularly preferred embodiments, this is carbon-containing bed through reduction or oxidation, or with the combination modification at room temperature of these steps.Also can use in oxidizing acid or in the alkali liquor steaming and decocting to produce porous surface.

Kind, temperature and activatory time by applied oxidant or Reducing agent can change hole size and pore structure.In particularly preferred embodiments, the medical implant by the activatory carbon coating of the present invention can be used for active substance controllable release to external environment from base material by the porosity of regulating this carbon-coating as required.

This coating is porous after preferred activated, particularly is nano level porous.At this, can be used as pharmaceutical carrier as medical implant of the present invention with bank effect, particularly when this implant itself also had loose structure, at this moment the activated carbon based layer of this implant can be used as the film that discharges by rule.

In preferred embodiments, the adjusting of this porosity can lead to the filler that in containing carbon coating, exists such as polyvinylpyrrolidone, Polyethylene Glycol, aluminium powder, fatty acid, little wax emulsion or emulsion, paraffin, carbonate, dissolved gases or water, solvent, acid or alkali liquor can be water-soluble the washing out or realizing of salt by distillation or oxidisability or non-oxidizable thermal decomposition.Suitable method is described among the inventor's the DE10322187 or PCT/2004/005277, and its content is all drawn this with for referencial use.

The structuring on the surface that this porosity also can be by containing powdered rubber such as metal dust, white carbon black, phenol resin powder, fiber, particularly carbon fiber or natural fiber when needing produces.

This activation or another probability that produces porosity are carbon-containing bed with suitable element sputter (Besputtern), or also available so-called " ion-bombardment " is as with bombardments such as noble gas ions.

Can carry out so-called CVD-process (Chemical Vapour Deposition to activated layer at another optional processing step when needing, chemical Gasphasenabscheidung) or CVI-process (Chemical Vapour Infiltration) handle, with this surface texture of further modification or pore structure and its characteristic.The precursor gases that at high temperature decomposes with suitable carbon is handled this carbonization coating for this reason.The preferably coating of diamond-like carbon thereafter.But also other elements of deposit such as silicon.These class methods be prior art oneself know.

Can be with nearly all known under the CVD-condition, have enough volatile saturated hydrocarbons and unsaturation hydrocarbon as the decomposable precursor of carbon.For example be that methane, ethane, ethylene, acetylene, carbon number are C ₁-C ₂₀Linearity and ramose alkane, alkene and alkynes, aromatic hydrocarbon such as benzene, naphthalene etc., and once and repeatedly alkyl replaces, alkenyl replaces and the aromatic compounds of alkynyl substituted such as toluene, dimethylbenzene, cresol, styrene etc.

Can use BCl as pottery-precursor ₃, NH ₃, silane such as SiH ₄, tetrem oxosilane (TEOS), dichlorodimethylsilane (DDS), methyl trichlorosilane (MTS), silicochloroform base two chloroboranes (TDADB), six (dichloromethyl silicyl) oxides (HDMSO), AlCl ₃, TiCl ₃Or its mixture.

This class precursor with the mixture of noble gas such as nitrogen, argon etc. at least being that 0.5-15 volume % exists than small concentration.Also can in corresponding precipitation mixture, add hydrogen.At 500--2000 ℃, preferred 500--1500 ℃, this described compound decomposition becomes hydrocarbon fragment or carbon or ceramic precursor under preferred 700--1300 ℃ the temperature especially, its deposition substantially evenly distributedly in the pore system of the coating of high temperature pyrolysis, modification pore structure there and cause basic hole dimension and pore size distribution uniformly.

Can dwindle hole in implant carbon-containing bed, closure/sealing fully as required by the CVD-method up to this hole.The absorption characteristic and the mechanical property of the implant surface that customizable thus adjusting is activated.

By silane or siloxanes, when needing and hydrocarbon be the CVD of blended silane or siloxanes can be through the carbonaceous implant coating of the formation modification of carbide or oxycarbide as improving its oxidative resistance.

In preferred embodiments, can activate the implant of coating by means of the additional coating of sputtering method or modification by the present invention.Can apply carbon, silicon or metal or metallic compound with suitable sputtering target by the prior art known method for this reason.By introduce with CVD or PVD silicon compound, titanium compound, zirconium compounds or tantalum compound or metal in carbon-containing bed with form can improve this layer stability and oxidative resistance carbide mutually.

In another preferred embodiment of activation step, can to carbon-containing bed as even carry out thereafter machined through the C-of sputter layer, to produce porous surface.As denuding this layer as required and cause porous layer with suitable method.A kind of preferred probability is that abrasion is this carbon-containing bed in ultrasonic tank, and the abrasive solids through adding different grain size or hardness in this groove is by to the suitable energy of ultrasonic tank input and suitable frequency and according to producing required layer defects action time and producing porosity thus.

Preferably adopt and be added with aluminium oxide, silicate, aluminate etc., the moisture ultrasonic tank of preferred aluminium oxid-dispersion.But also available arbitrarily other suitable solvent that is suitable for ultrasonic tank replaces or uses mixture with water.

For example, handle the implant that scribbles carbon in the moisture ultrasonic tank of the aluminium oxid-dispersion of preferred 1%-60% and obtain the abrasive carbon-coating of nanoscale that its average pore size is 5nm-200nm by being added with aluminium oxide.

In addition, by metal, particularly transition metal and/or nonmetallic ion are implanted the further surface characteristic of this implant of modification; As implanting these chemical compounds of introducing nitride, oxynitride or carbonitride, particularly transition metal by nitrogen.Implant the porosity and the intensity of going back the correctability surfacing by the ion of carbon in addition.

Preferably this carbon-containing bed be that the aperture is 0.1-1000 μ m after activated, the porous layer of preferred 1-400 μ m.Also can realize microporous layers with activation step of the present invention.

Especially preferably this carbon-containing bed be that the aperture is 1-1000nm after activated, the nano porous layer of preferred 5-900nm.

In particularly preferred embodiment of the present invention, this activation is finished during carbon-containing bed preparation process, as one or more layers porous is carbon-containing bed by applying, the carbonization of material by producing carbon, be coated with carbon and/or by can be decomposed absorbable or biological suitable coating undecomposable or absorbable polymer by multiporous biological by CVD or PVD and realize.

Special preferably by polymeric film with foaming in case of necessity or the polymeric film coating implant that contains filler, then at 200--3500 ℃, excellent deliver to 2000 ℃ in oxygen-free atmosphere the carbonized polymers film to apply one or more layers porous carbon-containing bed, also can in air flow, carry out partial oxidation thereafter when needing.Correlation method is described in DE 10324415 or PCT/EP2004/004987, or among DE 10333098 or the PCT/EP2004/004985, its content is all drawn this with for referencial use.

For example in wanting the polymeric film of carbonization, sneak into Polyethylene Glycol and can cause defective in crosslinked polymer, its through heat treatment or in suitable solvent stripping can cause the porous carbon-coating.By the molecular weight and the Polyethylene Glycol-solid content of selective polymerization objects system, Polyethylene Glycol, scalable is used corresponding porosity, particularly the degree of scalable particle mean size, pore size distribution and porosity.The hole that can produce 10-1000nm for example by the molecule 1 000-8000000 dalton who selects Polyethylene Glycol, the hole that produces 50-1000nm in preferred embodiments.Can produce 5%--80%, the porosity of preferred 20%-60% by between 10%--80%, changing solid content.

