CN104524637A - High-molecular biological ceramic composite nanometer particle biodegradable stent and manufacturing method thereof - Google Patents

Abstract

The invention relates to biodegradable medical equipment such as a stent made of biodegradable polymerized biological ceramic nanometer particle compounds. The medical equipment of the invention comprises at least one biological ceramic nanometer particle dispersed in (at least) one biodegradable polymer. The biodegradable polymer comprises, but not limited to, biodegradable polyester. Methods and devices for dispersing one or more biological ceramic nanometer particles in polymers are not the same. The biological ceramic nanometer particle comprises, but not limited to, amorphous calcium phosphate (ACP), dicalcium phosphate (DCP), tricalcium phosphate (TCP), pentacalcium hydroxyapatite (HAP), tetracalcium phosphate carbon monoxide (TTCP), and compositions or equivalent substances of the above substances. Other embodiments comprise a method for manufacturing the biodegradable stent by using the polymerized nanometer particle compounds.

Description

High-molecular biologic Ceramic Composite nano-particle Biodegradable scaffold and preparation method thereof

Invention field

The present invention relates to the Biodegradable scaffold that the bioceramic nano-particle at least incorporated in a kind of Biodegradable polymeric is formed.The bioceramic nano-particle incorporated wherein can improve the biocompatibility of this biodegradable polymer, changes its biological degradation rate and strengthens its mechanical performance.

The present invention finds at least a kind of bioceramic nanoparticle to be dissolved into by extruding or injection moulding process multiplely to have in the polymer of biocompatibility, and forms tubular structure, the making of convenient Biodegradable scaffold subsequently.The present invention also finds that this tubulose finished product has good biocompatibility, can strengthen mechanical performance and improve degradation speed.

Present invention also offers the method adopting high-molecular biologic ceramic composite to make implantable biodegradable armarium, such as, make the biodegradable support that effectively can control medicine sustained release.The present invention also finds to adopt the biopolymer nanoparticles complex armarium of this invention manufacture to have the equipment radial strength of high biocompatibility, good biological degradation rate and enhancing simultaneously.Therefore, the invention provides one and incorporate the implantable medical device and other auxiliary facilities that the good bioceramic nano-particle of at least one biocompatibility and degradable polymer form.According to invention and preparation method thereof, present invention also offers the armarium incorporating at least one bioceramic nano-particle.

On the one hand, the present invention relates to nano grain reinforced implantable medical device, this equipment includes at least one bioceramic nano-particle to be dissolved into the good polymer of various biocompatible.The nano-particle incorporated wherein contributes to the biocompatibility of raising equipment, improves the degradation rate of equipment, strengthens the mechanical performance of equipment simultaneously.

In certain embodiments, suitable bioceramic nano-particle is selected from calcium phosphate family, include but not limited to amorphous calcium phosphate (ACP), dicalcium phosphate (DCP), tricalcium phosphate (TCP), hydroxyapatite five calcium (HAP), tetracalcium phosphate carbon monoxide (TTCP) etc., and the chemical substance of the combination material of above-mentioned substance or equal calcium phosphate.

In certain embodiments, be applicable to polymer of the present invention and comprise Biodegradable polymeric.In certain embodiments, adopt polyester as Biodegradable polymeric.In certain embodiments, suitable polyester polymer includes but not limited to poly (glycolide-lactide) (PLGA), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly-D, the mixture of Pfansteihl (PDLA), PGA (PGA), poly-D, L-Acetic acid, hydroxy-, bimol. cyclic ester and above-mentioned substance.

On the other hand, the invention provides the method making the implantable medical device that nano-particle incorporates, more particularly, be a kind of method making Biodegradable scaffold, comprise the cut etc. of the synthesis of polymer/nanoparticle composites, the shaping of polymer/nanoparticle composites pipe, polymerization and nano-particle molecularly oriented and support.In certain embodiments, adopting various nanotechnology to make can the polymer of compound and nano-particle crystallization, squeezes out nano-particle pipeline by extruding or injecting the polymer/nanoparticle composites being positioned at more than melting point polymer simultaneously.Wherein in an embodiment, can start extruding or inject before in advance the polymer of nano-particle size mix with nano-particle, then via extruder by temperature higher than melting point polymer mixture extrude formation solidify pipeline configuration.

In certain embodiments, in order to the degree of crystallinity of the mechanical strength and granule that improve pipeline, hollow molding technology can be used to carry out further radial and axial deformation to pipeline, thus determine the direction of polymer and nano-particle molecule.Pipeline after distortion can adopt laser to cut according to holder design.Background of invention

In the U.S., since 1900, the number of dying of illness because of coronary artery disease (CAD) is in the first place that various diseases causes total number of persons of dying.This disease becomes the number one killer of people of the United States' health.Although medical skill is in constantly progress, such disease is still the reason the most general causing westerner to die of illness.For the treatment of CDA, comparatively generally adopt bracket for eluting medicament (DES) at present.DES not only can increase operational probalility of success, and because the demand of carrying out urgent coronary artery bypass surgery (CABG) can be reduced and make operation become safer.Therefore, in the U.S., the utilization rate of case (PCL) medium-height trestle of about 2,000,000 percutaneous coronary interventions has exceeded 85%.The direct total cost of annual operation has exceeded 200,000,000 dollars.Although comparatively general to the use of DES, still also exist and such as need to carry out for a long time spending the defects such as high Antiplatelet therapy and endovascular stent remain.The time that coronary stent provides a supporting role after surgery can not more than six months.But, because support is still positioned at internal blood vessel, therefore likely cause potential long-term complications.In addition, residual metal rack prevents blood vessel to return to naturalness, and then cannot carry out reparation and the Artery Remodeling of endothelium.These shortcomings cause current DES to there are two main problems, and one is in-stent restenosis; Another is then that advanced thrombus is formed.

