CN101437471A - Methods of polymeric stent surface smoothing and resurfacing to reduce biologically active sites - Google Patents

Abstract

The present invention provides methods for fabricating a stent using a chemical treatment to smooth, polish or strengthen the stent. One such treatment involves exposing the stent to acetone or a similar solvent. In certain embodiments, the additional step comprises placing the stent in a bath containing acetone, or a similar solvent, where the bath also contains the polymer the stent is composed of. The acetone bath step may be conducted at a temperature that is below the glass transition temperature. The present invention also provides for methods of fabricating a stent using an acetone bath that comprises poly (lactic) acid. Other embodiments provide for methods of fabricating a stent using an acetone bath that comprises poly (lactic) acid and polyethylene glycol.

Description

Make polymeric stent surface smoothing and resurfacing to reduce improving one's methods of biologic activity position

Background of invention

In various operations, get involved in cardiology and the radiology process, the use of support is accepted rapidly by understanding more widely along with the empirical accumulation of holder device and along with the advantage of support becomes.Support is used in the body cavity usually to keep open access, such as prostate-urethra, and esophagus, biliary tract, intestinal, and different coronary artery and vein, and more the cardiovascular vascular such as the femoral artery of far-end.

Support is generally used for treating atherosclerosis, and atherosclerosis is a kind of wherein by the cholesterol crystallization, non-viable non-apoptotic cell, and lipid is built up the pond, and blood vessel focus that excessive fibre composition and calcium deposition are formed or speckle are in the disease of individual arterial wall inner accumulated.Treat an atherosclerotic successful method and be and inserting the sacculus that aerofluxus is shunk with the contiguous intracavity in speckle or atherosclerotic lesion site.This sacculus is inflated speckle is exerted pressure and speckle " is broken " then.This method has increased the cross-sectional area of lumen of artery.Make the people unfortunately, applied pressure also makes tremulous pulse be subjected to wound, and in the case of 30-40%, vascular narrows down once more gradually in initial stenotic lesions position or be closed once more.This narrowing down once more is called as restenosis.

The common method that prevents restenosis is to launch metal rack at narrow lesions position.Although metal rack has the necessary mechanical strength of the retracted form that prevents restenosis, they can cause biological question in endarterial existence, comprise vasospasm, and compliance does not match, even inaccessible.In addition, permanently transplant metal rack at intra-arterial and have inherent remarkable risk, comprise the erosion of blood vessel wall.Support also is moved from their initial on position sometimes, and this has increased the probability of the obstruction of potential stent-induced.If metal rack when particularly being moved, causes the stimulation to the intracavity surrounding tissue.In addition, because metal is harder than intracavity surrounding tissue usually, this can cause anatomy or physiological compliance not to match, thus damaged tissue or cause undesirable biological answer-reply.In addition, support can cause forming thrombosis with contacting often of blood in blood vessel.Support also allows the cell proliferation relevant with impaired arterial wall to move through the support mesh, and cell continues propagation and finally causes angiostenosis there.Further, metal rack has negative recoil to a certain degree usually.At last, in fact metal rack prevents or the blood vessel of the nature that suppresses to take place is in vivo reinvented to fixed maximum gauge by mooring vascular rigidly.

Because the problem of using metal rack to produce, but other people recently after deliberation the use of bio-absorbable and biodegradable stock support.But this support prepares the bio-absorbable of used routine or can biological resorbent material be selected as loss along with the time and is absorbed or degrades.This degraded can be carried out intervention procedure such as lower carriage or tremulous pulse again operation subsequently.It is also known that but some bio-absorbable and biodegradable material tend to have the excellent biocompatibility feature, particularly compare with the most normally used biocompatible metals.But another advantage of bio-absorbable and biodegradable support is an engineering properties can be designed to eliminate in fact or reduce usually rigidity and the hardness relevant with metal rack.This is useful, because the rigidity of metal rack and hardness can promote the tendency in support damage vascular or chamber.The ion of novel biodegradable support is included in United States Patent (USP) 5,957, described in 975 those, this patent is as with reference to incorporating in full this paper into.

Yet many biodegradable supports still have problems.For example, having been found that support continues to be exposed under the blood can cause undesirable thrombosis.Especially, the support with irregular or sharp surface is undesirable, because the blood particle accumulates in the irregular surface, thereby promotes thrombosis.Therefore, the problem that still has the limit bracket surface reaction.

Therefore, wish to make support with less irregular or sharp surface.Also wish to reduce or eliminate reactive amino, it will reduce or eliminate platelet adhesion.The inventor has found to make and has caused the new method that irregular and sharp edge reduces and platelet adhesion reduces.