Combination results and this another carbon-containing bed example of activation are to sneak into white carbon black in polymeric film.Porous matrix be can prepare by particle mean size in the selective polymer and solid content, can its porosity and average pore size be regulated by using by selecting suitable polymeric objects system, white carbon black-granularity and solid content.Be 10nm-1mm for example by adding particle mean size, preferred 10nm-1000nm's and solid content be 20-80%, it is 30-60% that the carbon black pellet of preferred 30-60% can produce average pore, and at this moment the hole size that is produced is adjustable as 10-1000nm, preferred 10-800nm.

In addition, by before or after activation step to further this carbon-containing bed surface characteristic and the porosity of modification of the optional parylene processing of implant.At this moment this implant is at first at high temperature.Handle with paracyclophane under common about 600 ℃, at this moment on implant surface, form the polymeric film of forming by poly-(right-xylylene).This film is changing into carbon in the carburising step by own perception method thereafter.

As long as need, in particularly preferred embodiments, the implant of this activated mistake can further apply the surface modification of chemistry or physics.Also can draft the purifying step that is used to remove final residual thing and impurity.Can use acid particularly oxidizing acid or solvent for this reason.Preferably steaming and decocting in acid or solvent.Can produce the carboxylated of this activated carbon-coating by steaming and decocting in oxidizing acid.

This implant of the present invention can conventional method before medical application or carrier band active substance sterilization, for example by pressing full-boiled process, oxirane-sterilization or through gamma-irradiation.

By the present invention, all possible activation method can make up mutually, and also can be combined with the functionalization step that describes below.

Functionalization

This implant can revest its a large amount of functions by suitable measure.Orthopedics and surgical implant or endovascular prosthese useful as drug carrier or drug-reservoir.The biocompatibility of the thing that the present invention implants and functionally can produce required influence and change by introducing additive, filler, protein.Can reduce thus or eliminate fully by the implant of the present invention preparation in vivo rejection or improve the effectiveness of this implant or produce adjection.

Functionalization among the present invention means its result usually and makes this carbon-containing bed measure that obtains other additional function.Functionalization of the present invention be with material introduce carbon-containing bed in or with material be fixed on carbon-containing bed on.Suitable material is selected from pharmaceutically active substance, connector, microorganism, plant cell or zooblast and comprises human cell or cell culture and tissue, mineral, salt, metal, synthetic or natural polymer, protein, peptide, aminoacid, solvent etc.

Can make through suitable activatory implant functionalization by the present invention, at this moment can may make it become bio-compatibleization through following method before or after the carrier band active substance, promptly give its at least one deck can decompose by biology or the extra play of absorbable polymer, but biology can decompose or the polymer of absorption such as ossein, albumin, gelatin, hyaluronic acid, starch, cellulose such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose-phthalic acid ester; Casein, glucosan, polysaccharide, fibrinogen, poly-(D, the L-lactide), poly-(D, the L-lactide-co-glycolide), poly-(Acetic acid, hydroxy-, bimol. cyclic ester), poly-(hydroxyl butyl ester), poly-(alkyl carbonate), poly-(ortho esters), polyester, poly-(hydroxyl glycerol three valeric acids), poly-diethyleno dioxide ketone (dioxanone), poly-(PETP), poly-(malic acid), poly-(hydroxymalonic acid), poly-anhydride, polyphosphazene, poly-(aminoacid) and its copolymer or the biological nondecomposable or polymer that absorbs are to the extra play of small part coating.Especially preferably anion, cation or amphoteric coating such as alginate, chondrus ocellatus Holmes polysaccharide, carboxy methyl cellulose; Chitosan, poly-L-Lysine; And/or phosphocholine.

Also can be on activation carbon-containing bed in the functionalization step of the inventive method coating active substance such as medicine and medicament or be introduced in this layer.This is useful especially in the time active substance can not being applied directly on the implant or introduce in the implant, as coming to this under the metal situation.

As can apply molten lipophilic active substances of shipwreck such as paclitaxel on the metal surface, it is easy to form crystalline film.Common fixable amount is limited, and its release is uncontrollable.Directly cause maximum carrier band amount to be about 3mg/mm in this metal surface of coating with paclitaxel ², it causes being to the maximum 30% uncontrollable desorbing in the release under the physiological condition in 1-5 days in physiological buffer solution.

By the activatory unbodied bed thickness of category of glass that preferably is of the present invention is 80nm-10 μ m, preferred 100nm-5 μ m and porosity are preferably 5nm-1 μ m, the carbon-coating of preferred 5nm-1000nm, be 5-50% for example at porosity, preferred 10-50% and average pore size are 5nm--1 μ m, but the acceptable activity amount reaches 100 times that contain the implant carrier band amount carbon non-activated coating or simple metal during preferred 5nm-500nm, and can carry out controllable release according to porosity or hole size and surface characteristic when needing.

Be 0.5-3.0 μ m/mm in the carrier band amount in embodiments of the invention ²Paclitaxel and bed thickness be 200nm the hydrophobic carbon surface condition under, for example can be as required when 50nm hole size and 5% porosity are arranged under physiological condition in 25-35 days with the coated paclitaxel amount of constant day release rate controllable release 70-100%.

In particularly preferred embodiments, by this any carbon-containing bed proper functionization also fixedly peptide and protein and glycoprotein and lipoprotein.

Functionalised forms of the present invention is the covalency or the non--covalency absorption of material, provides these materials and affinity additament (as so-called affinity labelling) or peptide, albumen, glycoprotein or the lipoprotein of labelling to be combined into possibility.

This class material for example is that ion, cation, particularly metal cation such as cobalt cation, nickel cation, copper cation, zinc cation, antibody, calmodulin, CaM, chitin, cellulose, sugar, aminoacid, glutathion, streptavidin, Strep-tactin or other are used in conjunction with the mutant of the material of strepto-labelling (Strep-tag) or SBP-labelling institute labelling or in conjunction with the S-albumen of the material of S-labelling institute labelling etc.

The additament of this affinity appends at the C-of chief series end or N-end with suitable manner and wants on fixed peptide, protein, glycoprotein or the lipoprotein, carries out with preparation of recombinant gene technology or biotinylation mode usually.Affinity additament preferably, poly arginine-additament (Arg-tag) of forming by 5-6 kind arginine particularly, polyhistidyl-additament (His-tag) promptly is generally the polyhistidyl sequence of any length of 2-10 residue, sequence is the FLAG-additament (FLAG-tag) of DYKDDDDK, strepto--additament (Strep-tag) is as Strep-tag II sequence WSHPQFEK, S-additament (S-tag) with amino acid based residue KETAAAKFERQHMDS, the peptide (calmodulinbinding peptide) that links calmodulin, CaM, the binding district of cellulose family is particularly wanting fixed peptide, albumen, C-end in the chief series of glycoprotein or lipoprotein, terminal or other position of N-, the SBP-additament (SBP-tag) that contains sequence MDEKTTGWRGGHVVEGLAGELEQLRARLEHHPQGQREP, polyhistidyl-additament (Polyhistidine-tag), the district (chitin-bindingdomains) that links chitin, glutathione-S-transferase-labelling (Gluthatione-S-Transferase-tag), the albumen (Maltose-binding Protein) that links maltose, phage t7 and V5 epi-position, also any other affinity additament.

Being equivalent in the modification of the material that will apply on the carbon surface of functionalization may be to purify and the system in the chromatograph labelling particularly usually.

The functionalization of carbon surface can realize that this layer can be accepted and the accrete bonding of affinity by the absorption of respective substance in carbon-containing bed and/or on carbon-containing bed.Meet material accordingly and for example be the cation on the alkaline poly arginine of being bonded to that is incorporated in the carbon-coating, as can with cobalt cation, nickel cation, copper cation, the zinc cation of polyhistidyl-additament bonding.