In-stent restenosis (ISR) refers to that tremulous pulse softened after implant frame becomes narrow again.The most important reason of this phenomenon is caused to be the breeder reaction of inner membrance.Here inner membrance refers to the cellular layer that intravascular space is made up of connective tissue and smooth muscle cell (SMC).ISR always is problem maximum in PCI.The DES just emerged recently successfully solves this difficult problem.Originally, having carried out in six months after balloon dilatation, restenosis rate has reached more than 50%.This probability is dropped to 20-30%, even lower than 10% by the implantation of support.But if the blood vessel of patient is less or suffer from the disease of the aspect such as diabetes and arteriectasia, the incidence rate of ISR still very high (, between 30-60%, DES is then between 6-18% for the ISR incidence rate of bare mental stents).

Thrombosis: although the incidence rate of this clinical problem of restenosis is close to 10% after implanting DES, can solve by repeatedly implanting this method of DES.Problem maximum is at present exactly the formation that the implantation of support can cause thrombosis.Once formation thrombosis, myocardial infarction is very likely caused even to be died suddenly.Early stage at implant frame, no matter be bare mental stents (BMS) or DES, thrombotic sickness rate is substantially identical.But if the Implantation Time of support is more than 12 months, the thrombosis sickness rate relevant to the latter DES is apparently higher than the former, and reason is wherein the antiplatelet treatment of premature termination.Although the thrombotic pathogeny that people cause the overlong time because of stenter to implant is not extremely understand, substantially can determine to combine with nondegradable polymer coating result in allergy because antiproliferative treats the delay endothelialization caused.In this process, also may there is active drug and fail complete eluting and the impact stayed that disables.

On the one hand, in order to the generation preventing advanced thrombus from forming complication, while reduction high risk patient restenosis incidence rate, guarantee therapeutic effect with regard to needing; On the other hand, in order to the patient enabling this equipment cure more state of an illness complexity, just need the induction system improving product.Emerging technology that Here it is institute facing challenges.Current, for above-mentioned purpose, research worker have developed various New-support successively, has the support adopting Biodegradable polymeric coating, also has the support unit of non-loaded any polymer.In addition, the novel biological agent that can improve endothelialization while Inhibit proliferaton also comes out.This kind of preparation can be used alone and also can use in conjunction with above-mentioned achievement in research collocation.From the front data that recent Abbott ' s ABSORB tests, complete biodegradable support (BDS) is proved the bracket for eluting medicament becoming a new generation clinically.

The falsework adopting the material of biological absorbable and degraded to make has a series of advantage.Again implant frame or insert the Invasive procedures such as one section of artificial blood vessel when As time goes on the rack making material of traditional biological absorbable or degraded can contribute to implementing restenosis such as in situ occurs.And compared with the metal rack allowing arterial wall form fixed geometry, the biological absorbable of a new generation and the support of degraded are that vascular remodeling creates condition.Except the advantage without the need to surgical removal support, the material of biological absorbable and degraded has excellent biocompatibility.This feature just seems particularly outstanding when the biocompatibility metal with routine contrasts.Another large characteristic of this kind of New-support is exactly that its mechanical performance can design, and greatly reduces the hardness of support itself with this.This point metal rack cannot be accomplished.Because intensity is excessive, metal rack is injured blood vessel or inner chamber often.Biodegradable support is being numbered 5, the United States Patent (USP) of 957,975 and be numbered 10/508, also mentions in the U.S. Patent application of 739.Quote in this as list of references entirety.Table 1 compared for the potential advantage of fully biodegradable support by non-biodegradation support.

The biodegradable polyester polymer comprising polylactic acid (PLA), PGA (PGA) and copolymer p LGA thereof is at present for making the main material of BDS.The advantage of polyester polymer is that its catabolite is converted to as water and carbon dioxide by the effect of enzyme in tricarboxylic acid cycle, and excretes eventually through respiratory system.However, still there is following several subject matter in biodegradable support: 1) in polymer degradation processes, the acidic metabolite of constantly accumulation easily causes the serious inflammatory reaction of blood vessel wall, thus causes the restenosis even more serious than metal rack.2) because radial support power is not enough, fully can not support the blood vessel wall of retraction, thus make blood vessel generation elastical retraction.Also there is following limitation in simple polymer support: radioparency can make it accurately locate, but also limit the mechanical performance of support simultaneously.In order to solve this two problems, just need the pillar thickening support, and the pillar thickened can be had higher requirement to its profile and transportation performance.

In sum, the invention provides a biodegradable mounting system adopting Biodegradable polymeric-bioceramic nano-particle complex to make.This system has stronger mechanical performance, good biocompatibility and adjustable degradation rate.

Brief summary of the invention

On the one hand, the invention provides the support of the biological absorbable that adopts Polymer-bioactive ceramic nanoparticles complex to make.In this support, having at least a kind of bioceramic nano-particle to be dissolved in the middle of at least one biodegradable polymer, more precisely, is a kind of biodegradable polyester polymer.The bioceramic nano-particle incorporated in this Biodegradable polymeric includes but not limited to combined article or the equivalent material of amorphous calcium phosphate (ACP), dicalcium phosphate (DCP), tricalcium phosphate (TCP), hydroxyapatite five calcium (HAP), tetracalcium phosphate carbon monoxide (TTCP) and above-mentioned substance.

On the other hand, the present invention comprises the armarium of the biological absorbable that adopts polymer-nanoparticle complex to make.In the device, having at least a kind of nano-particle to incorporate in (at least) a kind of biodegradable polymer, more precisely, is a biodegradable polyesters base polymer.The combination material of amorphous calcium phosphate (ACP), dicalcium phosphate (DCP), tricalcium phosphate (TCP), hydroxyapatite five calcium (HAP), tetracalcium phosphate carbon monoxide (TTCP) and above-mentioned substance or equal material is included but not limited to by the bioceramic nano-particle incorporated in this Biodegradable polymeric.

On the other hand, the present invention contains a kind of method adopting polymer-nanoparticle complex to make implantable medical device.The method comprises following operation: the cut etc. of the shaping of the mixing of nano-particle and component of polymer, polymer nano granules multiple tube, nano-particle molecularly oriented and support.

