CN1694770A

CN1694770A - Metallic structures incorporating bioactive materials and methods for creating the same

Info

Publication number: CN1694770A
Application number: CN 02827647
Authority: CN
Inventors: M·E·格尔特纳; M·施莱辛格
Original assignee: Medlogics Device Corp
Current assignee: Medlogics Device Corp
Priority date: 2001-11-28
Filing date: 2002-11-27
Publication date: 2005-11-09

Abstract

One embodiment of the invention is directed to a method comprising providing an electrochemical solution comprising metal ions and a bioactive material such as bioactive molecules, and then contacting the electrochemical solution and a substrate. A bioactive composite structure is formed on the substrate using an electrochemical process, where the bioactive composite structure includes a metal matrix and the bioactive material within the metal matrix.

Description

The metal structure and the cross reference of the method that produces this metal structure that comprise bioactive materials with relevant application

The application requires the patent protection interests of following United States Patent (USP) provisional application submission date: 60/364,083 of the submission of submitting to November 28 calendar year 2001 in 15,60/333,523 and 2002 on March.The application also requires the interests of 10/196,296 submission date of U.S. Patent application of patent protection submission on July 15th, 2002.For all purposes are introduced all these U.S. Patent applications as a reference in full at this.

Background of invention

Medical treatment device comprises far-ranging treatment, prevention or diagnostor, generally all provides certain machinery, electricity, dynamo-electric or other structural behaviour, is used for carrying out to patient's body or in patient's body specific therapeutic process.(both can be provisional particularly as implant, also can be nonvolatil, but it is particularly nonvolatil), make the design of medical treatment device comprise the acceptable enough bio-compatibility characteristics of host's health (host body) toward the contact attempt, otherwise health may repel, or in other words, described device can not get desirable effect.Particularly, often design medical treatment device and have such surface characteristic, it is best installing-be organized in these lip-deep interactions.Therefore, for best effect is provided, surface modification and surfacing have been carried out a large amount of research and development.Particularly, in order to obtain needed device-organizational interface, apply is to provide outer surface layer significant problem to medical treatment device always.

It is interior or regional for fixed point bioactive materials to be sent into the different zone of human body, and for example tubular cavity (lumens), chamber (cavities), tissue or other space, structure or zone also disclose many medical treatment devices and relevant system and method.Described bioactive materials comprises for example medicine (for example chemical or biological compound etc.), and they have curative effect, for example medicine of the medicine of short and long-term treatment, for example hormone therapy to the disease of treatment.

For the bioactive materials fixed point is shipped to the remote zone of human body (for example tubular cavity, chamber, tissue or other human region or space), so that obtain treatment, protection or the diagnosis effect of expection there partly, various dissimilar medical apparatus systems and method are disclosed previously.

A kind of medical treatment device of particular type is support (stents), and it has become the major part research that biologically active agents such as administering medicine are carried out and the problem of business development.The most typical inner chamber support that forms cylindric or tubular wall type is significant especially, is inserted into body cavity, makes them attached on the body lumen wall, in case blocking-up or contraction for example keep body cavity not closed.Described support mainly is used in vascular system, for example is used in crown, peripheral and cerebrovascular system.The prevailing support that uses today is by stainless steel or Ni-Ti alloy (Nitinol (Nitinol) for example ^TM) produce, but some different alloys are also disclosed, for example be subjected to a lot of cobalt-chromium alloys of paying close attention in recent years always.Employing is transferred to (translumenal) interventional method treatment disease in chamber through skin, for example coronary artery disease, external perihaemal canal disease and cranial vascular disease, the described endovascular stent of general most uses.

Also in other body cavity, use support, comprising for example hepatobiliary system.The indication of hepatic duct support comprises narrow and malignant tumour.As long-term solution, often observe described support and have limited effect.For alleviating (palliative) treatment, usually mostly in the hepatobiliary system of living, place nonvolatil metallic support less than six months patient.

Although observed widely-used conventional bracket various benefits are arranged, also notice various shortcomings.An importance,,, observed unfortunate and harmful treatment situation particularly for endovascular support for the support implant in the chamber.For example in the case of mounting bracket in blood vessel, a described reaction is to form thrombus on support or around support, and this release that may cause local embolism or closed thromboembolism can cause the downstream ischaemic.Another important example is that the inner chamber of restenosis or " ISR " has the tendency of repelling mounting bracket.To studies show that of blood vessel " ISR " Pathological Physiology, put into lumen of vessels soon at support, smooth muscle cell proliferation and/or thrombosis are just arranged.Thrombosis rate or mounting bracket mortality were 20-50% at six months at present, and this forces reinstalls support and/or undergo surgery rectification.Even annual after support is put into coronary artery, cut again that coronary artery undergos surgery above 1,000,000 times.

In recent years, the many research and development in field of stents are all at making their be fit to delivery of biologically active material---anti-restenosis agent, so that prevent the various side effects of adopting conventional uncoated support to observe, and for example thrombosis and/or ISR.These supports are generally known as " bracket for eluting medicament (drug eluting stents) ".Worked out the anti-restenosis agent that several types uses in bracket for eluting medicament, comprising anticoagulant, but most of type is smooth muscle cell mitosis, migration and the hyperplasia of the most important ISR process that specifically observes at following.Resist with ISR in the chamber wall tissue around for example some support is discharged into medicines such as rapamycin or paclitaxel.

The previous many distinct methods that adopt support to discharge anti-restenosis medicaments that disclose are as bracket for eluting medicament.Some example comprises with the conventional bracket of overcoat combination or special stand or support and adds other compound that adds sleeve pipe or parts of preserving and discharging medicine, for example " support of coating ".Many other latest developments are at medicine being coated on the outer surface of support itself, for example being coated on the typical net metal pillar brace (strut scaffolding) of conventional stent designs.

In a concrete example, hydrophobic medicine paclitaxel directly is coated on the outer surface of stent strut.According to the disclosure about this example, the high hydrophobicity matter of medicine can remain on the support medicine in the process of delivering and be implanted to damaging part, and significantly " washing off " can not arranged in moisture blood bank (blood pool) environment.It is said that medicine can be discharged in the wall then lentamente.

In the various bracket for eluting medicament of studying, on the outer surface of network pillar, apply to preserve and the coating that discharges valuable anti-restenosis agent special use is significant.Many described coatings all have been the polymer of this effect, comprising the degradable polymer that discharges medicine by depolymerization, or the polymer (for example normally nondegradable polymer) that provides medicine from wherein be diffused into the surrounding liquid environment, to adopt.The example more specifically of the degradable and nondegradable polymer that adopts in bracket for eluting medicament includes but not limited to PLA, poly-ethanedioic acid (polyglycolic acid) and polymethyl methacrylate.

The polymer coating that is used for bracket for eluting medicament has some restriction, problem in some aspects, on general and the support with medical treatment device on the storage and the dissolution medium of medicine relevant.Observed each example of described restriction.

According to an example, the coating of polymerization is delivery of biologically active material quickly generally.Though this may be favourable with desirable in many cases,, may wish that the elution time of medicine is longer than the time of using described polymer coating to reach for some predetermined dosing mode.On the other hand, the degradation kinetics of polymer, particularly to different patients, uncertain often.Therefore, can how soon to be discharged by described polymerisation medium be difficult to the bioactive materials of prediction in the polymerisation medium.If medicine discharges too soon or be too slow, just can not reach desired therapeutic effect from medium.

In another example, the many polymeric materials that produce inflammatory reaction have been observed, comprising previous disclosed bracket coating type.For example, observed some polymer coating on endovascular support, can on vascular wall, produce inflammatory reaction, ISR is increased the weight of.

The adhesive force that waits different basically matrixes is very difficult according to another example, to reach and keep polymeric material to metallic matrix in vivo---for example support---in manufacture process.The performance of coupling off resonance, for example different calorifics and/or mechanical property (for example expansion characteristics of metallic support) between polymeric material and the beneath matrix is the reason that causes this difficulty.Between rack body and the last polymeric material inadequate bonding/adhere to, may cause that these two kinds of support compositions separate in time---a kind ofly do not wish the performance that in the medical treatment device of implantation, has.Consider this restriction, must make its adhesion to support reach maximum many polymer coated modifications, described modification tends to take into account the ability of preserving and discharging medicine.

Aforementioned another example about two partially polymerized coatings that uses on bracket for eluting medicament is disclosed previously.A predetermined part mainly provide structure to coating and in use stick to stent strut around; Predetermined another part mainly is to preserve and the release medicine.In order for example to obtain coating requisite globality on support when expanding, in two partial coatings, first must have certain ratio to second portion.For this reason, the volume that needs restriction second portion coating to reach, thus limited the medication amount that can preserve and discharge.

Being used for another restriction of the polymer coating of bracket for eluting medicament, is to adopt polymeric material to be difficult to little metallic matrix is obtained uniform coating.When little metal objects such as support make hour (for example diameter is less than 3mm), adopt polymeric material that its coating has evenly just been become the comparison difficulty.When coated polymer, because it is a thickness, be difficult, and can not duplicate its form exactly so be coated in equably on the object.Especially in the zones of different of support, for example on the summit of stent strut bending or the junction between stent strut, this is a challenge, and the material of thickness may accumulate under capillary effect there.In the occasion of not wishing to have the polymer build-up consequence, can take into account the bending and the expansion characteristics of coated support.In addition, and preserve and to discharge the degree of irregularity of polymer coating of medicine corresponding, along support and around support drug delivery be uneven and uncertain.The degree that the tissue dispensing that prediction is adhered to along support reaches is very important, increases or reduce the drug effect that dosage can be taken into account expection according to predetermined baseline.Many research and development in order to obtain acceptable uniform coating, must significantly improve or the strict parameter that keeps the polymer-coated process, or increase processing step in many cases at overcoming this restriction.

The typical restriction of another of the medication coat of polymerization is that generally the bioactive materials storage volume than them is big and loose for the storage of polymerization and dissolution medium.On the one hand, support is designed to have the waveform device of specific pillar thickness, so that make the mechanical support property on vascular wall reach maximum, be shipped to damaged part and passing in the process of damaged part delivery simultaneously, consider to make the overall size minimum and make chamber wall disturbance minimum along the blood flow zone.The polymer coating that will be used for bracket for eluting medicament is applied to these stent strut, has increased the size of the coated pillar that obtains.Described increase is directly proportional with treatment or the necessary coating amount of the necessary injection volume of preventive effect that preservation reaches expection.If can increase the storage density of bioactive materials storage medium, that is desirable because when the volume of dissolution medium hour, often also can be in long-time the bioactive materials of release predetermined.

According to another important restriction, polymer coated generally be subjected to them can be by the restriction of the ability of handling with the biologically active agents of only particular type of preserving or discharging.Though biologically active agents can be hydrophobic, hydrophilic, organic, inorganic or be different in other words that polymer coated often only being fit to some kind of these types of biological active ingredients required interaction takes place on structure and activity.Therefore, some drugs may not use with specific coating, can not use with some combination or " cocktail " of a kind of coating with multiple medicine to be coated on the identical matrix.Yet, especially be equal to occasion on a kind of matrix " cocktail " of several formulations need being coated to support, need coating to use with the biologically active agents of various kinds.

Be used for polymer coated another restriction in addition of many medical treatment devices.For example, when in the long time, providing bioactive materials, particularly in vivo in the environment, need make bioactive materials stable to the patient.Some polymeric material may not provide stable storage condition to bioactive materials, particularly when liquid can leak in the polymeric material.In another example, have more macroporous polymer and can protect microorganism in the dissolution medium hole of polymerization, therefore can increase the danger of infection.In another example, machined parameters and/or material (for example temperature, solvent or others) that some polymer coating requires may be harmful by the medicine of coating preservation and release to attempt.Therefore, in the production process of bracket for eluting medicament or other medical treatment device, must comprise a plurality of steps, so that coated polymer and medicine is entered in the polymer.According to another example, polymer coating just under development can influence volume at present, but can not influence the major function of support, and support provides structural support, and body cavity is strutted.If the storage medium of bioactive materials has influence on the mechanical strength of object, that also is desirable.

In addition, coated beneath matrix often needs the surface of conduction, and for example under the situation of electrode, many polymer can not provide described electric conductivity, and these polymer may be not suitable for preserving and discharging some drugs.In addition, for described electric conductivity is provided, must make polymer coating layer modification, electric conductivity may exert an influence to the characteristic and the complexity of other expection.In addition, every may part, Ni-Ti (for example NiTi support) etc. for example, coated device can be benefited from improving radiopacity.In other words most polymer coating especially for the coating of bracket for eluting medicament, or, is used to apply the coating of biologically active agents, all can not provide this benefit, or in other words, need improve significantly just radiopacity can be provided.For the coating of medical treatment device, the coating especially for preservation and/or delivery of biologically active preparation need provide other benefits such as surface conductivity or radiopacity.

Although occupy remarkable advantages at polymer coating aspect the research and development of bracket for eluting medicament, the alternate manner that adopts support and preservation of other medical treatment device and delivery of biologically active preparation is also disclosed.In one aspect, some existing disclosure is attempted wall, sleeve pipe or other chamber or the Chu Chizhong of drug deposition to the surface that forms medical treatment device itself, is used for preserving and biologically active agents such as release medicine.Other example of the coating that is used for bracket for eluting medicament is disclosed, particularly, comprising for example pottery and hydrogel.

At least another disclosed example provides the metal structure of sintering, and planning provides the surface of porous with it for delivering the preparation for the treatment of.Sintering generally comprises the granule that adopts the method motlten metal that heat and/or pressure is welded together them.The sintered metal structure of porous generally has bigger hole.When in the hole of sintered metal structure that bioactive materials is packed into, bigger pore-size may make bioactive materials discharge soon.Also be because adopt higher temperature to form sintering structure, after the structure that forms porous, the general bioactive materials that must will comprise bioactive molecule is packed in the sintering structure, thereby when the biologically active agents sex change or when in other words being subjected to cause thermal damage, " altogether-and deposition " impossible often.The general spended time of this method may be difficult to some bioactive molecule is injected the prefabricated hole of sintering structure in some cases.Therefore, it is very difficult fully filling sintering structure with them.When the impregnation sintering structure, bioactive molecule may be in carrier, for example in water or other material.The surface tension of carrier may hinder the thorough saturated sintering structure of bioactive molecule.As a result, sintering structure may fully not filled bioactive molecule.

