CN106730049A - A kind of biocompatibility Inner standpipe material - Google Patents

A kind of biocompatibility Inner standpipe material Download PDF

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Publication number
CN106730049A
CN106730049A CN201611208251.4A CN201611208251A CN106730049A CN 106730049 A CN106730049 A CN 106730049A CN 201611208251 A CN201611208251 A CN 201611208251A CN 106730049 A CN106730049 A CN 106730049A
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microcavity
small peptide
matrix
composition
ala
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CN106730049B (en
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石佳明
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SHENZHEN HNO MEDICAL TECHNOLOGY Co.,Ltd.
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石佳明
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/622—Microcapsules

Abstract

A kind of biocompatibility endoprosthesis materials, it includes：Matrix, the material of described matrix is tissue degradable in vivo, and described matrix is tubulose, the surfaces externally and internally for possessing tubulose, and inner surface constitutes the passage that tissue fluid passes through, such as blood.There is the structure of connection interior outside on the surface；Microcavity：The microcavity is obtained in the connectivity structure on matrix bodies with axially vertical cross-wise direction, and the microcavity is located on the thickness direction in hole, the substantially perpendicular relation of surfaces externally and internally of its plane being open and tubular bracket；Composition：It is loaded in microcavity, can degrade release Fe3+；Small peptide layer：Small peptide layer is located on the surfaces externally and internally of matrix material, and the small peptide can be self-assembly of hydrogel, and the hydrogel formed after the small peptide self assembly being capable of the specific regeneration covered with endodermis of climbing beneficial to endothelial cell；The prosthese can assign it needed for biocompatibility, while support support force is kept, possess EC layer of balance and climb and cover, suppression ISR, and in the self performance of in good time recovery organization, particularly blood vessel.

Description

A kind of biocompatibility Inner standpipe material
Background technology
The invention belongs to field of medical materials, it is related to a kind of prosthetic material, is a kind of possess biocompatibility particularly Timbering material, is more suitable for, for blood vessel inner bracket material.
Body includes various passages, such as artery, other blood vessels, and other bodily lumens.Sometimes these passages can be blocked Fill in or die down.For example, passage can be blocked by tumour, it is narrow by patch, or died down due to aneurysm.When these situations occur When, passage can again be opened or strengthened using medical built-in prothesis, or even be replaced.Built-in prothesis are usually to be placed in vivo Tubular element in tube chamber.The example of built-in prothesis includes support, coated prosthese, stent graft and vessel sealing pin.
Support (stent, Si Tengte), venous filter, expandable frame and similar implantable medical device, unite below Referred to as support, they are radially distensible endoprosthesises, usually being capable of in the implantable intravascular and footpath after being imported through skin To the blood vessel implant of expansion.In the implantable various body cavitys of support or various vasculars, such as vascular system, uropoiesis pipeline, courage Pipe, fallopian tubal, coronary vasodilator, secondary vascular etc..Support can be used to support body vessel and prevent from entering promoting circulation of blood in vascular system ISR after Tuboplasty.They can be self expandable, such as expanded by inner radial power when being installed on sacculus, Or the combination (hybrid expansible) of self expandable and balloon expandable.
Known building material for support includes polymer, organic fabric and biocompatible metal.Have been used for construction branch The alloy of the metal and/or these metals of frame and/or its component include but is not limited to stainless steel, iron, magnesium, gold, silver, tantalum, titanium, The marmem of chromium, cobalt and NiTi etc.The conventional degradation material of support includes, polymer, such as PLA (PLA), metal, such as iron, magnesium etc., but, polymer, such as PLA are easily caused in acid matrix in degradation process Microenvironment, and sour environment can be unfavorable for the further reparation and growth of organizational environment, metal, such as magnesium and iron, its degraded speed Spend it is fast or excessively slow, while there is the poor defect of biocompatibility.
Since inserting human body from first bare mental stents (BMS) in 1985, list has been solved support Successful treatment with interventional Pure balloon expandable epoch restenosis rate problem very high, the Main Means as clinical treatment.ISR (ISR) is local vascular A kind of after damage repairs reaction, in blood platelet after its formation mechenism is mainly arterial endothelium and smooth muscle cell (SMC) is damaged The knots such as the SMC caused under various biological factor effects such as attached wall, factors stimulated growth breeds and divided a word with a hyphen at the end of a line to inner membrance, thrombosis Really.Support inserts the damage that process is caused to local vascular inner membrance, have stimulated endangium hyperblastosis and smooth muscle cell Hyperplasia.Thrombus is re-formed etc. and causes ISR, and the case for still having 20%~30% can occur in-stent restenosis, in glycosuria In disease, Small vessel, Long lesion, Chronic total occlusion and bifurcated lesions patient, ISR incidences may be up to 30%~ 70%.Therefore, ISR has turned into the topmost reason of influence stenter to implant operation long-term efficacy.