On the other hand, the present invention contains a kind of method for adopting the composite of the polymer containing bioceramic nano-particle to make Biodegradable scaffold.The method is made up of following operating process: the cut etc. of by multiple nanotechnology, nano-particle and polymer being carried out to the mixing of pre-crystallized process and polymeric composition, the shaping of polymer pipe containing nano-particle, polymer and nano-particle molecularly oriented and support.Combination material or the equivalent material of amorphous calcium phosphate (ACP), dicalcium phosphate (DCP), tricalcium phosphate (TCP), hydroxyapatite five calcium (HAP), tetracalcium phosphate carbon monoxide (TTCP) and above-mentioned substance is included but not limited to by the nano-particle incorporated in polymer.

In the ideal case, adopt the biodegradable support that the composite of the polymer of invention makes, the degradation time of its biocompatibility, material and mechanical performance at least improve 10% than the pure polymer support not incorporating nano-particle.Sometimes even up to 50%.Ideally, the biocompatibility of support, the degradation time of material and mechanical performance can promote 90%, 95% or 98% than the pure polymer support not incorporating nano-particle.

Accompanying drawing explanation

Fig. 1 illustrates the experimental biodegradable bracket for eluting medicament that the present invention relates to.

Fig. 2 morphologically compares the support adopting PLGA/ACP mixture and simple PLGA coating.Please note the rack surface nano-porous structure adopting PLGA/ACP mixture coating.

Fig. 3 compares the biocompatibility of the stenter to implant experimental mouse large artery trunks after month (form compares) adopting PLGA-ACP mixture, PLGA polymer and ethylene-vinyl acetate copolymer/Vinalac 5920 (PEVA/PBMA) to make respectively.A: Injury score B: inflammatory score C: restenosis ratio D: endothelialization is marked: * P<0.05 vs. PLGA/ACP, #P<0.05 vs. PLGA ,+P>0.05 vs. PLGA.

Fig. 4 is from the support after histopathologic angle compares the implantation experimental mouse large artery trunks 28 days adopting PLGA/ACP mixture, PLGA polymer and PEVA/PBMA copolymer to make respectively.Deck panels on A:PBMA/PEVA B:PLGA C:PLGA/ACP(: × 4; Lower floor's panel: 20 × upper deck panels grid spaces please note much thick than in C of neointima in A and B.Arrow shows the measured value of thickness.

Fig. 5 compares the trimestral support of implantation experimental mouse large artery trunks adopting PLGA/ACP mixture and PEVA/PBMA copolymer to carry out face coat respectively from histopathologic angle.A:PBMA/PEVA B:PLGA/ACP upper strata: 4x; The upper deck panels grid spaces of lower floor: 20x please notes the scar tissue (blue arrow in B, lower floor's panel) adopting and healed in the slough (red arrow in A, lower floor's panel) of the support group of PEVA/PBMA coating and PLGA/ACP group.

Fig. 6 compares the mechanical performance of the support adopting PLGA/ACP mixture and PLGA to make respectively.A: maximum tensile load (A, 96.29 ± 2.15N vs. 71.11 ± 3.21N, n=6, P<0.001).B: maximum radial intensity (B, 470 ± 3.20N vs. 400 ± 2.09N, N=6, P<0.001).

               

Fig. 7 illustrates the overview of the support external degradation of the PLGA/ACP mixture coating adopting different proportion.

Fig. 8 illustrates the overview of the scaffold degradation after the implantation experimental mouse large artery trunks 28 days of the PLGA/ACP mixture coating adopting different proportion.

Detailed Description Of The Invention

The main body of the support that employing (adopting at least partly) polymer based composite makes all is related in the multiple embodiment of the present invention.The complex used is made up of the bioceramic granule be dispersed in a kind of biodegradable polymer.Bioceramic granule is biological absorbable.In some embodiments, the bioceramic particles effect of dispersion polymer-matrix, complex and rack body degradation speed in vivo.In addition, in some embodiments, bioceramic granule contributes to the mechanical performance strengthening complex and rack body.And in another part embodiment, bioceramic granule by and the acid product that produces of polymer degradation processes improve complex so that the biocompatibility of rack body.Deliver document from the multiple of inventor, the support adopting bioceramic polymer-matrix to make in the present invention, have benefited from bioceramic granule, its degradation rate, mechanical performance and biocompatibility can be changed.

Support is all cylindrical usually, for strutting and extending blood vessel stage or other anatomical lumen such as such as urethra and bile duct etc.The restenosis that the narrow or blood vessel that strutted caused by the atherosclerosis that support is mainly used in treating blood vessel or cardiac valve occur.

The support be used for the treatment of relates to conveying and the expansion of support.Here " conveying " refers to support is sent to the destination needing treatment by inner chamber in body, such as endovascular bad segments.Here " expansion " refers to the process of support expansion in the area for treatment of interior intracavity.The conveying of support is as follows with expansion concrete steps: the one end first support being placed on conduit, then by inner chamber in the feeding body of standoff for catheter cartridge one end.After conduit arrives the place needing treatment, support is launched, withdraws conduit subsequently.For Qiu Rang easily extensible support, support is mounted on conduit Qiu Rang.During mounting bracket, usually need support pressure to be held on Qiu Rang.As needed stent, inflate in Qiu Rang.After Qiu Rang cools down, just conduit can be withdrawn.And for the support that can launch voluntarily, just need by constraint auxiliary members such as example telescopic sheaths, support to be fixed on conduit.After arrival assigned address, detach sheath just expandable stents.

Be applicable to support of the present invention and comprise the various support articles for use for goals of medicine, these supports for any technical ability consummation intervention doctor be all familiar.Comprising but the support being not limited to such as can launch voluntarily Yu intravascular stents such as Qiu Rang easily extensible supports.The support that can launch voluntarily related in relevant the present invention, the numbering of promulgating to Wallsten and Wallsten et al. is respectively 4,655,771,4,954,126 and 5, and the United States Patent (USP) of 061,275 is all mentioned.About suitable balloon expandable support, that promulgates to Pinchasik et al. is numbered 5,449, mentions in the United States Patent (USP) of 373.