In order to further specify, the support of previous disclosed example plan impregnation sintering in the solution that adds medicine will be treated preparation with the form of fluid and will be added in the support of former sintering.The treatment preparation can be dissolved in the solvent or be suspended in the liquid mixture.Average pore size is bigger 10 times than the granularity of the treatment preparation that suspends, and is the expected results that carries out sintering according to this part disclosure.In addition, also disclosing working pressure helps the fluid of adding medicine to enter in the hole chamber of support.

As mentioned above, wish to be increased in the ability that stores the bioactive materials capacity in the bioactive composite material, so that for example can in long-time, bioactive materials be discharged to the patient.On the other hand, because liquid (blood, water etc.) can enter in the hole of material, so the stability of bioactive materials is restricted.Described high temperature also can make the matrix under this method and some incompatible, the matrix that is heated under may making structurally or on function descends, matrix of the matrix of some polymerization or other material etc. for example, Ni-Ti matrix (for example NiTi support) particularly, have a series of material properties that when being heated, may descend, for example super-elasticity or shape-memory properties.

Previous disclosed other coating examples adopt electro-plating method that metal is plated on the surface, for example are plated on the matrix, so that make or be plated to medical treatment device.Plating generally comprises and the surface is exposed to comprise in the environment of metallic particles.Apply electric charge or electric current, make the metal deposition from the teeth outwards.Though the structure that plated metal preparation is relevant with medical treatment device can provide some benefits in some cases, in some cases,, then be favourable if can carry out described metal under the situation of electric current and/or applied current and deposit not needing to form.

Other are intended for the example of the coating of bracket for eluting medicament, require for example to form multiple coating material in a plurality of layers on matrix.In a described example, can use a layer attached to the layer on the matrix and another preservation and release medicine.In another example, a coating can be preserved one type bioactive materials, and another coating is preserved the bioactive materials of another kind of type.In another example, a coating is kept at medicine on the support, seals ground floor with the top layer that adds, and provides in other cases to discharge by the irrealizable drug slow of ground floor.The expectation that another example provides is a multi-layer biological simulation coating, and plan is the predetermined analog cell wall construction that improves coated surface biological compatibility.

These other examples of the mode of previous disclosed coating or use medical treatment device delivery of biologically active preparation, correspondingly be subjected to and the similar various restrictions of the top polymer coated one or more restrictions that have, wherein unconditionally comprise: to the processing restriction of beneath matrix or coated biologically active agents; The even distribution of coating or medicine; Adhesive force; Bio-compatibility (for example toxicity, or other disadvantageous biological respinse); Processed complex; Size; The density and the volume of the medicine that can preserve and discharge; The time control that medicine discharges; High impedance; Low radiopacity; Or coating is to the influence (for example mechanical property, expansion characteristics, surface conductance and radiopacity etc.) of lower substrate predetermined function.

In the following United States Patent (USP) of authorizing, disclose and the medical treatment device of general background is provided for this specification, or other structure, or other more detailed various examples of method: the US-4 of Feldstein, 358,922,4,374,669 of Mac Gregor, Mallory, 4,397,812 of Jr, Spencer, Jr. 4,547,407,4 of Morimoto, 729,871, people's such as Lee 4,917,895, people's such as Feldstein 5,145,517, people's such as Maybee 5,338,433, people's such as Ogiwara 5,464,524, people's such as Kinsella 5,616,608,5 of Tuch, 624,411, people's such as Tartaglia 5,700,286, people's such as Lam 5,725,572, people's such as Moller 5,772,864, people's such as Yan 5,843,172, people's such as Ragheb 5,873,904, people's such as Campbell 5,958,430,5,972 of Johnson, 027,5,976,169 of Imran, 6 of Hines, 019,784, people's such as Ding 6,042,875, Santini, people's such as Jr. 6,123,861, people's such as Goldstein 6,143,037, people's such as Callol 6,174,329, people's such as Shigeru 6,180,162,6,231,600 of Zhong, 6 of Yan, 240,616,6,253 of Johnson, 443, people's such as Yang 6,258,121, people's such as Wright 6,273,913,6,280,411 of Lennox, people's such as Tam 6,287,249, people's such as Michal 6,287,285, people's such as Barry 6,306,166, people's such as Larson 6,309,380,6 of Richter, 315,794, people's such as Zhong 6,322,847, with people's such as Taskovics 6,447,664.In this disclosure of introducing these documents in full as a reference.

People's such as people's such as other various example: Yang US 2001/0032014 and Bates US 2002/0098278 is also disclosed in following US patent application publication.In this disclosure of introducing these documents in full as a reference.

In the PCT patent application of publishing, other the various examples with following international publication number are disclosed: people's such as Bar-Shalom WO 89/03232, people's such as Wolff WO91/12779, people's such as Tarasevich WO 91/17286, people's such as Heath WO 93/19803, people's such as Ragheb WO 98/36784, people's such as Barry WO 99/08729, people's such as Richter WO 99/25272, people's such as Ragheb WO 00/10622, people's such as Barry WO00/? 84, people's such as Boock WO 00/27445, people's such as Hampikian WO00/29501, people's such as Palasis WO 00/32238, people's such as Kamath WO 00/32255, people's such as Yang WO 01/01890, people's such as Leclerc WO 01/14617, people's such as Ahola WO 01/15751, people's such as Eidenschink WO 01/70294, people's such as Kopia WO01/87372, WO 02/058775 with people such as Segal.In this disclosure of introducing these documents in full as a reference.

In the following european patent application of publishing, disclose people such as other examples: Mitchell 0 568 310, people's such as Eury people's such as EP 0 734 721, Fearnot people's such as EP 0,747 069, Wright EP 0 950 386.In this disclosure of introducing these documents in full as a reference.

Though aforementioned preparation or some examples that are coated in the structure of using in the medical treatment device can provide some benefit, if but the painting method and the matrix that overcome one or more restrictions that these attempted to overcome in the past can be provided is favourable, for example (but being not limited to) can provide less and/or finer and close surperficial filling pore (packed surface pores) in some cases, in coating procedure, bioactive materials is deposited in the coating, under the temperature that reduces, process, predictable uniform coating cladding thickness is provided on matrix and unmanageable matrix (for example NiTi) is provided adhesive force of raising etc.

In view of above-mentioned previous intention with other, the present invention will set forth still also indivedual and simultaneous various restrictions and demand.

Summary of the invention

Some aspect of the present invention is at the structure that comprises metal matrix, method and device, comprises bioactive materials (for example medicine) in the described metal matrix.In some method aspect these, bioactive materials is included in the metal matrix.In certain embodiments, matrix can be crystallization, and grain boundary can be arranged.According to these embodiments, the diffusion of bioactive materials can for example be carried out along grain boundary and metal crystallite.Bioactive materials can for example nanometer and zone in metal matrix less than nano-scale in, for example in pore region.In certain embodiments, bioactive materials can be stored in the metal matrix, can discharge from metal matrix then.Bioactive materials can spread by metal matrix, or metal matrix is subjected to etch (apace and/or lentamente), along with time delivery of biologically active material.This can carry out under the situation of the storage of the polymerization of not using bioactive materials and dissolution medium.

An embodiment according to these aspects is at comprising following method: (a) provide electrochemical solution, comprising metal ion and bioactive materials; (b) electrochemical solution is contacted with matrix; (c) adopt electrochemical method to form the biologically active composite construction on matrix, wherein the biologically active composite construction comprises metal matrix and the bioactive molecule within metal matrix.

At the biologically active composite construction, the biologically active composite construction comprises according to another embodiments of these aspects: (a) metal matrix, and wherein metal matrix is to adopt the chemical method preparation; (b) bioactive molecule in metal matrix.

At medical treatment device, medical treatment device comprises according to another embodiments of these aspects: the biologically active composite construction, and comprising first kind of material, second kind of material and bioactive materials from the reducing agent of first kind of material is derived.Second kind of material can be for example phosphorous, and it is derived from reducing agents such as inferior sodium phosphate.In certain embodiments, first kind of material is metal material (for example nickel, cobalt etc.), and first kind of metal material and second kind of material can be made the metal matrix that comprises bioactive materials.

Others of the present invention are at various medical treatment devices, and medical treatment device comprises the biologically active composite construction, or all are made up of the biologically active composite construction.

Others of the present invention are at the method for using the biologically active composite construction.

Another aspect of the present invention provides a kind of medical treatment device, wherein has matrix and the coating that comprises nickel on matrix.According to a kind of mode of this aspect, matrix also comprises nickel.According to a very favorable embodiment of this mode, matrix comprises Ni-Ti alloy.According to another embodiment, the characteristic of the matrix of coating is that the nickel that it discharges in moisture environment is basically less than the nickel that is discharged separately by nickeliferous matrix under the situation that contains nickel coating in nothing.According to a kind of very favorable variation pattern of this embodiment, the characteristic of the matrix of coating is that the nickel of release is than uncoated matrix low at least 25%.In another kind of variation pattern, the characteristic of the matrix of coating is that the nickel of release is than uncoated matrix low at least 50%.According to the another kind of mode of this aspect, matrix comprises support.According to an embodiment of this mode, support comprises the interconnected network of Ni-Ti pillar.According to another embodiment of this mode, support comprises the interconnected network of the pillar that is made of Ni-Ti alloy.

Another aspect of the present invention provides a kind of inner chamber support, wherein comprises cradle wall with outer surface and the coating on cradle wall, and cradle wall comprises the reducing agent and the biologically active agents of metal, metal.According to a kind of mode of this aspect, metal is included in the bivalent metal ion in the aqueous solution.According to another kind of mode, metal is included in the trivalent metal ion in the aqueous solution.

Another aspect of the present invention is a kind of medical treatment device, wherein comprise matrix with external coating, external coating comprises first kind of material, second kind of material and biologically active agents, wherein first and second kinds of properties of materials are, when they generate cation and the anion that is enough to take place electrochemical deposition process in the aqueous solution time.

Another aspect of the present invention is a kind of method of coated medical devices, comprising: the matrix with outer surface is provided; On the outer surface of matrix, form coating with employing coating, biologically active agents is deposited in the coating.A kind of mode of this aspect also comprises: delivery of biologically active preparation from coating.An embodiment of this mode also comprises: when delivery of biologically active preparation from coating, keep the coating in the coating basically.The another kind of mode of this aspect comprises, forms coating under the situation that does not heat superficies basically, comprises that in one embodiment the heating outer surface is no more than 120 °F.The another kind of mode of this aspect comprises and does not adopt polymeric material to form coating.The another kind of mode of this aspect comprises: adopt first kind of material and second kind of material preparation coating, second kind of reducing agent (even electronics moves to first kind of material) that material is first kind of material.An embodiment of this mode comprises provides metal ion as first kind of material with provide anion as second kind of material, and for first kind of material is reduced into uncharged state, second kind of material can make negative electrical charge move to first kind of material.

The another kind of mode of this aspect comprises the solution of first kind of coating of preparation, second kind of coating and bioactive materials, and wherein first and second kinds of coating is made the coating in the coating together.An embodiment of this mode also comprises makes this solution contact with matrix.A kind of variation pattern of this embodiment comprises matrix is immersed in this solution tank.The very favorable variation pattern of another of this embodiment comprises that also adopting solution to contact with matrix forms dope layer lentamente.

Another aspect is included in the solution that uses in the process of matrixes such as coated medical devices, comprising: the solution of at least a coating and at least a bioactive materials.According to a kind of mode of this aspect, at least a coating comprises metal ion.According to the another kind of mode of this aspect, bioactive materials comprises anti-restenosis agent.According to an advantageous embodiment of this mode, anti-restenosis agent comprises one of following at least reagent: anti-proliferative agent, antimitotic agent, antimigration agent, antiinflammatory, adhesion inhibitors, blood platelet coagulation inhibitor or anticoagulant.According to another kind of mode, this solution comprises moisture liquid, and it is anionic first kind of material and be cationic second kind of material that at least a coating is included in the moisture liquid.According to another embodiment of this mode, adopt first and and second kind of material use electrochemical method on matrix, to form deposited film.In a kind of very favorable variation pattern of this embodiment, adopt first and second kinds of materials to use no electric electrochemical method on matrix, to form deposited film.

Another aspect of the present invention comprises a kind of medical treatment device, wherein has matrix and increase the coating of medical treatment device radiopacity on matrix.In a kind of mode, coating comprises the metal that increases the medical treatment device radiopacity.In another kind of mode, matrix is a metallic matrix.In another kind of mode, matrix is a support.In another kind of mode, coating comprises first kind of coating and second kind of coating, and wherein one of at least the first and second kinds of coating can increase the radiopacity of matrix.In another kind of mode, coating comprises bioactive materials.In an embodiment of this mode, coating also comprises first and second kinds of coating and bioactive materials combination.In another very favorable variation pattern of this embodiment, coating is the composite interstitial substance with first and second kinds of coating and bioactive materials.In another characteristic of this embodiment, first and second kinds of coating can be metal one of at least.In another characteristic that the variation pattern of this composite interstitial substance can advantageously comprise, matrix is support, and bioactive materials is the material of anti-ISR.

Another aspect of the present invention is the medical treatment device with outer surface, and outer surface comprises unsintered composition metal matrix, comprising at least a metal and bioactive materials.The matrix of employing medical treatment device is the delivery of biologically active material in vivo.

Another aspect of the present invention is the medical treatment device with outer surface, and outer surface comprises metal matrix and comprise the hole of bioactive materials that pore diameter is less than about 1 μ m.In a kind of mode, bioactive materials is anti-restenosis agent.In another kind of mode, medical treatment device comprises support, and outer surface is positioned on the stent strut.In another kind of mode, pore diameter is less than about 100 .