The absorption of antibody M1 on carbon surface makes in conjunction with FLAG-additament, streptavidin or Strep-tactin or other and is used for becoming possibility in conjunction with the mutant of the material of strepto--labelling or SBP-labelling institute labelling, or make the absorption from the teeth outwards of S-albumen, with the material of bonding S-tag labelling.

In another embodiment, this functionalization is the calmodulin, CaM that is applied to be adsorbed on the carbon surface.Thus can be on carbon-containing bed the material of bonding calmodulin, CaM-bonding-peptide-labelling.

In another embodiment, this functionalization realizes by adsorbing fiber is plain, so that can be combined with the material of bonding cellulose district institute modification, or the material that provides with bonding bonding chitin district of the absorption by chitin.

Available similarly glutathion functionalization is used the material of the protein labeling of bonding maltose with in conjunction with the material by glutathione-S-transferase-labelling institute labelling with combination with maltose or amylose.

This area professional can select a suitable affinity-system to meet the possible condition of gene technology, to meet the functional and structural characteristics of peptide, albumen, glycoprotein or lipoprotein.

For example have hole size and be 100-900nm, porosity and be 30-60% and bed thickness and be on the porous carbon surface of 1-5 μ m and can obtain containing 0.1-8 μ g/mm by spraying or dipping by Strep-tactin solution ²The carbon-coating of adsorbed Strep-tactin through functionalization.The carbon-coating of functionalization can be accepted the g/mm as 0.1-10 μ by this way ²The IL-2 with the Strep-tag labelling of recombinant.

In another embodiment, this carbon-coating mixes with cobalt ion, at this moment this porous carbon matrix contain the 0.1-50% that the cobalt amount is a solid content, in category of glass porous carbon-coating, preferably reach 60%.Be 50% at porosity, bed thickness is by the metal-doped recombinant IL-2 that can adsorb poly arginine-tag institute labelling of 0.1--100 μ g in matrix under the 500nm-1000nm situation.

Another embodiment for example is the absorption by union body-material, preferably as be hydrogel carboxymethylated glucosan absorption and make the carbon surface layer functionalization, it can physical property mode bound substances, preferred bonding biomolecule or active substance, and or have a chemical reactivity, so that available covalent bond comes these materials of bonding, preferably by forming amino-compound, sulfur hydrocarbon compound or aldehyde compound.

This area professional can select the union body of adequate types according to the coordination type for use.

For producing amino key, functionalization carbon-coating in the following manner in preferred embodiments: the absorption of carboxymethylated glucosan, passing through thereafter cultivated the modification the carboxymethyl base is converted into N-hydroxy succinic acid imines ester in NHS/EDC.

Adsorbable in this way and ester is the ligand of covalency amino-key.Unreacted ester can be by for example cultivating and passivation once more in ethanolamine-hydrochloric acid-solution of 1M in another step.Thereby generation contains every mm of carbon composite layer as the porous of being made up of category of glass carbon and carbon black pellet ²The functionalization of adsorbing the carboxymethylated glucosan of 1 μ g, but its covalent bonding 0.01-5000 μ g/mm ²Molecular weight be the peptide of 60-90.

In addition, in the functionalization step of method, by the present invention's activatory porous layer carrier band medicine or medicament, microorganism, cell and/or tissue, or provide diagnostic auxiliary agent such as labelling or contrast agent to locate coated implant in vivo, the radioactive radiation body of therapeutic amount or diagnostic amount for example also can be provided.

Coating layer of active substance

In preferred embodiments, by the activatory implant of the present invention carrier band active substance in the functionalization step.Can contain carbon coating and upload the band active substance containing the carbon coating neutralization by means of suitable adsorption method such as absorption, absorption, physical absorption, chemisorbed, be to contain carbon coating by the active substance solution in suitable solvent, active substance dispersion liquid or active substance suspension impregnation under the simple scenario.According to applied active substance and its chemical characteristic, active substance contain the carbon coating neutralization contain on the carbon coating covalently or non-covalently in conjunction with being a kind of preferred scheme.

In preferred embodiments, this active substance is the form coating with the solution in suitable solvent or solvent mixture, dispersion liquid or suspension, then carries out drying when needing.Suitable solvent for example comprises methanol, ethanol, just-propanol, isopropyl alcohol, the butoxy diglycol, butyl cellosolve, the butoxy isopropyl alcohol, the butoxy propanol, just-butyl alcohol, tert-butyl group alcohol, butanediol, the butyl capryl alcohol, diethylene glycol, the dimethoxy diglycol, dimethyl ether, dipropylene glycol, ethoxydiglycol, ethoxy ethanol, ethohexadiol, glycol, hexylene glycol, 1,2, the 6-hexanetriol, hexanol, hexanediol, the isobutoxy propanol, the isoamyl glycol, the 3-methoxybutanol, methyl cellosolve, the methoxyl group isopropyl alcohol, the methoxy butanols, methoxyl group PEG-10, dimethoxym ethane, the methyl hexyl ether, methyl propanediol, neopentyl glycol, PEG-4, PEG-6, PEG-7, PEG-8, PEG-9, the PEG-6-methyl ether, pentanediol, PPG-7, PPG-2-Buteth-3, the PPG-2 butyl ether, the PPG-3 butyl ether, the PPG-2 methyl ether, the PPG-3 methyl ether, the PPG-2 propyl ether, propylene glycol, third glycol, third glycol-butyl ether, third glycol-propyl ether, oxolane, trimethyl hexanol, phenol, benzene, toluene, dimethylbenzene; Also water, when needing in containing the mixture of dispersing aid, and above-mentioned mixture.

Preferred solvent comprises and is selected from one or more following organic solvents: ethanol, isopropyl alcohol, just-propanol, dipropylene glycol methyl ether and butoxy isopropyl alcohol (1,2-third glycol-just-butyl ether), oxolane, phenol, benzene, toluene, dimethylbenzene, preferred alcohol, isopropyl alcohol, just-propanol/and or dipropylene glycol methyl ether, particularly isopropyl alcohol and/or just-propanol.

Also can be in the hole in activated porous is carbon-containing bed the active substance of occlusion suitable dimension.

The carrier band of this active substance can be temporary transient, and promptly this active substance can discharge after medical device is implanted, and perhaps this active substance is that extended immobilization is in containing carbon coating or contain on the carbon coating.This medical implant that contains active substance can static, dynamic or quiet dynamic combined be realized the active substance carrier band thus.Therefore produce based on carbon-containing bed multi-functional coatings by the present invention's preparation.

Under with static carrier band active substance situation, this active substance for good and all is fixed on the coating or in the coating basically.To this applicable active substance is inorganic substances such as hydroxyapatite (HAP), fluor-apatite, tricalcium phosphate (TCP), zinc; And/or organic substance such as peptide, protein, Hydrocarbon such as monosaccharide, oligosaccharide and polysaccharide, lipid, phospholipid, steroid, lipoprotein, glycoprotein, glycolipid matter, Dan Baijutang, DNA, RNA, signal peptide or antibody or antibody fragment, biological absorbable polymer such as polylactone acid, chitosan and pharmaceutically-active material is arranged or the compositions of mixture of substances, these materials etc.