Being applicable to support of the present invention is biodegradable non-metal frame, includes but not limited to adopt the support that the complex of carbon, carbon fiber, cellulose acetate, celluloid, silica gel, polyethylene terephthalate, polyurethane, polyamide, polyester, poe, condensing model, polyether sulfone, Merlon, polypropylene, polyethylene, politef, polylactic acid, polyglycolic acid, condensing model, polycaprolactone, poly(hydrobutyl ester) or above-mentioned substance makes.Other polymer being applicable to make non-metal frame is shape-memory polymer.This base polymer relevant, promulgates to be numbered in the United States Patent (USP) of 5163952 to Froix have detailed introduction.This patent is quoted as a reference herein.Adopt and comprise the support that the shape-memory polymer containing acrylic acid methyl ester. and acrylic acid polymer makes and can launch according to the state remembered, be pressed on the internal chamber wall of target blood.Related description, refer to promulgate be numbered 5603722 to Phan, United States Patent (USP).This patent is quoted by its entirety as a reference.

On the one hand, be suitable for Biodegradable polymeric of the present invention to comprise and anyly there is biologically inert and the polymer (such as there is biocompatibility, avoid stimulating bodily tissue) of any inflammatory reaction can not be caused.In certain embodiments, being suitable for polymer of the present invention is biodegradable polyester polymer, include but not limited to poly (l-lactic acid), poly-D, Pfansteihl, poly-(Pfansteihl/D, Pfansteihl), poly-(Acetic acid, hydroxy-, bimol. cyclic ester/lactide), poly (glycolide-lactide), poly-(Pfansteihl/caprolactone), poly-(Acetic acid, hydroxy-, bimol. cyclic ester/caprolactone), poly-(D, Pfansteihl/caprolactone) and above-mentioned substance complex.PLA and PGA is because they can generate lactic acid and glycolic respectively in degradation process as desirable medical material.These natural metabolite can be converted into water and carbon dioxide by the enzyme in tricarboxylic acid cycle, are excreted by eventually through respiratory system.In addition, PGA by decomposed, and can be excreted by urine under the effect of esterase.Owing to possessing excellent hydrophobicity, PLA more can resistant to hydrolysis than PAG.Therefore, as improved the ratio of PLA to PGA in PLGA copolymer, the process of copolymer degradation can be extended.

On the one hand, the bioceramic nano-particle that the present invention relates to includes but not limited to any ceramic masses compatible with human body.From more wide significance, comprise any type inorganic substances compatible with human body or organic/inorganic hybridization material.Bioceramic material includes but not limited to aluminium oxide, zirconium oxide, apatite, calcium phosphate, silicon-based glass, devitrified glass and RESEARCH OF PYROCARBON.Bioceramic material is biological absorbable and/or active material.When bioceramic participates in physiological process, can become very active.Such material also can have inertia, and namely under human normal physiological condition, it can not be absorbed or degrades or play an active part in physiological process.Bioceramic nano-particle is apatite and other calcium phosphate, include but not limited to hydroxyapatite (Ca.sub.10 (PO.sub.4) .sub.6 (OH) .sub.2), fluor-apatite (Ca.sub.10 (PO.sub.4) .sub.6F.sub.2), carbonization apatite (Ca.sub.10 (PO.sub.4) .sub.6CO.sub.3), tricalcium phosphate (Ca.sub.3 (PO.sub.4) .sub.2), OCP (Ca.sub.8H.sub.2 (PO.sub.4) 6-5H.sub.2O), calcium pyrophosphate (Ca.sub.2P.sub.2O.sub.7-2H.sub.2O), tetracalcium phosphate (Ca.sub.4P.sub.2O.sub.9) and dicalcium phosphate dihydrate (CaHPO.sub.4-2H.sub.2O).Term " bioceramic " also can refer to the biological active glass ceramic mixed by such as SiO.sub.2, Na.sub.2O, CaO and P.sub.2O.sub.5 etc.For bioactivity glass Bioglass.RTM on sale on the market, it adopts SiO.sub.2, Na2O, K.sub.2O, CaO, MgO and P.sub.2O.sub.5 mixture to manufacture.Other has realized business-like bioactivity glass and has included but not limited to:

45S5:46.1 mol % SiO.sub.2, 26.9 mol % CaO, 24.4 mol % Na.sub.2O and 2.5 mol % P.sub.2O.sub.5；

58S:60 mol % SiO2, 36 mol % CaO, and 4 mol % P.sub.2O.sub.5；

S70C30:70 mol % SiO2, 30 mol % CaO.

A/W is the devitrified glass that another kind can commercially be sold.

The pottery that bioceramic granule partly or entirely can adopt biodegradable, biological absorbable or possess biological stability is made.The bioceramic of biological absorbable comprises hydroxyapatite, various bioglass material, tetracalcium phosphate, amorphous calcium phosphate, Alpha's tricalcium phosphate and beta tricalcium phosphate.The bioceramic with biological stability comprises aluminium oxide and zirconium oxide.In some embodiments, in complex, the concentration of bioceramic granule can regulate according to the degradation time of target degradation rate and support.The change of bioceramic granule density why can affect degradation rate be because pH value be exposed to the quantity of polymer-matrix in catabolite and there occurs change.In the embodiment enumerated, the concentration of bioceramic granule (such as 10:90,20:80,30:70,40:60,50:50,60:40,70:30,80:20,90:10) between 99:1 to 1:99 in scaffold complex.

The bioceramic preparation that the present invention relates to includes but not limited to complex or the equivalent material of amorphous calcium phosphate (ACP), dicalcium phosphate (DCP), tricalcium phosphate (TCP), hydroxyapatite five calcium (HAP), tetracalcium phosphate carbon monoxide (TTCP) and above-mentioned material.

For example, ACP is the important intermediate product that a kind of inside and outside forms apatite, has the feature of highly dissoluble and biological degradability.It is mainly blended in biopolymer using the form of powder or granule as inorganic constituents, regulates the mechanical performance of target complex, biodegradability and biological activity with this.In view of similar with inorganic constituents in bone, ACP usually improves remineralization as the bioactive additive in armarium.Owing to having good dissolubility, the coating containing ACP can discharge ion in hydrophily is situated between, and allows the saturation of Ca2+ and PO43 ion reach optimum level, to contribute to the formation of apatite.The ion of release can neutralize acid product because complex biological degraded is formed, reduce biological absorption and the generation that diminishes inflammation.