Summary of the invention

The invention provides and use chemical treatment so that support is level and smooth, the method for polishing or the manufacturing support strengthened.This processing comprises is exposed under acetone or the similar solvent support.The inventor has determined, by to additional this independent additional step of support manufacture process, perhaps combines with other processing, can produce excellent support.In certain embodiments, additional step comprises support is placed in the bath that contains acetone or similar solvent that wherein this bath also contains the polymer of forming support.The acetone bath step is carried out being lower than under the temperature of glass transition temperature usually.Preferably, the acetone bath step is being lower than 65 ℃, more preferably less than 60 ℃, most preferably is lower than under 55 ℃ the temperature and carries out.In certain embodiments, 25 ℃ temperature most preferably from about.

Additional step causes the surface reaction of support to reduce.Be that additional this step helps to polish sharp surface and the irregularity that produces during manufacture surprisingly.Although do not wish to be bound by any specific theory, the inventor believes that this manufacture process will reduce or eliminates platelet adhesion or any involving triggered thrombotic blood constituent by reducing or eliminating reactive amino.

The present invention also provides the method for using the acetone bath that comprises polylactic acid to make support.Other embodiment provides the method for using the acetone bath that comprises polylactic acid and Polyethylene Glycol to make support.

Detailed Description Of The Invention

Definition:

" can biological resorbent polymer " used herein be meant that its degradation by-products can be assimilated by biology or excretory polymer by the intravital natural way of people.

" acetone bath " used herein is meant the bath that comprises one or more solvents, and wherein solvent can be acetone, chlorinated hydrocarbon and/or ketone.The polymer support manufacture method comprises polymer support partly or wholly is immersed in the acetone bath.

" curling (Crimping) " used herein is meant a kind of like this method, this method is included in Qi Bishang and has radially processing on the polymer cylindrical appliance of slit or opening, thus make device reduced and do not influence the wall of cylindrical appliance or the thickness of pillar in fact.This method also causes the increase of cylindrical appliance length usually.

" degradable polymer " used herein or " biodegradable polymer " is meant such polymer, when placing this polymer in the human body or aqueous solution and imitating the temperature, osmolality, pH etc. of physiological medium and do not involve preferably that this polymer unwinds is monomer and oligomer when keeping under the condition of enzymatic degradation, thereby make the risk minimization of the antigen-antibody defense system that triggers human body.

" final reservation shape and diameter " used herein is meant and launches to arrive the particularly blood vessel particularly of the vascular in people's object of mammalian object, the required diameter of the support of the target location in pipeline (duct) or the pipe (tube), length, design and wall thickness.

" negative recoil " used herein is meant that the size or the undesirable of diameter of expansible support after initial the expansion dwindle.

" just recoiling " used herein is meant in the size of the support of the final diameter that is had required final diameter by training but also launch fully to reach required or the increase of diameter.

" relaxation relevant recoil " used herein is meant the slow change of the size of polymeric device, causes because the time dependence of the molecular conformation that takes place according to the known behavior of viscoelastic polymer material is slowly reset institute.This rearrangement is because due to the thermal agitation, thermal agitation causes polymeric material to be worked as reaching when it has been handled typical heat power balance under the storage condition lentamente under different environmental conditions.Promptly to be in glassy state following time very slow when material below Tg for relaxation.

" Tg " or " glass transition temperature " is meant that polymer becomes the temperature of glassy state from rubbery state, and vice versa.

The invention provides and use chemical treatment so that support is level and smooth, polishing and/or strengthen and make the method for support.The inventor has determined by additional one or more additional treatment step of support manufacture process have been made excellent support.This processing can be used the gas or the steam of the preferred acetone of solvent on support, particularly use the steam of linear flow rate.Additional step can comprise also and will be placed in the bath that contains the preferred acetone of solvent that wherein this bath also contains the polymer of forming support.For bathe handling, this step is carried out being lower than under the temperature of glass transition temperature usually.Preferably, bathe step,, most preferably be lower than under 55 ℃ the temperature and carry out more preferably less than 60 ℃ being lower than 65 ℃.In certain embodiments, most preferably be lower than about 50 ℃ temperature.

Additional one or more step causes the surface reaction of support to reduce.Be that additional this step helps to polish sharp surface and the irregularity that produces during manufacture surprisingly.Although do not wish to be bound by any specific theory, the inventor believes that this manufacture process will reduce or eliminates platelet adhesion by reducing or eliminating reactive amino.

The present invention also provides the method for using the acetone bath that comprises polylactic acid to make support.Other embodiment provides the method for using the acetone bath that comprises polylactic acid and Polyethylene Glycol to make support.

I. exemplary support manufacturing and character

Support can by any biodegradable, biocompatible, can biological resorbent polymer, the preferred thermoplastic polymer formation.Used herein can biological resorbent polymer be its catabolite by natural way by internal metabolism or in the body excretory polymer.Preferably, support of the present invention is by degradable and can biological resorbent polymer formation, and the Tg that this polymer has is higher than 37 ℃ at least 8 ℃, preferably is higher than 37 ℃ at least 20 ℃.The polymer of support can be homopolymer or copolymer.Preferably, support is made up of one or more unbodied thin layers that can biological resorbent polymer, that is, the polymer that is used to form support preferably is not a crystalline state.Do not produce crystalline residue when also being preferred for forming the polymer degradation in vivo of support.The chain of also having considered polymer can be crosslinked or noncrosslinking.Yet, if allow device training, curl and unfolded hot feature and viscoelasticity characteristic are fully kept, slight crosslinked is acceptable.