Under with dynamic carrier band active substance situation, consider in advance after this medical device implants, to discharge this coated active substance.This coated implant can be used for therapeutic purposes in this way, is released in active substance coated on this implant continuously at the introducing point place of implant.Being suitable for the applicable active substance that active substance discharges when dynamic active substance carrier band for example is hydroxyapatite (HAP), fluor-apatite, tricalcium phosphate (TCP), zinc; But and/or polymer such as polylactone acid, the chitosan etc. of organic substance such as peptide, protein, Hydrocarbon such as monosaccharide, oligosaccharide and polysaccharide, lipid, phospholipid, steroid, lipoprotein, glycoprotein, glycolipid matter, Dan Baijutang, DNA, RNA, signal peptide or antibody or antibody fragment bio-absorbable, and pharmaceutically-active material or mixture of substances are arranged.

Be used on the medical implantable device that contains coating of the present invention, carrying out static state and/or dynamically the have pharmaceutically-active suitable material or the mixture of substances of carrier band comprise active substance or active compound composition, it is selected from heparin, synthetic hyparinoids from animal organs (as Fondaparinux), trematodiasis element, Antithrombin III, Drotrecogin α; Cellosolve such as Alteplase, fibrinolysin, molten kinases, the factor (Faktor) XIIa, prourokinase, urokinase, alteplase, streptokinase; Anticoagulant such as aspirin, ticlopidine, clopidogrel, abciximab, glucosan; Corticosteroid such as other beclomethasone, acetic acid Ketocyclopentane contract omcilon, increase the weight of the contract strong pine of hydroxyl, Desoxymetasone, dexamethasone, Flucinolone, topsyne, flurandrenolide, 9-of betamethasone, Bake Luo Misong, betamethasone, budesonide, cortisone, Clobetasol, clocortolone, third and remove fluorine topsyne, Fluticasone, chlorine fluorine pine, halogen doubly his rope, hydrocortisone, methyl meticortelone, Mo Meitasong, bold and vigorous Buddhist nun's Kazon, prednisone, meticortelone, omcilon; So-called non-steroid anti-inflammatory agent such as diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketone Luo Mike, meclofenamic acid ester, mefenamic acid, meloxicam, nabumetone, naproxen, Ao Shapu piperazine, piroxicam, disalicylic acid, benzene go out greatly, TOL, celecoxib, Lip river cloth of fragrant former times; Cytostatics such as alkaloid and podophyllotoxin such as vinblastine, vincristine; Alkylantien such as nitroso-group carbamide, mistake nitrogen-analog; Cytotoxic antibiotics is as red rhzomorph, amycin and other anthracene nucleus system and similar substance, bleomycin, the mitomycin of softening; Antimetabolite such as folacin, purine analogue or pyrimidine analogue; Paclitaxel, how western Ramulus et folium taxi cuspidatae, sirolimus; Platinum compounds such as carbonyl platinum, cisplatin or oxalyl platinum; Amsacrine, irinotecan, Imatinib, topotecan, interference element-α 2a,, interference element-α 2b, hydroxyurea, Miltex, spray Tuo Tading, porphin nurse, A Diliu dissolve, Bexaroten, retinoic acid; Androgen antagonist and estrogen antagonist; Antiarrhythmics, the particularly antiarrhythmics of I class such as quinidine type antiarrhythmics such as quinidine, Dysopyramid, ajmaline, NPAB, cream of tartar neo-gilurytmal; Lignocaine type antiarrhythmics such as lignocaine, mexiletine, phenytoin, Tocainide; IC class antiarrhythmics such as propafenone, flecainide (acetate); II class antiarrhythmics, beta receptor blocker such as metoprolol, esmolol, propranolol, metoprolol, atenolol, oxprenolol; III class antiarrhythmics such as atlansil, sotolol; IV class antiarrhythmics such as sulfur nitrogen ketone, verapamil, amine Gallate valeronitrile; Other antiarrhythmics such as adenosine, alotec, ipratropium bromide; At the preparation of myocardium moderate stimulation angiogenesis such as VEGF (VEGF), basic fibroblast growth factor (bFGF), non-viral DNA, viral DNA, endothelial cell growth factor (ECGF): FGF-1, FGF-2, VEGF, TGF; Antibody, monoclonal antibody, anti-caline; Plant cell, endothelium progenitor cell (EPC); Digitalis glycoside such as Acetyldigoxin/lanitop, Digitoxin, digoxin; Heart glucosides such as strophanthin, Proscillaridin; The effective antiadrenergic drug energy of resisting hypertension such as maincenter material is as methyldopa, imidazoline receptor agonist; The calcium channel blocker of dihydropyridine type such as nifedipine, nitrendipine; ACE-inhibitor: Quinaprilat, cilazapril, moexipril, Trandotapril, spirapril, imidapril, Trandotapril; Vasotonia titanium-II-antagonist: Candesartancilexetil, valsartan, telmisartan, Olmesarten-medoxomil, eprosartan; The effective α of periphery-acceptor blocker such as prazosin, ebrantill, Kui Evil piperazine, bunazosin, terazosin, WY-21901; Vasodilation such as nepresol, diisopropylamine dichloroacetic acid ester, Minoxidil, sodium nitroprusside; Other resisting hypertension such as indapamide, Dihydroergotoxine Benzocaine, dihydroergotoxine methanesulfonates, cicletanine, bosentan, hydrogen fluorine cortisone, phosphodiesterase inhibitor such as Milrinone, methimazole and anti-low osmoticum are as particularly adrenergic and dopaminergic material such as dobutamine, epinephrine, ethyl phenylephrine, norfenefrine, norepinephrine, Dioxifedrine, dopamine, gutron, veritol, first phenalgin pyridazine; With part adrenoceptor-agonist such as dihydroergotamine; Fibronectin, poly-D-lysine, ethylene vinyl acetate, inflammatory cytokine such as TGFB, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6, growth hormone; And adhesiveness material such as cyanoacrylate, beryllium, silicon; With somatomedin such as erythropoietin, hormone such as corticotropin, promoting sexual gland hormone, growth hormone (Somatropin), thyrotropin, Desmopressin, terlipressin, oxytocin, western bent Li Kesi, Corticorelin, leuprorelin, triptorelin, GnRF, ganirelix, buserelin, how method Rayleigh, Goserelin and regulate peptide such as somatostatin, octreotide; Bone and cartilage stimulator polypeptide, bone morphogenetic protein (BMPs), particularly recombinant BMP-2 ' s such as recombinant human BMP-2 (rhBMP-2), bisphosphonates (as profit plug phosphine enzyme sodium, fluorine hydroxyl disodium diphosphate, according to this Alendronate, Zoledrons  ure, clodronic acid, etodolac, A Lun acid, Tiludronic Acid), fluoride such as fluorophosphoric acid disodium, sodium fluoride; Calcitonin, dihydrotachysterol; Somatomedin and cytokine such as epidermal growth factor (EGF), platelet-derivative growth factor (PDGF), fibroblast growth factor (FGFs), transforming growth factor-b (TGFs-b), transforming growth factor-a (TGF-a), erythropoietin (Fpo), insulin like growth factor-I (IGF-I), insulin like growth factor-II (IGF-II), interleukin-1 (IL-1), interleukin II (IL-2), interleukin-6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-a (TNF-a), tumor necrosis factor-b (TNF-b), interferon-g (INF-g), colony stimulating factor (CSFs); Monocyte chemoattractant protein, fibroblast stimulating factor 1, histamine, fibrin or fibrinogen, endothelin-1, Angiotensin II, collagen, bromocriptine, Methylsergid, methotrexate, carbon tetrachloride, thioacetamide and ethanol; Silver (ion), titanium dioxide, antibiotic and infection element as particularly beta-lactam-antibiotic such as beta-lactamase-responsive penicillin such as benzylpenicillin (benzylpenicillin), phenoxymethyl penicillin (penicillin V); The penicillin of anti-beta-lactamase such as Aminopenicillin such as amoxicillin, ampicillin, Bacampicillin; Acyl amino penicillin such as Mezlo, piperacillin; Penicillin carboxy, cephalosporin such as cefazolin sodium, cefuroxime, CFX, cefotiam, cephalo chlorine, cefadroxil, cefalexin, Lorabid, cefixime, CEFUROXIME AXETIL, ceftibuten, Cefpodoxime Proxetil; Aztreonam, Ertapenem, Meropenem; Beta-lactamase-inhibitor such as sulbactam, Sultamillin Tosilate; Tetracycline such as doxycycline, minocycline, tetracycline, duomycin, oxytetracycline; Aminoglycoside such as gentamycin, neomycin, streptomycin, tobramycin, amikacin, netilmicin, paromomycin, Fu Shi silk rhzomorph, spectinomycin; Macrocyclic lactone antibiotic such as azithromycin, clarithromycin, erythromycin, Roxithromycin, spiramycin, josamycin; Lincosamide such as clindamycin, lincomycin, gyrase inhibitors such as Fluorochinolone are as ring Xisha star, ofloxacin, Moxifloxacin, norfloxacin, Gatifloxacin, enoxacin, fleroxacin, levofloxacin; Chinolone such as pipemidic acid; Sulfophenyl acetyl methoxy piperazine, trimethoprim, sulfadiazine, sulphur ammonia methoxy pyrazine; Glycopeptide antibiotic such as vancomycin, romote antiquity rhzomorph; Poly-peptide antibiotic such as polymyxin, as colistin, polymyxin-B, nitroimidazole-derivant such as metronidazole, tinidazole; Aminoquinolone such as chloroquine, flumequine piperidines, oxychloroquine; Biguanide such as proguanil; Quinine alkaloid and di-amino-pyrimidine such as pyrimethamine; Amphenicole such as chloromycetin; Mycobutin, dapsone, fusidic acid, fosfomycin, nitre Fu Latai, Telithromycin, S-314, fosfomycin, two isethionic acid pentane miaows, rifampicin, tauroflex, Atovaquon, Linezolid; Viral inhibitors is as ring VCV, ganciclovir, famciclovir, phosphorus formic acid, inosine-(Dimepranol-4-acetamidobenzoat), watt ganciclovir, valaciclovir, Xi Duoluowei, Bromovinyl Deoxyuridine; Degeneration-resistant virus activity material (the nucleoside analog reverse transcription is mould-inhibitor and nucleoside analog reverse transcription be mould-derivant) as lamivudine, prick western cytidine, 2 ', 3 '-didanosine, zidovudine, Tenofovir, stavudine, A Bokawei, non-nucleoside like the thing reverse transcription mould-inhibitor: amprenavir, that Wei of indole, Saquinavir, Lopinavir, ritonavir, viracept see nelfinaivr; Amantadine, ribavirin, zanamivir, Olympic Competition Ta Miwei and lamivudine, with and make up arbitrarily and mix.

