CN101076363A - Pro-fibrotic coatings - Google Patents

Abstract

Pro-fibrotic coatings for medical articles are described that include a pro-fibrotic polymer such as collagen. The pro-fibrotic coatings can also include a thromboresistant polymer. The coatings can be formed by activation of photoreactive groups pendent or independent of the coating materials.

Description

Pro-fibrotic coatings

Cross reference with related application

The provisional application serial number 60/623,565 that submit to the 28 days October in 2004 that the requirement of this non-provisional application has in person, title is " pro-fibrotic coatings "; The provisional application serial number 60/623,563 that submit to the 28 days October in 2004 that has with me, title is the priority of " pro-fibrotic coatings with regulator ", with these applications with integral body by with reference to being incorporated herein.

Technical field

The present invention relates to provide the method for pro-fibrotic coatings for medical article.Medical article with pro-fibrotic coatings can be used to promote the formation of fibrosis piece, and described fibrosis piece can be used for the function of intracorporeal space filling and for example stop blooding and closure.

Background technology

Provide in the situation of material surface at needs, proved that the method for surface applied implantable medical goods is valuable with character that uncoated surface do not have.For example, polymer composition has been applied to medical article to improve the wettability and the lubricity on surface.Coating also can provide the feature of the biological function that improves goods.Especially, bioactivator may reside on the product surface or from product surface and sends, and in blood and blood vessel component, acts on therefore that body processes is for example stopped blooding and blood vessel takes place with part or systemic effect.

Face coat for example uses on the fabric at implantable medical article, to promote local-acknowledgement, causes thrombosis shape to be given birth to.Be present on the face coat the thrombosis material can for medical article for example the heart sticking patch sealer function is provided, its cardiac sticking patch is made of porous material typically.The sealer coating can promote thrombosis to reply on the surface of coating.Reply for example relevant cell and the substrate factor surface combination of fibrin and device for example of relevant factor with thrombosis, along with the past of time, for the surface provides the sealer function with tissue repair.Thrombotic replying can cause tissue ingrowth to be gone in the hole of apparatus surface, and the new tissue that forms can provide closing function.

The thrombosis material has been used for also that for example closed hoop, line or string combine with vascular occlusion device.These closing devices are typically by the target position of catheter delivery in the bodily lumen, for example aneurysm.For example closed hoop is advanced in the aneurysm, has occupied this aneurysm until this ring.Plan these rings and come the space to fill aneurysmal sack by encircling metathetical volume itself, perhaps, if this ring is short thrombotic, then with the synergy of accumulating of biomaterial, wherein this biomaterial with near encircling, induce thrombosis relevant.

Utilize the thrombosis ring can for treatment aberrant angiogenesis situation for example aneurysm benefit is provided, but also have various viewpoints to propose objection.For example, an objection is that promotion thrombosis can be filled aneurysm and do not cause thromboembolism (due to the part grumeleuse that drops) from aneurysm.In this case, the thrombosis coating should promote grumeleuse to form ideally, reduces the danger of thromboembolism simultaneously.More particularly, the thrombosis coating should be improved sophisticated speed of grumeleuse and character, and forms the covering of neointima and new endothelium subsequently near aneurysmal cervical region.

The closed hoop of being made by the platinum that does not have coating is guided out (even having also) very little biological response, therefore for promoting in the aneurysm that thrombosis is unfavorable fast.In order to improve thrombotic replying, be platinum closed hoop coating with collagen.But, be coated in the less stable of the collagen on the ring, ring is delivered to aneurysmal method can damages this coating.Therefore, the coating that prior art shows is to be designed for to be guided out the thrombotic of relatively poor character and to reply, and therefore, durability is relatively poor.

Except the difficulty of fixing protein (for example collagen) from the teeth outwards, also have other shortcoming, and with the coated substance that uses these types, the material that particularly derives from animal is relevant.For example, collagen and gelatin normally derive from animal, and are used for many coatings applications that need thrombosis to reply.A problem relevant with using these materials is and since in their production batch with batch between inherent difference, be difficult to produce the coating composition of unanimities from these animal sources.

In many cases, the collagen that uses in packaging technique is from cattle.In these situations, may be that the bovine collagen goods can comprise and do not want the pollutant that have, they are not wish to be incorporated in the human patients.An example of undesirable pollutant is Protein virus (prionic) granules that cause mad cow disease (BSE).

BSE,, be also referred to as bovine spongiform encephalopathy, be to be called a kind of in the carrying out property neurological disorder group of transmissible spongiform encephalopathy or TSEs (because of the deteriorated area of similar sponge in the brain is named).Report various forms of TSE, comprised scrapie of sheep and the Chronic consumptions of elk and mule deer.Believe that generally the animal part of use recirculation has caused the kind cross-contamination of scrapie and even the bovine spongiform encephalopathy of sheep, the human variant form that beef that picked-up is polluted and cattle goods can cause these diseases, i.e. creutzfeldt-Jacob disease (CJD).

Other focus is that the goods that derive from animal may provide other not want the pollutant that have, for example antigenic factor.These antigenic factors can promote near the partial immunne response of the product of implanting, and harm its function.These factors also can cause infecting and local inflammation.

In a word, prior art shows that the coating in health on the equipment therefor can provide hemostasis and inaccessible function, wherein designs coating and comes the lip-deep thrombosis of guiding device to reply, and has relatively poor character usually.These coatings are not suitable for promoting local-acknowledgement, form thrombosis on the apparatus surface that causes applying.

The invention summary

The invention provides chemical compound, compositions and method and the coated article that can be used to prepare goods with pro-fibrotic coatings.The present invention also comprises the application of the goods with pro-fibrotic coatings, and is as described herein, is used for medical purpose.

The goods of coating can provide fast and the fibrosis of localization is replied according to the present invention, cause near the generation with fibrin clot of accumulating of the coagulation factors coated article.In some respects, pro-fibrotic coatings can be used for promoting the space to fill in the intravital zone of having sent coated article.Pro-fibrotic coatings can form on various medical articles.The medical article of this coating can be delivered to the body region that needs hemostatic function then.Aspect more of the present invention, for example form pro-fibrotic coatings on the surface of vessel sealing ring at vascular occluding device.

In another aspect of the present invention, pro-fibrotic coatings is to form having on the goods of porous surface.Useful especially implantable goods with porous surface comprise for example surgical patch of fabric.

Coating of the present invention is the fibrin clot at the machineization of formation, has at formation further and reduces the possible grumeleuse that thromboembolism enters blood flow.The grumeleuse relevant with coating surface can be brought into play the effect of hemostatic barrier, prevention or reduce at least body fluid for example blood move into or by the grumeleuse zone.

When uniting use with implantable medical article, pro-fibrotic coatings of the present invention provides numerous significant advantages.

An advantage relates to character and the durability that pro-fibrotic coatings improves.This coating can form on the surface of goods, and does not have or have only unconspicuous blemish.For example, the surface imaging of coating shows this coating not division or layering, so just can not cause having problems during use.Because pro-fibrotic coatings of the present invention forms well, they have in use shown the durability of improving, and therefore provide extra safety for the patient.

Another advantage relates to the ability of control coating thickness.This is useful especially for the less implantable goods that have complex geometric shapes or have a surface that is difficult to apply.In some respects, this coating can be less than 5 μ m, for example about 2-3 μ m.In yet another aspect, this coating can be thicker, for example greater than about 5 μ m.Fill function when the needs implementation space, when for example treating aneurysm, thicker coating is useful.

Another advantage relates to the lubricity on coated surface.Especially, pro-fibrotic coatings can improve the lubricity on the surface of coated goods.Therefore can promote goods coated in therapeutic process in conduit, to move and enter target position.With the goods of pro-fibrotic coatings coating, for example line, ring and string can be delivered to intravital target position, aneurysm for example, and have only lower frictional resistance.

The pro-fibrotic material also is designed on the surface of device and forms stable coating.When the intravital target position that this coating is sent, this coating is stable, is stable at least at first.In some cases, this coated substance can be that part biological is degradable at least, can be from surface erosion.

Aspect more of the present invention, can utilize photoreactive group, and allow pro-fibrotic polymer and medical article covalent bond, or become stable with combining of medical article.This provides the pro-fibrotic polymer of improvement and the coalition of medical article.Method for example is delivered to target position with the goods that apply will can not damage pro-fibrotic coatings significantly.

In some respects, pro-fibrotic coatings of the present invention comprises the pro-fibrotic agent, pro-fibrotic polymer for example, and it can be fixed in the surface of implantable medical device by using one or more potential reactive groups.Potential reactive group for example photoreactive group can side be hung on the pro-fibrotic polymer, do not rely on the pro-fibrotic polymer, or the both is.Photoreactive group can side be hung on the pro-fibrotic polymer and be activated and the pro-fibrotic polymer scale is incorporated into the surface of device, or one or more other components for example are present on the polymers compositions in the coating.

Some preferred aspect, photoreactive group comprises aryl ketones, for example 1-Phenylethanone., benzophenone, anthraquinone, anthrone and anthrone-sample heterocycle (promptly at 10 heterocyclic analogs), or (for example, cyclosubstituted) derivant of their replacements with anthrone of N, O or S.The example of preferred aryl groups ketone comprises the Hete rocyclic derivatives of anthrone, comprises acridone, xanthone and lucanthone, and their cyclosubstituted derivant.

Aspect more of the present invention, pro-fibrotic coatings comprises pro-fibrotic polymer, photoreactive group and polymerizable groups.Preferred polymerizable groups is that side is hung on polymer, pro-fibrotic polymer for example, or randomly, other are not the polymer of pro-fibrotic polymer.This polymer can have one or more polymerizable groups.For example, in some respects, polymerizable groups can be the vinylated unsaturated group that side is hung on the pro-fibrotic polymer.The activation of polymerizable groups can promote the radical polymerization of pro-fibrotic polymer and the formation that coating is gone up on the surface.Can pass through the activation light reactive group and initiated polymerization.