Another aspect of the present invention is the medical treatment device with matrix, and matrix comprises metal and the coating on matrix, and coating comprises identical metal.In a kind of mode aspect this, metal is a nickel.In an embodiment kind of this mode, matrix is a Ni-Ti alloy.In the another kind of variation pattern of this embodiment, coating does not comprise titanium.In another kind of mode, metal is a cobalt.In an embodiment of this mode, matrix comprises cobalt and chromium.In a kind of variation pattern that can advantageously be applied to this embodiment, coating comprises cobalt and chromium.In another kind of mode, matrix comprises the alloy of this metal and second kind of metal, and coating does not comprise second kind of metal.In another kind of mode, coating comprises biologically active agents.In a very favorable embodiment of this mode, biologically active agents is anti-restenosis agent.In the very favorable mode of another kind, matrix is a support.

Another aspect of the present invention is the medical treatment device with matrix and the coating on matrix, wherein, adopts coating to comprise various types of bioactive materials.In a kind of mode, adopt coating to comprise water miscible or non-water-soluble bioactive materials or these two.In another kind of mode, adopt coating to comprise organic material or inorganic material or these two.In another kind of mode, matrix is a support.In another kind of mode, in coating, comprise the bioactive materials of at least a type in all kinds.

Another aspect of the present invention is the medical treatment device with matrix and the coating on matrix, and coating comprises metal matrix.Metal matrix comprises metal, and also have according to following properties characteristic one of at least: (i) bioactive materials is in metal matrix; Or be in metal matrix (ii) than the radiopaque relatively material of matrix; Or (iii) metal matrix is unsintered, do not electroplate and do not have radioactive metal matrix; Or (iv) metal matrix is the metal matrix that adopts no electric electrochemical method deposition; Or (v) the reduction of metal ion agent that is generated in moisture fluid by the metal material of deriving is in metal matrix.

Described medical treatment device according to this aspect---wherein comprises the coated matrix with any these characteristics---and is considered to the very favorable independent aspects of the present invention, thereby thinks that further the combination that comprises all or any two kinds or multiple these characteristics is some independently favourable aspects.Therefore, a favourable aspect of the present invention is the medical treatment device with the matrix that applies with metal matrix, comprises bioactive materials in metal matrix.Another favourable aspect is the medical treatment device with the matrix that applies with metal matrix, comprises in metal matrix than the radiopaque relatively material of matrix.Another favourable aspect is the medical treatment device with the matrix that applies with metal matrix, and metal matrix is unsintered, and is that do not electroplate and cold.Another favourable aspect has the metal matrix coating that adopts no electric electrochemical method deposition, another aspect is the metal matrix coating that comprises first kind of metal material and second kind of material, and the latter derives from the reduction of metal ion agent that metal generates moisture fluid solution.

Another aspect of the present invention is to have the matrix be made up of at least two kinds of metals and the medical treatment device of the coating on matrix.The characteristic that coating one of also has in the following properties at least: (i) coating comprise in the matrix in these two kinds of metals first kind of metal and in the blood environment floating coat rate of release of this first kind of metal be lower than rate of release from independent matrix basically; Or (ii) coating comprises first kind of metal in these two kinds of metals in the matrix, but does not comprise second kind of metal in these two kinds of metals.

Described medical treatment device according to this aspect---wherein comprises the coated matrix with any characteristic in these characteristics---and is considered to the very favorable independent aspects of the present invention, thereby thinks that further the combination that comprises all or any two kinds or multiple these characteristics is independently favourable aspect more of the present invention.Therefore, favourable aspect of the present invention is the medical treatment device with matrix and the coating on matrix, coating be included in two kinds of metals in the matrix first kind of metal and in the blood environment floating coat rate of release of this first kind of metal be lower than rate of release from independent matrix basically.Another favourable aspect is the medical treatment device with matrix of coated coating, and coating is included in first kind of metal in two kinds of metals in the matrix, but this coating does not comprise second kind of metal in these two kinds of metals.

In a kind of mode aspect this, two kinds of metals in matrix comprise two kinds of matrix materials the most general.In another kind of mode, these two kinds of metals comprise two kinds of main metals in the metal alloy of making matrix.In another kind of mode, can also in matrix or coating, provide other metal.

Another aspect of the present invention is the medical treatment device that comprises matrix and bioactive materials.Matrix has to small part and is metal and has the outer surface in many zones, adopt these zones to comprise bioactive materials and in patient's body from matrix the delivery of biologically active material.Bioactive materials is included in these zones.Medical treatment device according to this aspect, also have according to one of at least characteristic in these regional following properties on the outer surface: (i) when outer surface was exposed in patient's the blood environment, they were small enough to anti-basically sealing and are penetrated in the bioactive materials that wherein comprises; Or (ii) their diameter less than about 1 μ m; Or (iii) their diameter less than about 10 times bioactive materials size.Think that it is the very favorable independent aspects of the present invention that described medical treatment device---wherein comprises the coated matrix with any characteristic in these characteristics---, thereby think that further the combination that comprises all or any two kinds or multiple these characteristics is some independently favourable aspects.

Another aspect of the present invention is the medical treatment device that comprises the biologically active composite construction, and the biologically active composite construction has metal matrix and the bioactive materials in metal matrix.The biologically active composite construction forms at least a portion of support.

Another aspect of the present invention is the medical treatment device that comprises matrix and the coating on outer surface of matrix.Have one or more characteristics in the following properties according to the coating of this aspect: (i) coating have on the outer surface of matrix less than the coating layer thickness of about 5 μ m and in coating the bioactive materials of treatment level; Or (ii) coating comprises metal matrix and the bioactive materials in metal matrix; Or (iii) coating comprises not electroplated metal matrix.Coated matrix according to this aspect also has the characteristic that forms support at least a portion.

Described medical treatment device according to this aspect---wherein comprises and has the coated matrix of described any these characteristics just now---and is considered to the very favorable independent aspects of the present invention, thereby thinks that further the combination that comprises all or any two kinds or multiple these characteristics is some independently favourable aspects.

Another aspect of the present invention, be at least in part by according to comprising that following one or multinomial method prepare the method that metal matrix prepares medical treatment device: (i) nothing of metal electricity electrochemical deposition and second kind of material of deriving by the reduction of metal ion agent that metal generates in the aqueous solution; Or (ii) prepare metal matrix, biologically active agents is deposited in the metal matrix; Or (iii) do not using the electric current that applies and not under the situation of sintering, metal matrix is made coating on the matrix; Or (iv) do not using the electric current and the temperature that apply to be lower than under about 120 situation, metal matrix is made coating on the matrix.According to the method for this aspect, also comprise at least a portion of metal matrix being made medical treatment device.

Described method according to this aspect---has the method for the metal matrix of described any these characteristics just now comprising preparation---and is considered to the very favorable independent aspects of the present invention, thereby thinks that further the combination that comprises all or any two kinds or multiple these characteristics is some independently favourable aspects.

Another aspect of the present invention is to comprise that by employing following one or multinomial method prepare the method that metal matrix prepares medical stand at least in part: (i) under the situation of the electric current that does not use to apply, metal matrix is made coating on the matrix; Or (ii) bioactive materials is deposited in the metal matrix.According to the method for this aspect, also comprise at least a portion of metal matrix being made support.The another kind of mode of this method is included in to be lower than under the situation of sintering not or in temperature and implements this method in about 120 environment.

Another aspect of the present invention is the solution that uses in the process of preparation medical treatment device at least a portion.According to the solution of this aspect, comprise bioactive materials and the combination of another kind of material in fluid, adopt this fluid on the matrix that is contacted by solution, to form the electrochemical deposition thing of bioactive materials and other material.

In various alternate manner of the present invention---to be favourable alternative other embodiments in aspect that provide above---the be included in preparation medical treatment device in the advantageous embodiments of metal matrix structure, the metal matrix structure comprise nickel, cobalt or chromium one of at least with the combination one of at least of phosphorus or boron.In more favourable specific embodiments, phosphorus combination in nickel and the metal matrix (for example becoming the outer surface of medical treatment device such as support) is provided, maybe can provide cobalt and chromium in metal matrix with phosphorus or boron combination.

Also can be combined into the various alternate manners of other embodiments with above-mentioned aspect, the structure that comprises the combination and/or the acquisition of no electric electrochemical deposition and other deposition process, the combination of for example sintering and/or electroplated metal and metal matrix nothing electricity electrochemical deposition etc.For example adopt these diverse ways can prepare the metal matrix of multilayer, thereby favourable composite construction is provided.In further embodiments, can make polymer, pottery, hydrogel or other coating and relevant method, be combined into other embodiments and variation pattern, provide according to other benefits independently of the present invention with top various aspects.

Can be applied to very favorable other modes of above-mentioned various aspects, the medical treatment device of implantable rack form is provided.In some typical embodiments, support comprises the matrix of pillar form, and pillar is interconnected to net, forms expandable tubular body, is used to keep inner chamber to open and is in swelling state.Various coatings, metal matrix and matrix that each independent aspects comprises according to described support mode, have particularly advantageous application.

Though at length narrated medical treatment devices such as support, should be appreciated that embodiment of the present invention are not limited to support, or thus, also be not limited to macro-scale devices.For example embodiment of the present invention can be applied to any device or material, irrelevant with size, comprising the material of artificial heart, plate, screw, " MEMS " (little electrochemical appliance) and nanoparticle-based and device etc.Narrate other embodiment of medical treatment device and material according to embodiments of the present invention below.

Illustrate in greater detail these and other aspect of the present invention, mode, embodiment, variation pattern and characteristic with detailed description with reference to the accompanying drawings.

The accompanying drawing summary

Fig. 1 illustrates the schematic diagram of biologically active composite construction on matrix and the matrix.

Fig. 2 illustrates the schematic diagram of a biologically active composite construction part that comprises bioactive materials.

Fig. 3 illustrates the device of the biologically active composite construction that is included between matrix and the protective layer.

Fig. 4 (a)-4 (c) illustrates and puts into support coronarius.

Fig. 5 illustrates the flow chart of typical method according to embodiments of the present invention is described.

Fig. 6 illustrates the curve that the medicament elution gradient that Johnson ﹠ Johnson's (Johnson and Johnson) Bx speed support (Bxvelocity stents) (stainless steel)---has biologically active composite construction according to embodiments of the present invention---is followed in explanation.

The curve of the medicament elution gradient that Fig. 7 illustrates explanation and follows support (stainless steel)---use Ni-Ti alloy and biologically active composite construction make---according to embodiments of the present invention.

Detailed Description Of The Invention

I. definition

Some term used in this application is described below.

Term used in this application " anti-narrow again " is relevant with compound, preparation or other material, generally mean those at least part of impact preventions or suppress again narrow " bioactive materials " (following horse back definition) that narrow again is that for example blood vessel plasty, atherectomy, mounting bracket or other pipeline form again or inner chamber is implanted the reaction that the relevant blood vessel of operation damages to getting involved with inner chamber. The example of anti-restenosis agent comprises anti-mitosis agent, anti-proliferative agent, migration inhibitor, anti-scorching agent, antithrombotic agents (for example thrombin inhibitor), anti-blood platelet coagulating agent (for example blood platelet adheres to/coagulation inhibitor), healing agent endothelium accelerator for concrescence for example, or slow down, prevent or otherwise get involved again other preparation of narrow process of biology.

Term " bioactive materials " means at the compound that has corresponding biologically active on the organism or in organism, preparation or any other material, comprising the disease (medical condition) to patient body---for example dysfunction relevant with organization of human body or function or unusual situation, or by medical procedure for example medical treatment get involved the disease cause, or in other words, the disease relevant with the medical procedure such as medical treatment intervention---the given activity for the treatment of, prevention or diagnosis is provided.

The example of bioactive materials comprises the medicine for contraception and hormone replacement therapy (hormone replacement therapy), and is used for the treatment of the medicine of osteoporosis, cancer, epilepsy, Parkinson's disease and pain. Other examples of bioactive materials include but not limited to: anti-inflammatory agent, anti-infectious agent (for example antibiotic medicine and disease-resistant poison), anodyne and analgesic combination, antiasthmatics, anti-convulsions medicine, antidepressants, antidiabetic, antineoplastic, anticarcinogen, schizophrenia and cardiovascular disease medication for example resist narrow compound and anticoagulant compound again. Other examples that are used as the molecule of bioactive materials comprise: virus, growth factor receptor inhibitors, growth factor receptor body, antimetabolite, integrin blockers or all or part of in-sense that works or the antisense nucleoside acid gene of hormone, the growth factor, the generation growth factor.

The below is can be the example of other dissimilar compounds of bioactive materials: inorganic, organic or organic metal; Hydrophilic or oleophylic; Hydrophobic or thin oil; Water-soluble or non-water-soluble; Peptide or protein; Polypeptide; Polysaccharide (for example heparin); Oligosaccharides; Monose or disaccharide; For molecule, compound or other preparation or material, aforesaid any class (labels) can both be used in fact. Other example comprises: living materials, for example living cells or scenescant cell, bacterium, virus, plasmid, gene, other hereditary material or other composition or their part; With artificial particle or other material, for example carry biological associated materials or the active material of band.

Bioactive materials also can be included in the parent material that produces metabolic alterations, division (for example molecule composition of division) or have corresponding biologically active in body after otherwise processed or modification. These bioactive materials can be included in other place may think that they are relative inertness at biology, or in other words, before described modification to the inoperative described parent material of concrete outcome of the disease that is treated.

Can prepare combination, mixture or other preparation of any previous embodiment, and think that still they are bioactive materials in predetermined meanings. The present invention is directed to some aspects of bioactive materials, can comprise any or all of previous embodiment.

Term " electrochemical deposition " means electro-deposition (plating) and without electro-deposition (see following method explanation).