Support

Particularly preferred embodiment of the present invention is that the blood vessel built-in prothesis (intraluminal prosthesis) of coated mistake is as support, coronary vasodilator support, endovascular stent, peripheral bracket etc.

Using the inventive method can be to carry out functionalization with plain mode with bio-compatible ground, for example can prevent thus with the endermic restenosis of wearing normal appearance in the angioplasty of chamber of common support.

As containing fixing on the carbon coating, particularly paclitaxel, rapamycin or dexamethasone in porous, can discharge by the temporary transient part of these active substances and react with the local inflammation that stops or be suppressed in the vascular wall tissue by suitable actives matter.The application of this active substance and effectiveness are that prior art is known.But the respective coatings system by prior art has but limited applicability, particularly because insufficient carrier band, it causes inadequate bioavailability, also have the insufficient of this active substance not exclusively discharge or between coating system and active substance because of undesirable physics or the caused incompatibility of Chemical Exchange effect.

In a preferred embodiment of the invention, preparation and activation bed thickness are 80nm--10 μ m, hole size be 5nm--1 μ m and porosity be 1-70% category of glass carbon-coating or contain the composite layer of carbon black pellet, preferably, consequently can absorb the active substance of q.s by introducing filler and its removal from carbon-coating of following or to sneak into oval or the acicular and granularity of sphere be the porous matrix that carbon black pellet produced of 10nm-200nm by a kind of.Long-pending can the raising of this support-implant surface arrives 2000m thus ²/ m ³

In the preferred embodiment of the invention, by to containing carbon coating improves this coating as the activation under high temperature in air hydrophilic, it replenishes has on the one hand increased biocompatibility, makes this layer to active substance on the other hand, and particularly the hydrophilic active material has acceptability.

In particularly preferred embodiments, press support, particularly coronary stent and peripheral bracket carrier band pharmaceutically active substance or active material admixture or the carrier band cell or the cell culture thing of the inventive method.For being suitable for local tissue reaction or the cell proliferation that suppresses cell adhesion, platelet aggregation, complementary activation or inflammation, for example can give this rack surface with following active substance: heparin becomes hyparinoids from animal organs (as Fondaparinux), trematodiasis element, Antithrombin III, Drotrecogin α; Cellosolve (Alteplase, fibrinolysin, molten kinases, factor Faktor XIIa, prourokinase, urokinase, alteplase, streptokinase), anticoagulant (aspirin, ticlopidine, clopidogrel, abciximab, glucosan), corticosteroid (other beclomethasone, the acetic acid Ketocyclopentane omcilon that contracts, increase the weight of betamethasone, Bake Luo Misong, betamethasone, budesonide, cortisone, Clobetasol, clocortolone, third contract hydroxyl by force the pine, Desoxymetasone, dexamethasone, Flucinolone, topsyne, flurandrenolide, 9-removes the fluorine topsyne, Fluticasone, fluorine chlorine pine, halogen is his pine doubly, hydrocortisone, methyl meticortelone, Mo Meitasong, sprinkle Buddhist nun's Kazon, prednisone, meticortelone, omcilon), so-called non-steroid anti-inflammatory agent (diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketone Luo Laike, the meclofenamic acid ester, mefenamic acid, meloxicam, nabumetone, naproxen, the Ao Shapu piperazine, the pyrrole chlorothiazide, disalicylic acid, Soviet Union goes out big, TOL, celecoxib, Lip river cloth of fragrant former times).Cell inhibitor (alkaloid and podophyllotoxin such as vinblastine, vincristine; Alkylantien such as nitroso-group carbamide, mistake nitrogen-analog; Its anthracene nucleus system of cytotoxic antibiotics such as daunorubicin, amycin and tool and similar substance, bleomycin, mitomycin; Antimetabolite such as folacin, purine analogue or pyrimidine analogue; Paclitaxel, how western Ramulus et folium taxi cuspidatae, sirolimus; Platinum compounds such as carbonyl platinum, cisplatin or oxalyl platinum (Oxaliplatin); Amsacrine, irinotecan, Imatinib, topotecan, interferon-' alpha ' 2a,, interferon-' alpha ' 2b, hydroxyurea, Miltex, thiophene Tuo Tading, porphin nurse, Ah 's stream Tianjin, Bexaroten, vitamin A; Androgen antagonist and estrogen antagonist).