Polymerization with pro-fibrotic polymer of polymerizable groups can form the overlay of the pro-fibrotic polymer that is bonded to each other, if or in coating, comprise other polymerizable materials, the pro-fibrotic polymer is bonded to each other, and combines with other materials of existing in the coating.Aspect this, do not need the surface of device and the combination between the pro-fibrotic polymer.

The pro-fibrotic polymer can be based on natural polymer, for example collagen, perhaps synthetic polymer.

In another aspect of the present invention, pro-fibrotic coatings comprises pro-fibrotic cation type polymer and photoreactive group.When forming coating, can the activation light reactive group, make the pro-fibrotic cation type polymer be attached to the surface of goods.The pro-fibrotic cation type polymer can attract consumingly with promote coated surface on fibrin clot form relevant platelet and protein.

In another aspect of the present invention, pro-fibrotic coatings comprises non-pro-fibrotic polymer and the photoreactive group that derives from animal.The non-pro-fibrotic polypeptide that derives from animal can be to have the active peptide of collagen, for example synthetic collagen.

Aspect this, can realize the safety that the goods that apply improve, because these coatings do not rely on for example existence of bovine collagen of material that derives from animal, may be relevant and derive from the material of animal with the pollutant that derive from animal.Therefore, in these areas, use the non-pro-fibrotic material that derives from animal,, also greatly reduced the probability of in body, introducing the pollutant that derive from animal even without elimination.The use of pro-fibrotic coatings of the present invention can improve coating bulk property and concordance, because it has avoided using batch-batch differences that may have from the material of animal product.

In another aspect of the present invention, pro-fibrotic coatings comprises for example pro-fibrotic polymer of pro-fibrotic agent, and antithrombotic agent, and the both may reside in the coating.Be present in antithrombotic agent in the pro-fibrotic coatings and can regulate the fibrosis that causes by the pro-fibrotic agent and reply, and improve the character of coating.

Antithrombotic agent can be regulated the speed that fibrosis is replied, and makes near the suitable grumeleuse of formation coated articles.The existence of antithrombotic agent can not stop grumeleuse to form, but can regulate speed and the scope that grumeleuse forms, with the possible latent consequences of avoiding grumeleuse to form, for example embolus.

Therefore, in another aspect of the present invention, pro-fibrotic coatings comprises pro-fibrotic agent, antithrombotic agent and photoreactive group.In one aspect of the invention, the pro-fibrotic agent is the pro-fibrotic polymer.Can use various synthetic or natural pro-fibrotic polymer, for example collagens.

Photoreactive group can side be hung on the pro-fibrotic polymer or not rely on pro-fibrotic polymer and/or antithrombotic agent.In some respects, photoreactive group is present in the crosslink part that the pro-fibrotic polymer scale can be incorporated on the antithrombotic agent.

In some cases, when on the surface that pro-fibrotic agent and/or antithrombotic agent can be attached to device after the activation or another component when forming pro-fibrotic coatings, independently photoreactive group can be used as the coupling part.For example, the pro-fibrotic polymer for example collagen can comprise and reacted and the pro-fibrotic polymer scale is incorporated into the photoreactive group that the side on the antithrombotic agent is hung.

Aspect other, photoreactive group is present on the polymerization initiator, activates the formation of this initiator with the overlay that promotes one or more polymeric materials, and wherein polymeric material is pro-fibrotic polymer, antithrombotic agent or its combination.For example, coating can comprise by reactive polymerizable groups bonded comprise the pro-fibrotic polymer for example collagen the layer, by reactive polymerizable groups bonded comprise antithrombotic agent the layer or comprise bonded pro-fibrotic polymer and antithrombotic agent combination the layer.This coating also can comprise the combination of these layers.

In one aspect, this coating comprises, comprises the layer by the bonded PEG of reactive polymerizable groups and comprises layer by the bonded collagen of reactive polymerizable groups.

The present invention also pays close attention to the various methods that form pro-fibrotic coatings on medical article.This method comprises and will comprise the sedimentary step of first compositions of antithrombotic agent, will comprise the sedimentary step of second compositions of collagen and activation light reactive group to form the step of pro-fibrotic coatings.In the method, photoreactive group may reside in first coating composition, is present in second coating composition, does not rely on first and second coating compositions, or their combination.

The another kind of method that forms pro-fibrotic coatings on medical article comprises that deposition comprises the step of compositions of collagen and antithrombotic agent and activation light reactive group to form pro-fibrotic coatings.In the method, photoreactive group may reside in first coating composition, second coating composition, does not rely on first and second coating compositions, or their combination.

The another kind of method that forms pro-fibrotic coatings on medical article comprises that deposition comprises first compositions that antithrombotic forms polymer (comprising polymerizable groups), deposition comprises second compositions of collagen (comprising polymerizable groups) and activated polymerization initiator to form pro-fibrotic coatings.In these methods, polymerization initiator may reside in first coating composition, second coating composition, does not rely on first and second coating compositions, or their combination.

Can add material arbitrarily in pro-fibrotic coatings, the preferred polymerizable material of a class comprises the hydrophilic or the polymers capable of swelling of the polymerizable groups with side extension.The polymer of these types is useful in pro-fibrotic coatings, because they can provide the space filling property for coated device.These materials can be by acting on the repertoire of device, for example by improving sealing function or improving the character of goods by the ability of improving the closed body region of goods.

Therefore, in another aspect of the present invention, can form coating by the coating composition of the polymer that comprises swellable, pro-fibrotic polymer and photoreactive group.In some cases, swollen polymerization property can provide antithrombotic character, for example PEG.

Detailed Description Of The Invention

By all being incorporated herein with reference to all publications and patent that this paper is mentioned.Publication and patent that this paper discloses are only used for disclosing of they.But can not be interpreted as admitting not give the inventor, comprise all publications and/or the preceding right of patent that this paper quotes in all publications and/or patent.

Chemical compound of the present invention, compositions, method and apparatus can be used to promote reply with the pro-fibrotic of the goods of pro-fibrotic material coating of the present invention.Fibrosis is replied the formation that can promote the fibrin clot that links to each other with goods, and this fibrin clot can provide the space to fill function and be used to realize near the goods hemostasis or closure.

According to the present invention, pro-fibrotic coatings provides on the surface of medical article.This medical article can be to be incorporated into the goods that are used to prevent or treat medical disease in the mammal arbitrarily, wherein needs to promote the formation of the fibrin clot that links to each other with coated goods.These goods can be subcutaneous, percutaneous or introduce by operation, in the inner chamber that is placed in organ, tissue or organ, and for example tremulous pulse, vein, ventricle or atrium.Medical article with pro-fibrotic coatings can provide one or more functions, comprises as the body fluid barrier of blood flow for example.

Medical article with pro-fibrotic coatings also can have the goods of two or more " parts " (for example, can amalgamation together forming the assembly of the medical article of goods) by assembling and prepare, and wherein at least one part has pro-fibrotic coatings.The all or part of of medical article can have pro-fibrotic coatings.In this focus, the present invention also pays close attention to the part (for example, the goods that do not assemble fully) of the medical article with pro-fibrotic coatings.

Pro-fibrotic coatings can form on the surface of the goods that are intended to have hemostatic function, and the mobile barrier that provides of body fluid is provided.In many cases, need to form these artificial barriers, to guarantee to be intended to function at the intravital implantable goods of people.For example, in some cases, pro-fibrotic coatings promote to stop body fluid in vivo from a formation that flows to the barrier at another place.In some cases, provide a kind of prevention liquid to flow to a certain zone, for example bullate barrier of aneurysm in the body.

Promoted the formation of the fibrin clot that is connected with apparatus surface at pro-fibrotic coatings after, agglomerative zone generally becomes the body fluid impenetrability that flows.The impenetrability of when relating to the function in fibrin clot zone, using be meant the remarkable transmission that has reduced larger volume liquid or liquid by or enter coagulation region.For example, coagulation region can be the blood-transmitted impenetrability.

The pro-fibrotic polymer can be used to various extensively different goods that coating is provided." goods " used herein use with its most generalized implication, and the article that comprise for example are medical treatment devices.These goods can include but not limited to, blood vessel implant and graft, graft, operation device; Synthetic prosthese; The artificial blood vessel comprises built-in prothesis, stent graft and endovascular stent combination; Minor diameter graft, abdominal aortic aneurysm graft; Wound dressing and wound treatment device; Hemostatic barrier; Net and hernia thromboembolism; Sticking patch comprises metrorrhagia sticking patch, atrial septal defect (ASD) sticking patch, patent foramen ovale (PFO) sticking patch, ventricular septal defect (VSD) sticking patch and other general heart sticking patch; ASD, PFO and VSD closure; Percutaneous closing device, mitral valve repair device; The left auricle filter; The valvoplasty device; Conduit; Central vein visit conduit, blood vessel visit conduit; The pustule drainage catheter; Drug infusion catheter, parenteral feeding catheter, intravenous catheter (for example, treating), apoplexy treatment conduit, blood pressure and structural transplantation conduit with antithrombotic agent; Stapling apparatus and the closure that coincide; The aneurysm discharger; The biosensor that comprises glucose sensor; The birth control control device; The mammary gland implant; Cardiac sensor; The infection control device; Film; Organization bracket; With organize relevant material; Comprise shunting, the glaucoma guiding shunting of cerebrospinal fluid (CSF) shunting; Tooth apparatus and dental implant; Ear's device is ear drainage tubes, tympanostomy exhaustor for example; The eye device; The cover capsule part of cover capsule and device comprises that capsule is overlapped in medication infusion pipe box capsule, sheathed catheter capsule, the stitching of drain pipe box capsule, implantation; Spinal column and neurological apparatus; Nerve regeneration conduit; The neurological conduit; Neural sticking patch; Orthopedic device is the orthosis articulation implant for example, bone reparation/intensifying device, repair of cartilage device; Urology Surgery device and urethra device be Urology Surgery implant, bladder device, kidney device and haemodialysis equipment for example, the colostomy bag auxiliary equipment; The biliary drainage product.