Bracket for eluting medicament (DrugElutingStent, DES) came out in 2002, and compared with BMS, DES is in inhomogeneity There is significant advantage in the coronary artery pathological changes of type, percutaneous coronary intervention (pci) (PCI) postoperative restenosis incidence is big Width reduction.But when DES starts to be widely used in clinic, the problem that advanced thrombus are formed in the support but emersion water surface.Its Mechanism includes that blood vessel is incomplete to the high response of drug/polymer coating, support endothelialization and adherent bad etc..Medicine exists Intercellular membrane hyperplasia is greatly suppressed during the degraded release of polymer, while stenter to implant ISR problem is reduced Cause cell climb skin reduce and so that support is difficult to the problems such as well being healed with vascular wall.Although the extension antiplatelet treatment of duplex Journey may reduce the generation of advanced thrombus in support, but bring hemorrhage risk simultaneously.
The coating stent of medicine of common pre- anti-restenosis is mainly and contains the medicines such as rapamycin, taxol, antibody at present Thing coating bracket, but coating medicine, such as rapamycin etc., mainly suppress propagation and the migration of smooth muscle, but also press down simultaneously The propagation of endothelial cell processed, destroys vessel endothelialisation, postpones the normal healing of blood vessel.
It is known, can exist by the electric charge of rack surface, suppress blood coagulation so as to ISR caused by anti-tampon. US2006/0106451 discloses an electronics anticoagulation supporting structure.The supporting structure includes a pair of coaxial metal supports, its With one layer of dielectric substance between support.Preferably, a battery is used to connect near or adjacent in the support arrangement Upstream end.The positive terminal of battery sets up an electric connection and negative pole end and sets up one with interior metal support with external metallization support It is electrically connected with, this shows the characteristic of similar electric capacity.Negatively charged interior metal support repels blood platelet, with antithrombotic shape Into effect.CN104093431 discloses the support with electret structure coating, and electret structure is by coating five oxidations Two tantalums or polytetrafluoroethylene (PTFE) are formed in support.But the above structure preparation technology is complicated, while needing to introduce human body group Knit the incompatible or composition that cannot degrade, the biocompatibility reduction of support is easily caused, so as to equally suppress endothelial cell Propagation, postpone blood vessel normal healing.
Endothelial cell (EC) layer is an important composition of normal blood vessels wall, there is provided blood flow and vascular wall surrounding tissue One interface.Endothelial cell also participates in physiological activity, such as blood vessel generation, inflammation and anti-tampon.(Rodgers GM.FASEB J.1998；2：116-123.).The endothelial cell of activity " can discharge a series of VSMC growth factors or inhibiting factor, so that Adjust the stability of endangium structure.In ripe interior cutaneous vessel, endothelium can effectively keep VSMC stable states.But work as pathology When learning structural change, such as when blood vessel tears by sacculus or stent-expansion, this equilibrium state will be broken, and cause endothelium VSMC Hyperplasia, so as to cause ISR of Endothelial Dysfunction generation etc..
By the local delivery vascular endothelium growth factor after structural transplantation enters (VEGF, a kind of endothelial celi Disintegrating agent) promote the endothelial cell (CN103566418B) is grown on rack surface, but it is proved the effect of single dose delivering It is that very low and generation effect is inconsistent.Therefore, this method is not that can accurately repeat very much each time.Also in having used The graft of chrotoplast inoculation synthesis, but the clinical effectiveness of endothelium inoculation is typically poor, it is likely that because cell is to graft EC functions are lost without adhesion property and/or because of isolated operation.CN105327399 provides a kind of structure side of artificial blood vessel Method, it introduces with hydrophily and negative electrical charge polypeptide gene on surface and promotes the prokaryotic system expression of cell adhesion polypeptide gene Carrier (Journal of DonghuaUniversity (EnglishEdition), 2012,29:26-29；Bio-Medical MaterialsandEngineering,2014,24:2057-2064) surface hydrophilicity and negative electrical charge, are improved, is improve Endothelialization potentiality, are conducive to organization healing and anti-freezing solid, but the technology is applied to structure artificial blood vessel, wherein the material for using Including terylene, it is clear that for the intravascular stent field for needing to be degraded after hemadostewnosis treatment is completed, the material exists natural Non-biocompatible, the mechanic properties required for intravascular stent can not be provided, meanwhile, just as described above, endothelium is thin If born of the same parents' propagation is unable to maintain that stable state can cause the formation of reangiostenosis on the contrary.