Term " medical treatment device " means the organism to living, particularly for human body, be external device or structure for example, but they are used for organism alive, for example particularly to human body, in body, external or otherwise carry out treatment, prevention and diagnosis function. Medical treatment device comprises for example many dissimilar permanent or provisional implantation things. Other illustrative example of medical treatment device include but not limited to: conduit; Wire; Womb contraceptive ring; Device (for example air bag or cage shape thing (cages)) with inflatable element; Drug delivery equipment is comprising for example plaster (patches); The blood vessel conduit is for example implanted thing, stent graft and fistula; Support; Implant thing; Plate; Screw; Spinal cord cages; Dental implants; Tooth filling; Braces; Synthetic joint; Embolization device; The ventricle servicing unit; Artificial heart; The heart valve; Embolism filter (for example vein filter device); U-loop; Clip; Suture; Prosthese net (prosthetic meshes); Network for location; Ablation (ablation) or stimulating electrode device; Artificial or electronic heart pacemaker; The artificial or electronic heart pacemaker wire; The defibrillation device; The nerve stimulation device; Nerve stimulation device wire; Sub-intra-uterine device (" IUD ' s "); Syringe; Current divider; Sleeve pipe; With implantable or outside sensor. Medical treatment device is not subjected to the restriction of size, and comprising micron mechanical device and nano-machine device, they play a role in human body or at human body surface. Embodiment of the present invention just comprise described medical treatment device.

Term " implantation thing " means the category of the medical treatment device in the implanted patient body within a certain period. They can be diagnostic or therapeutic, and are long-term or short-term, permanent or provisional.

Term " self assembly " means the nanometer assemble method of manufactured materials or coating, and this kind method forms minute spontaneous carrying out since one. Self-assembling method commonly used is included in the organic monolayer self assembly on the matrix. A combination that example is linear organic molecule and matrix of this kind method. Each molecule comprises sulphur hydroxyl (S-H part). The surperficial coupling of the sulphur hydroxyl of each molecule and gold, the other end of molecule then stretches out from the surface of gold. Electroless deposition methods is to form to divide since one spontaneously and automatically catalytically to go on, and also can be seen as self-assembling method.

Term " support " means and adopts it to be attached on the wall of body cavity or road, gap (interstitial tract), in order to make it open. They can be permanent also can be provisional implantation thing. Support generally can be regulated between radial contraction state (for example delivering by the inner chamber of delivering catheter lumen) and radial expanded state (for example radially being attached on the wall of chamber). Various types of expandable stents comprise wall construction tubulose or the part tubulose, wherein has the net that is interconnected to by the separated pillar in space, this kind structure can for example adopt laser cutting or adopt the method for photoetch to cut down from pipe, also can be by the forming ring fix tightly of some adjacency is made. The most frequently used support that expands is metal (for example pillar). The dissimilar example of described expandable stent comprises: the air bag that can expand (for example stainless steel, or cobalt-chromium); The air bag of self-expanding (for example nickel-titanium alloy, for example Nitinol^TM). Support also can be nonmetallic, for example polymerization. That support also can be made helical form or other banded structure that can fold, in order to deliver and to implant, can reconfigure between the pucker ﹠ bloat state, support can be made composite construction with other materials such as implanting thing, makes support-implantation thing (for example treating abdominal aortic aneurysm).

Can use support to keep tubular cavity open, for example at present around, the crown and cerebrovascular, digestive organs, hepatic duct, urinary system, liver parenchyma (for example porto-system bypass (porto-systemic shunts)), and the support that uses in the backbone (such as merging skeleton (fusion cages)) etc. Conventional bracket is generally greater than about 2-3mm, but also considers less support, for example particularly to some specific indication. For example, can in little gap, use support, between ventricle and coronary artery, or between coronary artery and coronary vein, produce conduit. In eyes, support can be used for sinuys venosus sclerae treatment glaucoma. Also can come inaccessible tubular cavity with support, such as being used for the inaccessible fallopian tubal of tubal ligation and inaccessible tumour or aneurysmal branch vessel (feeder vessels) etc.; Described inaccessible support generally comprises bioactive materials such as adding fibrin, to cause inaccessible thrombosis. Inaccessible support is expanded in by inaccessible chamber, it is shunk from the outside of blood vessel wall around in the chamber.

Term " electro-deposition " means the method for carrying out electrochemical deposition process at sacrifice property matrix. After deposition process, matrix is etched away, stay independently structure.

II. preparation method

Embodiment of the present invention comprise the method for preparing bioactive composite material. In one embodiment, the method comprises provides electrochemical solution, comprising metal ion and bioactive materials. Electrochemical solution can be adopt metallic salt, solvent and reducing agent preparation without electrodeposition bath, or adopt negative electrode (depositing base), anode and comprise the electrodeposition bath of the electrolyte solution compositions of the metal ion that will be reduced. In bath, also complexing agent, stabilizing agent and buffer can be arranged. After making electrochemical solution, matrix contacts with electrochemical solution. For example, matrix can be immersed in the bath that comprises electrochemical solution.

Can before the contact electrochemical solution, prepare matrix for electrochemical process first. In a preparation process, carry out the anode process. In this process, matrix is immersed in the salt acid bath. Make electric current pass through solution, produce little etch pit at matrix. Described etch pit can promote to adhere to. Also can be with sensitization agent and/or catalyst deposit on matrix, this helps to produce nuclearing centre, and guiding generates the biologically active composite construction. Also can adopt for example purging method, remove the loose nuclearing centre that adheres to from matrix surface.

After the contact electrochemical solution, adopt electrochemical method to form the biologically active composite construction at matrix. Electrochemical method can be electrolytic method or chemical plating method (be electro-deposition or without electro-deposition). After forming the biologically active composite construction, from the bath that comprises electrochemical solution, take out the combination of biologically active composite construction/matrix.

After from bathe, taking out the combination of biologically active composite construction/matrix, if necessary, can further processing will should be made up. For example, in certain embodiments, can form protective layer at the biologically active composite construction. Narrate in more detail below protective layer and other procedure of processing subsequently.

Comprising the according to embodiments of the present invention device of biologically active composite construction shown in Fig. 1 and 2. Draw device 100 among the figure, comprising biologically active composite construction 101, comprising metal matrix 10 and the bioactive materials in metal matrix 10 14. Biologically active composite construction 101 is on matrix 12. Bioactive materials is to the ratio of metal part in the biologically active composite construction, and is higher than the ratio of bioactive materials in comprising the conventional biologically active composite construction of metal matrix

Embodiment of the present invention have many advantages than the conventional method of preparation biologically active composite construction. The first, when adopting electrochemical method to add bioactive materials in the metal matrix, electrochemical method does not damage bioactive materials. Different from the high temperature process (for example sintering) of preparation metal matrix, embodiment of the present invention can be carried out under the temperature of not damaging bioactive materials (for example protein). The second, in certain embodiments of the invention, it is easier than being added in the common metal matrix that bioactive materials is added in the metal matrix. For example, in embodiments of the invention, generally do not exist with employing and comprise the problem that the prefabricated metal matrix of the solution impregnation of carrier and bioactive materials is relevant. Therefore, biologically active composite construction according to embodiments of the present invention, the ratio of bioactive materials can be higher than the biologically active composite construction of routine. The 3rd, in certain embodiments, prepared biologically active composite construction in the zone of unusual limitation, time of appointment in mode fast and/or slowly, at some months delivery of biologically active material within the time in several years. Adopt embodiment of the present invention, bioactive materials can carry out controlled and/or adjustable release. The 4th, when bioactive composite material is form with layer when being positioned on the metallic matrix, bioactive composite material can have similar character with metallic matrix. For example, the ductility of bioactive composite material and elastic modelling quantity can be basically same with beneath matrix phase. In another embodiment, the metal matrix of biologically active composite construction and matrix can be the metal matrix in the embodiment of the present invention. They can have similar thermal coefficient of expansion, therefore, have reduced these two kinds of materials because the possibility that thermal coefficient of expansion may separate. The 5th, in embodiments of the invention, the biologically active composite construction can be made identical composition and thickness. Be positioned on the metallic matrix with complicated shape if the biologically active composite construction is the form with layer, then this layer can be consistent with complicated shape at an easy rate. The below provides other advantage of embodiment of the present invention.

A. the preparation of matrix

Can adopt embodiment of the present invention to apply any suitable matrix. Matrix can be porous or solid, can have flat or uneven surface (for example crooked surface). Matrix also can be flexible or rigidity. In certain embodiments, matrix can be rack body, implant, particle, ball and electrode etc.

Matrix can comprise any suitable material. For example, matrix can comprise metal, pottery, polymerization material or composite. For example, matrix can comprise the metals such as stainless steel or Nitinol (Ni-Ti alloy). In addition, matrix can comprise the polymerization material, comprising fluoropolymers such as polytetrafluoroethylene (PTFE) interior. In certain embodiments, matrix can comprise the material of sacrifice property. Sacrificial material is the material that can for example adopt engraving method to remove, and then stays independently biologically active composite construction.

Before matrix forms the biologically active composite construction, can adopt any suitable method to prepare matrix. For example, can be before carrying out electro-less deposition process (if the surface of matrix itself is not from catalysis), the surface of sensitization and/or catalysis matrix. Can adopt the metals such as Sn as the sensitization agent. Many metals (for example Ni, Co, Cu, Ag, Au, Pd and Pt) all are good in catalyst. Palladium (Pd), platinum (Pt) and copper (Cu) are the catalyst examples that can generate " general " nuclearing centre. In addition, many nonmetal also be good catalyst.

Before forming the biologically active composite construction, if necessary, also can wash and/or the precleaning matrix. Before carrying out electrochemical process, can use any suitable flushing and/or precleaning liquid or gas to remove impurity from matrix surface. In some comprises embodiment without electro-deposition, except before carrying out electrochemical process, after sensitization and/or catalysis, also can adopt the distilled water flushing matrix, remove loose sensitization agent and/or the catalyst molecule that adheres to. In addition, also can adopt in certain embodiments the anode cleaning process or sometimes can adopt the negative electrode cleaning process to replace flushing, generation can improve the etch concave point of adhesion.

B. electrochemical method

In embodiments of the invention, adopt electrochemical method to prepare the biologically active composite construction. Electrochemical deposition process comprises electrolysis (electricity) deposition and without electro-deposition.

In embodiments of the invention, bioactive materials and metal ion source are added in the electrochemical bath together. Bioactive materials can comprise any concrete material above-mentioned and other material. For example, bioactive materials means active or relevant active ingredient (living agent) on any organic, inorganic or biology. Bioactive materials also can comprise the bioactive molecule on the biology, for example medicine. In embodiments of the invention, bioactive materials is solubilized or undissolved in electrochemical solution.

Bioactive materials also can comprise particle (for example granularity is the about 10 μ m of 0.1-). Particle can comprise the bioactive materials of crystal form. On the other hand, particle comprises polymer, pottery or the metal that can store bioactive materials. Particle preferably is not dissolved in the electrochemical solution. In this case, the particle stabilizers such as surfactant can be added in the electrochemical solution, to improve the uniformity of particle in solution.

Do not think bound by theory, can think when carrying out electrochemical deposition process according to some embodiment that " codeposition " occurs for the crystal of nanometer size (metallic atom of crystallization) and bioactive materials. At first, this process occurs on the surface of matrix. Behind deposition tens nano metals, at the metal that has deposited codeposition occurs. Therefore, bioactive materials and metallic atom can deposit basically simultaneously. When codeposition metallic atom and bioactive materials, just bioactive materials is added in the metal matrix. These crystal just are limited in bioactive materials in the formed biologically active composite construction.

By making bioactive materials with the metal codeposition, the concentration of bioactive materials in the biologically active composite construction is high. In addition, in embodiments of the invention, there be not the problem relevant with adopting bioactive materials dipping loose structure. In embodiments of the invention, bioactive materials is full of the hole in the metal matrix basically, so the load of bioactive materials in metal matrix is maximum.

As described, electrochemical process comprises electrolysis (electricity) deposition process and electro-less deposition process. In electrolysis (electricity) deposition process, anode is connected with negative electrode and connects by electrolyte on the electricity. When electric current flow through between electrode, metal just was deposited on the negative electrode, and meanwhile, metal both can dissolve from anode, also can derive from electrolyte solution. For example in metal plating industry and electronics industry, electrolyting precipitation process is well-known.

The typical reaction program of metallic reducing is as follows in electrodeposition process:

M ²⁺ _Solution+ ze → M _{Lattice (electrode)}

In this equation, M is a metallic atom, M ²⁺Be the metal ion with z unit charge, e is electronics (a tape unit electric charge).Reaction on negative electrode is a reduction reaction, and negative electrode is the place that electro-deposition takes place.The anode of oxidation takes place in addition.In order to connect circuit, provide electrolyte solution.Oxidation and reduction reaction are that carry out in the place that separates in solution.In electrolytic process, when matrix was used as the negative electrode of this process, matrix was a conductor.Concrete electrolytic deposition conditions such as current density, concentration of metal ions and bioactive materials concentration can be determined by those of ordinary skill in the art.

Also can adopt electroless deposition methods to prepare the biologically active composite construction.In electro-less deposition process, there is not electric current to pass through solution.Oxidation and two kinds of processes of reduction take place but go up (promptly on matrix) at same " electrode ".Here it is, and electroless deposition causes the reason of metal deposition and acquisition anodic product (for example nickel and nickel-phosphorus)

In electro-less deposition process, fundamental reaction is:

M ²⁺ _Solution+ Red _Solution→ M _{Lattice (surface of catalysis)}+ Ox _Solution

In this equation, R is a reducing agent, and it is transferred to matrix and metal ion with electronics.Ox is the oxidized byproduct of this reaction.In chemical plating method, the response location that electron transfer occurs in matrix (originally is the nucleation site on the matrix; These positions form the position of some tens nanometer sizes then) on.Reaction is reduced into the metal self-catalysis of metal matrix form then at first by matrix catalysis.