In some embodiments, pro-fibrotic coatings is used for combining with closing device the arbitrary portion that is used for target region in the closed shape.Closing device comprises implantable medical treatment device, and the target region that it can be delivered to health is intended to have prevention body fluid and flows through or enter the function in the zone of delivery apparatus (for example, hemostatic function).With the formation of bonded thrombosis of closing device and grumeleuse generally be in order to reach hemostatic function.Can be by delivery apparatus to target region and allow pro-fibrotic coatings to promote fibrin clot to form to realize closure, therefore, the physics closure target region.Comprise that for vascular system tremulous pulse, vein, fistula and aneurysmal selectivity closure are useful especially owing to have the closed goods of pro-fibrotic coatings, the device after these coatings also can be used for other body cavity, for example fallopian tube, bile duct or the like.Pro-fibrotic coatings is for being useful especially with being inserted into that aneurysmal vascular occlusion ring, line or string combine.

In exemplary method, send have pro-fibrotic coatings the vascular occlusion ring in aneurysm.Pro-fibrotic coatings can promote fibrosis to reply, and causes accumulating fast of the interior grumeleuse component of aneurysm.Little by little and preferably, the grumeleuse obturation aneurysm, stoped the inflow of blood, therefore reduced the danger of aneurysm rupture basically.In some respects, the present invention relates to prepare and utilize the vascular occlusion ring with pro-fibrotic coatings, it can promote the formation that can not shift out fibrin clot from aneurysm of machineization in the aneurysm.

Vascular occluding device can comprise line, ring, braid and string, and it can have spiral wound configuration.Exemplary ring diameter generally is 2.2mm or littler, more particularly scope be 0.2mm to 2.2mm, can be by diameter 1.25mm or littler, for example to be 0.125mm constitute to the line of 1.25mm scope.This installs 0.5 to 100 centimetre typically of exemplary length range.

In some embodiments, for example form by platinum, gold or tungsten by metal for vascular occluding device, although also can use other metals, for example alloy of rhenium, palladium, rhodium, ruthenium, titanium, nickel and these metals, for example rustless steel, titanium/nickel and nitinol alloy.Preferred becket mainly comprises platinum.

In another embodiment, vascular occluding device comprises polymer strands, line or ring.Useful especially device comprises the polymer with hydrogel character.The useful polymer of the type device is comprised poly-(urethanes), poly-(acrylate), poly-(methacrylate), poly-(vinylpyrrolidone), cellulose acetate, ethylene-vinyl alcohol copolymer, poly-(acrylonitrile), poly-(vinyl acetate), cellulose acetate-butyrate, NC Nitroncellulose, the copolymer of urethanes/carbonic ester, copolymer or its mixture of styrene/maleic acid.

In some embodiments, the polymer string comprises hard hydrogel nucleus and is surrounded by soft hydrogel foam that this foam surrounds by the gel external coating.In other embodiments, ring or line comprise the polymer of soft biocompatibility, for example ePTFE, urethanes, polyolefin and nylon.

Pro-fibrotic material of the present invention can be deposited on the hydrogel surface of these devices, shines the coating that comprises the pro-fibrotic polymer with activation light reactive group and formation then.

The present invention also is provided at the method for preparing pro-fibrotic coatings on the porous surface of medical article.Pro-fibrotic polymer of the present invention can be deposited on the porous surface of medical article, forms pro-fibrotic coatings.This porous surface can be constituting by a kind of or similar or different biomaterials.The pro-fibrotic coatings compositions can prepare in the mode of filling the hole of this product surface with coated substance and/or use.This can pass through, and for example for example the viscosity and the activation photoreactive group that is used for combining with the pro-fibrotic polymer of apparatus surface of coating composition realize governing factor.

Goods with " porous surface " are meant to have any goods that contain the surface hole, that pro-fibrotic coatings can form thereon.The preferred physics size in these holes allows tissue ingrowth to enter in this hole.Porous surface can link to each other with non-hole surface, for example, and the support that can provide support to porous surface.

This medical article can comprise the non-hole surface of porous surface with pro-fibrotic coatings and pro-fibrotic coatings of no use coating, and non-hole surface also can be chosen wantonly with the pro-fibrotic coatings coating, or applies with the material that is different from pro-fibrotic coatings.The all or part of of porous surface can apply with pro-fibrotic coatings.

In many cases, the porous surface of goods is fabrics or has the character of fabric sample.Porous surface can be to be formed by the textile that comprises knit materials, braided material (knitted materials) and knitted material (braided materials).Useful especially textile material is the knit materials that can form with any suitable knit materials known in the art.

Porous surface can be the surface of graft, sheath, lid, sticking patch, cover, crust, sheath or the like.The goods of these types can performance medical article itself function, or be used for combine (its example will further hereinafter Oak Tree) with other parts of medical article.

For example, pro-fibrotic coatings can be used for that for example heart sticking patch, sheath and graft are connected with fabric.In these embodiments, pro-fibrotic coatings can be used to the bonded stanch fibre albumen of the goods grumeleuse that produces and apply.The goods of these coatings can be used to prevent and treat at blood in human body in liquid and flow to the position that coated articles is intended to play a role.

Porous surface can comprise arbitrarily the suitably biomaterial of type.Useful biomaterial can inweave in the fiber to prepare fabric as herein described.That useful material comprises synthetic addition or condensation polymer, for example polyester, polypropylene, polyethylene, polyurethanes and politef.Polyethylene terephthalate (PET) is a polymer commonly used in fabric.Be used to constitute the fiber of fabric in preparation, for example monofilament and many filament fibers, the time also can use these mixture of polymers.Fabric commonly used comprises, for example nylon, velvet and DACRON ^TM

This fabric is optional to comprise that hardened material to improve the physical property of goods, for example improves the intensity of graft.These materials can improve the function of implanting goods.For example strengthening material can improve the opening of graft.

Porous surface also can be realized by dipping axle in these polymer.

Surgical patch can use in many therapys to stop blood flow.Surgical patch with neoteric pro-fibrotic coatings as described herein can produce and the bonded fibrin clot of this sticking patch fast, has therefore improved hemostatic function.

The porous surface of other special concerns comprises the surface of heart sticking patch.It is hemorrhage that they can be used to reduce the stitching thread relevant with the cardiovascular reconstruction.This sticking patch can be used to penetrate the sealing around sewing up.The material that is usually used in the heart sticking patch comprises PTFE and DACRON ^TM

The thickness of the material that uses as porous surface can be selected according to purposes.But general thickness on average is about 1.0mm or littler, typically at about 0.10mm in the scope of 1.0mm.

The porous surface of other special concerns comprises graft, particularly has the graft of the outside of three-dimensional pattern.The example of three-dimensional pattern graft comprises the outside of the three-dimensional pattern with velvet, has those of three-dimensional pattern or smooth interior.The graft that is made of knitting textile is well known in the art, is described in following document: for example, U.S 4,047, and 252; U.S.5,178,630; U.S.5,282,848; And U.S.5,800,514,, they are incorporated herein with integral body by reference at this.

This medical article can be by the suitable arbitrarily biomaterial or the combination manufacturing of biomaterial.Preferred biomaterial comprises those that synthetic polymer forms, comprises the oligomer, homopolymer and the copolymer that are formed by addition or condensation polymerization effect.The example of suitable addition polymer includes but not limited to, esters of acrylic acid is for example by acrylic acid methyl ester., methyl methacrylate, hydroxyethyl methylacrylate, 2-(Acryloyloxy)ethanol, acrylic acid, methacrylic acid, acrylic acid glyceride, glyceral methacrylate, Methacrylamide and acrylamide; Vinyl is ethylene, propylene, vinyl chloride, vinyl acetate, vinylpyrrolidone, vinylidene difluoride for example.The example of condensation polymer includes but not limited to nylon-type, for example polycaprolactam, polylauryllactam, polyhexamethylene adipamide and polyhexamethylene dodecyl diamidogen, and polyurethanes, Merlon, polyamide, polysulfones, poly-(ethylene terephthalate), polylactic acid, polyglycolic acid, polydimethylsiloxane and polyether-ketone.

Pro-fibrotic used herein " coating " can comprise one or more " layers of coating ", and the layer of each coating comprises one or more coating materials.

In some cases, pro-fibrotic coatings is to be made of the monolayer material that comprises the pro-fibrotic polymer.In other situation, this coating comprises the overlay that one deck is above, and at least one overlay comprises the pro-fibrotic polymer.If there is more than one layer in pro-fibrotic coatings, these layers can be made of identical or different material.When overlay can comprise identical or different material, the overlay that comprises the pro-fibrotic polymer was made generally in implanting coated article and can be used for body fluid in body the time or after implanting.

When needs formed the coating that the space filling function that links to each other with goods is provided, it was useful especially having a plurality of overlays.The overlay physics of product surface occupies the space in the body region of the goods of accepting to have pro-fibrotic coatings.

The pro-fibrotic coatings material can deposit to and be fit to fixedly any surface of pro-fibrotic coatings material.In many aspects, the pro-fibrotic electrodeposition substance can with the surface of reaction-ity group reaction on.In other words, photoreactive group can form covalent bond with surface mass, therefore with pro-fibrotic coatings material and surface combination.

The all or part of surface of device can have intermediate layer or substrate overlay, can promote the fixing of pro-fibrotic material.This may also be referred to as " articulamentum " or " binder course ".Articulamentum can provide and can react with photoreactive group, and forms the material of covalent bond.Suitable substrate or inter coat comprise the material that can extract hydrogen.These also can comprise functional group for example reactive group or silylation.Polymer is the preferred substance that uses in the intermediate layer.