On the one hand, the Biodegradable scaffold adopting polymer/nanoparticle composites to make also can contain therapeutic agent or other specific benefit agent.These preparations can along with the biodegradation of support also slowly intravasation auxiliary treatment.Available therapeutic categories is various.As for the effective dose of therapeutic agent, then by veteran doctor and other factor, such as the state of an illness, the performance of therapeutic agent self and destination organization etc. are common determines.Therapeutic agent can comprise one or more preparations following: anti-thrombotic agents, anti-proliferative agents, anti-inflammatory agents, anti-migration preparation, affect extracellular matrix and generate the intervention preparation with the preparation of tissue, anti-tumor agent, antimitotic agent, anesthetis, anticoagulant, vascular cell growth promoter and inhibitor, cholesterol-lowering agent, vasodilation and endogenous vasoactive mechanism.Therapeutic agent can be put into filament or spread upon the surface of filament with the form of coating.About the therapeutic agent that is suitable for and incorporate the details of mode, please refer within 24th, submit to respectively at JIUYUE in 2008 11 days and December in 2010 be numbered 12/209,104 and 61/427, the patent application of 141 and temporary patent application.

In some embodiments, in order to the mechanical performance of lifting bracket, bioceramic nano-particle can be added in polymer.Support must meet following mechanical requirements: first, and support must the load of resisting structure, and namely support is subject to the radial compression force from blood vessel when support blood vessels wall.Therefore a qualified support must possess enough radial strengths.The radial strength of support refers to the intensity of support circumferencial direction, for resisting radial compression force.Radial strength also can be called as ring-type or hoop strength.Support should be able to maintain normal size and shape after deployment within its whole life-span, resists the pressure from each side simultaneously, comprising the cyclic loading caused because of heartbeat.For example, under the effect of radial pressure, support can inwardly shrink, and in the ordinary course of things, be the contraction allowing support generation minimum degree, this is conducive to support and plays its effect.In addition, in order to deal with bending, expansion and cyclic loading, require that support must possess enough pliabilities.The pliability of support longitudinal direction is very important.The blood vessel access of such support just by bending, to adapt to different rest.Finally, support also must possess biocompatibility, in order to avoid cause any bad vascular reaction.Support is in the extendible grid be made up of interconnective structural unit or patterning.The cylinder-shaped body of support adopts the material comprising steel wire, flexible pipe or flaky material to make.Conveniently support bending with place, the main body of support have employed and radial compressiblely to design with expansion.Conventional bracket realizes expand and contract by the motion of independently structural unit.In some embodiments, can by adding bioceramic nano-particle to the biocompatibility of the support improving present invention and relate in biodegradable material.Biocompatibility is associated with the performance of biomaterial under different occasion.It refers to that material possesses when not indicating the place to use of material and method specific performance (such as can cause immunoreation slight in set organism or reactionless, or with special cell type or tissue fusion) or refer to the equipment success clinically that adopts biomaterial to make, and this success is more partial to experience.

As everyone knows, because the catabolite of biodegradable polyesters material can transform into water and carbon dioxide under the effect of enzyme in tricarboxylic acid cycle, and be excreted eventually through respiratory system, thus this material is widely used in the biodegradable product making the fields such as osteanagenesis, cardiovascular devices, drug conveying instrument.But in degradation process, polyester polymer can generate the acid intermediate product that can cause arterial tissue's inflammation.In order to neutralize these acid intermediate products, just need to add bioceramic nano-particle, to improving the biocompatibility of support.

In addition, in some embodiments, the degradation speed of polymer-nanoparticle complex is modified by regulating the pH value of near support.Here " regional area " refers to the interior zone of complex, surf zone or near zone.The adjustment of the local pH degradation products by the bioceramic granule on internal stent or support is realized, and without the need to systematically to patient injection alkalescence or acidic materials.

In order to ensure the service life of support, relatively not too active material usually all can be adopted to make support.Introducing degradable or corrodible support is needs in order to cater to short term therapy.Generally speaking, be used for the treatment of the support of angiostenosis, its service life can not be very long.For example, the desirable or required stent in the treatment time may lower than 18 months or 1 year, or between 3-12 month or 4-8 month.Therefore, the degradation speed of support should be made adjustment according to clinical needs.

Following environmental factors can affect the speed of degraded, includes but not limited to the specific performance of other ion and concentration in the oxygen content in solution near hydrionic concentration (pH value), polymer in solution, solution, flow, temperature and pulsating stress (fatigue of degrading) with the solution of polymer contact.Wherein the change of PH can affect the kinetics of degradation reaction, passivation or form the ability of protective layer.As for passivation, the Forming ability of protective layer depends on the solubility of protective layer material.And the solubility of material depends on the pH value in degraded environment.In the section Example that the present invention relates to, the large I for the bioceramic granule in complex has multiple.For example, bioceramic granule includes but not limited to nano-particle and/or microparticle.Here " nano-particle " refers to that characteristic length (such as diameter) is between the granule of 1-1000nm even between 1-100nm.Here " microparticle " refers to the granule of characteristic length between 1000nm is to 10 microns.In addition, the shape of bioceramic granule is not restricted to one pattern yet, and includes but not limited to spherical with threadiness.

In some embodiments, the large I of bioceramic granule regulates according to the mechanical strength required and degradation rate.Relatively microparticle, bioceramic nano-particle is more effective in the rate of corrosion of amendment polymer-matrix.Because nano-particle has the surface to volume ratio larger than bulky grain, therefore, expect that it can more uniformly contact with catabolite better.In some embodiments, the lifting of selected degradation rate, mechanical strength and biocompatibility is all realized by the concentration of bioceramic granule in complex.The change of bioceramic granule density why can affect degradation rate, mechanical strength and biocompatibility be because pH value be exposed to the quantity of polymer-matrix in catabolite and there occurs change.In the embodiment enumerated, the concentration of bioceramic granule (such as 10:90,20:80,30:70,40:60,50:50,60:40,70:30,80:20,90:10) between 99:1 to 1:99 in scaffold complex.