Suitable biodegradable polymer can include but not limited to poly-L-lactide, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly-D, L-lactide, the copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, poly-hydroxyl valerate, poly butyric ester, PTMC, poly-orthoformate, polyanhydride, and polyphosphazene.The example of type that is applicable to the polymer of support of the present invention includes but not limited to lactyl stereocopolymer (the PLAx copolymer of being made up of L and D unit; wherein X is the unitary percentage ratio of L-lactyl) (55＜Tg＜60); copolymer (the PLAxGAy of lactic acid and glycolic; wherein X is the unitary percentage ratio of L-lactyl; Y is the unitary percentage ratio of glycolyl; thereby make the Tg of copolymer be higher than 45 ℃); and lactic acid-ethanol-gluconic acid copolymer; wherein the unitary OH of glucose acidic group can be substituted (pLAxGayGLx more or less; wherein X is the unitary percentage ratio of L-lactyl; Y is the unitary percentage ratio of glycolyl; with Z be the unitary percentage ratio of glucose acidic group, thereby make the Tg of terpolymer be higher than 45 ℃).Other suitable polymer includes but not limited to polylactic acid (PLA), polyglycolic acid (PGA), lactide glycolide copolyesters (PLAGA copolymer), poly-gluconic acid (the copolymer of trimethylene carbonate and Acetic acid, hydroxy-, bimol. cyclic ester, the copolymer of poly-Acetic acid, hydroxy-, bimol. cyclic ester or lactide acid or polylactic acid and 6-caprolactone), condition is that the glass transition temperature Tg of polymer is at least 45 ℃ or higher.

In a preferred version, support comprises the polylactic acid stereocopolymer that is obtained by L-and DL-lactide.This polymer is known as " PLAX " in this article, and wherein X is illustrated in the percentage ratio of the monomeric mixture L-lactic acid units that is used for making lactide.Preferably, X is 10 to 90, more preferably 25 to 75.In another preferred version, support comprises the poly (lactic acid-glycolic acid) copolymer by L and DL lactide and Acetic acid, hydroxy-, bimol. cyclic ester preparation.This polymer is known as " PLAXGAY " in this article, and wherein Y is illustrated in the unitary percentage ratio of monomeric mixture glycolic that is used for making copolymer.Preferably, copolymer does not contain the glycolyl repetitive, because known the having more than lactyl repetitive of this monomer causes inflammatory.Preferably, use zinc metal or zinc lactate to prepare polymer as initiator.Have good initial engineering properties in order to ensure support, the molecular weight of the polymer in having the second volume lifetime section preferably is higher than 20,000 dalton, more preferably 100,000 dalton or higher.Polydispersity, I=MwMn preferably is lower than 2, and will can not reflect the existence of determining according to size exclusion chromatography (SEC) less than 2,000 daltonian low-molecular-weight oligomers largely.

Randomly, the polymeric layer that is used to make support is impregnated with anticoagulant such as heparin, and antioxidant regulate the chemical compound of cell proliferation, or anti-inflammatory drug is sent with the medicine that localization is provided such as corticosteroid such as vitamin E.This drug use technology known in the art is incorporated in the polymeric layer.Described reagent also can be incorporated in the base polymer that constitutes rack body, as long as this combination does not produce pronounced side effects to the required physical property in support is between such as radial struts expansion and degradative phase.For endovascular stent, the thickness of preferred film is that about 0.05mm is to 0.2mm.

Further, in some embodiments, the chemical compound of support available adjustment wound healing coats, and perhaps the support polymer can comprise the chemical compound of regulating wound healing.Usually, the chemical compound of regulating wound healing can be following any chemical compound: itself and fibrin crosslinked with provide cell particularly inner skin cell viscosity echo mobile substrate; Early stage component or auxiliary matrix as extracellular matrix form; Combine with collagen protein or interact with the substrate aminopolysaccharide; Macrophage, fibroblast, endotheliocyte, smooth muscle cell and epidermis cell had chemotactic character; Influence the result and the effect of cytoskeleton and encourage the particularly material of endothelial cell migration of cell migration; Promote opsonification and phagocytosis; Form the component that fiber links (fibronexus); Form the skeleton of collagen deposition; Or otherwise promote to heal.