But for the heart tonifying effect that is suitable for system by the following active substance of the activatory support carrier band of the present invention: antiarrhythmics, the particularly antiarrhythmics of I class (quinidine type antiarrhythmics: quinidine, Dysopyramid, ajmaline, NPAB, Detajmium Bitartrate; Lignocaine type antiarrhythmics: lignocaine, mexiletine, phenytoin, Tocainide; IC class antiarrhythmics: benzyl acetophenone heart amine, flecainide (acetas)), II class antiarrhythmics (beta receptor blocker) (metoprolol, esmolol, propranolol, metoprolol, atenolol, oxprenolol), III class antiarrhythmics (atlansil, sotolol), IV class antiarrhythmics (sulfur nitrogen ketone, verapamil, amine Gallate valeronitrile), other antiarrhythmics such as adenosine, alotec, ipratropium bromide; Reagent at myocardium moderate stimulation angiogenesis: as VEGF (VEGF), basic fibroblast growth factor (bFGF), non-viral DNA, viral DNA, endothelial cell growth factor (ECGF): FGF-1, FGF-2, VEGF, TGF; Antibody, monoclonal antibody, anti-caline; Plant cell, endothelium progenitor cell (EPC).Other cardiac tonic is: digitalis glycoside (Acetyldigoxin/lanitop, Digitoxin, digoxin), other heart glucosides (strophanthin, Proscillaridin).Resisting hypertension (the effective antiadrenergic drug energy of maincenter material: methyldopa, imidazoline receptor agonist; The calcium channel blocker of dihydropyridine type such as nifedipine, nitrendipine; ACE-inhibitor: Quinaprilat, cilazapril, moexipril, Trandotapril, spirapril, Imidapril, Trandotapril; Vasotonia titanium-II-antagonist: Candesartancilexetil, valsartan, telmisartan, Olmesarten-medoxomil, eprosartan; The effective α of periphery-acceptor blocker such as prazosin, ebrantill, Kui Evil piperazine, bunazosin, terazosin, WY-21901; Vasodilation such as nepresol, diisopropylamine dichloroacetic acid ester, Minoxidil, sodium nitroprusside), other hypotensive agent such as indapamide, Dihydroergotoxine Benzocaine, dihydroergotoxine methanesulfonates, cicletanine, bosentan.Other phosphodiesterase inhibitor (Milrinone, methimazole) and anti-low osmoticum, as particularly adrenergic and dopaminergic material (dobutamine, epinephrine, ethyl phenylephrine, norfenefrine, norepinephrine, two hydrogen ephedrine, dopamine, gutron, veritol, first phenalgin pyridazine), part adrenoceptor-agonist (dihydroergotamine), be another kind of antihypotensive such as Fludrocortison at last.

For improving tissue adherence, particularly applicable component is extracellular matrix, fibronectin, poly-D-lysine, ethylene vinyl acetate, inflammatory cytokine under the peripheral bracket situation: TGF β, PDGF, VEGF, bFGF, TNF α, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6, growth hormone; And adhesiveness material such as cyanoacrylate, beryllium or silicon.

Other have the suitable substance of system and/or office of portion effect is somatomedin, erythropoietin.

Also can in bracket coating, provide hormone, as corticotropin, promoting sexual gland hormone, growth hormone, thyrotropin, Desmopressin, terlipressin, oxytocin, 3: PN: WO0018423 PAGE: 26 claimed protein, Corticorelin, leuprorelin, triptorelin, GnRF, ganirelix, buserelin, naphthalene method Rayleigh, Goserelin and regulate peptide such as somatostatin/or Pu Deding.

Another embodiment is to provide functionalization by carbon surface carrier band cell, as using versatility germ line cell, endotheliocyte or conjunctive tissue cell.These can be obtained by organism, are undertaken by cell culture or change with gene technology at laboratory.

As in special embodiment, the blood vessel implant carrier band endotheliocyte that provides activated carbon-coating is cultivated thing, at this moment this endotheliocyte cultivate thing can be in advance in bioreactor as substrate or as cultivating thing and being suitable for the carrier system of cell culture.Appropriate method to this is described among DE 10335131 or the PCT/EP04/00077, and its content is drawn this as a reference.

Therefore be 200-3000m as surface area of the present invention ²/ m ³But nanoporous activation carbon-coating carrier band endotheliocyte after cultivating, its possible cell density reaches 10 ¹-10 ¹⁶Cell/ml layer volume, preferred 10 ²-10 ¹²Cell/ml.

Rectificating surgery implant

Under surgery and rectificating surgery implant situation, advantageously activation has one or more layers carbon-containing bed implant and makes this layer be coarse pored.Suitable hole size is 0.1-1000 μ m, preferred 1-400 μ m.Impel integration better to go into peripheral cell tissue or osseous tissue by growth.

To orthopedics and non-rectificating surgery implant and by cardiac valve or artificial heart's parts of functionalization of the present invention, can also the carrying active material, be suitable for local restrain cell adhesion, platelet aggregation, complementary activation or inflammatory tissue reactions or cell proliferation its with at the identical active substance of described stent applications.

In addition, for stimulating tissue growth, particularly being suitable for better implant under the rectificating surgery implant situation integrates and also can use following active substance: bone and cartilage stimulator polypeptide, bone morphogenetic protein (BMPs), particularly recombinant BMP-2 ' s such as recombinant human BMP-2 (rhBMP-2), bisphosphonates (as risedronate sodium, fluorine hydroxyl disodium diphosphate, her this Alendronate, Zoledronsaure, the two phosphonic acids of chloromethane, etodolac, A Lun acid, Tiludronic Acid), fluoride (fluorophosphoric acid disodium, sodium fluoride); Calcitonin, dihydrotachysterol.All somatomedin and cytokine (epidermal growth factor (EGF), platelet-derivative growth factor (PDGF), fibroblast growth factor (FGFs), transforming growth factor-b (TGFs-b), transforming growth factor-a (TGF-a), erythropoietin (Fpo), insulin like growth factor-I (IGF-I), insulin like growth factor-II (IGF-II), interleukin-1 (IL-1), interleukin II (IL-2), interleukin-6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-a (TNF-a), tumor necrosis factor-b (TNF-b), interferon-g (INF-g), colony stimulating factor (CSFs)).Except that the inflammatory cytokine that oneself mentions, other promotion adheres to and promotes that the material of integrating is monocyte chemoattractant protein, fibroblast stimulating factor 1, histamine, fibrin or fibrinogen, endothelin-1, Angiotensin II, collagen, bromocriptine, Methylsergid, methotrexate, carbon tetrachloride, thioacetamide and ethanol.