Aspect more of the present invention, medical article is metallic or the vascular occlusion ring or the line of metal-containing alloy, and it comprises the intermediate layer between pro-fibrotic coatings layer and containing metal line or ring and the pro-fibrotic layer.Combining between the intermediate layer can be used for the pro-fibrotic layer and encircle.For example, the intermediate layer can allow the pro-fibrotic polymer scale to be incorporated on line or the ring as the target spot of photoreactive groups.This intermediate layer can comprise can with polymer or other suitable chemical compounds of activatory photoreactive group reaction of the present invention.This polymer or other suitable chemical compounds can be the chemical compounds that comprises silane, maybe can have for example amino of reactive functional groups.

Aspect other, the vascular occlusion goods are cylindrical articles of polymer material of the present invention, and for example pro-fibrotic coatings can deposit polymer string thereon.The vascular occlusion goods can comprise the polymer material with hydrogel character.The photoreactive group that links to each other with coated substance can be activated and form pro-fibrotic coatings.For example, having the pro-fibrotic polymer of the photoreactive group that side hangs can be by photoreactive group and hydrogel surface covalent bond.

Usually, can carry out the part that coating process applies the whole of medical article or needs.Coating process can be direct expectation function based on goods.In some cases, needing only to produce pro-fibrotic on the part of goods replys.For example in the situation of vascular occlusion ring, line or string, need only to cover a part that is inserted into ring, line or string in the aneurysm.

The material that is used to form pro-fibrotic coatings can deposit on the surface with any suitable coating process.These methods include but not limited to, spray-painting, dipping, injection and grooming.The method for optimizing that applies the surface of medical article with chemical compound as herein described is a spray-painting.

Aspect more of the present invention, the pro-fibrotic polymer is a natural polymer, for example peptide or protein.Pro-fibrotic peptide or proteinic example include, but not limited to thrombin and collagen, for example people's recombinant collagen (FibroGen, South San Francisco, CA).Collagen peptide and modified collagen can be used to prepare pro-fibrotic coatings.This paper has also described the pro-fibrotic polypeptide of other concerns.

In one embodiment, pro-fibrotic coatings comprises the non-pro-fibrotic polypeptide that derives from animal." animal " used herein relates to inhuman animal, typically uses domestic animal, and the animal that comprises for example is cow (cattle), pig (pig) and chicken, typically extracts collagen from them.

Other useful pro-fibrotic agent can comprise platelet factor 1-4, platelet activating factor (acetyl glyceryl ether phosphoryl choline); P-selectin and vWF ELISA (vWF); Thromboplastin; Plasminogen activator initiator-1; Thromboxane; Thromboplastic thrombin-like enzyme comprises cerastotin and afaacytin; Phospholipase A ₂Ca ²⁺-dependency agglutinin (C-type agglutinin); In conjunction with glycoprotein receptor and induce the accumulative factor for example aggretin, rhodocytin, aggregoserpentin, triwaglerin and Equinatoxin; The glycoprotein ibalpha agonist comprises mamushigin and alboaggregin; The vWF interaction factor comprises botrocetin, bitiscetin, cerastotin and ecarin.

Other factors relevant with the grumeleuse cascade, comprise protein factor, (for example comprise coagulation factor I-XIII, Fibrinogen, haemoglutinin, factor III, calcium, labile factor proaccelerin (accelerator globulin), proconvertin (convertin), antihmemophilic globulin, Plasma Thromboplastin Component, Thrombokinase (autoprothrombin C), plasma throml oplastin antecedant (PTA), Hageman factor (HF) and fibrin stabilizing factor (FSF, fibrinase, protransglutaminase)).

In some respects, pro-fibrotic coatings comprises the pro-fibrotic cation type polymer.

This pro-fibrotic cation type polymer preferably has positive charge is enough to attract platelet and coagulation factors to arrive the polymer on applying device surface.This pro-fibrotic cation type polymer for example can comprise primary amine groups.Exemplary cationic polymer comprises glucosan and has the poly-imines of amido, for example deae dextran (divinyl aminoethyl glucosan) and polymine (PEI).Preferred synthetic pro-fibrotic cation type polymer is a polymine.The exemplary cationic polymer from natural comprises chitin and chitosan (D-acetylation chitin).

This pro-fibrotic cation type polymer can be homopolymer or homopolymer.This pro-fibrotic coatings can comprise the mixture of the different cationic polymers that can promote that fibrosis is replied.

Other suitable pro-fibrotic cation type polymers comprise positively charged group for example trivalent or quadrivalent cation group.The example of suitable trivalent or quadrivalent cation group comprises quaternary ammonium, tetravalence  and trivalent sulfonium group.These polymer can prepare by different technologies.Have primary, secondary, tertiary amine or its combination of polymers can tetravalenceizations, to produce charged quaternary amine on polymer.Can be by alkyl halide with successfully alkylation of amine, to provide quaternary amine by the Menshutkin reaction.

Can use various schemes to prepare to have the pro-fibrotic cation type polymer of the photoreactive group that side hangs.For example, can be by polymer and the deutero-photoreactive group reaction of benzyl halogen with tertiary amine, the pro-fibrotic cation type polymer that has the photoreactive group of side extension by synthetic preparation.This reaction allows photoreactive group to be attached on the polymer, simultaneously tertiary amine groups is transformed into charged quaternary amine base.

Also can be by monomer with photoreactive group and monomer copolymerization, by the synthetic pro-fibrotic cation type polymer for preparing photoreactive group with side extension with cation group.In some embodiments, can use individual monomer to prepare the pro-fibrotic cation type polymer with photoreactive group and cation group.Randomly, in copolyreaction, can comprise other monomers.This paper has exemplified the method for preparing the pro-fibrotic cation type polymer.

Alternately, or in addition, can the activation light reactive group and the pro-fibrotic cation type polymer is covalently bound to other pro-fibrotic cation type polymers, if in coating composition, there is another component, perhaps can be covalently bound on this another component.Usually, this approach can be used to promote to comprise the formation of the overlay of pro-fibrotic cation type polymer on the surface of goods.

Generally need use size to be fit to form coating and to produce the pro-fibrotic polymer that fibrosis is replied.Aspect more of the present invention, this coating comprises that mean molecule quantity (Mw) is at least about 2 * 10 ³Da is preferably about 2 * 10 ³Da to 2 * 10 ⁶Pro-fibrotic cation type polymer in the Da scope.

Aspect more of the present invention, the pro-fibrotic polymer has the photoreactive group that one or more sides are hung.The photoreactive group that side is hung can be located along the length of pro-fibrotic polymer, at one or two end of polymer, or on both.Photoreactive group can provide the generation of pro-fibrotic coatings at product surface in this arrangement of pro-fibrotic polymer.

Photoreactive group comprises the reactive moieties that one or more outer energy to specific use (for example irradiation) are replied, to produce active substance, for example nitrence, Cabbeen and excited state ketone of active substance for example, thus with contiguous target chemistry structure covalent bond.The example of these photoreactive group such as U.S.5,002,582 is described.Can the selective light reactive group with the different piece of faradism magnetic spectrum, the ultraviolet of electromagnetic spectrum, visible light or infrared ray part typically." irradiation " is meant and uses electromagnetic radiation from the teeth outwards.

Can be from the pro-fibrotic polymer one type of the preferred light reactive group hung of side be the photoreactivity aryl ketones.The example of photoreactivity aryl ketones includes but not limited to, 1-Phenylethanone., benzophenone, anthraquinone, anthrone and anthrone-sample heterocycle (promptly at 10 heterocyclic analogs with anthrone of N, O or S), or (for example, cyclosubstituted) derivant of their replacements.The example of preferred aryl groups ketone comprises the Hete rocyclic derivatives of anthrone, comprises acridone, xanthone and lucanthone, and their cyclosubstituted derivants.

Other suitable photoreactive group comprise the nitrine class, for example, and aryl azide (C ₆R ₅N ₃) for example aziminobenzene, particularly 4-fluoro-3-nitrobenzophenone nitrine, acyl azide (CO-N ₃) for example nitrine formic acid ethyl azide, nitrine formic acid azidomethyl phenyl nitrogenize thing, sulfonyl nitrine (SO ₂-N ₃) for example benzenesulfonyl nitrine and phosphoryl nitrine (RO) ₂PON ₃For example diphenyl phosphoryl azide and diethyl phosphoryl azide.

Other suitable photoreactive group comprise diazonium compound, for example, and diazoparaffins (CHN ₂) for example Azimethylene. and diphenyl diazomethane, diazo-ketones (CO-CHN ₂) for example diazobenzene ethyl ketone and 1-Trifluoromethyl-1-diazonium-pentanone, diazo acid ester (O-CO-CHN ₂) for example tert-butyl group diazo acid ester and phenyl diazo acid ester, and β-ketone-α diazo acid ester (CO-CN ₂-CO-O-) 3-trifluoromethyl-3-phenyl diazirine for example, and ketenes (CH=C=O) for example ketenes and hexichol ketenes.

Exemplary photoreactive group is as shown in table 1 below.

Photoreactive group	The key that forms
		Aryl azide	Amine
Acid azide	Amide
		Azido-ester	Carbamate
The sulfonyl nitrine	Sulfonamide
		The phosphoryl nitrine	Phosphamide
Diazoparaffins	New C-C key
		Diazo-ketones	New C-C key and ketone
Diazo acid ester	New C-C key and ester
		β-ketone-α diazo acid ester	New C-C key and 'beta '-ketoester
The aliphatic azo	New C-C key
		Diazirines	New C-C key
Ketenes	New C-C key
		Photoreactivity ketone	New C-C key and alcohol

In some embodiments, photoreactive group does not rely on the pro-fibrotic polymer.For example the photoreactive group of dependent/non-dependent can be the part of photoreactivity cross-linking compounds.When being activated, the photoreactive group of photoreactivity cross-linking compounds can be incorporated into the pro-fibrotic polymer scale surface of device, another component of coating composition, or the layer of another coating, to form pro-fibrotic coatings.Suitable photoreactivity cross-linking agent has two or more photoreactive group.The photoreactivity cross-linking agent can have identical or different photoreactive group.Exemplary photoreactivity cross-linking agent is described among 414,075 (people such as Swan) and U.S. publication number 2003/0165613 A1 (people such as Chappa) at the applicant's U.S.5.Also can be referring to U.S.5,714,360 (people such as Swan) and 5,637,460 (people such as Swan).