Electroless deposition solution can comprise metal ion and bioactive materials.Narrated suitable bioactive materials above.The solvent that uses in electroless deposition solution can comprise water, so deposit solution is moisture.Sedimentary conditions such as the composition of pH, sedimentation time, bath and depositing temperature can be selected by those of ordinary skill in the art.

In embodiments of the invention, can use any suitable metal ion source.Metal ion in the electrochemical solution can obtain from the soluble metal salt class, then they is added in the electrochemical solution.In solution, the ion that forms metallic salt can dissociate mutually.Be fit to the example of the metallic salt of nickel ion, comprise nickelous sulfate, nickel chloride and nickel sulfamic acid.Be fit to the example of the metallic salt of copper ion, comprise mantoquita and cuprous salt, for example stannous chloride or cuprous sulfate.Be fit to the example of the cationic metallic salt of tin, can comprise stannous chloride or stannous fluoboric acid.In the electroless deposition field, also know to be fit to other suitable salt that other metal of deposition uses.If preparation metal alloy matrix can adopt dissimilar salts.

Electrochemical solution also can comprise reducing agent, complexing agent, stabilizing agent and buffer.The metal ion of the state of oxidation in the reducing agent reducing solution is so metal ion is deposited as metal on the surface of matrix.Typical reducing compound comprises for example amine borine (amine borane) and phosphite inferior sodium phosphate for example of boron compound.Adopt complexing agent that metal is remained in the solution.Use buffer and stabilizing agent to improve the useful life of bath and the stability that improvement is bathed.Use the pH of buffer control electrochemical solution.Can use stabilizing agent to keep solution even.Typical stabilizing agent comprises the ion of lead, cadmium and copper etc.Reducing agent, complexing agent, stabilizing agent and buffer are well-known in the electroless deposition field, can be selected by those of ordinary skill in the art.

For instance, nickel-phosphor alloy matrix can be with bioactive materials electroless depositions such as medicines on matrix.Before metallization, matrix may need activation and/or catalysis (adopting for example Sn and/or Pd).In order to produce this alloy substrate, typical electroless deposition solution comprises NiSO ₄(26g/L), NaH ₂PO ₂(26g/L), acetate-Na (34g/L) and malic acid (21g/L).This solution can be form bath, can comprise the ion of deriving from aforementioned salt.In bath, also bioactive materials can be arranged.In this embodiment, inferior sodium phosphate is a reducing agent, and nickel ion is by the ortho phosphorous acid sodium reduction.The temperature of bathing depends on required electroplating time from room temperature to 95 ℃.PH is generally about 7 (these processing conditions also can use in other embodiments) of about 5-.Will be immersed in the solution by coated matrix then, can on matrix, form the biologically active composite construction behind the preset time.Ni ion in solution is deposited on the matrix with nickel-phosphor alloy (oxidation reaction) with the form of pure nickel (reduction reaction); Bioactive materials forms the biologically active composite construction along the grain boundary codeposition of crystal with the metal matrix that is deposited.Bioactive materials can be with the nickle atom codeposition.The scope of phosphorus amount is general＜and 1%-＞25% (mole %), can adopt method known to those skilled in the art to change.

Though preferable alloy atom and bioactive materials codeposition, codeposition is not necessary in some embodiments.For example in other embodiments, can on matrix, form the extremely thin metal level of about tens nanometers.Bioactive materials absorption, covalent bond or be deposited on the metal level top of nano thickness then.Then add other metal levels then.Can absorption, covalent bond between metal level or deposit other bioactive materials layers.Such method can be produced fine and close bioactive composite material.

The metal matrix of biologically active composite construction can comprise any suitable metal.Metal in the metal matrix can identical or different with parent metal (if matrix be a metal).Metal matrix can comprise for example noble metal or transition metal.Suitable metal comprises nickel, copper, cobalt, palladium, platinum, chromium, iron, gold and silver and their alloy.The example of suitable nickel-base alloy comprises Ni-Cr, Ni-P and Ni-B.Can adopt suitable electrochemical method deposition any of these or other metal material.The metallic salt that can select to suit provides suitable metal ion for the metal matrix that will prepare in electrochemical solution.

Metal matrix also can have the space in lattice.Average void size is generally less than about 1 μ m.For example in certain embodiments, the average-size in space can be less than about 100 (for example less than about 10nm) in metal matrix.Bioactive materials can be added in the space of metal matrix.

In the bioactive composite material of preparation, the percentage by volume height of bioactive materials.For example in embodiments of the invention, bioactive materials can account for the percentage of biologically active composite construction, preferably is higher than approximately 10%, or is higher than about 25%.

The biologically active composite construction can be any suitable form.For example, bioactive composite material can be the form that is positioned at the layer on the matrix.This layer can have any suitable thickness.For example, in certain embodiments, the thickness of this layer can be less than about 100 μ m (the about 10 μ m of for example about 0.5-).In another embodiment, the thickness of this layer can be greater than about 1mm.In other embodiment, the biologically active composite construction needs not be the form of layer.For example in certain embodiments, the biologically active composite construction can be short grained form.

It is favourable adopting electroless deposition methods to prepare the biologically active composite construction.The first, when adopting electroless deposition methods, the size of crystal, the percentage of bioactive materials can be controlled then.This area those skilled in the art can regulate pH, the temperature of deposition bath and become gradation parameter, change the percentage by volume of bioactive materials in prepared metal matrix.The second, adopt chemical plating method, can adopt the biologically active composite construction to coat matrix equably with complex geometric shapes.When in the solution when moisture, viscous effect in electro-less deposition process, in fact do not preponderate (comparing) with the polymeric material that applies viscosity.The 3rd, in electro-less deposition process, sedimentary condition is moderate, carries out in room temperature or near room temperature and at Human Physiology pH or under near Human Physiology pH.In the process of preparation bioactive composite material, do not damage bioactive materials.The 4th, according to embodiments of the present invention method economy and can formation scale, cost is effective more than other method of preparation biologically active composite construction.

C. following process

After making the biologically active composite construction, can choose wantonly and adopt any suitable method further to process.For example, in certain embodiments, on the top of biologically active composite construction, form protective layer.Fig. 3 illustrates device 100, comprising the biologically active composite construction 10 of layer form between matrix 12 and protective layer 20.

Protective layer can comprise any suitable material, and can be any suitable form.Protective layer can be unbodied or crystallization, can comprise metal, polymer and pottery etc.Protective layer also can be (continuous) porous or solid.

Protective layer can adopt any suitable method deposition.For example can adopt above-mentioned method (for example electro-deposition and electroless deposition) to form protective layer, also can adopt method for distinguishing to form protective layer.In addition, also can adopt methods such as dip-coating, spraying and vapour deposition to form protective layer.

In embodiments of the invention, the thickness of protective layer can change.For example in certain embodiments, the thickness of protective layer can be greater than about 100 μ m.Certainly, the thickness of protective layer may depend on the final use that is produced device.

In embodiments of the invention, protective layer can be a layer unique on the biologically active composite construction.The suitable protective layer that can on the biologically active composite construction, add in other embodiments, any number of plies.For example, forming tens layers on the biologically active composite construction is feasible to the single ply protective layer of hundreds of layer (some layer wherein or all these layers can be bioactive).

In certain embodiments, protective layer can improve the performance of biologically active composite construction.For example, protective layer can comprise the film (for example 4 collagen types) that covalently bind on the biologically active composite construction.The function of protective layer can be to bring out endothelium to be attached on the surface of biologically active composite construction, and the bioactive materials in the biologically active composite construction spreads below protective layer simultaneously.In another embodiment, there is growth factor in the protective layer on the biologically active composite construction, for example endothelial growth factors (EGF) or VEGF (VEGF).Discharge growth factor and bring out endothelial growth from protective layer, the biologically active composite construction also discharges the smooth muscle cell growth inhibitor simultaneously.

In other embodiments, protective layer can improve the radiopacity of the medical treatment device that comprises the biologically active composite construction, and beneath biologically active composite construction discharges the molecule of carrying out another kind of function.For example can discharge medicine from the biologically active composite construction, prevent the smooth muscle cell undue growth, the protective layer on the biologically active composite construction has but improved the radiopacity of prepared medical treatment device simultaneously.For example comprise the protective layer of Ni-Cr (nickel-chromium) and/or gold, can be deposited on the top of the biologically active composite construction that comprises Ni-P, improve the radiopacity of the device that comprises the biologically active composite construction.Below protective layer, in 30-60 days time, from the biologically active composite construction, discharge for example sirolimus of smooth muscle cell inhibitor.

Also can use protective layer to change the release dynamics of bioactive materials in lower floor's biologically active composite construction.For example can adopt the chemical nickel plating-chromium, nickel-phosphorus or the cobalt-chrome coating that do not have bioactive materials as protective layer.This thing active material material layer at first before entering surrounding environment of will seeking survival by adding.Thereby delayed the release of bioactive materials.Can regulate the release dynamics of prepared medical treatment device in this way.

In addition, protective layer comprises polymeric material (or other material).In this case, in protective layer, can comprise with the biologically active composite construction in the identical or different bioactive materials of bioactive materials.For example, when protective layer comprises the storage of polymerization and dissolution medium, can from protective layer, discharge (for example several days) bioactive materials wherein rapidly, and the material in the delivery of biologically active composite construction to spend some months to arrive the time in several years.In this embodiment, prepared medical treatment device can comprise the storage that comprises polymerization and protective layer and the storage of metal and the combination of dissolution medium of dissolution medium.

Suitable polymer blend (being that they do not bring out any disadvantageous tissue reaction) of bio-compatible preferably in protective layer, and can be degradable.Described polymer can comprise the polyester or the copolyesters of lactone group, for example polyactide, polycaprolactone-glycolide, poe, polyanhydride; Polyaminoacid; Polysaccharide; Polyphosphazene; With poly-(ether-ester) copolymer.

In protective layer, also can use the polymer of nonabsorbable bio-compatible.Described polymer can comprise for example dimethyl silicone polymer; Poly-(ethane-acetic acid ethyenyl ester); Acrylate-based polymer or copolymer, for example poly-(methacrylic acid ethoxy methyl esters); The polymer of fluoridizing, for example polytetrafluoroethylene (PTFE); And cellulose esters.

In other embodiments, the protective layer on the biologically active composite construction can be the individual layer (SAM) of self assembly.The thickness in monolayer of self assembly in certain embodiments can be less than 1nm (being monolayer).In one embodiment, the individual layer of mercapto can be adsorbed on the Ni-based matter of biologically active composite construction by thiol functionalities, and can self assembly on Ni-based matter.The adding of self-assembled monolayer can allow different surface coordination bodies to use with the biologically active composite construction.That is to say that various ligands or coordination part can be attached to monomolecular from outwardly directed each ends of biologically active composite construction.

In another embodiment, on matrix, form after the biologically active composite construction, can remove matrix.This can electro-deposition biologically active composite construction independently.For example, as mentioned above, when the preparation medical treatment device, can on matrix, form the biologically active composite construction.Yet, not that matrix is retained on the final medical treatment device, thus can etching of substrates, from formed biologically active composite construction, remove it.For example can comprise can etched material for matrix.Can comprise metal for example aluminium or copper or polymeric material by etched material.

Matrix is the material of sacrifice property, can adopt matrix as preparing the independently core of biologically active composite construction (mandrel).Behind etching of substrates, make independently biologically active composite construction.For example can in this way prepare support.At US-6, can find in 019,784 to use and sacrifice the particulars that the property matrix prepares support.Introduce this part United States Patent (USP) in full as a reference at this.

Independently the size of biologically active composite construction can be extremely several meters of several approximately nanometers (for example nano particle).For example, independently the thickness of biologically active composite construction can be thick less than about 1mm.The same in other embodiments, can independently form protective layer on the biologically active composite construction.

III. delivery of biologically active material from the biologically active composite construction

In the medical treatment device of Shi Yonging, can there be biologically active composite construction according to embodiments of the present invention in vivo.When using, they can be implanted in patient's the body, also can patient's external use they.Use described medical treatment device, wish in some cases from the medium-term and long-term delivery of biologically active material of biologically active composite construction.

In certain embodiments, bioactive materials can spread from the metal matrix of biologically active composite construction.Fig. 6 and 7 (narration in more detail below) illustrates the experimental result that adopts embodiment of the present invention.Shown in Fig. 6 and 7, in embodiments of the invention, can in long-time, (for example about 10 or about more than 20 days) discharge medicine.Under the situation of bound by theory not, in the embodiment shown in Fig. 6 and 7, releasing mechanism shows as simple diffusion.Bioactive materials is by metal matrix, promptly by spreading between single crystallite and the grain boundary.The composition switch of bioactive materials and metal film is diffused in the liquid on metal film and liquid surface then.

In addition, the metal matrix of biologically active composite construction can etch, discharges bioactive materials wherein.For example, metal matrix may be subjected to electrolytic etching easily.The metal matrix of biologically active composite construction can be used as anode, when electric current when comprising composite construction as the circuit of anode, can cause the corrosion of metal matrix.As the result of corrosion process, from metal matrix, discharge bioactive materials.This in vivo and all be useful in teat glass.By adopting corrosion process, can at the appointed time in patient's body or in the zone of diagnosis detection range inner height limitation, discharge controllable a small amount of bioactive materials (for example medicine or DNA).

Corrosion can be carried out apace or lentamente.In quick corrosion process, adopt external power source that electric current is applied to rapid corroding metal matrix on the biologically active composite construction.In slow corrosion process, the metal of metal matrix and adjacency or the current potential of solution are different, can cause the oxidation of bioactive composite material matrix metal.For example, when two sheet metals are in contact with one another on electricity, or the metallic region of two adjacency will cause galvanic corrosion when being in different electrochemical potentials.These two metal parts will constitute a galvanic cell, and the metal part (promptly more active metal) that wherein electrochemical potential is minimum can be corroded.