Special embodiment

In addition, also can provide antibacterium-anti-infective coating or dipping to replace medicine, can use following material or mixture of substances: silver (ion), titanium dioxide, antibiotic and infection element for this reason the activatory implant of the present invention, support etc.Beta-lactam-antibiotic (beta-lactam-antibiotic: beta-lactamase-responsive penicillin such as benzylpenicillin (benzylpenicillin), phenoxymethyl penicillin (penicillin V) particularly; The penicillin of anti-beta-lactamase such as Aminopenicillin such as amoxicillin, ampicillin, Bacampicillin; Acyl amino penicillin such as Mezlo, piperacillin; Penicillin carboxy, cephalosporin (cefazolin sodium, cefuroxime, CFX, cefotiam, cephalo chlorine, cefadroxil, cefalexin, Lorabid, cefixime, CEFUROXIME AXETIL, ceftibuten, Cefpodoxime Proxetil) or other is as aztreonam, Ertapenem, Meropenem.Other antibiotic is beta-lactamase-inhibitor (sulbactam, the easypro benzene of toluenesulfonic acid west material), tetracycline (doxycycline, minocycline, tetracycline, duomycin, oxytetracycline), aminoglycoside (gentamycin, neomycin, streptomycin, tobramycin, amikacin, how to replace the card star, paromomycin, framycetin, spectinomycin), macrocyclic lactone antibiotic (azithromycin, clarithromycin, erythromycin, Roxithromycin, spiramycin, josamycin), lincosamide (clindamycin, lincomycin), gyrase inhibitor (Fluorochinolone such as ciprofloxacin, ofloxacin, Moxifloxacin, norfloxacin, Gatifloxacin, enoxacin, fleroxacin, levofloxacin; Other Chinolone such as pipemidic acid), Elix and trimethoprim (sulfadiazine, sulfalene, trimethoprim), glycopeptide antibiotic (vancomycin, Teicoplanin Targocin), poly-peptide antibiotic (polymyxin such as colistin, polymyxin-B), nitroimidazole-derivant (metronidazole, tinidazole), Aminochinolone (chloroquine, ammonia first quinoline hydroxy piperidine, hydroxychloroquine), biguanide (proguanil), quinine alkaloid and di-amino-pyrimidine (pyrimethamine), Amphenicole (chloromycetin) and other antibiotic (Mycobutin, dapsone, fusidic acid, fosfomycin, nifuratel, Telithromycin, S-314, fosfomycin, three isethionic acid pentane miaows, rifampicin, tauroflex, Atovaquon, Linezolid).Other viral inhibitors is acyclovir, ganciclovir, famciclovir, phosphorus formic acid, inosine-(Dimeprano-4-acetamidobenzoat), watt ganciclovir, valaciclovir, Xi Duoluowei, Bromovinyl Deoxyuridine.Also have in addition anti-anti-virus active substance (the nucleoside analog reverse transcription is mould-inhibitor and nucleoside analog reverse transcription be mould-derivant: lamivudine, prick western cytidine, 2 ', 3 '-didanosine, zidovudine, Tenofovir, stavudine, A Bokawei; Non-nucleoside like the thing reverse transcription mould-inhibitor: amprenavir, that Wei of indole, Saquinavir, Lopinavir, ritonavir, viracept see nelfinaivr) and other viral inhibitors such as amantadine, ribavirin, zanamivir, Olympic Competition Ta Miwei, lamivudine.

In particularly preferred embodiment of the present invention, can be before or after the carrier band active substance by the present invention preparation carbon-containing bed by means of other reagent its chemistry of modification and physical characteristic, for example its hydrophilic of modification, hydrophobicity, electric conductivity, adhesiveness or other surface characteristic suitably.Applicable for this reason material is biodegradable or not biodegradable polymer, as biodegradable is: collagen, albumin, gelatin, hyaluronic acid, starch, cellulose (methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose-phthalic acid ester); Also have casein, glucosan, polysaccharide, fibrinogen, poly-(D in addition, the L-lactide), poly-(D, the L-lactide-co-glycolide), poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly-(hydroxyl butyl ester), poly-(alkyl carbonate), poly-(ortho esters), polyester, poly-(hydroxyl glycerol three valeric acids), poly-diethyleno dioxide ketone, poly-(terephthaldehyde's acetoacetic ester), poly-(malic acid), poly-(hydroxymalonic acid), poly-anhydride, polyphosphazene, poly-(aminoacid) and all its copolymers.

Not biodegradablely be: poly-(ethane-acetic acid ethyenyl ester), siloxanes, acrylate copolymer such as polyacrylic acid, polymethylacrylic acid, polyacrylonitrile acrylate; Polyethylene, polypropylene, polyamide, polyurethane, poly-(ester-urethane), poly-(ether-urethane), poly-(ester-carbamide), polyethers such as poly(ethylene oxide), poly(propylene oxide), poly alcohol, polytetramethylene glycol; Ethene polymers such as polyvinylpyrrolidone, poly-(ethylene-alcohol), poly-(ethylene-acetate ester-phthalic acid ester); Parylene.

Usually can prepare the polymer that contains anion (as alginate, chondrus ocellatus Holmes polysaccharide, carboxymethyl cellulose) or cation (as chitosan, poly-L-Lysine etc.) or both sexes (phosphocholine) is suitable for.

These polymer can be coated on the implant surface, and it can cover wholly or in part.

Be the release characteristics that contain active substance of modification by the implant of the present invention's coating, polymer that can be by for example applying other with produce the specific characteristic relevant with pH or with the characteristic of temperature correlation.PH-sensitive polymers for example poly-(acrylic acid) and derivant, for example: homopolymer is as poly-(amino carboxylic acid), poly-(acrylic acid), poly-(methyl-acrylic acid) and its copolymer.Be suitable for equally polysaccharide as cellulose acetate ester-phthalic acid ester, hydroxypropyl emthylcellulose-phthalic acid ester, hydroxypropyl emthylcellulose-succinate, cellulose acetate ester-benzenetricarboxylic acid ester and chitosan.Thermosensitive polymer for example is poly-(N-N-isopropylacrylamide-be total to-sodium-acrylate-be total to-the n-N-alkyl acrylamide), poly-(N-methyl-N-n-propyl group acrylamide), poly-(N-methyl-N-isopropyl propyl group acrylamide), poly-(N-n-propyl methyl amide), poly-(N-N-isopropylacrylamide), poly-(N-n-diethyl acrylamide), poly-(N-isopropyl methyl acrylamide), poly-(N-cyclopropyl acrylamide), poly-(N-ethyl acrylamide), poly-(N-ethyl-methyl acrylamide), poly-(N-methyl-N-ethyl acrylamide), poly-(N-cyclopropyl acrylamide).Other polymer with hot gel-characteristic is that hydroxypropyl-cellulose, methyl-cellulose, hydroxypropyl methyl-cellulose, ethyl-hydroxyethyl-cellulose and poly alcohol are as F-127, L-122, L-92, L-81, L-61.

This active substance can be adsorbed on (non--covalency, covalency) in the carbon-containing bed hole on the one hand, and its release is at this moment mainly controlled by hole size and hole geometry.The porous carbon-coating is its release of correctability, for example pH-dependency by the additional modification of chemical modification (anion, cation).Another Application is the release that contains active ingredient carriers, be microcapsule, liposome, Nano capsule, nano-particle, micelle, synthetic phospholipid, gas-dispersion, emulsified body, microemulsified body, nanosphere etc., it is adsorbed in the hole of carbon-coating, so closes by treatment to discharge.Additional covalency or non--covalent modified this hole that makes by carbon-coating are sealed, with the protection bioactive substance.Above-mentioned polysaccharide, lipid etc. belong to the row of consideration, but also can consider described polymer.

Can divide into physical barriers layer such as inert biodegradable material (as poly-1-lysine, fibronectin, chitosan, heparin etc.) and biological activity barrier layer with by carbon-containing bed other additional coatings of the prepared porous of the present invention the time.The biological activity barrier layer can be the steric hindrance molecule, but it is through physical property bioactivation and release of active agent or its carrier.Enzyme for example, it facilitates release, activation bioactive substance or in conjunction with non--active coating, and cause exposing to the open air of active substance.Here in the main carbon-coating that the special mechanism implemented and characteristic not only can be used for preparing by the present invention, and may be used in the layer of additional coating.

Be discharged into other zone by applying the polymeric layer that above-mentioned improvement discharges and/or adjusting this active substance of this carbon-containing bed Controlled Pore Structure system from implant.Be 12 hours to 1 year or several years accessible release time, preferred 24 hours, 48 hours, 96 hours, 1 week, 2 weeks, January, March.