Promote the example of the chemical compound of wound healing to include but not limited to protease; Vaso-active substance such as 5-hydroxy tryptamine and histamine; Fibronectin; Collagenase; The former activator of plasmin; The neutral protein enzyme; Elastin laminin; Collagen protein; Proteoglycan such as chrondroitin-4-sulphuric acid; Dermatan sulfate; And heparin sulfate, sulphuric acid aminopolysaccharide and non-sulfuric acid aminopolysaccharide; Epidermal growth factor (EGF); Hormones such as estradiol, testosterone or Progesterone; Macrophage derived growth factor (MDGF); Platelet derived growth factor (PDGF); Thrombin; Insulin; Some lymphokine; Vascular endothelial cell growth factor (VEGF); Fibroblast growth factor; Supplemental factor is such as ferrum; Copper and vitamin C; Adrenomedullin; Angiogenin; Angiogenin-1; The angiogenin relative growth factor; Brain origin neurotrophic factor; Corticotropin releasing hormone; Cyr16; Erythropoietin; The follicle element that stops; Hepatocyte growth factor; Interleukin (IL-3, IL-8); Mid-term the factor; Neurokinin A; Neuropeptide tyrosine (NPY); Multiple effect growth factor; The granule protein precursor; Proliferin; The secreted neural element; The P material; Transform growth because of in; VG5Q; Raise the factor of adventitial cell; And becaplermin.

Considered that support can be by any way manufacturing.In a preferred version, support is formed by biodegradable polymer belt, and this polymer belt comprises the head with seam and comprises and the locking of its longitudinal edge vicinity or the tongue of locking mechanism.Cylindrical parts with inner surface and outer surface forms by a part of tongue being inserted through seam, so that the cylindrical parts with first minimizing diameter structure to be provided.After launching, cylindrical parts is in the second deployment diameter configuration, and wherein far-end blocking mechanism and the inner surface of head engage and prevent that the radius of polymer support from subsiding or recoil.In second preferred version, support is formed by the polymer belt of a plurality of interconnection, and wherein each polymer belt comprises head with seam and comprises tongue with the blocking mechanism of its longitudinal edge adjacency.

In one embodiment, support forms by the cut cylindrical tube.In another embodiment, the following formation of support: the smooth polymer sheet of laser cut stent form curls into this pattern the shape of cylindrical stent then and provides vertical welding to form support.In another embodiment, the following formation of support: the polymer sheet that chemical etching is smooth, then this pattern is curled and welding to form support, perhaps the polymer line coiling is formed support.

In another preferred version, support also can form by the molding of thermoplastic polymer or the reaction injection molding(RIM) of injection moulding or thermoset copolymer material.For example, in one embodiment, polymeric material is poured into forms two-dimensional grid in the mould.Then should be smooth grid reel and weld endways or gluing cylindrical to form.In other embodiments, polymeric material is injected into forms cylindrical stent in the three-dimensional mould.In addition, can extrude or the polymer filaments of melt-spun chemical compound, these filaments can be cut then, form ring-type element, welded closed, and wrinkling formation hat will be preced with by heat or solvent then and be welded together to form support.At last, can go too far or encircle, the pipe fitting compacting is formed hat, merge by welding or laser hat is joined together to form support from the tubulose cutting of getting the raw materials ready.

Usually, pillar is arranged in such pattern, thereby this pattern is designed to contact the chamber wall of vascular and the opening that keeps vascular.All pillar patterns known in the art are used to realize specific design object.

Considered that crimped stent can be in conjunction with slit or open space, dwindled temporarily and do not change wall thickness in fact with the diameter that allows cylindrical tube.In addition, embody support of the present invention and can comprise tusk and corresponding interlocking structure, its operation is to keep the expansion form.In addition, the polymer-matrix support that has embodied the structure that is limited by line or belt shape circle or helical form or knitting mesh configuration is the possible example of self-expanding cribbing.The important design character of other of support comprises radius or circle intensity, expansion rate or area coverage and vertically motility.With respect to another pattern and attempted to optimize for those parameters that have importance for the concrete application by a preferred pillar pattern.

Considered that also biodegradable support also can have the arrangement pattern of vivo degradation.The polymer architecture of support allows degradation speed to have any different.For example referring to United States Patent (USP) 5,957,975, it is as incorporating this paper into reference to full text.In one embodiment, support comprises at least one columniform in fact parts, and it has two openings and a plurality of zone that centers on the cylindrical parts circle spacing and extend to another opening from an opening of cylindrical parts.Each zone is fabricated or is designed to have useful life in the required body.One or more zones that at least one zone is designed to have than other have useful life in the short body.This means that useful life's zone is very fast in the longer body degrades than having after expansion in this zone with useful life in the shorter body.Therefore, when launching in the tube chamber of frame designed in accordance with this invention the patient, cylindrical parts obtains one or more cracks, and it launches the back extends to cylindrical parts from an opening of cylindrical parts in required predetermined amount of time another opening at support in patient's body.Determined this decomposition in the section or become fragment to consider that tube chamber passes through expanding of tremulous pulse remodeling process at the fixed time after expansion.