Accordingly, it is desirable to provide a kind of timbering material, for being implanted into, to assign the biocompatibility needed for it, is keeping branch While frame support force, possess EC layers of balance and climb and cover, suppress ISR, and recovering blood vessel self performance in good time.
The content of the invention
It is a kind of timbering material for possessing biocompatibility particularly the present invention relates to a kind of prosthetic material, is more suitable for , for blood vessel inner bracket material.
The material possesses matrix, it is preferred that the material of matrix is tissue degradable in vivo, polymer, such as polyester, Condensing model, polyaminoacid, poly phosphazene, poly- polysaccharide etc. and its copolymer and mixture, including PLA, polyglycolic acid, poly- (breast Acid-glycolic), polycaprolactone, shitosan, glucan, chitin, poly- capric anhydride, one kind of polyvinyl alcohol etc. or its mixture Or it is several；Metal, such as iron, magnesium, ferroalloy or magnesium alloy.Described matrix is tubulose, the surfaces externally and internally for possessing tubulose, inner surface Constitute the passage that tissue fluid passes through, such as blood.There is the structure of connection interior outside, such as hole, the hole on the surface Can be circle, ellipse, rectangle, rhombus etc..
There is microcavity in the connection interior outside structure, for example, the hole position is cut in matrix bodies and axially vertical Possess microcavity on the direction of face, the release Fe that can degrade is mounted with microcavity3+Material, it is preferred that the material is in organizer The composition of the material of interior controlled degradation, preferably microencapsulation form, the composition is included as the degradable polymerization of " shell " Thing, and as the Fe of " core "3+Water soluble chelate compound/complex compound, it is preferred that be amino acid chelated iron, such as histidine or half Cystine chelated iron.
The material possesses small peptide layer, and the small peptide layer is located on the surfaces externally and internally of matrix material, and the small peptide can be certainly Assembling forms hydrogel, it is preferred that the sequence of the small peptide of surfaces externally and internally is different.The hydrogel energy formed after the small peptide self assembly The enough specific regeneration covered with endodermis of climbing beneficial to endothelial cell.
Matrix material
Matrix material of the present invention possesses biodegradability, and possesses excellent biocompatibility.According to reality The application feature on border, skilled person will appreciate that, can for example be gathered by changing the composition or preparation method of matrix material The degree of polymerization/the molecular weight of compound, polymer and metal it is compound, multilayer degradation material it is compound etc., in the support in body Interior tube chamber is degradable after support function needed for completing, and controls its degradation cycle between 60 days to 24 months.
Microcavity
Microcavity is needed in the hole position in obtaining the microcavity on matrix bodies with axially vertical cross-wise direction.Can be with Understand, the plane and tubular bracket of the microcavity, i.e. its opening are obtained on the thickness direction through the hole of the support The substantially perpendicular relation of surfaces externally and internally.The microcavity has hemispherical or avette shape or with spheroid profile, its Described in the bottom of microcavity can be the close-shaped of arbitrary shape, particularly spill or non-concave.It should be noted that microcavity The shape and number of (such as micropore) determine the useful load for loading material first, and next determines the time used by release.Root According to specific feature, can be to the volume (i.e. the volume of each microcavity and thus the total measurement (volume) that provides) provided by microcavity by can Three parameters being used singly or in combination are controlled, make a reservation for and limit.
Volumetric void fraction parameter includes：The diameter dimension of (a) microcavity；The depth and shape of (b) microcavity closed bottom, to depth The purpose being controlled is to avoid causing mechanical weakness and potential rupture or fracture or crack in support；C () is present in branch The total number of the microcavity on frame.
In the present invention, it is preferred that its average diameter size is micron order, such as 25-150 μm, the depth dimensions of its bottom Between the 1/5-1/3 of the hole (if being non-hole shape, be its shape most short side) diameter, and the sum of the microcavity Mesh is more than 20 and less than 80.In one embodiment, the total number of microcavity is 30-60 on the support of 15mm.