On the other hand, the chemical compound that comprises photoreactive group for example, to promote to have the reagent of polymerizable groups, for example has the polymerization of the pro-fibrotic polymer of polymerizable groups as photoinitiator.

In another embodiment of the invention, pro-fibrotic coatings comprises pro-fibrotic polymer, photoreactive group and polymerizable groups.In some cases, polymerizable groups is that side is hung on the pro-fibrotic polymer.For example, the pro-fibrotic polymer for example collagen can be modified and have one or more polymerizable groups.In other situation, polymerizable groups is present in the chemical compound that is not the pro-fibrotic polymer.In some preferred embodiments, the polymerizable groups side is hung on other polymer, polymeric antithrombotic agent for example as herein described or hydrophilic polymer.

Polymerizable groups can be the unsaturated group of vinylation, is selected from vinyl, acrylic, methacrylic acid group, ethyl propylene acidic group, 2-phenylacrylic acid base, acrylamido, methacryl amido, methylene-succinic acid base and styryl.

Under polymerizable material was present in situation in the pro-fibrotic coatings compositions, photoreactive group can promote the generation of Raolical polymerizable, caused shape to give birth to the overlay of polymeric material.Other reagent that promote polymer layer to form may reside in the said composition.They can comprise, for example can improve the polymerization accelerant that polymerization is renderd a service.The example of useful promoter comprises the N-vinyl compound, particularly N-vinylpyrrolidone and N-ethylene caprolactam.Based on the volume of coating composition, the operable concentration of these promoter is for example about 0.01% to about 5%, and preferred about 0.05% to about 0.5% weight.

In another aspect of the present invention, pro-fibrotic coatings comprises the pro-fibrotic agent, for example pro-fibrotic polymer and antithrombotic agent, and the both may reside in the coating.

The bonded pro-fibrotic agent of coating on use and the goods and the combination of antithrombotic agent can be regulated speed and the scope that grumeleuse forms by different approach.For example, can or be blended in the single layer of coating, perhaps can combine with coating independently of one another, for example in isolating layer pro-fibrotic polymer and antithrombotic agent dispersion.The mode of the surface engagement of pro-fibrotic polymer and antithrombotic agent and coating can depend on selected particular polymers and reagent, and the surface nature of this medical article (for example, material, porosity and configuration).

In some cases, pro-fibrotic polymer and antithrombotic agent may be incorporated in the coating composition, and are deposited on the medical article.In coating composition, for example can there be the pro-fibrotic agent and the antithrombotic agent of accurate amount, be used for realizing the suitable speed of grumeleuse formation and the coating of scope to produce design.In other cases, the ratio of pro-fibrotic agent and antithrombotic agent be can set, the suitable speed of grumeleuse formation and the coating of scope are used for realizing to produce design.Give this instruction, those skilled in the art can select arbitrary or more pro-fibrotic agent and arbitrary or more antithrombotic agent, so that required effect to be provided.

In one aspect of the invention, have been found that comprise about 10% or the coated composition of more substantial antithrombotic agent special pro-fibrotic coatings is provided.For example antithrombotic agent can be to have polymerizable groups, for example material of PEG macromonomer.

In other situations, the pro-fibrotic agent can combine with coating, and its mode is to contact with the pro-fibrotic agent with allowing blood constitutent before antithrombotic agent contacts in blood constitutent.For example, can prepare the coating that has the layer that comprises the pro-fibrotic agent and comprise the layer of antithrombotic agent, contiguous comprising the layer of antithrombotic agent with the surface of coated articles.Exemplary coating comprises first overlay with PEG that is adjacent to the surface and second overlay that contains collagen.

In some embodiments, pro-fibrotic coatings comprises pro-fibrotic agent, antithrombotic agent, photoreactive group and polymerizable groups.In some cases, polymerizable groups side from the pro-fibrotic polymer is hung.For example, can modify the pro-fibrotic polymer to have one or more polymerizable groups.In other cases, polymerizable groups side from antithrombotic agent is hung.In other cases, polymerizable groups is present on the chemical compound that is not the pro-fibrotic polymer.In some preferred embodiments, polymerizable groups is from other polymer, and side is hung in the hydrophilic polymer for example as herein described.It is contemplated that also coating composition can comprise the two or more different chemical compounds with polymerizable groups, for example polymer.

In certain aspects, this coating comprises pro-fibrotic agent and antithrombotic agent, and wherein antithrombotic agent comprises the photoreactive group that side is hung.Can following formation coating: comprise the compositions of pro-fibrotic agent and antithrombotic agent by deposition from the teeth outwards, handle the photoreactive group that this surface hangs from the antithrombotic agent side with activation then, form coating.For example, the antithrombotic agent with photoreactive group that side hangs can be selected from the derivative heparin of light and the derivative hyaluronic acid of light, the derivative ethene polymers from lysine, the derivative PEG of light and the derivative fatty acid of light of light.

Antithrombotic agent can be regulated the speed that fibrosis is replied, to form suitable grumeleuse on the surface of coated articles.

A kind of preferred antithrombotic agent is Polyethylene Glycol (PEG).The surface that covers with Polyethylene Glycol demonstrates biocompatibility, repels because the character of PEG has obtained non-immunogenic, nonantigenic and protein.

Can PEG be fixed on the coating with photoreactive group.In some respects, use PEG to form coating with polymerizable groups.Can comprise that the coating composition of acetylizad PEG and the combination that polymerization initiator for example has the polymerization initiator of photoreactive group form the overlay that comprises PEG by deposition.

Other example of antithrombotic agent comprises heparin, heparin derivatives, heparin sodium, low molecular weight heparin, hirudin, lysine, prostaglandin, argatroban, Forskolin, vapiprost, prostacyclin and prostacyclin analogs, D-ph-pr-arg-chloromethyl ketone (synthetic antithrombase), dipyridamole, glycoprotein iib/iiia platelet membrane receptor antibody, be total to protein I Ib/IIa platelet membrane receptor antibody, lepirudin 023 ludon, thrombin inhibitor (for example from Biogen commercial distribution), chondroitin sulfate, modified glucan, albumin, streptokinase, the former activator of tissue plasminogen (TPA), urokinase, nitrous oxide inhibitor or the like.Antithrombotic agent can be the inhibitor of GPIIb-IIIa platelet receptor complex also, and it has mediated platelet aggregation.The GPIIb/IIIa inhibitor can comprise monoclonal antibody Fab fragment c7E3, is also referred to as abciximab (ReoPro ^TM) and synthetic peptide or intend for example eptifibatide (Integrilm of peptide ^TM) or tirofiban (Agrastat ^TM).

Randomly, different with pro-fibrotic agent or antithrombotic agent polymer or chemical compounds can be included in the pro-fibrotic coatings.Can select this polymer or chemical compound to change or improve the character of the pro-fibrotic coatings that forms by pro-fibrotic agent and antithrombotic agent.For example, this polymer or chemical compound can change elasticity, flexibility, wettability or the adhesion properties (or its combination) of the coating that forms from the teeth outwards.

Use the technology that pro-fibrotic agent and antithrombotic form the coating of material and comprise, for example flood, spraying, grooming or the like.According to description of the invention, those skilled in the art can estimate the adaptability of the polymer composition that uses with the specific medical goods, the adaptability of the application technology that reaches.

This pro-fibrotic polymer can disperse or fusion forming the pro-fibrotic coatings useful reagent with other.These can comprise other non-fibrosis or non-antithrombotic polymeric material.

Randomly, different with the pro-fibrotic agent polymer or chemical compounds can be included in the pro-fibrotic coatings.Can select this polymer or chemical compound to change or improve character by the pro-fibrotic coatings of pro-fibrotic polymer formation.For example, this polymer or chemical compound can change elasticity, flexibility, wettability or the adhesion properties (or its combination) of the coating that forms from the teeth outwards.

In some respects, the polymer of hydrophilic or swellable can be included in the coating that comprises the pro-fibrotic polymer.The polymer of these types is useful in pro-fibrotic coatings, because they can provide the space filling property for the device of coating.These materials also can be by acting on the repertoire of device, for example by improving closure function or improving the character of goods by the ability of improving goods obturator inner region.

The polymer of hydrophilic or swellable can comprise the polymerizable groups that side is hung, and can comprise the pro-fibrotic polymer in formation and maybe can be from the pro-fibrotic polymer use in the method for isolating overlay.

For example, comprise that the compositions of the polymer of hydrophilic or swellable has the polymerizable groups and the polymerization initiator that can be deposited on apparatus surface of side extension.The overlay that comprises the polymer of hydrophilic or swellable can form by the beginning polymerization of polymer.The compositions that comprises the pro-fibrotic polymer subsequently can deposit from the teeth outwards.This pro-fibrotic polymer also can comprise polymerizable groups.Initiated polymerization that can be by the pro-fibrotic polymer forms the overlay that comprises the pro-fibrotic polymer comprising on the layer of hydrophilic or polymers capable of swelling.

The polymer of useful especially hydrophilic or swellable comprise poly-(vinylpyrrolidone) (PVP), poly-(ethylene glycol) (PEG), poly-(oxirane), poly-(ethyoxyl azoles quinoline), poly-(expoxy propane), polyacrylamide (PAA), poly-(vinyl alcohol) (PVA), its copolymer or the like.One or more polymerizable groups can side be hung from the polymer of swellable.Also can use the mixture of polymers capable of swelling.

In some respects, the polymer of hydrophilic or swellable, for example PEG can have antithrombotic formation character.

The polymer that it can be used for mixing to pro-fibrotic coatings the swellable of the polymerizable groups with side extension, the polymers capable of swelling that also can use the polymerizable groups that does not have the side extension is with shape layer coating.Therefore, in another aspect of the present invention, can form coating by the coating composition that comprises polymers capable of swelling, pro-fibrotic polymer and photoreactive group.