Example I

Each zone with support of useful life in the consubstantiality not is by the whole bag of tricks manufacturing.Preferably, produce in the polymeric layer of this support by useful life in useful life or the longer body in having predetermined second body and have in first body useful life's zone in the promptly shorter body of useful life and manufactured.Having useful life's zone in first body has the polymeric layer of useful life in second body by heating zone separately reaches certain hour and is being enough to cause that polymeric chain takes place to prepare under the temperature of local part degraded.This processing, it can use the hot pin of pilot-operated type, laser beam or thermal air current to realize, makes that the polymer in heat affected zone is more responsive to hydrolytic degradation.As an alternative, having the zone of useful life in first body can be by preparing in separately regional of polymeric layer in conjunction with the acid ion of sufficient amount in the polymeric layer of useful life in having second body.Preferably, acid ion is provided by the chemical compound that is insoluble to blood.

Example II

Zone with useful life in first body also can be in having second body be assigned time enough and is produced with the incomplete fracture of inducing the polymeric chain in the zone separately by will zone separately being exposed to β ray or gamma-radiation in useful life's the thin polymer film.If the thickness of polymeric layer is lower than 0.3mm, the zone that then has a useful life in first body also can be in having second body produces by introduce the mechanical weakness zone to polymer in useful life's the thin polymer film.A kind of method of introducing mechanical weakness be by will be separately polymer thickness in the zone reduce or formation hole in zone separately.Zone with useful life in first body also can be in having second body produces by separately zone is applied mechanical stress in useful life's the thin polymer film.Yet a kind of processing in back is difficult to control, is more not preferred therefore.Different useful lifes also can produce by one or more different coatings are provided on the zones of different of biodegradable support.

EXAMPLE III

Another method that is used for producing polymeric layer (one of them zone or a plurality of isolated zones have useful life in first body and other zone has useful life in second body) is that band or fiber that degraded faster can biological resorbent polymer are incorporated into the thin film that the polymer that slowed down by degraded is made.For example, can be with in PGA or any other the fiber of bioresorbable polymer of very fast degraded or the zone separately of the mesh of band or the polymeric film that parallel array is embedded into the PLA that can be designed to degrade more slowly.Embedding can be by realizing between two molten sheet that mesh or fiber are inserted into the polymer of degraded more slowly.If relative solubility is compatible, then fiber or mesh can place the organic solution of the polymer of degrading more slowly and form required polymeric film by the evaporation organic solvent.Be used for describing in mesh that embedding made by a kind of polymer licenses to people such as Vert on July 21st, 1981 to an example of the method for the polymeric layer of being made by second polymer the United States Patent (USP) 4,279,249, it is as with reference to incorporating this paper in full into.Have the required region shape and the support of orientation from polymeric layer formation then, by for example punching press of standard technique, adopt laser beam, or any technology that other is used for producing polymer film that use this area is carried out.

The initial cylindrical polymeric device that forms from any of these method can be built as has final reservation shape, length, and wall thickness and diameter, all these are in the application that is customized for support and will be used.For example, use for cardiovascular, the initial polymeric device that is formed by these methods can have from 0.5 centimetre to about 3 centimetres final predetermined length.Use for some, initial cylindrical polymeric device can have from 0.50 millimeter to 8.0 millimeters final predetermined diameter with from 0.05 millimeter to 0.5 millimeter final intended wall thickness.As an alternative, the initial cylindrical appliance that is formed by any of these method can have the diameter littler than final predetermined diameter.

Initial therein cylindrical polymeric device has than final predetermined diameter in the situation of minor diameter more, forms slit or opening as mentioned above in cylindrical appliance, then with the cylindrical appliance distortion or expand and reach final shape and diameter.This can finish by inflatable device is inserted in the support such as sacculus.

In case it is the formation support is immersed in support in the bath that comprises acetone at least, dry then.Be, the inventor finds support is immersed in the result who has sharp surface of beyond thought minimizing and irregularity in this bath with astonishing, and described result measures according to scanning electron microscopy.Support can carry out drying by any way, but preferred support is under atmospheric pressure dry, reaches constant weight up to them.Can measure residual acetone by gas chromatography or thermogravimetry and prove bone dry.

EXAMPLE IV

Total time that support floods in bath is crucial, because acetone bath may be dissolved support.In this embodiment, support is immersed in and amounts to 0.5 second in the bath.

In other embodiments, support is immersed in and reaches in the bath at least about 0.1 second, preferred maximum 1 second.Considered that also total dip time can be used as the method for useful life in the body of one or more sections of other change support.

The acetone bath step is carried out under the temperature of the glass transition temperature that is lower than the polymer that forms support usually.Preferably, the acetone bath step is being lower than 65 ℃, more preferably less than 60 ℃, most preferably is lower than under 55 ℃ the temperature and carries out.In certain embodiments, most preferably be lower than about 50 ℃ temperature.The also preferred temperature of using the glass transition temperature that is lower than support is because this has reduced the exposure of support under unfavorable temperature conditions.

If the surface tension of the solvent that uses during solvent is bathed is too high, then it can suppress to cause the different in kind of support on its length in the inner surface that solvent enters support.If wish, this can be avoided by following measure: operate in the atmospheric pressure that solvent is bathed the top, add in bathing and reduce the capillary reagent of solvent, stir or change stream by the support chamber.