In the present invention, it is undesirable to be load in microcavity material useful load and loading density it is excessive, do not expect its dress yet Carry that depth is too deep or excessively shallow so as to cause to load material too fast or cross On The Drug Release, present invention contemplates that be can be more Active component therein is discharged after the time of delay, described active component can be understood as release Fe as herein described3+'s Material.
Degraded release Fe3+Material
The material is the material of the controlled degradation in organizer, is a kind of composition, said composition to mix, it is miscible etc. Form is obtained, preferably a kind of composition of microencapsulation form, and the composition is included as the degradable polymer of " shell ", and As the Fe of " core "3+Water soluble chelate compound/complex compound, it is preferred that be amino acid chelated iron, such as histidine or cysteine Chelated iron.
Degradable polymer is the polymer of controlled degradation well known to those skilled in the art, for example, polyester, condensing model, Polyaminoacid, poly phosphazene, PLA, polyglycolic acid, poly- (lactic acid-ethanol), polycaprolactone, shitosan, glucan, crust Element, polyvinyl alcohol, collagen, gelatin and starch etc., the degradation cycle of these polymer can be known by those skilled in the art Mode it is modified, molecular weight control, concentration control, morphology Control etc. are adjusted, will not be repeated here.Degraded week Phase is between 7 days -3 weeks.Too fast degraded is easily caused the too fast release of wherein " core " moieties, it is impossible to the group needed for obtaining Knit, the normal generation of such as endodermis, so as to the risk for causing ISR increases, and excessively slow degraded is easily caused hyperblastosis Stable state is unable to maintain that, is unfavorable for preventing for ISR situation.
Fe3+Water soluble chelate compound/complex compound, it is preferred that be amino acid chelated iron, such as histidine or cysteine chela Close iron.It is understood that Fe3+It is weaker with the ionic bond adhesion formed in amino acid, can keep in pH environment in vivo Solubility faster higher, makes Fe3+Sufficient chemism is discharged or possessed in the form of an ion.Wherein, Fe3+Water-soluble chela Compound/complex compound weight content in the composition is 0.5-2%, preferably 0.8-1.5%
Small peptide layer
The small peptide can be self-assembly of hydrogel, and can it is specific beneficial to endothelial cell it is quick climb cover with it is interior The regeneration of cortex.
Preferably, the sequence of the small peptide of surfaces externally and internally is different, without homotactic small peptide self assembly can be produced to be formed Hydrogel, it is to be understood that two kinds of small peptides can contact with each other in the structure with connection interior outside.
It was found that, two kinds of different small peptides are respectively：
Sequence 1：(Arg-Ala-Asn-Ala)4-Arg-Ser-Lys-His-Ala-Lys；
Sequence 2：(Arg-Ala-Asn-Ala)4-Glu-Asp-Asp-Asp-Glu；
Or,
Sequence 3：(Arg-Ala-Asn-Ala)4-Glu-Glu-Tyr-Ile-Ser-Ser-Asp；
Sequence 4：(Arg-Ala-Asn-Ala)4-His-Lys-Lys。
Above-mentioned sequence can be in human body pH environment issue and be conigenous assembling, produce hydrogel, be that climbing for endothelial cell is covered Induction and matrix are provided with growth.It will be appreciated by persons skilled in the art that the hydrogel of generation possesses nanofiber form.
But, it is in Fe3+In the presence of, easily it is complexed with it, i.e. Fe3+Several peptide molecules can be assembled to arrive Around it, so that the peptide molecule to form nanofiber is consumed, along with consumption, by the morphogenetic hydrogel of the nanofiber Fade away its form, it is understood that is that hydrogel is in Fe3+In the presence of there occurs " degraded ".
Preferably, above-mentioned small peptide layer is coated in the surface of matrix material in method well known to those skilled in the art, is formed Thickness between 0.5-3mm.
The invention further relates to above-mentioned prosthetic material, specifically a kind of timbering material for possessing biocompatibility, is more suitable for Blood vessel inner bracket material preparation method.