In the multiple embodiments that the present invention relates to, the bioceramic granule of dispersion can be used as reinforcing material to promote the mechanical performance of the such as polymer-matrix such as toughness and intensity.Usually, fracture toughness is larger, and the resistance to crack extension ability of material is stronger.The effects of implantable armarium in use as being subject to stress such as part such as support will bear larger stress and strain.To be placed on the support of crooked position, it may be subject to the concentrated strain of this region height and rupture.Bioceramic granule by straining the mode that is dispersed on larger material volume to reduce the concentration degree of strain, thus increases the fracture toughness of support.In addition, bioceramic granule also can by the power dissipation that absorbs from the stress applied in bioceramic polymer based composite.Therefore, stress and strain is not the state presenting a kind of high concentration in the support adopting bioceramic-polymer-matrix mixture to make, but is decomposed into and the component of stress of countless independently granule interaction and strain.When crack as appearance initial on material begins to extend, crack can become less and less under the effect of above-mentioned mechanism.Therefore, granule has the effect of dispersive stress energy.In addition, the use of nano-particle more contributes to the mechanical performance of lifting bracket.Weight ratio one timing between granule and polymer-matrix, along with the reduction of granular size, in scaffold units volume, the amounts of particles of dispersion just can increase.So, the amounts of particles being responsible for bearing dispersive stress also can increase.Therefore, the complex containing nano-particle can improve the mechanical performance of support more equably.In addition, the bioceramic granule of dispersion can increase the intensity of complex.As previously mentioned, in order to support blood vessels, support must possess larger radial strength.The complex of the bioceramic granule containing dispersion may more be superior to independent polymer in intensity.Research worker believes that bioceramic granule effectively can improve intensity and the toughness of support in support useful life all or in part.In the ordinary course of things, bioceramic uniform particles is distributed in polymer-matrix is more satisfactory.Distribution of particles is more even, and the performance of complex and the armarium that adopts this complex to manufacture is also more unified.For example, equally distributed granule, the toughness of its complex, modulus, intensity also can increase with same amplitude with degradation rate.In other embodiment involved in the present invention, contain the steps such as the making of the implantable medical devices such as the formation of bioceramic-polymer based composite, such as support.Therefore, in some embodiments, in order to obtain polymer based composite, just need polymer-matrix to mix with bioceramic granule, and mixture is squeezed into for example pipe-like.After this, these tubes can be used to make support further.The pattern of support utilizes laser to cut out on pipeline.

Mixing and extrusion process can be carried out under low temperature such as room temperature (20-30 degree Celsius) or temperature higher a little (between room temperature and 50 degrees Celsius).In other embodiments, mixing or extrusion process then need be carried out under being for example equivalent to the high temperature of the 50-75% of polymer melt temperature.And in some embodiments, mixing or extrusion process then need higher than polymer melt temperature or fusion temperature 75% high temperature under carry out.Mixing or allotment carry out at lower than the temperature below bioceramic granule fusing point.Also the temperature of obvious chemical degradation can be there is lower than bioceramic granule in temperature here.In some embodiments, mixing is all adopt identical equipment to carry out with allotment.In concrete operating process, polymer beads and bioceramic granule can be loaded in the mixing plants such as such as extruder.This kind equipment has mixing and the function be shaped concurrently.In addition, also the compound mixture be made up of polymer and bioceramic granule can be mixed separately on the same device.For example, complex is shaped by extruder or batch blender.In certain embodiments, at high temperature before mixed biologic ceramic particle and polymer, all can in advance by bioceramic granule with in powder or granular polymer mix.Complex can be admitted in extruder and be squeezed into duct-like object.Bioceramic granule can reduce as caking occurred or forming block the uniformity that granule disperses in polymer-matrix.The granule of caking is difficult to spread out in the composite.As lumpd, then can cause the change on material property.The granule of caking can form space at the complex moiety of support, thus causes crack or cause stent failure.Mechanical agitation in traditional single-screw extruder or batch process cannot smash the granule of caking completely, therefore causes bioceramic granule to mix with the uneven of complex.Multiple method can be adopted to increase the uniformity of bioceramic Granular composite in polymer-matrix, reduce granule comprising the mode by machinery and probability of luming occurs polymer.Just take these these class methods in section Example, such as stir polymer and the bioceramic granule lumpd when high shear stress.In some embodiments, the shear stress that granule bears is higher than the fracture strength of agglomerated grain.In certain embodiments, the shear stress born with mixture comes mixed polymer and bioceramic granule higher than this mode of fracture strength of the bioceramic granule of caking.Therefore, the maximum shear stress produced in mixed process is higher than the fracture strength of the bioceramic granule of caking.The granule of caking in this case may be broken, thus be more uniformly distributed in polymer.Research worker thinks that the shear stress that single-screw extruder produces usually will lower than the fracture strength of the bioceramic granule of caking.In this case, the mixing apparatus of the fracture strength of the bioceramic granule adopting the shear stress of multiple generation higher than caking is just needed.Such plant equipment includes but not limited to two bolt compresses machine or kneading machine.In whipping process, once shear stress is higher than the fracture strength of bioceramic granule of caking, the granule of caking just can be broken, thus evenly dispersion in the polymer.Polymer and bioceramic granule are poured in mechanical stirring equipment in batches and processed with high shear stress.In addition, also the polymer of mixing and bioceramic particle composites together can be poured in mechanical stirring equipment and processed with high shear stress.Bioceramic and the time of polymeric blends under high shear stress effect sufficiently long, to reduce the caking rate of granule.For example, mixing time can between 5-30 minute, 8-20 minute or 10-15 minute.In a certain embodiment, the complex formed by the polymer beads through surface modified processes by this mode.In the ordinary course of things, in composite, base and decentralized photo/good being combined with of enhancing item help the mechanical performance improving material itself.For example, polymer-matrix is combined tightr with granule, and the lifting amplitude of the strength of materials and toughness is also larger.In some embodiments, in order to improve the cohesive between granule and polymer-matrix, adhesion promotor can be used.In a certain embodiment, in adhesion promotor, couplant can be comprised.Here " couplant " refer to can with the aitiogenic chemical substance of both bioceramic granule in composite and polymer-matrix.Couplant is equivalent to an interface between polymer and bioceramic granule, forms a chemical bridge between, to improve both cohesives.Adhesion promotor includes but not limited to silane and non-silane coupling agent.For example, binding agent can comprise 3-TSL 8330, APTES, amino propyl methyl diethylsilane, organic trialkyl silane, titanate, zirconates and organic acid-chromium chloride coordination compound.In some embodiments, before mixing with polymer-matrix, the surface of adhesion promotor to bioceramic granule can be adopted to process.In a certain embodiment, the solution containing adhesion promotor can be adopted to process bioceramic granule.Process includes but not limited to adopt adhesion promotor or the solution containing adhesion promotor to carry out coating, dipping or injection.In addition, the gas containing adhesion promotor also can be adopted to process granule.In a certain embodiment, solvent that hybrid bonding promoter and distilled water and solvent prepares is comprised to the process of bioceramic granule and granule is poured in mixed solution.After the centrifugal mode separation solution of employing and bioceramic granule, drying is carried out to granule.Dried granule can be used for preparing complex.In another embodiment, in the process of preparation complex, adhesion promotor can be poured in granule.For example, when extruding, adhesion promotor is mixed with bioceramic granule/polymeric blends.Embodiment