Acetone concentration in the bath can be any concentration of being determined by those skilled in the art, to reduce the sharp edge and the irregularity of support, reduces the surface reaction of support, and/or reduces reactive amino.The concentration that preferably is dissolved in the polymer in the acetone bath is at least about 0.05% weight/volume, most preferably at least about 5% weight/volume.

In addition, certain embodiments of the present invention provide and added polylactic acid (PLA) in acetone bath, poly-L-lactide, poly DL-lactide, L-lactide monomer and/or DL-lactide monomer.Further considered and in acetone bath, added one or more polyethers.Considered that polyethers can include but not limited to Polyethylene Glycol, poly(ethylene oxide), crown ether, or its mixture.Preferably, the polyethers that is added in the acetone bath is Polyethylene Glycol (PEG).In a preferred version, acetone bath contains the PLA-PEG diblock copolymer.The concentration of PLA and/or PLA-PEG diblock copolymer is preferably greater than about 10% weight/volume, more preferably from about 5% weight/volume greater than about 0.1% weight/volume.That has considered also that acetone bath can contain other also can be included in polymer, chemical compound and/or the chemical substance of support in forming.For example, if the support polymer contains biodegradable polymer such as polycaprolactone, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly 3-hydroxy butyrate, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly-D, the L-lactide, the copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester, polycaprolactone, poly-hydroxyl valerate, poly butyric ester, PTMC, poly-orthoformate, polyanhydride, polyphosphazene, or its mixture, then also can in acetone bath, add described polymer.

Further, also considered to use other solvent to replace acetone, perhaps can be in acetone be comprised in bath.For example, can be used on chlorinated hydrocarbon or the halogenated hydrocarbon that solvent in the bath comprises one or more types.Chlorinated hydrocarbon includes but not limited to: dichloromethane, 1,1,1,2-trichloroethane, 1,1-dichloroethanes, trichloroethylene (trichloroethlene), gamma hch, Polychlorinated biphenyls, two oxa-glutinous rehmannias, furan, perchloroethylene, chloroform, methoxychlor, benzene hexachloride, Niran, dieldrin, heptachlor, methoxychlor, toxaphene, carbon tetrachloride, or its mixture.

Also considered in bath to use and derived from the solvent of ketone but not acetone perhaps comprises the solvent and the acetone that derive from ketone in bath.The member of ketone comprises the organic compound that only contains with the bonded carbonyl of carbon atom.The ketone of considering includes but not limited to acetoacetic acid, 1-Phenylethanone., butanone, C-11 ketone, Ketohexamethylene, diacetone alcohol, diisobutyl ketone, isophorone, methyl amyl ketone, methyl ethyl ketone, methyl isoamyl ketone, methyl iso-butyl ketone (MIBK), beta-hydroxy-butanoic acid ester, or its mixture.Can be used on other useful solvent in the bath and composition thereof and comprise aldehydes, it also can help some polymer of using in the center rest.In some embodiments, can in bathing, add to regulate and condense or the medicine or the chemical compound of wound healing.

Further, the step of acetone bath can be carried out at the point of any time during the support manufacturing.Preferably, the acetone bath step appears at the ending that support is made.More preferably, the step of acetone bath appears at before support trained.

The training of II. exemplary support and curling

Although at final reservation shape, size and diameter, train cylindrical appliance to the temperature of the Tg that is higher than the polymer that forms device by heater.This device be heated continue enough to erase the relevant memory of previous technology time and be endowed the cylindrical polymeric device with the new final reservation shape and the memory of diameter.It is believed that this conditions permit polymer chain self relaxation and the typical entanglement from previous the processing stage are recombinated typically tangles under the cylindrical appliance high temperature compatible with size with shape final or distortion.When the initial diameter that has when the cylindrical polymeric device is lower than final predetermined diameter, wish to be heated to considerably beyond the temperature of the Tg of polymer.This heating steps erased polymer chain by the anisotropic stress memory relevant of extruding or moulding technology promotes with first pre-treatment.By 80 ℃ down heating form by PLA75 and reach 30 minutes and obtained good result from the cylindrical polymeric device that 1.0 mm dias are deformed to the laser instrument precut of 4 mm dias.From about 45 ℃ to about 120 ℃ temperature and 5 minutes or the higher time should be suitable for training by PLAx (0＜X＜100), PLAxGAy (0＜X＜25 and 75＜Y＜100), or the support made of any PLAxGAyGLz.

Then the cylindrical polymeric device is curled." curling " used herein is meant a kind of like this method, this method is included in Qi Bishang and has radially processing on the cylindrical polymeric device of slit or opening, thus make device reduced and do not influence the wall of cylindrical appliance or the thickness of pillar in fact.This method also can cause the increase of cylindrical appliance length.

For the trained cylindrical appliance that curls, attach it on the device that has than minor diameter.The temperature of trained cylindrical diameter by cylinder being heated to the Tg that is lower than polymer pressurizeed equably to the outer surface of the wall of cylindrical appliance simultaneously and is reduced.