Methods described includes：
Matrix material is obtained, described matrix is tubulose, the surfaces externally and internally for possessing tubulose, inner surface constitutes tissue fluid and passes through Passage, such as blood.There is the structure of connection interior outside, such as hole, the hole can be circular, oval on the surface Shape, rectangle, rhombus etc.；
Using known technology, such as laser engraving, microetch technology, in the thickness direction through the above-mentioned hole of the support Upper acquisition microcavity；Preferably, the microcavity has hemispherical or avette shape or with spheroid profile, its average diameter Size is micron order, such as 25-150 μm, and the depth dimensions of its bottom (is its shape if being non-hole shape positioned at the hole Shape most short side) diameter 1/5-1/3 between, and the total number of the microcavity is more than 20 and less than 80.In one embodiment, The total number of microcavity is 30-60 on the support of 15mm；
Obtained in the form such as mixing, miscible, preferably a kind of composition of microencapsulation form, the composition includes conduct The degradable polymer of " shell ", and as the Fe of " core "3+Water soluble chelate compound/complex compound, it is preferred that be chelating amino acids Iron, such as histidine or cysteine chelated iron.The degradable polymer is controlled degradation well known to those skilled in the art Polymer, for example, polyester, condensing model, polyaminoacid, poly phosphazene, PLA, polyglycolic acid, poly- (lactic acid-ethanol), poly- Caprolactone, shitosan, glucan, chitin, polyvinyl alcohol, collagen, gelatin and starch etc., degradation cycle between 7 days -3 weeks, It is preferred that between 10 days -2 weeks.Wherein, Fe3+Water soluble chelate compound/complex compound weight content in the composition be 0.5-2%, It is preferred that 0.8-1.5%；
Using known technology, such as technique such as dipping, spraying, ink-jet or atomization loads above-mentioned group in the microcavity Compound, wherein Fe3+Water soluble chelate compound/complex compound load capacity on the prosthese axial length of every mm be 4-15 μ g, preferably 5-10μg；
Using known technology, such as technique such as dipping, spraying, atomization or ink-jet, on two surfaces of described matrix It is respectively coated with small peptide coating, it is preferred that the sequence of the small peptide of surfaces externally and internally is different, and two kinds of small peptides can contact with each other, preferably , contacted with each other in the structure with connection interior outside；In one embodiment, also containing active in the small peptide coating Composition, for example, rapamycin, taxol, sirolimus, VEGF, dexamethasone or combinations thereof etc., it is preferred that contain ground Sai meter Song, is disappeared with the structure for delaying hydrogel.
Technique effect
The self assembly that the present invention passes through small peptide coating, specific quickly climbing beneficial to endothelial cell is formed in prosthetic surface The hydrogel with the regeneration of endodermis is covered, the hydrogel can discharge Fe in the micro-cavity structure of prosthese3+Water soluble chelate compound/ Gradually recurring structure disappears/degrades, so that the balanced growth of recovery organization particularly endodermis, it is to avoid endothelium work(after complex compound Can the disorderly ISR for producing.Therefore, the biocompatibility needed for prosthese of the present invention can assign it, is keeping support While support force, possess EC layers of balance and climb and cover, suppress ISR, and in good time recovery organization, particularly blood vessel itself Performance.
Those skilled in the art will readily appreciate that the present invention can be used to carry out various treatments in vivo individual.According to Hereinafter illustrative description, with reference to several embodiments of the invention or embodiment, other objects of the present invention, feature and Advantage will be become apparent, and the embodiment or embodiment are given merely in an exemplary manner, and it is never in any form Limitation the scope of the present invention.
Embodiment
Embodiment 1
The preparation of the prosthese (preferably endovascular stent) with microcavity and small peptide coating
Step 1：The matrix material of prosthese, the tubular material of degradable pure iron are obtained, and makes it that there is connection on the surface The hole of interior outside；
Step 2：Using laser-engraving technique, microcavity is obtained on the thickness direction through the above-mentioned hole of the prosthese；Institute Stating microcavity has domed profiles, and its diameter dimension is 30 μm, and the depth dimensions of its bottom is the 1/3 of the bore dia, and institute The total number for stating microcavity is 30；
Step 3：Using routine techniques, the composition of microencapsulation form is obtained, the composition is included as the bright of " shell " Glue, and used as the histidine chelated iron of " core ", wherein histidine chelated iron weight content in the composition is 0.5%, described The degradation cycle of gelatin is 7 days or so；
Step 4：Using spraying coating process, above-mentioned composition, the wherein load of histidine chelated iron are loaded in the microcavity Amount is 4 μ g on the prosthese axial length of every mm；
Step 5：Using impregnation technology, small peptide coating, and two kinds of small peptides are respectively coated with two surfaces of described matrix Can contact with each other, two kinds of sequences of small peptide are respectively previously described sequence 1 and sequence 2；
Step 5：Dry, sterilizing, packaging obtains the prosthetic material.