Be used for the polymer-coated application technology of pro-fibrotic and comprise, for example flood, spraying, grooming or the like.

Formation has the coating of desired thickness, comprises deposited coatings material from the teeth outwards, handles this deposited material and forms overlay with the activation light reactive group, and repeated deposition and treatment step have the coating of a plurality of overlays with formation then.Also can comprise drying steps in the method.

Aspect more of the present invention, need provide a kind of and have the coating of filling function in the space and produce the surface that fibrosis is replied.For example, in the time need sealing a certain zone of health with goods, can form pro-fibrotic coatings on goods, this coating can increase the size of goods and the surface that can attract grumeleuse-formation component is provided.In some embodiments, the thickness of pro-fibrotic coatings is 10 microns or bigger in other embodiments greater than 5 microns.

In some embodiments, pro-fibrotic coatings of the present invention can comprise that one or more can strengthen the bioactivator of pro-fibrotic function of surface.Can comprise with the bioactivator of being paid close attention to that the pro-fibrotic combination with polymers is used, for example cell response regulator, microtubule inhibitor, remodeling inhibitor, statins, steroid and vasodilation.Can be resorbent if pro-fibrotic coatings is a biology, this bioactivator can discharge along with the degraded of pro-fibrotic material coating.

The present invention will be by further describing with reference to following non-limiting example.Those skilled in the art can make a lot of changes and not depart from the scope of the present invention apparently in described embodiment.Therefore, scope of the present invention is not limited to described in this application embodiment, and comprises the embodiment of the language description by claim and the equivalents of these embodiments.Except as otherwise noted, all percentage ratios are weight ratios.

Embodiment 1

The preparation of PEI-BBA

Preparation has the derivative polymer of light of the amino of side extension.

With polyaziridine (PEI; The 24.2wt.% solid; 2000kg/mol Mw; BASF Corp.) vacuum drying, and the PEI of 1.09g is dissolved in 90: 10 (v/v) chloroforms of 19ml: in the methanol solution.Then this PEI solution is cooled to 0 ℃ in ice bath.The BBA-Cl (4-benzoyl Benzenecarbonyl chloride .) that adds 62mg in the 2.8mL chloroform is with its dissolving.Stir then down the BBA-Cl chloroformic solution is joined refrigerative PEI chloroform: in the methanol solution.To react to stir and spend the night, and progressively be heated to room temperature.(thin layer chromatography (TLC) does not have unreacted BBA-Cl in the mixture after analyzing and being presented at 2.5 hours).Then reaction solution is transferred in the big flask, added 1 normal concentrated hydrochloric acid and 77.5mL deionized water.Remove organic solvent in 40 ℃ of following vacuum, become clarification until PEI aqueous solution outward appearance.The PEI solution dilution being become ultimate density then is 10mg/mL, uses as coating solution.

Embodiment 2

The preparation of light-space-PEI

Stir down, will be at (the 436.5g/mole of the BBA-EAC-NOS among the 3.0ml DMSO (dimethyl sulfoxine); 110mg; 0.253mmole; According to U.S.6,121,027 embodiment 2 preparations; By with reference to being introduced into this paper) join PEI (2,000,000g/mole; 1.0g; 5 * 10 ⁴Mole) 19ml CHCl ₃/ CH ₃In OH (90/10) cooling solution.Stir down solution is heated to ambient temperature overnight.The solution that will comprise the BBA-EAC-NOS-PEI product then places 75ml H ₂O and HCl (12M; 1.9ml: in mixture 23mmole).Mixture is placed on the rotary evaporator to remove organic solvent then.Last this solution of dilute with water obtains the BBA-EAC-PEL of 10mg/ml.

Embodiment 3

Synthesizing of APTAC-polyaziridine (APTAC-PEI) polymer

Combine with the polyaziridine polymer with the quaternary ammonium group of following method chlorination (acrylic aminopropyl) trimethyl-ammonium form: get 5g polyaziridine (10,000Mw; Polysciences, Warrington PA) is dissolved in the deionized water of 10ml, obtains 50%PEI solution.75% chlorination (the 3-acrylic aminopropyl) trimethyl-ammonium salt solution (APTAC that in 50%PEI solution, adds 16g; Simga-Aldrich Corp., St.Louis, MO).Mixture vibration under 55 ℃ of PEI and APTAC is spent the night.Resulting product is heavy-gravity, amber solution, will be stored under its room temperature in the bottle of sealing.

By NMR (nuclear magnetic resonance, NMR) the monitoring vinyl proton of APTAC molecule in the employed isocyatic small-scale reaction in preparation APTAC-PEI, shown that at room temperature 16 hours internal reactions have finished 99%.

Use the APTAC of aforesaid 2.4: 1 w/w ratios and PEI (12g APTAC and 5g PEI (10,000Da)), PEI polymer when evaluation thinks that the Mw of final APTAC-PEI is than beginning (10,000Da) high about 3.4 times (34,000Da).

Embodiment 4

Synthesizing of APTAC-EITC-polyaziridine (BBA-EITC-PEI) polymer

Will be as embodiment 3 synthetic APTAC-PEI polymer vacuum dryings, and be dissolved in 90: 10 (v/v) chloroforms: in the methanol solution.Then this APTAC-PEI solution is cooled to 0 ℃ in ice bath.Then BBA-Cl (4-benzoyl Benzenecarbonyl chloride .) is dissolved in the chloroform, and under agitation joins refrigerative APTAC-PEI chloroform: in the methanol solution.To react to stir and spend the night, and progressively be heated to room temperature.Then reaction solution is transferred in the big flask, added 1 normal concentrated hydrochloric acid and deionized water.Remove organic solvent in 40 ℃ of following vacuum, become clarification until BBA-APTAC-PEI aqueous solution outward appearance.

Embodiment 5

The preparation of the APTAC-PEI polymer of different molecular weight

From Polysciences, Warrington, PA obtain the PEI polymer that Mws is 750,000 (750K) Da, 10,000 (10K) Da, 2,000 (2K) Da and 800Da.In order to prepare the PEI that combines 50% APTAC, use the APTAC and PEI of 2.4: 1 w/w ratios with PEI polymer of different molecular weight size.In order to prepare the PEI that combines 20%APTAC, use the APTAC and PEI of 0.96: 1 w/w ratio with PEI polymer of different molecular weight size.In each preparation, use reagent and the response time of describing in detail as embodiment 3.

Use has the APTAC-PEI polymer that appointment is big or small and have the BBA photoreactive group of side extension based on the synthetic schemes preparation of embodiment 4.

Embodiment 6

Trimethylolpropane ethoxylate (20/3 EO/OH) triacrylate macromonomer

Preparation (Compound I)

Following synthetic macromonomer (at the synthetic schemes of present embodiment ending expression) based on PEG.

Stir down, with trimethylolpropane ethoxylate (PEG-triol; 100.0g, 98.6mmoles; Average Mw about 1.104; Cat.No.41,617-7; Aldrich ChemicalCompany, Inc., Milwaukee WI) is dissolved in the toluene of 200ml and refluxed 1 hour.PEG-three alcoholic solutions are cooled to about 80 ℃.At this moment, stir the 4-methoxyphenol (MEHQ that adds 50mg (0.403mmoles) in the downhill reaction solution; J.T.Baker, Phillipsburg, NJ), the acrylic acid of 42.7g (0.592moles) (J.T.Baker, Phillipsburg, NJ) and the sulphuric acid of 10ml (0.188moles) (Aldrich ChemicalCompany, Inc., Milwaukee, W1).Reaction solution is heated to backflow.React then, until the water that produces about 6.0ml, and by Dean ﹠amp; The Stark accepter is collected (about 1 hour).Reactant mixture is cooled to 50 ℃, and pours in the sodium bicarbonate solution (270g is at the deionized water of 2.5L) under stirring.Separate organic layer, use deionized water wash, and dry on sodium sulfate.Film distillator (Pope Scientific, Inc., Saukville, WI) separation PEG-triacrylate with wiping.

PEG-triacrylate macromonomer product is represented by Compound I.

The 34th page

Embodiment 7

Light-collagen preparation

Be prepared as follows the deutero-IV-Collagen Type VI of photoreactivity (light-collagen).People's Placenta Hominis IV-Collagen Type VI is from Sigma Chemical Co., St.Louis, Mo.Synthetic different basic bi-functional cross-linking agent (BBA-EAC-NOS) also is used for light derivatization collagen.

BBA-EAC-NOS comprise benzophenone photoreactive group (BBA), at interval base (EAC) and amine reactivity heat chemistry conjugated group (N-oxygen butanimide, NOS).By 4-benzoyl Benzenecarbonyl chloride. and the synthetic BBA-EAC of 6-lpsilon.Activate the carboxyl of esterification BBA-EAC to obtain BBA-EAC-NOS by carbodiimide then, synthesized the NOS ester of BBA-EAC with N-hydroxy-succinamide.

On protein, come light derivatization IV-Collagen Type VI through the NOS of BBA-EAC ester covalent bond primary amine.Collagen in every mole is the ratio adding BBA-EAC-NOS of 10-15moles BBA-EAC-NOS.

Embodiment 8

4,5-two (4-benzoyloxy phenyl methylene oxygen) benzene-1,3-disulfonic acid disodium salt [DBDS]

Synthetic

Be prepared as follows 4,5-two (4-benzoyloxy phenyl methylene oxygen) benzene-1,3-disulfonic acid disodium salt [DBDS].With a certain amount of (9.0g, 0.027moles) 4,5-dihydroxy 1,3-benzenedisulfonic acid disodium salt monohydrate join in the 250ml three neck round-bottomed flasks that overhead, air inlet and reflux condenser are housed.Add a certain amount of (15g, 4-bromomethyl benzophenone (BMBP) 0.054moles), the oxolane (THF) of 54ml and the deionized water of 42ml then.In the argon atmosphere, stirring down, this flask of heating extremely refluxes.In the All Time that refluxes, all keep the argon atmosphere.