In another embodiment, mechanical energy such as ultrasonic energy are applied on the biologically active composite construction.Mechanical energy has been quickened the diffusion rate of bioactive materials in the biologically active composite construction.In this embodiment, etch can take place and also etch can not take place in metal matrix.Under the situation of the medical treatment device of support or other implantation, ultrasonic energy can be imposed on the patient non-invasively, make can be in needs from support the delivery of biologically active material.For example, after implant frame, can application examples such as the ultrasonic energy of several days, a few week or some months.

IV. medical treatment device

Embodiment of the present invention comprise any suitable medical treatment device that comprises the biologically active composite construction.For example, medical treatment device comprises the capsule of support, orthopaedic implant, cardiovascular implant, electrode, sensor, administering medicine, perform the operation clip, micromachine and nano-machine device according to embodiments of the present invention.Fig. 4 (a)-4 (c) is illustrated in the schematic diagram of the support 150 in the artery.

In other embodiments, the biologically active composite construction is applied in the blood or tissue of contact medical treatment device, this depends on the endothelium healing on biocompatible implant surface.These devices comprise ventricular assist device (VADs), whole artificial heart (TAHs) and heart lobe.Compare with the support with noncontinuous surface (wire netting that for example has window (windows)), these devices have continuous surface.They rely on from the cell of blood flow inoculation.Therefore, the biologically active composite construction can comprise growth factor.The biologically active composite construction provides and can make endothelial cell adhering to and attaching surface that subsequently growth course is carried out easily from the teeth outwards.Described growth factor comprises any host of integrins, selectins, growth factor and peptide, and they can help and promote the migration of cell and adhere to.

The biologically active composite construction also can be used for drug release device, for example the ball that can take in or the device that can move in blood flow.These devices can be taked sphere, square or cylindrical, and its size is enough to be fit to body cavity.Can they be put into human body through skin or oral cavity.Utilize one of above-mentioned method from metal matrix, to discharge subsequently.Can produce that other this medicine of delivering carrier combinations stores and delivery device with biodegradable polymer etc.

In another embodiment, bioactive composite material can exist in the wall of microchip type device (microchip-type device) or passage.But the protective layer that can adopt etch covers the bioactive composite material in wall or the passage.For example, the metal matrix in the biologically active composite construction can comprise nickel or nickel alloy, and protective layer comprises gold.Optionally electric current is applied on the golden protective layer, thereby causes the protective layer etch.As the result of etch process, bioactive materials can freely diffuse out from each wall or passage.Another kind method can adopt electric current to cause delivery of biologically active material from each wall or passage.The bimetallic EMF (electromotive force) that is produced by two kinds of metallic combinations can cause corrosion slowly.Adopt the etch of the metal matrix of electric current initiation can cause release fast.Under these two kinds of situations, the magnitude of current that imposes on metal matrix is directly proportional with the bioactive materials amount of release.Compare with present design, this design has reduced the complexity of described device.

Except using in the treatment medical treatment device, when needing the accurately occasion of the bioactive materials of amount aspect space and/or the time control mode, the biologically active composite construction can also be used on diagnostic device and the bioassay.In the process of seeking medicine, can use them.Complexity in bioassay aspect the searching medicine increases, and utilizes living cells to carry out bioassay in many cases.Represent surface technology to make to study the effect of topochemistry composition in cell effect research and the effect of change in cell is cultivated of local environment such as pH.Utilize embodiments of the invention, can be in specific place of specific time with in the dynamic release of applying biological active material in diagnostic device and bioassay under the controlled amount.

In one embodiment, the surface underneath at cultured cell forms the biologically active composite construction.The biologically active composite construction can be a pattern form, and wherein the concentration of bioactive materials changes, and the biologically active composite construction also can be the layer that comprises a kind of molecular concentration.When suitable, the matrix by electrolytic etching dissolving biologically active composite construction almost is discharged into bioactive materials in the pericellular environment of being studied simultaneously.The magnitude of current that applies has determined d/d bioactive materials amount.

This technology means the environment in the analogue body, can use the molecule pair cell is specified in this technical research in the fixed time identical with other bioassay molecular action.For example, adopt well-known authentication method for example the fluorescence authentication method measure the occasion of G1 and G2, the influence of molecule X cell cycle (cell cycle) in processes such as G1 and G2.

Embodiment 1

Prepare 6 biologically active composite constructions.Each biologically active composite construction all comprises the nickel-phosphorus metal matrix that adopts electroless deposition methods to form on metallic matrix.Used matrix is a metal forming.3 matrixes comprise the 316L stainless steel of medical grade, and 3 matrixes comprise Nitinol.Respectively with fluorouracil, tetracycline and albumin with nickel-phosphorus codeposition on stainless steel and Nitinol matrix.

At first adopt processing step shown in Figure 4 to prepare each matrix.At first clean the surface (step 32) of matrix.Use the surface (step 34) of distilled water flushing matrix then.After flushing, adopt the surface (step 36) of Sn (II) sensitization matrix.The stannous chloride solution that can adopt 0.1g/L is as sensitized solution.After depositing Sn (II) on the surface of matrix, wash matrix once more with distilled water (step 38) at second rinsing step.Then, with Pd (II) catalyst deposit on the surface of matrix.The palladium chloride solution that can adopt 0.1g/L is as catalytic solution (step 40).Wash the surface of matrix once more at the 3rd rinsing step (step 42).Can adopt distilled water as flush fluid.After the 3rd rinsing step, the catalysis matrix prepares to carry out electroless deposition.Adopt above-mentioned catalysis process, prepare 3 stainless steels and 3 Nitinol matrixes.

Preparing 3 different electroless-platings bathes.These three different baths are identical, the bioactive materials difference that different is in each is bathed.Bathe 1 and comprise 5 FU 5 fluorouracil, bathe 2 and comprise tetracycline, bathe 3 and comprise albumin.Each bath all is under environmental pressure, and pH is about 7, about 40 ℃ of temperature.

Table 1
Table 1		Composition	Concentration
Nickel sulfamic acid	??29g/L	Composition	Concentration
Nickel sulfamic acid	??29g/L	Inferior sodium phosphate	??17g/L
Sodium succinate	??15g/L	Inferior sodium phosphate	??17g/L
Sodium succinate	??15g/L	Butanedioic acid	??1.3g/L
Bioactive materials: 5 FU 5 fluorouracil (bathing 1), tetracycline (bathing 2), and albumin (bathing 3)	(0.25g/L bathing 1), 0.25g/L (bathing 2) and 100 μ g/ml (bathing 3)	Butanedioic acid	??1.3g/L

Adopt electroless deposition methods (step 44) on matrix (3 stainless steel bases and 3 Nitinol matrixes), to make the biologically active composite construction of 6 layer forms respectively.The general time in bath has determined the thickness of biologically active composite construction.Each matrix is immersed about 10min in the bath, generate the thick layer of about 4 μ m.The concentration of bioactive materials has determined the concentration of bioactive materials in coating in the bath.For example, when adopting albumin as bioactive materials, the concentration in coating is albumin: metal is 1: 10 w/w, and the initial concentration of albumin in bath is 100 μ g/ml.

For each biologically active composite construction, the part by weight of bioactive materials and metal matrix material is listed in table 2.

For each biologically active composite construction, the following mensuration of the part by weight of bioactive materials and metal matrix.For each biologically active composite construction/matrix combination, measure before the deposition and post-depositional dry weight.After making them, each biologically active composite construction/matrix combination is placed in the electrobath, adopt the anode of biologically active composite construction as electrolytic circuit.When adding electric current in bath, the metal matrix of biologically active composite construction is corroded, and enters the electrobath from matrix.Use the amount of spectrophotometer then with bioactive materials in the optical method measuring bath.Numeral in the following Table 2 is a weight _X/ weight _Ni-P, wherein x represents bioactive materials, Ni-P is the metal matrix that adopts the electrochemical method deposition.Shown in the result in the table 2, bioactive materials all is high to concentration of metal in each case.

Table 2: bioactive materials is to the w/w concentration of the Ni-P matrix of deposition on Nitinol and 316L matrix
					Fluorouracil	Tetracycline	Albumin
Nitinol	??0.100mg/3mg	??0.3mg/4mg	??0.5mg/4.8mg		Fluorouracil	Tetracycline	Albumin
Nitinol	??0.100mg/3mg	??0.3mg/4mg	??0.5mg/4.8mg	The 316L stainless steel	??0.4mg/3mg	??0.5mg/4mg	??0.4mg/4mg

Embodiment 2

Adopt the support that applies with benchmark electroless deposition methods identical in embodiment 1 preparation.Yet, in this embodiment, adopt the Bx of Johnson ﹠ Johnson speed support (stainless steel) and the Smart of Johnson ﹠ Johnson support (Nitinol) as matrix, replace metal foil substrate.The biologically active composite construction of prepared layer form on support.

Fig. 6 illustrates the medicament elution gradient curve when adopting the Bx of Johnson ﹠ Johnson speed support (316 stainless steel) as matrix.Fig. 7 illustrates the medicament elution gradient curve when adopting the Smart of Johnson ﹠ Johnson support (Nitinol) as matrix.After being shown in and being eluted in the normal saline solution, the scale of curve y-axle still is retained in the bioactive materials amount on the support.

The anodizing process that adopts in support embodiment is similar with the anodizing process that is applied to once more on the metal foil substrate.After applying, the support that applies is placed in the normal saline solution, change solution every day.Fate with bracket coating anodization appointment.Adopt spectrophotometric detecting method to be determined at the bioactive materials amount that discharges under each situation.

As in Fig. 6 and 7, seeing, in long-time, from embodiment of the present invention, discharge molecule.In 40 days, discharge medicines such as a considerable number of fluorouracil, albumin and tetracycline.Do not see that coating has obvious corrosion.

Embodiment 3

For further validation range wide biological activity material can store and discharge, other experiments have been carried out in coating.Table 3 illustrates several experiments of carrying out according at the conventional method described in the embodiment 1, and for new bioactive materials, each experiment all has a time point.Δ A is from the sample that comprises corresponding bioactive materials with from the extinction rate variance between the wash-out bath of pure coating sample (being benchmark) acquisition.In this example, adopt above-mentioned method to apply 1cm ²Medical grade 316L stainless steel sample.Except tetracycline (antibiotic), fluorouracil (antimetabolite) and albumin (big protein), these experiments also illustrate the ability that stores and discharge rapamycin (the anti-restenosis compounds of height oleophylic), heparin (the big carbohydrate anticoagulant molecule of highly-hydrophilic) and hydrocortisone (anti-inflammatory compound of oleophylic).

Table 3 just illustrates after deposition and just in the absorptance of wash-out bath afterwards in 7 days in 0.9% saline solution.Δ A means and applies bioactive materials and do not apply extinction rate variance between the bioactive materials.Numeral in parantheses means the feature absorptance of every kind of material.

Table 3
Table 3				Time=0, Δ A	Time=0,7 days, Δ A
Rapamycin	??0	??1.85(274nm)		Time=0, Δ A	Time=0,7 days, Δ A
Rapamycin	??0	??1.85(274nm)	Heparin	??0	??2.4(230nm)
Hydrocortisone	??0	??1.2(250nm)	Heparin	??0	??2.4(230nm)

Embodiment 4

Be the embodiment of protective layer below.Adopt embodiment 1 described method, bioactivity coatings is applied to the Nitinol sample (can be on market from nitinol-based devices and (the Nitinol Devices and Components of parts Co., Ltd, Inc.) after purchase), sample is further handled in the negative electrode position that places it in second bath, comprises the chromic acid (CrO of 100g/L in the bath ₃) and the H of 1g/L ₂SO ₄On sample, apply 200-300mA/cm ²The about 20s of the about 10-of current density, generation can delay the protective layer of bioactive materials diffusion.The chromium protective layer has also increased the radiopacity of device.In these cases, the release of bioactive materials is delayed several days to several weeks.

Embodiment 5

For example according to the concrete aspect that provides above, no matter whether have biologically active agents or material in coating, each embodiment of the present invention can both provide valuable application aspect coated medical devices, therefore is considered to extensively favourable aspect of the present invention.

Adopt the following examples to illustrate a concrete described aspect, wherein adopt cited coating embodiment of the present invention, reduced the nickel that discharges from Ni-Ti alloy, this embodiment is used nickel-phosphorus coating solution and the painting method that does not comprise biologically active agents.

In independent experiment, with 1cm ²The anodization of Ni-Ti alloy sample, remove its surface fully and go up inactive oxide skin(coating), expose pure NiTi.Subsequently matrix is put into the electroless nickel bath (bathing 1) that does not comprise bioactive materials.Arrive strong self-catalyzed reaction outwardly in Nitinol.Behind 30s, from bathe, take out the Ni-Ti matrix, see glossiness coating.By scraping or adopting to clean and be with (scotch tape) can not remove this coating, this shows that it has good adhesive force to the Nitinol matrix.

The coating that will apply the Ni-Ti sample (Ni-P-NiTi) of new nickel-phosphorus is then put into 1.5ml 0.9% sodium chloride solution, at 37 ℃ of hatching 96h, removes sodium chloride solution then, changes another part 1.5ml solution, hatches 96h again.The parallel control sample of " as (as-received) of standard " Nitinol (NiTi) is also at 37 ℃ of hatching 96h and 192h.Nickel content in the solution of employing atomic absorption spectroscopy hatching sample.The result is expressed as follows with ppm:

	??Ni-P-NiTi(ppm)	??NiTi(ppm)
	??Ni-P-NiTi(ppm)	??NiTi(ppm)	The nickel that 96h discharges	??15.6	??19.6
The nickel that 192h discharges	??0.6	??1.2	The nickel that 96h discharges	??15.6	??19.6

Can see that when with uncoated Ni-Ti matrix control sample relatively the time, leach 96h from the Ni-Ti matrix after, the nickel that the sample of nickel coating-phosphorus leaches reduces by 25%, reduces by 50% in 96h subsequently.