Following examples are only limitted to the object of displaying, are not limited application of the present invention.The embodiment object hereafter enumerated is that the present invention is understood in help.Therefore, should not be construed as concrete material or operation that the present invention is only applicable to mention in following examples.

Embodiment 1 :the preparation of PLGA/ACP complex and pipe extrusion, in research process, can adopt the electric grinding machine of per minute 25000 PLGA to be polished into the granule of size at about 200nm.By the ACP(size of 4 grams: 100-150nm) adopt same polisher to stir 10 minutes after the PLGA nano-particle mixing of 200 grams, thus make mixing more even.Single-screw extruder extrudes PLGA and PLGA/ACP compound mixture at the temperature of 200 degrees Celsius.The tube squeezed out, its external diameter is 1.8mm, and thickness is 150um.Find through microscopic examination, the transparent colourless shape of pipeline extruded by simple PLGA; The pipeline extruded by PLGA/ACP complex is the white in bone then, and ACP even particulate dispersion is among PLGA polymer.

Embodiment 2: adopt PLGA/ACP complex to make support

The tube being extruded out in upper example can adopt femtosecond laser to cut according to design specification.The strut thickness of support and the consistency of thickness of pipeline, i.e. 150um.Fig. 1 shows the support adopting PLGA/ACP complex to make.

Embodiment 3: in embodiment 1, PLGA and PLGA/ACP complex is all adopt extruding machine to be squeezed into tube to the mechanical performance of the pipeline extruded by PLGA/ACP complex.The tube of extruding also will accept measuring mechanical property.In this example, conduit stretching/radial strength testing equipment (model: 4400R is utilized; Manufacturer: Instron, Inc. Norwood, MA) measure the stretching/radial strength of tube.As shown in Figure 6, adopt the tube that PLGA/ACP complex makes, its maximum tensile load (A when fractureing, 96.29 ± 2.15N vs., 71.11 ± 3.21N, n=6, P<0.001) and radial strength (B, 470 ± 3.20N vs. 400 ± 2.09N, N=6, P<0.001) be all higher than the tube adopting simple PLGA to make.

Embodiment 4:PLGA/ACP composite structure feature

In order to detect the architectural feature of PLGA/ACP complex, respectively PLGA and the PLGA/ACP complex (weight ratio: 98:2) of 1.75 grams is dissolved in oxolane (THF) solution of 1 milliliter.By ultrasound wave spraying coating system, solution is injected in the surface of metal rack subsequently.As shown in Figure 2, the rack surface being sprayed with PLGA solution is more coarse; The rack surface being sprayed with PLGA/ACP complex solution then presents uniform microcellular structure.

Embodiment 5: through the support of PLGA/ACP composite surface process in the degraded feature of in vitro

The object of this example is to show the degradation rate of the PLGA polymer scalable PLGA/ACP complex that with the addition of ACP.In this example, different PLGA can be adopted to allocate PLGA/ACP complex solution to the weight ratio of ACP such as 85:15,65:35 and 50:50 according to the method for embodiment 4.Subsequently deployed solution is injected directly on the surface of metal rack.All supports that jetted solution are put into saline, persistent oscillation 81 days in the water-bath of 37 degrees Celsius.At weekend weekly, support is weighed and calculates the polymer of degraded.Final data display is along with the change of ACP concentration in polymer, and degradation rate also changes thereupon (as shown in Figure 7).

Embodiment 6:PLGA/ACP complex degraded feature in vivo

In order to detect the PLGA/ACP complex degraded feature in vivo of invention further, by the PLGA/ACP composite coating of 65:35 on the surface of support.Subsequently by the large artery trunks of stenter to implant experimental mouse.1 week after the implantation, 3 week, 6 week and 12 week, careful separation goes out to implant the large artery trunks (n=often organizes 3) of support, and measures the weight of PLGA/ACP copolymer by microanalytical balance.The rack surface copolymer that final data show about 80% was degraded in 12 week after the implantation.

Embodiment 7: the organism internal contact compatibility of the PLGA/ACP complex of rack surface

The object of this example is the material showing invention, and its biocompatibility obtains lifting.In this example, by 45 through adopting ethylene-vinyl acetate copolymer/Vinalac 5920 (PEVA/PBMA, n=18), PLGA(n=9) or PLGA/ACP copolymer (n=18) (polymer average weight: 260 ± 10 g; Coating layer thickness: 30 ± 10 m) surface-treated metal rack (Stainless steel 316 L, 13mm) implant in the internal iliac artery of 45 SD rats.The experimental mouse survived was at a month (PEVA/PBMA:n=6; PLGA:n=5 and PLGA/ACP:n=6) with three months in (PEVA/PBMA:n=5; PLGA/ACP:n=5), the tremulous pulse being implanted support takes out, and analyzes from the angle of pathomorphology.