After realizing backflow, add 9.0ml (6N, sodium hydroxide solution 0.054moles) by reflux condenser.Stirring reaction is 3 hours under refluxing.Then, add the BMBP of second portion, 3.76g (0.014moles) and 3.6ml (6N, sodium hydroxide 0.022moles).After adding BMBP for the second time, reflux and continue reaction 12 hours down.

On rotary evaporator,, obtain the yellow paste of 46g at 40 ℃ of following vacuum evaporation reactant mixtures.Extract paste 3 times by in the chloroform at 50ml under 40 ℃, suspending in 30 minutes.Use centrifuge to come decant chloroform from solid.Extract the back the last time and on buchner funnel, collect solid, and air-dry 30 minutes.Use rotary evaporator to bathe under the pressure of relaxing the bowels with purgatives of warm nature at about 1mm this solid of drying 30 minutes then at 50 ℃.

Recrystallize drying solid from the methanol of the water of 67ml and 67ml, 26.8g.Dried purified product amount is 10.4g (theoretical yield is 19.0g), is 1.62 at 265nm place absorbance when concentration is 0.036mg/ml.

Also can be referring to U.S.6,278,018.

Embodiment 9

Four (4-benzoyl benzylic ether) [" four-BBE-PET "] of tetramethylolmethane are synthetic

In the argon atmosphere, following material was refluxed 34 hours: tetramethylolmethane [Aldrich] (2.0g; 14.71mmole, 60 ℃ and＜the following drying 1 hour of 1mmHg); 4-bromomethyl benzophenone (20.0g; 72.7mmole; Free radical bromation preparation by 4-methyldiphenyl ketone [Aldrich]); 80% (w/w) sodium hydride (NaH, 1.23g in liquid Paraffin [Aldrich]; 41.0mmole); And oxolane (THF, 120ml).

In reactant mixture, add the 80%NaH (2.95g of amount in addition then; 98.3mmole), under argon, mixture was refluxed 7 hours again.By adding glacial acetic acid (HOAc) the quencher reaction of 8ml.The reactant of centrifugal this quencher is to remove insoluble THF.

Decant liquid is 50ml chloroform (CHCl with three parts every part ₃) the washing insoluble matter.The liquid (mainly being THF) and the CHCl that merge decant ₃Washing liquid is also evaporated, and obtains the semi-solid residue of rough yellow of 18.7g.By flash chromatography, use 40mm (1.58 inches) diameter to take advantage of the long silicagel column of 200mm (8 inches), use CHCl ₃And ether (Et ₂O) eluting, according to the thick products of following table 2 purification parts (2g) (except as otherwise noted, all proportions is v/v in the table):

Table 2.

Solvent (v/v)	Solvent volume (ml)	Heat up in a steamer branch
			CHCl 3-100	500	01-22
CHCl 3/Et 2O-98/2	500	23-46
			CHCl 3/Et 2O-95/5	1000	47-93
CHCl 3/Et 2O-90/10	500	94-118

By merging and evaporated fraction 81-105 (expects that the thick product of 2.0g on placing post obtains 1.43g four-BBE-PET) and obtains faint yellow oily product (0.843g in theory; 59% theoretical yield).Pass through the light yellow product of analysis confirmation purification with Beckman Acculab 2 infrared spectrometers and Varian FT-80 NMR spectroscope.Disappearance at peak, 3500cm-1 place shows there is not hydroxy functional group.Nuclear magnetic resonance spectroscopy ( ¹H NMR (CDCl ₃)) be consistent with the product of expectation; Aliphatic methylene δ 3.6 (s, 8H), benzylic methylene δ 4.5 (s, 8H) and aromatic series δ 7.15-7.65 (m, 36H) with the tetramethylsilane internal standard substance.

Four (4-benzoyl benzylic ethers) (four-BBE-PET) of products known as tetramethylolmethane.

Embodiment 10

The PEG-collagenic coating

Followingly at first use non-polymeric initiator pretreatment ePTFE substrate.The concentration of preparation in IPA is the coating solution of four-BBE-PET (as embodiment 9 preparations) of 0.5% v/v.Then the ePTFE substrate is immersed in the coating solution of four-BBE-PET irradiation solution 3 minutes.3 minutes irradiation is carried out in centre position between 2 relative ELC-4000 lamps, and this lamp includes the 400 wattage metal halides/mercuryvapour bulb at the interval of 91cm (36 inches).Washing with after removing unconjugated four-BBE-PET dry substrate with IPA.Resulting substrate comprises the startup coating of four-BBE-PET.

After drying, with being impregnated in the aqueous solution (concentration of PEG-triacrylate macromonomer is about 10-20% v/v, and four-BBE-PET is about 0.5-2% v/v) that comprises PEG-triacrylate macromonomer and four-BBE-PET of starting with exsiccant substrate.Speed with 0.2 to 1.0cm/s reclaims substrate.The irradiation of wet method or dry method applies part 3 to 5 minutes (as mentioned above) again.

Flood this substrate then, reclaim from the IPA solution that comprises light-collagen (as preparation as described in the embodiment 7) with 0.2 to 1.0cm/s speed subsequently.The concentration of biocompatibility reagent is about 5-20% v/v.The irradiation of wet method or dry method applies part 3 to 5 minutes (as mentioned above) again.

Embodiment 11

EPTFE substrate with the coating of PEG-collagen

Preparation comprises the coating solution of the isopropyl alcohol (IPA) of polymeric stroma ground substance and initiator, and the following ePTFE substrate that is applied to.The sample condition of using in this experiment is summarized in the table 3.The coating solution compositions volume % of PEG-triacrylate macromonomer, the mg/ml of four-BBE-PET represents.The coating solution of all samples all is PEG-triacrylate macromonomer and the four-BBE-PET in IPA.The length of dip time is that substrate is immersed in the time in the coating solution, and the UV processing time is coating is attached to the time on the substrate with the rayed substrate.

Table 3

Sample number	Coating solution (PEG-triacrylate macromonomer/four-BBE-PET)	Dip time (minute)	The UV processing time
				1	10％ v/v/0.5mg/ml	10	3
2	10％ v/v/0.5mg/ml	10	5
				3	10％ v/v/0.5mg/ml	20	3
4	10％ v/v/0.5mg/ml	20	5
				5	15％ v/v/0.5mg/ml	10	3
6	15％ v/v/0.5mg/ml	10	5
				7	15％ v/v/0.5mg/ml	20	3
8	15％ v/v/0.5mg/ml	20	5

The ePTFE substrate is impregnated in the coating solution, in the UV chamber, comes the wet method irradiation to specify the long processing time then by the centre position between 2 relative ELC-4000 lamps that substrate placed the 400 wattage metal halides/mercuryvapour bulb that comprises interval 91cm (36 inches) distance.The ePTFE substrate reaches capacity in the IPA coating solution, to attempt to overcome the hydrophobic property of this material, being attached on the surface based on the hydrophobic coating of PEG.

The derivative biocompatibility reagent of light combines as follows with substrate.In 12mM HCl, obtain concentration and be light-collagen of 0.2mg/ml as preparation as described in the embodiment 7.Substrate is immersed in light-collagen solution, preserved 1 hour in solution under 4 ℃, (illumination system is purchased from DymaxCorporation each face, and Torrington CT) shone insoluble matter 60 seconds with Dymax Blue Wave Spot Cure System then.The ultraviolet tape of system is arranged on certain distance, to arrive 0.25mW/cm with about 0.5 at wave-length coverage 330-340nm ²Light partly provide coating for substrate.Between 60 seconds light period, slowly stir substrate, bathe in illumination evenly to guarantee substrate.

From light-collagen solution, remove substrate then.After from light-collagen solution, removing substrate, under 4 ℃ temperature, substrate is washed 2 times with aseptic PBS, washed 30 minutes at every turn.Then substrate was immersed in 70% ethanol washing 3 times (1ml/ washing) in aseptic PBS then 30 minutes.Under 4 ℃, substrate is kept among the aseptic PBS.

Embodiment 12

The collagen macromonomer is applied to the PEBAX substrate

Preparation collagen macromonomer as described below.Obtain I type beef tendon collagen from ReGen Corp.By under 37 ℃, on orbital shaker, cultivating 20 hours, this collagen (0.5g) is dissolved in the dry Methanamide of 20ml.Stir the TEA that adds 1.0g (9.8mmole) down, in ice-water bath with molecular balance 60 minutes.Add acryloyl chloride with every equal portions 0.25g (speed is per minute 1 equal portions) under stirring, the acryloyl chloride total amount of adding is 1.0g (11mmole).After adding the last time, solution was stirred in ice-water bath 2 hours.From ice-water bath, shift out reaction, continue at room temperature to stir 18 hours., and separate by comprising the product-collagen of polymerizable groups (in following table 4, being accredited as " collagen macromonomer ") with 6-8K MWCO Dialysis tubing by lyophilization with deionized water dialysis purification.

Obtain the PEBAX rod, and apply with the compositions of following table 4 general introductions.

Table 4

Sample number	Start solution	Coating composition
			0 (contrast)	Do not have	Do not have
1	DBDS	Collagen macromonomer (20mg/ml)
			2	DBDS	Collagen macromonomer (20mg/ml)
3	DBDS	Collagen macromonomer (30mg/ml)
			4	DBDS	Collagen macromonomer 30mg/ml
5	DBDS	Collagen macromonomer 20mg/ml; Light-collagen (20 μ g/ml)
			6	DBDS	Collagen macromonomer 30mg/ml; Light-collagen (20 μ g/ml

For all samples, can realize starting by the PEBAX substrate being immersed in the aqueous solution of DBDS that concentration is 5mg/ml.For all samples in the present embodiment and coating step, can carry out UV in 3 minutes by the centre position irradiation between 2 relative ELC-4000 lamps that the substrate in the solution placed the 400 wattage metal halides/mercuryvapour bulb that comprises interval 91cm (36 inches) distance and solidify.Washing sample is to remove unconjugated compound IV.