Embodiment 2
The preparation of the prosthese (preferably endovascular stent) with microcavity and small peptide coating
Preparation process is same as Example 1, and difference is：The matrix material used in step 1 is degradable poly caprolactone； A diameter of 50 μm of microcavity in step 2, the depth dimensions of bottom is the 1/4 of the bore dia, and microcavity total number is 40；Step 3 Described in shell be shitosan, degradation cycle is 1 week or so, and the core is cysteine chelated iron, and its center is in the composition Weight content is 0.8%；Load capacity is 8 μ g in step 4.
Embodiment 3
The preparation of the prosthese (preferably endovascular stent) with microcavity and small peptide coating
Preparation process is same as Example 1, and difference is：The matrix material used in step 1 is degradable pure magnesium；Step A diameter of 100 μm of microcavity in 2, the depth dimensions of bottom is the 1/5 of the bore dia, and microcavity total number is 60；Institute in step 3 Shell is stated for collagen, degradation cycle is 2 weeks or so, and the core is cysteine chelated iron, and its center weight in the composition contains Measure is 1.5%；Load capacity is 10 μ g in step 4；Two kinds of sequences of small peptide are respectively previously described sequence 3 and sequence in step 5 Row 4.
Embodiment 4
The preparation of the prosthese (preferably endovascular stent) with microcavity and small peptide coating
Preparation process is same as Example 1, and difference is：The matrix material used in step 1 is that polycaprolactone and shell are poly- Sugared mixture；A diameter of 150 μm of microcavity in step 2, microcavity total number is 80；Shell described in step 3 is poly- (lactic acid-glycolic Acid), degradation cycle is 3 weeks or so, and its center weight content in the composition is 2%；Load capacity is 15 μ g in step 4；Step Two kinds of sequences of small peptide are respectively previously described sequence 3 and sequence 4 in rapid 5.
Embodiment 5
The preparation of the prosthese (preferably endovascular stent) with microcavity and small peptide coating
Preparation process is same as Example 1, and difference is：Contain weight content 0.2- in step 5 in the coat of small peptide 0.6% dexamethasone.
Embodiment 6
The preparation of the prosthese (preferably endovascular stent) with microcavity and small peptide coating
Preparation process is same as Example 1, and difference is：Contain weight content 0.2- in step 5 in the coat of small peptide 0.6% rapamycin.
Comparative example 1
Preparation process is similar to Example 1, and difference is：There is no step 5, i.e., do not coat small peptide coating.
Comparative example 2
Preparation process is similar to Example 1, and difference is：There is no step 2-4, i.e., no micro-cavity structure and microencapsulation form Composition.
Comparative example 3
Preparation process is similar to Example 1, and difference is：A diameter of 30 μm of microcavity, the depth dimensions of bottom in step 2 It is the 1/8 of the bore dia, microcavity total number is 80.
Comparative example 4
Preparation process is similar to Example 1, and difference is：A diameter of 200 μm of microcavity, the depth gauge rule of bottom in step 2 Very little is the 1/4 of the bore dia, and microcavity total number is 120.
Comparative example 5
Preparation process is similar to Example 1, and difference is：A diameter of 40 μm of microcavity, the depth dimensions of bottom in step 2 It is the 1/2 of the bore dia, microcavity total number is 50.
Comparative example 6
Preparation process is similar to Example 1, and difference is：Shell described in step 3 is poly- (L- lactides), and degradation cycle is 45 days or so.
Comparative example 7
Preparation process is similar to Example 1, and difference is：Shell described in step 3 is oxycellulose, and degradation cycle is 5 It or so.
Comparative example 8
Preparation process is similar to Example 1, and difference is：Load capacity is on the prosthese axial length of every mm in step 4 It is 1 μ g.
Comparative example 9
Preparation process is similar to Example 1, and difference is：Load capacity is on the prosthese axial length of every mm in step 4 It is 30 μ g.