Final data are presented in all experimental grouies, and thrombotic incidence rate is significantly difference not.Behind month of implant frame, degree not obvious difference (contrast between PEVA/PBMA, PLGA and PLGA/ACP, the Injury score of three experimental group medium vessels damages; 1.05 ± 0.15,1.08 ± 0.09 and 1.07 ± 0.15; P>0.05).However, implant the experimental group of the support adopting PLGA/ACP coating, the scoring of its restenosis and tremulous pulse inflammation will be starkly lower than two other experimental group (PEVA/PBMA, PLGA and PLGA/ACP, restenosis percentage ratio: 27.54 ± 1.19,32.12 ± 3.93 and 21.24 ± 2.59; P<0.05; Inflammatory score: 1.77 ± 0.38,2.30 ± 0.21 and 1.25 ± 0.35; P<0.05) in addition, the endothelialization of PLGA/ACP group is marked than all high (PEVA/PBMA, PLGA and PLGA/ACP:1.17 ± 0.18,1.20 ± 0.18 and 1.78 ± 0.46 of two other group; P<0.05) (with reference to figure 3 and 4).

After implant frame three months, although in these two experimental grouies of PEVA/PBMA and PLGA/ACP, the degree of the blood vessel injury of experimental mouse and restenosis percent difference not obvious (PEVA/PBMA and PLGA/ACP: Injury score: 1.03 ± 0.04 and 1.08 ± 0.15; P>0.05; Restenosis percentage ratio: 25.73 ± 4.83% and 27.73 ± 4.47%; P>0.05), but the former occur the neointima (then not existing in PLGA/ACP group) of the necrosis of inflammatory cell infiltration more serious than the latter many (just have in 5 experimental mouse 2 occur this situations).The appearance of this situation shows that new intima very likely occurs to break and formation thrombosis (PEVA/PBMA and PLGA/ACP: inflammatory score: 2.27 ± 0.55 and 1.33 ± 0.33; P<0.05) in addition, compare with PLGA/ACP group, there is a small amount of endotheliocyte in PEVA/PBMA group and cover (PEVA/PBMA and PLGA/ACP: endothelium is marked: 1.20 ± 0.18 and 2.33 ± 0.33 on Wall of Artery; P<0.05) (with reference to figure 5).

Although be illustrated specific embodiments of the invention above, professional person should modify and change in broad scope of the present invention in the industry.Given this, attached claim contains amendment and the change of all permissions in essence of the present invention and scope.

Claims (10)

1. biodegradable support, its main body adopts Polymer-bioactive ceramic nanoparticles complex to make,

Complex comprise be dispersed in biodegradable polyesters base polymer can the bioceramic granule of biological corrosion,

The bioceramic granule of dispersion can change degradation rate, the mechanical performance strengthening rack body and biocompatibility; This biodegradable polyesters base polymer is selected from poly (glycolide-lactide) (PLGA), polylactic acid (PLA), poly (l-lactic acid) (PLLA), poly-D, the mixture of Pfansteihl (PDLA), PGA (PGA) or more material; This granule is selected from the mixture of amorphous calcium phosphate (ACP), dicalcium phosphate (DCP), tricalcium phosphate (α-TCP/ β-TCP), hydroxyapatite five calcium (HAP), tetracalcium phosphate carbon monoxide (TTCP) or more material.

2., according to the support that claim 1 is chatted, this complex is made up of the bioceramic granule of percentage by weight between 1 to 50.

3., according to the support that claim 1 is chatted, the corrosion of granule reduces the rate of corrosion of polymer, thus extends the time of support overall absorption.

4., according to the support that claim 1 is chatted, the corrosion of granule adds the rate of corrosion of polymer thus shortens time of support overall absorption.

5., according to the support that claim 1 is chatted, the basic catabolite of granule has neutralized the sour environment of polymer, thus inhibits tissue to be inflamed.

6., according to the support that claim 1 is chatted, its overall absorption time is greater than six months; Its bioceramic particle reinforce hot strength of mixture; Its bioceramic granule improves the biocompatibility of mixture.

7., according to the support that claim 1 is chatted, its bioceramic granule contains the adhesion promotor being positioned at particle surface,

This promoter contributes to strengthening the bonding strength between bioceramic granule and biodegradable polymer.

8., according to the support that claim 7 is chatted, this binding agent is selected from 3-TSL 8330, APTES, amino propyl methyl diethylsilane, organic trialkyl silane, titanate, zirconates and organic acid-chromium chloride coordination compound.

9., according to the support that claim 1 is chatted, rack body is incorporated at least one can in the therapeutic agent of slow eluting; This therapeutic agent is selected from anti-tumor agent or immunosuppressant; This anti-tumor agent is selected from mixture or the similar substance of paclitaxel, carboplatin, vinorelbine, amycin, gemcitabine, actinomycin D, cisplatin, camptothecine, 5-FU, cyclophosphamide, 1-β-D-arabinofuranosylcytosine hydrochloride and above-mentioned substance; This immunosuppressant is selected from mixture or the similar substance of sirolimus, Zuo Tamosi, tacrolimus, everolimus, Bai Oulinmosi, pimecrolimus, Se Puruilinmosi, sirolimus, TAFA 93, neuroimmunophilin and above-mentioned substance.

10. biodegradable rack making process is as follows: adopt Biodegradable polymeric to process bioceramic granule, form complex,

In the process, shear stress processable polymer and the granule of the fracture strength of the bioceramic granule higher than caking should be adopted, thus lower the caking probability of granule; Complex is squeezed into tube; Adopt tube to make support, the bioceramic granule of dispersion can revise degradation rate, the mechanical performance strengthening rack body and biocompatibility thereof; Mixed biologic ceramic particle and polymer in two bolt compresses machine or kneading machine is included in the step that bioceramic granule and Biodegradable polymeric are processed, reduces with this probability that caking occurs material; Here bioceramic granule refers to nano-particle; This nano-particle is selected from the mixture of amorphous calcium phosphate (ACP), dicalcium phosphate (DCP), tricalcium phosphate (α-TCP/ β-TCP), hydroxyapatite five calcium (HAP), tetracalcium phosphate carbon monoxide (TTCP) or more material.