Next, sample is immersed in the aqueous solution of collagen macromonomer of concentration shown in the table 4.Coating speed is as follows: sample 1-3 and 5-6 are 0.75cm/s; Sample 4 is 1.0cm/s.After collagen macromonomer coating step, wet method irradiation sample 2-6 reaches 5 minutes.Sample 1 is air-dry, be used for collagen macromonomer coating step subsequently, irradiation is dry 3 minutes then.

Then with sample 5 and the 6 following other coatings of accepting light-collagen (as embodiment 7 preparations).Preparation concentration is the aqueous solution of light-collagen of 200 μ g/ml.Speed with 0.75cm/s is immersed in substrate in light-collagen solution.Wet method irradiation substrate is 5 minutes then.

The sample of being finished is accepted FITC dyeing to be renderd a service to determine coating.For carrying out FITC dyeing, 10mg FITC (Isomer I, molecular probe F-1906) is dissolved in 100% ethanol of 2ml.Dissolved FITC is stored under-20 ℃ until using (concentration=5mg/ml).In use, in 0.1M borate solution pH9.0 with FITC to be diluted to 250 μ g/ml at 1: 20.Under room temperature and dark, sample is impregnated in the FITC stain 1 hour.After dyeing, from dyeing liquor, shift out sample, with borate buffer solution washing 4 times, then wash with water, air-dry then.By the fluorescence microscopy observing samples.

The result shows, the sample of all coatings is dyeed equably by strong and outward appearance, and consistent between sample and another sample.Contrast enhancing has subsequently shown discordance very little between several coatings.Wet method irradiation contains the coating 2 totally 5 minutes of 20mg/ml collagen macromonomer, shows the macromonomer coating of its staining power less than dry method irradiation under higher concentration and/or when containing the Topcoating of other light-collagen.

Embodiment 13

The collagen macromonomer is applied to silicone and titanium substrate

With first coating solution coating silicone and titanium, this first coating solution is by 20mg/mL PVP K90 (the International SpecialtyProducts in the 60%IPA/40% aqueous mixtures, Wayne, NJ), as U.S.5, the 15mg/mL light of 637,460 described preparations derivative poly-(vinylpyrrolidone) (light-PVP), the combined preparation of 0.5mg/mL four-BBE-PET and 1mg/mL DBDS.With speed in this solution the dip coated of substrate, air-dry 10 minutes or longer time, carry out UV irradiation 3 minutes then with 0.20cm/s.

The substrate that will have first overlay is at 10% (v/v) PEG macromonomer, 0.7%mg/mL tetramethylethylenediamine-two MBP-quaternary ammonium (TEMED-DQ) is (commercial available from SurModics, Eden Prairie, MN) in the aqueous solution with the speed dip coating of 0.75cm/s, and in solution with UV irradiation 3 minutes.

The substrate that will have first and second overlays then is at 10% collagen macromonomer, in the aqueous solution of 0.8%mg/mL tetramethylethylenediamine-two MBP-quaternary ammonium (TEMED-DQ) with the speed dip coated of 0.75cm/s, and in solution with UV irradiation 3 minutes.

Collagen macromonomer coating has the lubricity that surpasses the improvement with PEG skin or the outer field coating of PEG/ heparin.In addition, FTIC the analysis showed that before sample therein is with the endurancing of the cloth wiping of brackish water or IPA 20 times and after, the coating structure all is good.

Embodiment 14

The application and the analysis of the coating of collagen macromonomer on the polyurethanes substrate

Prepare various samples and optimize the coating agent of PEG macromonomer/photoinitiator (TEMED-DQ)/collagen macromonomer and collagen macromonomer/photoinitiator (TEMED-DQ) dip coating on the polyurethanes substrate.After carrying out coating,, comprise analyzing and carry out surface analysis with fast green dyeing and FITC by the imaging of collagen macromonomer coating.Before the coating operation described in detail below, use up-PVP/ four-BBE-PET the subcoat of (10/0.5mg/ml, in IPA, rising speed 0.10cm/s, air-dry, UV 3 minutes) and handle all samples.Every other coating solution all is aqueous.Subscript (is 1a, 1b) is meant a plurality of overlays of same sample, in order to represent two step coatings.

Table 5

Sample #	Rising speed	PEG macromonomer %v/v	Photoinitiator (TEMED-DQ)	Collagen macromonomer mg/ml	UV (minute)
						1a	0.50	5	0.5	--	3
1b	0.50	--	0.8	10	3
						2a	0.50	5	0.5	--	3
2b	0.50	--	0.8	15	3
						3a	0.50	10	0.7	--	3
3b	0.50	--	0.8	10	3
						4a	0.50	10	0.7	--	3
4b	0.50	--	0.8	15	3
						5	0.50	5	0.5	5	3
6	0.50	10	0.5	5	3
						7	0.50	5	0.5	15	3
8	0.50	--	10	0.8	1
						9	0.50	--	15	0.8	2
10 (2x dippings)	0.50	--	15	0.8	4

Before coating, all samples sonication 30 minutes in IPA is with the surface of cleaning substrate.Behind sonication, with the fabric wiping wipe samples of saturated IPA, and it is air-dry.

Not applying of each sample top, hang this zone of sample with alligator clamp than the zonule; Cover most sample surfaces with basal layer and PEG macromonomer/TEMED-DQ photoinitiator (being used to receive the sample of isolating PEG macromonomer/TEMED-DQ photoinitiator layer); To make an appointment with the sample of half to be impregnated in the collagen macromonomer solution (collagen macromonomer TEMED-DQ that as above enumerates or PEG macromonomer/TEMED-DQ/ collagen macromonomer) then.

After coating, with fast green (a kind of food colour, 0.5% w/w in water, about 1 minute stain dipping) dyeing all samples, also can be by the FITC double sample that dyes.

Following processing FITC sample: 10mg FITC dyestuff is dissolved in the 2ml ethanol, and being diluted to ultimate density by 1: 20 then in 0.1M borate buffer solution (pH～9.0) is 250 μ g/ml.Under the lucifuge condition, sample was flooded 1 hour in the FITC stain.Sample is washed 4 times with borate buffer solution, and observe by fluorescence microscopy; Catch imaging.

Except the above-mentioned sample of in substrate, enumerating, in FITC analyzes, can comprise uncoated reference substance and only have the basal layer (sample of light-PVP/ four-BBE-PET).The sample that only has basal layer can produce some background fluorescences; Skew on the adjusting microscope is caught imaging to estimate this effect after adjusting.

For PEG macromonomer/TEMED-DQ/ collagen macromonomer and PEG macromonomer/TEMED-DQ+ collagen macromonomer/TEMED-DQ prescription, use PEG macromonomer (10% v/v) demonstration of higher level to produce the coating that more all even concordance thickness is arranged.

Claims (21)

1. implantable medical article that comprises pro-fibrotic coatings, described pro-fibrotic coatings comprise (a) collagen, (b) antithrombotic agent and (c) photoreactive group.

2. the implantable medical article of claim 1, wherein photoreactive group is the photoreactive group that side is hung on the reaction of collagen.

3. the implantable medical article of claim 2, wherein the side photoreactive group that is hung on the reaction of collagen is attached to collagen on the antithrombotic agent.

4. the implantable medical article of claim 2, wherein the side photoreactive group that is hung on the reaction of collagen is attached to collagen on the surface of medical article.

5. the implantable medical article of claim 2, wherein collagen comprises type i collagen.

6. the implantable medical article of claim 1, wherein photoreactive group does not rely on collagen or antithrombotic agent.

7. the implantable medical article of claim 6, wherein photoreactive group is present in the polymerization initiator.

8. the implantable medical article of claim 6, wherein photoreactive group is present in the chemical compound with one or more photoreactive group.

9. the implantable medical article of claim 7, wherein collagen comprises the polymerizable groups of reaction.

10. the implantable medical article of claim 9 comprises the bonded collagen layer of polymerizable groups through reaction.

11. the implantable medical article of claim 7, wherein antithrombotic agent comprises the polymerizable groups of reaction.

12. the implantable medical article of claim 11 comprises the bonded antithrombotic agent layer of polymerizable groups through reaction.

13. the implantable medical article of claim 1, wherein antithrombotic agent is a polymer.

14. the implantable medical article of claim 13, wherein antithrombotic agent is a polymer.

15. the implantable medical article of claim 14, wherein antithrombotic formation polymer comprises PEG.

16. the implantable medical article of claim 1, wherein the thickness of pro-fibrotic coatings is less than 5 μ m.

17. the implantable medical article of claim 1 comprises vascular occluding device.

18. the implantable medical article of claim 1 comprises the heart sticking patch.

19. a method that forms pro-fibrotic coatings on medical article comprises the following step:

(a) deposition comprises first compositions of antithrombotic agent,

(b) deposition comprises second compositions of collagen, and wherein photoreactive group is present in first coating composition, in second coating composition, does not rely on first and second coating compositions, or in their combination and

(c) the activation light reactive group is to form pro-fibrotic coatings.

20. a method that forms pro-fibrotic coatings on medical article comprises the following step:

(a) deposition comprises the compositions of collagen and antithrombotic agent, and wherein photoreactive group is present in first coating composition, in second coating composition, does not rely on first and second coating compositions, or in their combination and

(b) the activation light reactive group is to form pro-fibrotic coatings.

21. a method that forms pro-fibrotic coatings on medical article comprises the following step:

(a) deposition comprises first compositions that antithrombotic forms polymer, and wherein antithrombotic formation polymer comprises polymerizable groups,

(b) deposition comprises second compositions of collagen, and wherein collagen comprises polymerizable groups,

Wherein polymerization initiator is present in first coating composition, in second coating composition, does not rely on first and second coating compositions, or in their combination and

(c) activation polymerizable initiator is to form pro-fibrotic coatings.