In some embodiments, polymer support is curled on such as the inflatable air bag pipe at inflatable device.In this case, the support assembly parts after curling comprise expandable airsac tube and by the square and expandable, trained polymer support stably disposed thereon.The diameter that allows cylindrical appliance reduces and the slit or the open space that do not change the wall thickness during curling in fact was introduced in the cylindrical appliance before cylindrical appliance is curled on the inflatable air bag pipe.Thereby allow columniform diameter to reduce but the final reservation shape of the enough low again trained cylindrical appliance of not erasing of described temperature and the memory of diameter thereby the heating-up temperature of cylindrical appliance during curling is enough high.In theory, this temperature is lower than the glass transition temperature of polymer.More preferably the, this temperature is about 50 ℃.Therefore, the heating-up temperature of trained cylindrical appliance during curling is lower than the heating-up temperature of cylindrical appliance at the cylindrical appliance training period.Further, different and different that required time of trained cylindrical appliance can be according to temperature, size and the composition of support of curling.

According to this method, the expansion of polymer support can be finished by any way.In one embodiment, only use sacculus as the carrier of support by body.In this preferred version, carry out support by the just recoil character of support and launch; Therefore, launch not rely on inflated.In another preferred version, sacculus is inflated and/or heats to start support and launch.The character that just recoils of having considered support is deployed into its final predetermined diameter with support.Being used to start the unfolded temperature of support can be any temperature of Tg that is equal to or less than polymer; Preferred this temperature is about body temperature.In more not preferred scheme, sacculus is inflated so that polymer support is expanded to be deployed into its final reservation shape.

On the other hand, method of the present invention is started with from the polymer pipe that its initial diameter is lower than final predetermined diameter.This pipe at first is heated to the temperature of the Tg that is close to or higher than polymer and is unfolded to provide diameter to equal the cylindrical appliance of final required diameter.Afterwards, cylindrical appliance is trained the trained cylindrical appliance that has the memory of final reservation shape and diameter to provide as mentioned above, and curling on airsac tube as mentioned above then comprises airsac tube and by the square and the assembly parts of expandable, trained polymer support stably disposed thereon to provide.

The present invention also provides and has comprised expandable airsac tube and according to the assembly parts of the polymer support of this method preparation.

Preferably, support of the present invention shows negative recoil seldom or that do not have relaxation to be correlated with when launching in the blood vessel at object.Advantageously, the diameter that has of assembly parts of the present invention allows in its blood vessel that can easily be inserted into object and advances to the target location.Show the geometry of expansion (just recoiling) and suitable tremulous pulse when preferably, support of the present invention does not launch to arrive its final diameter fully during it is launching.Just recoiling in several days will produce secular outside radial pressure.This outside radial pressure stablizes impaired tremulous pulse by help or vulnerable plaque helps positive blood vessel to reinvent, and helps the cell development to repair primary urgent unfolded damage, helps the safety of tissue flap, or the like.

In addition, support of the present invention stably is arranged on the sacculus, means that the requirement mechanical constraint prevents that support at room temperature promptly is deployed into its final diameter between the storage life.Therefore, although do not need, assembly parts of the present invention also randomly comprise the collapsible sheath that covers rack outer surface.This sheath is enough to prevent the distortion and the prevention of support or the expansion of support between the storage life of having slowed down.

III. the exemplary training that is used for definite support of the present invention and the curling time and the process of temperature

Thereby be suitable for training cylindrical appliance and be used to develop the negative recoil of antagonism and actual temperature and time with the support that is just recoiling can followingly be estimated: at first support of the present invention is clipped in airsac tube, then inflated is launched to start support.Sacculus is removed then support 37 ℃ of storages.Although between the storage life, because the just recoil character stent diameter of support may increase.If support shows seldom or negative recoil when storing under these conditions when reaching the time that 4-6 week or the preferred arterial wall of estimating recover from the PTC angioplasty, the time and the temperature of then training support and being adopted are suitable.In these cases, when wherein polymer support showed a small amount of recoil, cylindrical appliance was preferably trained under with low condition of repaying a spot of negative recoil greater than final predetermined diameter slightly at diameter.

Being suitable for crimped stent can be by the standoff airsac tube of the installation that allows assembly parts of the present invention at room temperature or stop under storage temperature and estimate to the temperature and time of the diameter that reduces.To be equivalent to staying than minor diameter of sacculus that aerofluxus shrinks sunken if the support that curls remains under these conditions, and time and the temperature used during then curling are suitable.

The rack mechanical character of giving such as the optimization that is just recoiling can realize by final products are stored under the room temperature that is lower than 20 ℃.Preferably, final products are about 6-8 ℃ of following cold preservation.