Cell culture experiments in vitro
3-6 generations are taken after the passage of transgenosis expansion of endothelial cells, with concentration 3 × 104Cell/ml is followed together with imitative tissue body fluid Support sample prepared by ring continuous pouring embodiment and comparative example, flow velocity gradually increases from 0.033 to 0.1ml/s in control sample cavity Height, 1 × 10 is about in the corresponding shear stress of vascular wall-2N/m2To 4 × 10-2N/m2Between, above circulation continuous pouring continues 1 Individual month, detected through light microscopic and Electronic Speculum, silver staining, observe its endothelialization degree, fluorescence microscope display endothelial cells secrete is extracellular Matrix situation, the results are shown in Table 1.
Table 1
Test above and show, endothelialization is more successfully made in preparation process condition lower support surface of the invention, and Endothelial cell also can extracellular matrix secretion, show that endothelial cell can be in rack surface normal growth.But the branch in comparative example The endothelial cell growth pattern on frame surface is undesirable.
Zoopery
Support inserts the foundation of model：
Three monthly ages small-sized health pig, the preoperative 3 days beginnings feed aspirin (300mg/d) and clopidogrel (75mg/ daily D), 10h fasting for solids and liquids.
The intramuscular injection of 0.05ml/kg dosage is pressed with the land peaceful II of dormancy to anaesthetize, lain on the back after Animal Anesthesia and be fixed on operating table, set up vein Path, trachea cannula and assisted mechanical ventilator
Skin and musculature are cut successively, thin vessels are ligatured, and separate femoral artery blood vessel, intravenous injection heparin (1mg/ Kg body weight), clamp the proximal part and distal end blocking blood flow of femoral artery respectively with blood vessel clip, indulged at the femoral artery of blocking blood flow To 1cm otch is cut, support prepared by the embodiment of sterilizing and comparative example is cut along femoral artery and is put into femoral artery inner support, planted Enter art selection blood vessel nearly stage casing as stenter to implant at, branch vessel is avoided as far as possible.The ratio between support and blood vessel diameter for 1.1~ 1.2:1, blood vessel otch is sutured with blood vessel suture, after unclamping near, distal end blood vessel clip, examine previous anastomotic whether there is oozing of blood, really Determine without layer-by-layer suture musculature and skin after oozing of blood, skin surface smears Iodophor, and is wrapped up with sterile gauze.Postoperative animal is given The U intramuscular injection 3d of penicillin 800,000 are given, prevention infection is normal to raise.
Each of the above embodiment and comparative example take 5 and are tested, and following result is average value.
After 2 months, euthanasia pig extracts the support in blood vessel out, is made 5 μm of paraffin sections of thickness, and shooting image is simultaneously Picture editting is carried out in Computer digital image analysis to obtain percent lumen stenosis, Hematoxylin-eosin (HE) dyeing observation Capillary situation in film in vascular thrombosis, inner membrance, adventitia, immunofluorescence dyeing observation endothelial cell, smooth muscle cell situation, The results are shown in Table 2.
Table 2
More than experiment show that compared with contrast groups, support of the present invention has patency rate very high, without thrombosis and Endometrial hyperplasia, there is capillary in film in adventitia, and has more been successfully formed autologous endothelialization, and display implantation after-poppet is gradually Recover the 26S Proteasome Structure and Function similar to normal blood vessels.

Claims (10)

1. a kind of biocompatibility endoprosthesis materials, it includes：
Matrix：The material of described matrix is tissue degradable in vivo, and described matrix is tubulose, the surfaces externally and internally for possessing tubulose, Inner surface constitutes the passage that tissue fluid passes through, such as blood, the structure on the surface with connection interior outside, such as hole；
Microcavity：The microcavity is in the hole position in acquisition on matrix bodies with axially vertical cross-wise direction, the microcavity position In on the thickness direction in hole, the plane of its opening and the substantially perpendicular relation of surfaces externally and internally of tubular bracket；
Composition：It is loaded in microcavity, can degrade release Fe3+；
Small peptide layer：The small peptide layer is located on the surfaces externally and internally of matrix material, and the small peptide can be self-assembly of hydrogel, institute Stating the hydrogel that is formed after small peptide self assembly being capable of the specific regeneration covered with endodermis of climbing beneficial to endothelial cell.
2. the prosthetic material described in claim 1, it is characterised in that：The material of described matrix is selected from, polymer, such as polyester, Condensing model, polyaminoacid, poly phosphazene, poly- polysaccharide etc. and its copolymer and mixture, including PLA, polyglycolic acid, poly- (breast Acid-glycolic), polycaprolactone, shitosan, glucan, chitin, poly- capric anhydride, one kind of polyvinyl alcohol etc. or its mixture Or it is several；Metal, such as iron, magnesium, ferroalloy or magnesium alloy.