This benefit that obtains from the sample that applies Ni-Ti according to the present invention, the present invention each extensively favourable aspect in be typical.In one aspect, will comprise the matrix modification of nickel, the nickel of release lacks than the matrix of not handling according to the present invention in other cases.This is valuable to far-ranging medical treatment device, particularly implant, owing to relate to bio-compatibility, particularly for nickel there being anaphylactoid patient crowd, implant has the shortcoming that discharges nickel in other cases.Do not need to add biologically active agents (if also need in the present invention, also can use these preparations) occasion of described value just can be provided, the example of described medical treatment device comprises, for example all Ni-Ti medical treatment devices are for example according to the device of support, filter, wire or the straightening of teeth of other illustrative embodiment.

In addition, use identical coating and painting method to following ability: (a) to suppress from described matrix, to discharge nickel, (b) provide the biologically active agents coating, (c) be increased in the below matrix radiopacity, or their any combination for example (a) and (b), (a) and (c) or (b) and (c), be the very favorable combination that may constitute according to the present invention, they should be considered to the independently extensive aspect of the present invention.

Comprising or do not comprising under the situation of biologically active agents, when the nothing electricity electrochemical deposition method according to the present embodiment prepares or applies sample, is conspicuous according to using other benefit of the present invention.In a specific embodiment, can use the coating and the method relevant of various prescriptions with them, increase the radiopacity of medical treatment device matrix.More specifically, radiopaque relatively materials such as employing chromium are cobalt-chromium combined preparation for example, often can increase the relatively low matrix material of radiation opaque, Ni-Ti alloy matrix etc. for example, or comprise similar radiation opaque material but compaction rate is lower, thereby the radiopacity of the lower matrix of radiation opaque material proportion.Therefore, comprising or do not comprising biologically active agents, and improving or do not improving under the situation of bio-compatibility result (for example having reduced the release of nickel), though the conspicuous described combination of those of ordinary skill can provide other tangible benefit, these painting methods and the coating sample that is obtained---employing has improved radiopacity according to the coating of the present embodiment---are considered to independently favourable aspect more of the present invention.

For the purpose of some highly beneficial aspect of the present invention is described, the application has narrated various specific embodiments.Yet, although many described specific embodiments all have concrete benefit, should not think that they all are conditional in all cases, in many aspects, they all are typical in aspect the present invention widely.For example, the application has provided concrete experiment embodiment to concrete painting method and result, but under the situation that does not deviate from preset range of the present invention, also can adopt other suitable coating prescription and biologically active agents etc. to replace described embodiment.

More specifically, in the experiment that embodiment quotes, generally all adopt the preparation method of nickel-phosphor coating that concrete favourable outcome is described.Yet, in described preparation method, also can use other suitable substitute material, still can realize various purpose of the present invention and aspect widely, for example comprise following preparation methods etc.: one of nickel or phosphorus reach wherein alternative suitable sub; Cobalt; Boron; Chromium; Or other suitable described mixtures of material of combination, alloy or the application.Therefore, concrete nickel-phosphorus assembled scheme is to illustrate the present invention aspect widely that comprises these other subs, for example in some aspects, the solution or the structure that relate to following material: use the metal or other material and their reducing agent (for example reducing agent of metal) that generate the nominal price ion; Cation and anion; The combination of positive divalence and negative divalence or trivalent material; On matrix, there is not the solution that electric electrochemical deposition uses; Adopt the aseptic structure of no electric electrochemical production or coating etc.By cited these of nickel-phosphorus electrochemical deposition method of using these embodiment aspect widely, comprise with or the biologically active agents or their suitable combination, mixture or the sub combination that do not specify with the application.

On the other hand, when concrete biologically active agents is used in appointment in the experiment at embodiment, be intended to illustrate other compound (, thinking that these structures are that independent Value is arranged very much) though concrete preparation is relevant with method with similar characteristics with these preparations.For example, tetracycline can have the characteristic of antibiotic to some adventive on the one hand, but when the inhibition cell was grown automatically, it had the characteristic of antiproliferative biologically active agents again, therefore, becomes the possible suitable sub of anti-restenosis agent.In another embodiment, when 5 FU 5 fluorouracil disturbs dna replication dna, mitosis and cell growth at it, has the characteristic of mitotic inhibitor; But it has the characteristic as following types of biological active ingredient example again: fluorouracil, uracil analogues and anti-restenosis agent.Albumin is the another kind of compound of paying special attention to by model experiment in this disclosure, and it has the characteristic of larger protein and following type compound: peptide, organic molecule, pharmaceutical carrier and growth factor.Rapamycin is the application's disclosed another kind of biologically active agents in some typical specific embodiments, and it has is the characteristic of highly oil loving anti-restenosis agent and anti-inflammatory preparation compound.Heparin is another described embodiment, has the characteristic of the anticoagulant-anti-restenosis agent of the big carbohydrate, anticoagulant, carbohydrate growth factor of highly-hydrophilic and combination.Hydrocortisone is another embodiment, is as the examples for compounds that has following properties at least: the antiinflammatory of height oleophylic.

Therefore, though each all represents these biologically active agents according to very favorable specific embodiments of the present invention, but under suitable situation, according to those skilled in the art, at least in part based on the summary of this piece disclosure, also think described their other sub, the for example analog of these concrete preparations or derivative or other sub or the combination between them or mixture or their the suitable sub that comprised all are included in the present invention widely in the preset range.

It is also understood that the coating of medical treatment device and preparation method and result are favourable being, can use or be used in combination a kind of painting method and result with the compound exchange of described change type.Can exchange or be used in combination various types of compounds, comprise the compound of any or multiple (for example combination) following type: organic, inorganic, water miscible, non-water-soluble, hydrophilic, hydrophobic, oleophylic, big molecule and little molecule, protein, monose and polysaccharide, carbohydrate, anti-restenosis compounds, anti-inflammatory compound, antithrombase compound, antimetabolite compound and antimicrobial compound etc. according to the coating of certain embodiments of the invention.

The application for example with reference to the described no electric electrochemical deposition method of embodiment, causes the generation of some metal matrix, and this method has described generative process and is easy to characteristics.For example prepared metal matrix also comprises metal except comprising another kind of nonmetallic materials, described nonmetallic materials are to derive from the reducing agent of the electron donor of the metal ion that forms the fluid environment of electrochemical deposition as metal.Described combination of materials does not adopt sintering or plating to wait the typical characteristics of the metal matrix of other deposition process preparation.In addition, the structure of prepared metal matrix and dimensional characteristic, has characteristic, so obtain for example to have only for example pore-size and other surface characteristic (for example smoothness, uniformity etc.) of just having of sintering method of other method by the process of molecule, nanoscale deposition.Therefore, thinking " metal matrix that does not have electric electrochemical production " or other similar explanation, is restrictive to the identifiable structure of uniqueness.

In yet another aspect, each others of painting method also are favourable with the observed result (for example with reference to embodiment) relevant with these embodiments.For example generally all observe the coating support that utilizes embodiment to illustrate, on the outer surface of stent strut, have the metal matrix coating of average thickness less than about 5 μ m.In one case, observe also that the very little coating of this thickness can be preserved and wash-out greater than the biologically active agents of 750 μ g.In another case, preservation and wash-out are at least about the biologically active agents of 1mg.Further observation shows, method and material according to use utilizes embodiment to illustrate can obtain the bioactivity composite coating of thickness less than 1 μ m, are thinned to 500 in many cases.

The structure that for example has described characteristics such as the density of the described biologically active agents of in matrix, preserving and from matrix, discharging and relative thickness, the biologically active composite construction of anti-restenosis agent particularly is provided on the support matrix, be considered to the independently very favorable aspect of the present invention, without limits to the concrete painting method that uses or material.

Think that also the application is fit to be used in combination with other method with reference to the described embodiment of no electric electrochemical deposition, comprising other method (for example sintering or plating) of other painting method, particularly metallizing interior.For example begin to use plating, sintering or the preparation of other method will adopt the present invention not have the matrix that electric electrochemical deposition embodiment applies.Or can be before no electric electrochemical deposition, afterwards or use described other method to carry out the surface modification of matrix in carrying out process.In this respect, think and no electric electrochemical deposition and electroplating deposition and/or metal sintering can be used in combination, form structure or coating surface.

Described each embodiment of the application can with radioactive material for example radioactive metal isotope combination use, for example provide partial radiation to tissue by the coating on the support or other implant.For example, can prepare the support of emitted radiation according to described the whole bag of tricks of the application and structure at least in part for radiation tubular cavity wall prevents ISR.This can replace from the wash-out bioactive materials of support own, or carries out with this and from the wash-out bioactive materials combination of support own.Yet, adopting cold metal to replace in the embodiment of metal matrix, obtain by simplifying and, having reduced danger patient and medical personnel to the benefit that other improvement that stores and handle brings.

Another similar aspect, relate to the occasion of support for certain embodiments of the invention are described in the application, the application also considers other medical treatment device or other aseptic structure or method are used as suitable sub.

By with further reference to each embodiment of enumerating above, the present invention also thinks in order to apply the matrix in the plan insertion live body, it is favourable that extensive use material of the present invention does not have electric electrochemical deposition, therefore in yet another aspect, comprise described method in gnotobasis and coating result widely.In one aspect,, can provide by the situation of end user or the sterilization of intervention side for later on according to unpasteurized described medical treatment device of the present invention.Yet, it is generally acknowledged the application to described each embodiment of medical treatment device, before planning to use them, need carry out described sterilization, should think the aseptic structure with various benefits that above-mentioned embodiment provides, be the independently valuable aspect of the present invention.

The application has narrated each embodiment with reference to very favorable no electric electrochemical deposition method with relevant structure.Yet be appreciated that also according to the many problems of these very favorable embodiment solutions and the favourable outcome of acquisition, also can obtain that this is conspicuous for those skilled in the art based on this part disclosure summary according to other replacement method.Therefore, although present invention includes described no electric electrochemical deposition embodiment, should think that also described sub is also in the broad range of the present invention aspect some with independent Value.For example do not leave of the present invention aspect under the situation of preset range, adopt other replacement method (for example particularly using other method of the pottery or the polymer that do not need sintering), also can obtain to provide structure and the method for the application to the described coating of electrochemical deposition, for example comprising the metal composite matrix that for example comprises bioactive materials interior.

For further understanding, the application regards electroless deposition methods as and is comprising the matrix of nickel---Ni-Ti matrix of promptly for example illustrational nickel coating-phosphor coating (wherein can comprise bioactive materials)---goes up very favorable method that deposition comprises the coating of nickel.In another embodiment, also can adopt the described no electric electrochemical method of the application, will comprise cobalt and chromium, also can also comprise the coating of bioactive materials, be deposited on cobalt-chromium matrix (for example support).Yet although the independent benefit that adopts described no electric electrochemical method to provide surpasses other sub, for the extensive aspect of setting forth described expected results, thinking to provide described other replacement method of similar results, also in the scope that the present invention is scheduled to.

Adopt term used in this application and the expression way term of book as an illustration; and without limits; be not intended to when using described term and expression way; with the equivalent of the characteristic of narrating or their some parts, think that various improvement can be in the scope of the present invention of requirement patent protection shown in the eliminating.In addition, under the situation of not leaving the scope of the invention, any one of any embodiment of the present invention or a plurality of characteristic, can with any one or a plurality of property combination of any other embodiment of the present invention.

For all purposes, introduce above-mentioned all U.S. Patent applications, patent and list of references in full as a reference at this.

Claims

1. method, comprising:

(a) provide electrochemical solution, comprising metal ion and bioactive materials;

(b) electrochemical solution is contacted with matrix; With

(c) adopt electrochemical method to form the biologically active composite construction on matrix, wherein the biologically active composite construction comprises metal matrix and the bioactive materials in metal matrix.

2. the process of claim 1 wherein that the metal ion in electrochemical solution derives from metallic salt, wherein electrochemical solution also comprises reducing agent.

3. the process of claim 1 wherein that electrochemical method is an electroless deposition methods.

4. the process of claim 1 wherein that the biologically active composite construction is positioned on the matrix with the form of layer.

5. the process of claim 1 wherein that matrix is the matrix of sacrifice property, wherein this method also comprises:

(d) from the biologically active composite construction, remove the matrix of sacrifice property.

6. the method for claim 5, wherein matrix and biologically active composite construction form the support that applies.

7. the process of claim 1 wherein that bioactive materials comprises medicine.

8. the process of claim 1 wherein that matrix comprises the combination of nickel, chromium, gold, silver, copper, cobalt or their alloy.

9. the process of claim 1 wherein that electrochemical method is a method for electrodeposition.

10. the method for claim 1 also comprises:

On the biologically active composite construction, form protective layer.

11. the method for claim 10, wherein protective layer comprises metal.

12. the method for claim 10, wherein protective layer comprises polymeric material.

13. the method for claim 10, wherein protective layer comprises the individual layer of self assembly.

14. the biologically active composite construction, comprising

(a) metal matrix, wherein metal matrix is to adopt electrochemical production; With

(b) bioactive materials in metal matrix.

15. the biologically active composite construction of claim 14, wherein the biologically active composite construction forms support.

16. the biologically active composite construction of claim 14, wherein the biologically active composite construction is positioned on the support with the form of layer.

17. the biologically active composite construction of claim 14, wherein bioactive materials comprises medicine.

18. the biologically active composite construction of claim 14, wherein metal matrix comprises metal alloy.

19. the biologically active composite construction of claim 14, wherein the average pore size of metal matrix is less than about 100 .

20. the biologically active composite construction of claim 14, wherein the biologically active composite construction is the form of layer.

21. the biologically active composite construction of claim 14, wherein the biologically active composite construction is the form of discrete objects.

22. support, comprising:

(a) metallic support body; With

(b) the biologically active composite construction of claim 14 is positioned on the metallic support body with the form of layer.

23. medical treatment device, comprising:

(a) matrix; With

(b) the biologically active composite construction of claim 14 is positioned on the matrix with the form of layer.

24. the verifying attachment of clinical diagnosis is comprising the biologically active composite construction of claim 14.