IV. the expansion of support

The polymer-matrix support is at first about 37 ℃ of preheatings 3 to 6 minutes.The preheating of support can be carried out by any method, is included in the interior or hot-air internal heating of blood flow in saline, the body.After preheating time, polymer-matrix support assembly parts of the present invention are introduced in the pipeline of mammalian object, and pipe or vascular for example in the blood vessel, preferably combine with guiding tube, and advance to for example stenotic lesions position, target location.After it was positioned at the target location, sacculus was promptly inflated to start the expansion of support.As an alternative, support can be placed on the expanding unit, and this expanding unit can the local heat support when support is properly oriented.During this process, the diameter of support increases, but the thickness of cradle wall is still identical in fact.

Further considered that the fragmentation of speckle and the expansion of support can carry out simultaneously.If use sacculus in this case, then sacculus is inflated and reaches about 8 to 12 atmospheric pressure so that plaque rupture and support launch.As an alternative, vascular can use angioplasty but not support is launched in advance.Afterwards, support is incorporated on the desired location of the independent preferred expansible balloon tube of pipe.

Except coronary artery, support of the present invention can be used in other tremulous pulse, such as for example femeroiliac tremulous pulse, carotid artery, awl-basilar artery, and other hollow passage inside, such as for example vein, ureter, urethra, bronchus, bile duct and pancreatic system, internal organs, eyes pipeline, and seminal fluid pipe and fallopian tube.In fact, further considered that some aspect of the present invention comprises the device of the substitute that can be used as vein, tremulous pulse and body interior conduit or tubular structure.

Although only write up preferred version of the present invention, because can reckoning with, those skilled in the art can change apparatus and method disclosed herein, additional, modify and improve, and do not depart from the scope of the present invention.Therefore, the present invention is not subjected to the demonstration of above-mentioned preferred version, but is limited by claim.

Claims (23)

1. reduce the sharp surface of polymer support and/or the method for irregularity, described method comprises: at least a portion of polymer support is immersed in the bath that comprises at least a solvent and at least a biodegradable polymer.

2. the method for the reactive amino on the minimizing polymer support, described method comprises:

Make biodegradable polymer support;

Preparation comprises the bath that is dissolved at least a biodegradable polymer at least a solvent;

At least a portion of biodegradable polymer support is immersed in the described bath reaches predetermined amount of time.

3. each method among the claim 1-2, the concentration that wherein at least a biodegradable polymer has is greater than 1% weight/volume.

4. each method among the claim 1-3, the concentration that wherein biodegradable polymer has is greater than 5% weight/volume.

5. each method among the claim 1-4 is wherein bathed and is comprised polyethers in addition.

6. the method for claim 5, wherein polyethers is a Polyethylene Glycol.

7. each method among the claim 1-6, wherein the temperature of Yuing is lower than the glass transition temperature of polymer support.

8. each method among the claim 1-7, wherein said polymer support is immersed in and reaches about 0.1 second in the bath.

9. each method among the claim 1-7, wherein said polymer support is immersed in and reaches about 0.5 second in the bath.

10. each method among the claim 1-9, wherein temperature is lower than 65 ℃.

11. each method among the claim 1-10, wherein the temperature of Yuing is lower than 50 ℃.

12. each method among the claim 1-11, the atmospheric pressure of wherein bathing the top is controlled.

13. each method among the claim 1-12, wherein bath comprises the capillary reagent that can reduce described bath in addition.

14. each method among the claim 1-13, the wherein said concentration that is dissolved in the biodegradable polymer at least a solvent is at least about 0.05% weight/volume.

15. the method for claim 14, the wherein said concentration that is dissolved in the biodegradable polymer at least a solvent is at least about 5% weight/volume.

16. each method among the claim 1-15, wherein said at least a solvent comprises acetone.

17. each method among the claim 1-15, wherein said at least a solvent comprises the chlorinated hydrocarbon or the halogenated hydrocarbon of one or more types.

18. the method for claim 17, wherein said at least a solvent is selected from: dichloromethane, 1, vinyl trichloride, 1, the 1-dichloroethanes, trichloroethylene, gamma hch, Polychlorinated biphenyls, two oxa-glutinous rehmannias, furan, perchloroethylene, chloroform, methoxychlor, benzene hexachloride, Niran, dieldrin, heptachlor, methoxychlor, toxaphene, carbon tetrachloride, and composition thereof.

19. each method among the claim 1-15, wherein said bath comprise at least a solvent from ketone in addition.

20. the method for claim 19, wherein said at least a solvent from ketone is selected from: acetoacetic acid, 1-Phenylethanone., butanone, C-11 ketone, Ketohexamethylene, diacetone alcohol, diisobutyl ketone, isophorone, methyl amyl ketone, methyl ethyl ketone, methyl isoamyl ketone, methyl iso-butyl ketone (MIBK), beta-hydroxy-butanoic acid ester, and composition thereof.

21. each method among the claim 1-15, wherein said at least a solvent comprises aldehyde.

22. each method among the claim 1-21, wherein said polymer support comprises identical polymer with at least a biodegradable polymer.

23. the method for claim 22, wherein said polymer support is made by the PLA-PEG diblock polymer.