3. the prosthetic material described in claim 1 or 2, it is characterised in that：The average diameter size of the microcavity is micron order, example Such as 25-150 μm, the depth dimensions of its bottom is located between the 1/5-1/3 of the bore dia, and the total number of the microcavity is more than 20 and be less than 80.
4. the prosthetic material described in claim 3, it is characterised in that：The composition is the composition of microencapsulation form, described Composition includes that as the degradable polymer of " shell " degradation cycle of the degradable polymer is between 7 days -3 weeks, and makees It is the Fe of " core "3+Water soluble chelate compound/complex compound, the Fe3+Water soluble chelate compound/complex compound weight in the composition Amount content is 0.5-2%.
5. the prosthetic material described in claim 4, it is characterised in that：The degradable polymer as " shell " is selected from, polyester, Condensing model, polyaminoacid, poly phosphazene, PLA, polyglycolic acid, poly- (lactic acid-ethanol), polycaprolactone, shitosan, Portugal gather Sugar, chitin, polyvinyl alcohol, collagen, gelatin and starch；The Fe as " core "3+Water soluble chelate compound/complex compound be ammonia Base acid chelated iron, the Fe3+Water soluble chelate compound/complex compound load capacity on the prosthese axial length of every mm be 4-15 μ g。
6. the prosthetic material described in claim 3, it is characterised in that：The sequence of the small peptide of surfaces externally and internally is different, two kinds of small peptide energy It is enough to be contacted with each other in the structure with connection interior outside.
7. the prosthetic material described in claim 6, it is characterised in that：Two kinds of different small peptides are respectively：
Sequence 1：（Arg-Ala-Asn-Ala）4-Arg-Ser-Lys-His-Ala-Lys；
Sequence 2：（Arg-Ala-Asn-Ala）4-Glu-Asp-Asp-Asp-Glu；
Or,
Sequence 3：（Arg-Ala-Asn-Ala）4-Glu-Glu-Tyr-Ile-Ser-Ser-Asp；
Sequence 4：（Arg-Ala-Asn-Ala）4-His-Lys-Lys。
8. the prosthetic material described in claim 7, it is characterised in that：The small peptide layer forms 0.5- on the surface of matrix material Thickness between 3mm, active component is also contained in the small peptide coating, is selected from, rapamycin, taxol, sirolimus, VEGF, dexamethasone or combinations thereof.
9. the preparation method of any described prosthetic materials of claim 1-8, including：
Matrix material is obtained, described matrix is tubulose, the surfaces externally and internally for possessing tubulose, it is logical that inner surface composition tissue fluid passes through Road, such as blood, the hole on the surface with connection interior outside, the hole can be circle, ellipse, rectangle, rhombus etc.；
Microcavity is obtained on the thickness direction through the above-mentioned hole of the support；The microcavity has hemispherical or avette shape Or with spheroid profile, its average diameter size is 25-150 μm, the depth dimensions of its bottom is located at the bore dia Between 1/5-1/3, and the total number of the microcavity is more than 20 and less than 80；
A kind of composition of microencapsulation form is obtained in the form such as mixing, miscible, the composition includes dropping as " shell " Depolymerization compound, and as the Fe of " core "3+Water soluble chelate compound/complex compound；The Fe3+Water soluble chelate compound/complex compound be Amino acid chelated iron；The degradable polymer is selected from, polyester, condensing model, polyaminoacid, poly phosphazene, PLA, PVOH Sour, poly- (lactic acid-ethanol), polycaprolactone, shitosan, glucan, chitin, polyvinyl alcohol, collagen, gelatin and starch etc., Degradation cycle is between 7 days -3 weeks；Fe3+Water soluble chelate compound/complex compound weight content in the composition be 0.5-2%；
Above-mentioned composition, wherein Fe are loaded in the microcavity3+Water soluble chelate compound/complex compound load capacity every mm vacation It is 4-15 μ g on body axial length；
Small peptide coating is respectively coated with two surfaces of described matrix, the small peptide of surfaces externally and internally is in the knot with connection interior outside Contacted with each other on structure.
10. purposes of any described prosthetic materials of claim 1-8 in built-in prothesis are prepared.
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