But implant of the present invention is also carrier band survivaling cell or microorganism and functionalization thus in special the application.It can be fixed on suitable porous carbon-containing bed in, at this moment can be to through the suitable film coating of fixed implant preparation like this, penetrable nutritional labeling of this film coating and the active substance that produces by cell or Institute of Micro-biology, but can not penetration cell itself.Therefore cell or microorganism can be provided by the film coating by biology.

Preparation example is as containing the implant of the cell that produces insulin in this way to use the technology of the present invention, and it can produce and uelralante according to the glucose level of surrounding tissue after implanting.

Claims (29)

1. method that is used to prepare the medical implant that functionalized surface is arranged, it comprises the following steps:

A) on the part surface at least of this implant, prepare a kind of carbon-containing bed medical implant of one deck at least that has;

B) activate by forming porosity that this is carbon-containing bed;

C) this is activated carbon-containing bed for functionalization.

2. the method for claim 1, it is characterized in that, this is carbon-containing bed be selected from carbon that high temperature pyrolysis produces, evaporation carbon, with carbon, metal carbides, carbonitride, metal oxynitrides or the metal oxycarbide of CVD method, PVD method or sputtering method coating, with and combination in any.

3. claim 1 or 2 method is characterized in that this implant is made by the material that is selected from carbon, carbon composite, carbon fiber, pottery, glass, plastics, metal, alloy, bone, rock or mineral.

4. the method that one of requires of aforesaid right, it is characterized in that this implant is selected from the implantation piece of prosthese, support, coronary stent, peripheral bracket, surgery in the implant of medical or treatment such as the blood vessel or rectificating surgery implant, false bone or pseudarthrosis, artificial heart, artificial heart valve, subcutaneous or intramuscular.

5. the method for one of aforesaid right requirement is characterized in that, this carbon-containing bed activation is to realize with suitable oxidant and/or Reducing agent.

6. the method for one of aforesaid right requirement is characterized in that, this is carbon-containing bed by with air, oxygen, nitrous oxide and/or oxidizing acid, at high temperature activates when needing.

7. the method for one of aforesaid right requirement is characterized in that, realizes activation by the abrasion in being added with the moisture ultrasonic tank of aluminium oxide, silicate and/or aluminate.

8. the method that one of requires of aforesaid right is characterized in that, this is carbon-containing bed to become cellular by activation, preferred coarse pored, and its aperture is 0.1-1000 μ m, also can be by the pre-structuring of substrate when needing.

9. the method that one of requires of aforesaid right is characterized in that, this is carbon-containing bed, and to become nanometer by activation poroid.

10. the method that one of requires of aforesaid right is characterized in that, this activated porous carbon-containing bed through volatile organic matter CVD and/or CVI is then closely knit and/or sealing.

11. the method for one of aforesaid right requirement, it is characterized in that, this activated carbon-containing bed functionalization comprises makes that this layer carrier band is at least a to be selected from following material: pharmaceutical actives, connector, microorganism, plant cell or zooblast comprise human cell or cell culture and tissue, mineral, salt, metal, synthetic or natural polymer, protein, peptide, aminoacid, solvent, ion, cation, particularly metal cation such as cobalt cation, nickel cation, the copper cation, zinc cation, antibody, calmodulin, CaM, chitin, cellulose, sugar, aminoacid, glutathion, streptavidin, Strep-tactin or other mutant or S-albumen, glucosan, with and derivant, mixture and compositions.

12. the method for one of aforesaid right requirement, it is characterized in that, this functionalization by in carbon-containing bed and/or on carbon-containing bed absorption the material suitable with affinity additament (affinity labelling) carry out, the selection of the material that this is suitable to make this material can with affinity additament bonding.

13. the method for claim 11 or 12 is characterized in that, these one or more materials by absorption, absorption, physical absorption, chemical absorbing, static, covalent bonding or the coating of non-covalent bonding or be fixed on carbon-containing bed on.

14. the method for claim 11 is characterized in that, this at least a material for good and all be fixed on basically one or more layers carbon-containing bed on.

15. the method for claim 11 is characterized in that, material, particularly pharmaceutically active substance that this is at least a to be applied on carbon-containing bed can controllably discharge from this layer.

16. the method for claim 15, it is characterized in that, this pharmaceutically active substance is microcapsule, liposome, Nano capsule, nano-particle, micelle, synthetic phospholipid, gas-dispersion, emulsified body, microemulsified body or nanosphere form to be introduced, it is adsorbed in the carbon-containing bed hole or on the surface, so closes by treatment release.

17. the method for one of claim 14-16 is characterized in that, coating influences the coating that active substance discharges, and it is selected from pH-sensitive polymer and/or temperature-sensitive polymer and/or bioactivation barrier layer such as enzyme.

18. the method for one of aforesaid right requirement, it is characterized in that this functionalization comprises the biological decomposable or absorbable polymer of coating such as collagen, albumin, gelatin, hyaluronic acid, starch, cellulose such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose-phthalic acid ester; Casein, glucosan, polysaccharide, fibrinogen, poly-(D, the L-lactide), poly-(D, the L-lactide-co-glycolide), poly-(Acetic acid, hydroxy-, bimol. cyclic ester), poly-(hydroxyl butyl ester), poly-(alkyl carbonate), poly-(former ester), polyester, poly-(hydroxyl glycerol three valeric acids), Ju diethyleno dioxide ketone, poly-(PETP), poly-(malic acid), poly-(hydroxymalonic acid), poly-anhydride, polyphosphazene, poly-(aminoacid) and its copolymer.

19. the method for one of aforesaid right requirement, it is characterized in that this functionalization comprises that the biological nondecomposable or absorbable polymer of coating is as poly-(ethane-acetic acid ethyenyl ester), siloxanes, acrylate copolymer such as polyacrylic acid, polymethylacrylic acid, polyacrylonitrile acrylate; Polyethylene, polypropylene, polyamide, polyurethane, poly-(ester-urethane), poly-(ether-urethane), poly-(ester-carbamide), polyethers (poly(ethylene oxide)), poly-(expoxy propane), poly alcohol, poly-(butanediol); Ethene polymers such as polyvinylpyrrolidone, poly-(ethylene-alcohol), poly-(ethylene-acetate ester-phthalic acid ester), with and copolymer.

20. one kind can be by the implant that functionalized surface is arranged of one of aforesaid right requirement preparation.

21. the implant of claim 20 is characterized in that, it is by rustless steel, titanium, tantalum, platinum, gold, platinum, alloy, particularly marmem such as nitinol or Nitinol, or is made by carbon fiber, full material with carbon element or carbon complex.

22. the implant of claim 20 or 21 is characterized in that, it also comprises multilamellar, and carrier band has the carbon-containing bed of active substance when needing.

23. the device of one of claim 20-22, it also comprises anion or cation or amphoteric coating, and it is selected from alginate, chondrus ocellatus Holmes polysaccharide, carboxy methyl cellulose; Poly-(methyl) acrylate, chitosan, poly-L-Lysine; And/or phosphocholine.

24. the support that scribbles active material layer of one of claim 20-23.

25. the cardiac valve that scribbles active material layer of one of claim 20-23.

26. the implant of one of claim 20-23, it is orthopaedic false bone or pseudarthrosis, substitutes the shape that part or vertebra substitute part at the bone of the chest of spinal column or waist.

27. the active substance reservoir that the subcutaneous and/or intramuscular with controllable release of one of claim 20-23 is implanted.

28. the implant of one of claim 20-27, it comprises coating or bonded microorganism, viral vector or cell or tissue.

29. the implant of claim 28 is used for the application of the biocompatibility that produces therapeutical effect or improve this implant after it introduces human body.