25. use the method for the biologically active composite construction of claim 14, comprising the biologically active composite construction is inserted in patient's the body.

26. the method for claim 25 also comprises when the biologically active composite construction is in patient's body, and biomolecule is diffused out from the biologically active composite construction.

27. the method for claim 25 also comprises when the biologically active composite construction is in patient's body the etch metal matrix.

28. the method for claim 25 also is included in the highly interior etch metal matrix in zone of limitation, discharges the bioactive materials of accurate controlled quentity controlled variable in the diagnostic check system.

29. comprise the medical treatment device of biologically active composite construction, wherein the biologically active composite construction comprises, second kind of material of have first kind of metal material of the characteristic that at least partly generates metal ion in the aqueous solution, deriving from the reduction of metal ion agent and bioactive materials.

30. the medical treatment device of claim 29, wherein the biologically active composite construction forms at least a portion of support.

31. the medical treatment device of claim 29, wherein first kind of metal material comprises one or more cobalts, chromium, nickel, gold, platinum, copper, silver, molybdenum or iron.

32. the medical treatment device of claim 29, wherein second kind of material comprises at least a phosphorus or boron.

33. the medical treatment device of claim 29 also comprises matrix and matrix, matrix comprises first kind of metal material and second kind of material, and wherein bioactive materials is in the substrate, and wherein the biologically active composite construction is positioned on the matrix with the form of coating.

34. the medical treatment device of claim 29, wherein bioactive materials comprises anti-restenosis compounds.

35. the medical treatment device of claim 29, wherein bioactive materials comprises anticoagulant compounds.

36. the medical treatment device of claim 29, wherein bioactive materials comprises growth factor.

37. the medical treatment device of claim 29, wherein bioactive materials comprises rapamycin.

38. the medical treatment device of claim 29, wherein bioactive materials comprises heparin.

39. the medical treatment device of claim 29, wherein bioactive materials comprises anti-inflammatory compound.

40. the medical treatment device of claim 39, wherein anti-inflammatory compound comprises hydrocortisone.

41. the medical treatment device of claim 29 also comprises:

Matrix;

Wherein the biologically active composite construction is included in the coating on the matrix.

42. medical treatment device, comprising:

Matrix is comprising metal;

Coating on matrix is comprising metal matrix;

Wherein metal matrix comprises metal, also comprise: (i) bioactive materials in metal matrix, or the (ii) radiopaque relatively material of ratio matrix in metal matrix, or (iii) unsintered, that do not electroplate and cold metal matrix, or (iv) do not have a metal matrix of electric electrochemical deposition, or (the v) reduction of metal ion agent that aqueous fluid, generates from the metal material of deriving.

43. medical treatment device, comprising:

Matrix is comprising first kind of metal and second kind of metal; With

Coating on matrix, comprising: (i) first kind of metal, in blood environment

The rate of release of first kind of metal is lower than the rate of release from independent matrix basically,

Or (ii) first kind of metal rather than second kind of metal.

44. medical treatment device, comprising:

Matrix with outer surface, outer surface comprise metal and many zones, these regional quilts

Be used for comprising bioactive materials and from the matrix in patient's body, discharge biological living

The property material;

The bioactive materials that in these zones, comprises;

Wherein these zones also have following properties: (i) when outer surface is exposed in patient's the blood environment, is small enough to anti-basically sealing and is penetrated in the bioactive materials that wherein comprises, or (ii) diameter less than about 1 μ m.

45. medical treatment device, comprising:

The biologically active composite construction wherein has metal matrix and the biology in metal matrix

Active material;

Wherein the biologically active composite construction forms at least a portion of support.

46. medical treatment device, comprising:

Matrix with outer surface; With

Coating on the rack body outer surface, comprising: (i) on the outer surface thick

Degree less than about 5 μ m and in coating the bioactive materials of treatment level, or (ii)

Metal matrix and the bioactive materials in metal matrix, or (iii) do not electroplate

Metal matrix;

Wherein the matrix that applies forms at least a portion of support.

47. the medical treatment device of claim 45 also comprises:

Matrix;

48. claim 41,42,43,44,46 or 47 medical treatment device, wherein matrix also comprises metal.

49. the medical treatment device of claim 48, wherein matrix also comprises metal alloy.

50. the medical treatment device of claim 49, wherein metal alloy comprises stainless steel.

51. the medical treatment device of claim 49, wherein metal alloy comprises first and second kinds of major metals.

52. the medical treatment device of claim 49, wherein metal alloy comprises Ni-Ti alloy.

53. the medical treatment device of claim 49, wherein metal alloy comprises cobalt-chromium alloy.

54. claim 41,42,43,44,46 or 47 medical treatment device, wherein matrix also is electro-deposition.

55. the medical treatment device of claim 54, wherein matrix also comprises the gold of electro-deposition.

56. the medical treatment device of claim 54, wherein matrix also comprises the cobalt-chromium of electro-deposition.

57. claim 41,42,43,44,46 or 47 medical treatment device, wherein matrix also comprises nonmetallic materials.

58. the medical treatment device of claim 57, wherein matrix also comprises polymer.

59. claim 41,42,43,44,46 or 47 medical treatment device also comprise:

Support with rack body;

Wherein matrix forms at least a portion of rack body.

60. the medical treatment device of claim 59, wherein:

Rack body comprises the cradle wall of tubulose, and cradle wall is in radial contraction and be radially expanded shape

Be adjustable between the attitude;

The support of radial contraction state is delivered to place in patient's intracoelomic cavity;

Be adjusted to the chamber wall of the support of radial expanded state in this place use attached to this place

On; With

Matrix forms at least a portion of tubular bracket wall.

61. the medical treatment device of claim 60, wherein:

The cradle wall of tubulose comprises the interconnected net of many pillars that is separated by void area; With

Matrix forms at least a portion of pillar.

62. the medical treatment device of claim 60, wherein the cradle wall of tubulose is expandable air bag.

63. the medical treatment device of claim 60, but wherein the cradle wall of tubulose is self-expanding.

64. the medical treatment device of claim 42, its floating coat is included in the bioactive materials in the metal matrix.

65. the medical treatment device of claim 42, its floating coat are included in the radiopaque relatively material of ratio matrix in the metal matrix.

66. the medical treatment device of claim 65, wherein radiopaque relatively material comprises than the more radiopaque metal of the metal in the metal matrix.

67. the medical treatment device of claim 65, wherein radiopaque relatively material comprises the also metal in metal matrix, but its compaction rate in coating is basically than having increased in metal matrix.

68. that the medical treatment device of claim 42, its floating coat comprise is unsintered, that electroplate and cold metal matrix.

69. the medical treatment device of claim 42, its floating coat comprises the metal matrix of no electric electrochemical deposition.

70. the medical treatment device of claim 42, its floating coat comprise the material that the reduction of metal ion agent that generates from metal is derived moisture fluid.

71. the medical treatment device of claim 43, its floating coat comprise first kind of metal, the rate of release of coating first kind of metal in blood environment is lower than the rate of release from independent matrix basically.

72. the medical treatment device of claim 71, the rate of release of its floating coat first kind of metal in blood environment is than the rate of release from independent matrix low at least 25%.

73. the medical treatment device of claim 71, the rate of release of its floating coat first kind of metal in blood environment is than the rate of release from independent matrix low at least 50%.

74. the medical treatment device of claim 43, its floating coat comprise first kind of metal rather than second kind of metal.

75. the medical treatment device of claim 71 or 74, wherein first kind of metal comprises nickel.

76. the medical treatment device of claim 75, wherein second kind of metal comprises titanium.

77. the medical treatment device of claim 44, wherein when outer surface was exposed in patient's the blood environment, these zones were small enough to anti-basically sealing and are penetrated in the bioactive materials that wherein comprises.

78. the medical treatment device of claim 44, wherein these regional diameters are less than about 1 μ m.

79. the medical treatment device of claim 44, wherein these regional diameters are less than about 100 .

80. the medical treatment device of claim 45, wherein the biologically active composite construction forms stent strut.

81. the medical treatment device of claim 45, wherein the biologically active composite construction forms the coating on the stent strut.

82. the medical treatment device of claim 46, its floating coat be included on the outer surface less than the thickness of about 5 μ m and in coating the bioactive materials of treatment level.

83. the medical treatment device of claim 82, its floating coat comprises the bioactive materials at least about 750 μ g.

84. the medical treatment device of claim 83, its floating coat comprises the bioactive materials at least about 1mg.

85. the medical treatment device of claim 82, its floating coat are included in the about 5 μ m of the about 3 μ m-of thickness on the outer surface.

86. the medical treatment device of claim 82, its floating coat are included in thickness on the outer surface less than about 3 μ m.

87. the medical treatment device of claim 83, its floating coat are included in thickness on the outer surface less than about 1 μ m.

88. the medical treatment device of claim 46, its floating coat comprise metal matrix and the bioactive materials in metal matrix.

89. the medical treatment device of claim 46, its floating coat comprise not electroplated metal matrix.

90. the medical treatment device of claim 43 also is included in the bioactive materials in the coating.

91. claim 44,45,64,82 or 88 medical treatment device, wherein bioactive materials comprises anti-restenosis compounds.

92. claim 44,45,64,82 or 88 medical treatment device, wherein bioactive materials comprises anticoagulant compounds.

93. claim 44,45,64,82 or 88 medical treatment device, wherein bioactive materials comprises growth factor.

94. claim 44,45,64,82 or 88 medical treatment device, wherein bioactive materials comprises rapamycin.

95. claim 44,45,64,82 or 88 medical treatment device, wherein bioactive materials comprises heparin.

96. claim 44,45,64,82 or 88 medical treatment device, wherein bioactive materials comprises anti-inflammatory compound.

97. the medical treatment device of claim 96, wherein anti-inflammatory compound comprises hydrocortisone.

98. claim 44,45,64,82 or 88 medical treatment device, also comprise first kind of bioactive materials with first kind of second kind of bioactive materials that bioactive materials is different.

99. the medical treatment device of claim 98, wherein first kind of bioactive materials is hydrophilic material, and second kind of bioactive materials is hydrophobic material.

100. the medical treatment device of claim 98, wherein first kind of bioactive materials comprises water-soluble basically material, and second kind of bioactive materials comprises water-fast basically material.

101. the medical treatment device of claim 98, wherein first kind of bioactive materials comprises organic material, and second kind of bioactive materials comprises inorganic material.

102. the medical treatment device of claim 44, its outer surface is included in the coating on the matrix, comprising the metal of metal matrix form and the bioactive materials in metal matrix.

103. claim 47,64,82,88,90 or 102 medical treatment device, wherein bioactive materials comprises the coating volume at least about 30%.

104. claim 42,43,44,45 or 46 medical treatment device, wherein medical treatment device is aseptic.

105. prepare the method for medical treatment device, comprising:

Adopt a kind of method to prepare metal matrix at least in part, this method comprises: (i) gold

The reduction of nothing electricity electrochemical deposition that belongs to and the ion that the aqueous solution, generates from metal

The agent second kind of material of deriving, or (ii) prepare metal matrix, make biologically active system simultaneously

Agent is deposited in the metal matrix, or is not (iii) adopting the electric current that applies and sintering not

Situation under, metal matrix is formed coating on matrix, or is not (iv) adopting

The electric current that applies and be lower than under about 120 situation in temperature, with metal matrix at base

Form coating on the body; With

Wherein metal matrix forms at least a portion of medical treatment device.

106. prepare the method for medical stand, comprising:

Adopt a kind of method to prepare metal matrix at least in part, this method comprises: (i) exist

Do not use under the situation of the electric current that applies, make metal matrix on matrix, form coating,

Or bioactive materials is deposited in the metal matrix; With

Wherein metal matrix forms at least a portion of support.

107. the method for claim 105 is comprising adopting no electric electrochemical deposition method to prepare metal matrix.

108. the method for claim 105 comprising the preparation metal matrix, makes biologically active agents be deposited in the metal matrix simultaneously.

109. the method for claim 108 comprising making metal matrix form coating on the surface of the matrix that comprises a medical treatment device part, makes biologically active agents be deposited in the metal matrix simultaneously.

110. the method for claim 108, comprising:

Make the metal matrix electro-deposition on the matrix of sacrifice property, make biologically active agents heavy simultaneously

Amass in metal matrix; With

From metal matrix, remove the matrix of sacrifice property.

111. the method for claim 105 comprising not using under the electric current that applies and the situation at sintering not, makes metal matrix form coating on matrix.

112. the method for claim 105 comprising not using the electric current that applies and being lower than under about 120 situation in temperature, makes metal matrix form coating on matrix.

113. the method for claim 106 comprising under the situation of not using the electric current that applies, makes metal matrix form coating on matrix.

114. the method for claim 106 is comprising bioactive materials is deposited in the metal matrix.

115. the method for claim 114 is comprising the form of metal matrix being made stent strut.

116. the method for claim 106 is comprising making metal matrix form coating on the tubular bracket body.

117. the method for claim 115 is comprising making metal matrix form coating on many pillars of tubular bracket body.

118. claim 107,108 or 114 method wherein also comprise and also adopt electro-plating method to prepare metal matrix.

119. the method for claim 105 or 106 also comprises:

Metal matrix is made first kind of metal matrix; With

Preparation and second kind of with first kind metal matrix contacting different with first kind of metal matrix

Metal matrix.

120. the method for claim 119 also comprises and adopts second kind of metal matrix of electro-plating method preparation.

121. the method for claim 105 or 106 also comprises to metal matrix and sterilizing.

122. the solution that in the process of preparation medical treatment device at least a portion, uses, comprising:

Fluid;

First kind of material in fluid; With

Bioactive materials in fluid;

Wherein adopt this solution on the matrix of this solution contact, to form the electrochemical deposition thing of at least the first kind of material and bioactive materials, thereby form at least a portion of medical treatment device.

123. the solution of claim 122, wherein fluid is a liquid.

124. claim 42,43,44,45 or 46 medical treatment device, wherein medical treatment device is cold basically.