A kind of Biodegradable scaffold with laminated coating
Technical field
The invention belongs to medical instruments field, relate to a kind of Biodegradable scaffold, comprise rack body, it is characterized in that having two-layer functional coating at least on the rack body surface with laminated coating.
Technical background
As the narrow important means of treatment human lumen, support has obtained application more and more widely.With the intravascular stent is example, and in the therapeutic process, support is transported to the blood vessel of pathological changes (narrow) by conduit, in the mode of balloon expandable or self-expanding, stent diameter is become big then, struts narrow positions.
Present widely used support is metal material, forever remains in the human body after treatment is finished.Can weaken the MRI or the CT image of blood vessel after permanent metal rack is inserted, in addition, also there is interference surgery myocardial revascularization in metal rack, hinders the formation of collateral circulation, suppresses the some shortcomings that the blood vessel positivity is reinvented.Based on such problem, Biodegradable scaffold has caused widely and has paid close attention to as possible solution.Biodegradable scaffold is made by degradable material, can play the effect of support blood vessels after implanting lesion locations in a short time.After treatment was finished, support was degraded in the human body environment and can be absorbed by the body, metabolic Organic substance, and final support disappears.
In order to prevent that the problem of restenosis from appearring in lesion vessels in a short time after treatment, Biodegradable scaffold can apply one deck and have inhibition inner membrance and the outgrowth medicine of smooth muscle cell, thunderous handkerchief mycin, paclitaxel etc. on the support top layer.
The common material that is used for Biodegradable scaffold as polylactic acid, polyglycolic acid, polycaprolactone, magnesium metal etc., all has the characteristic of whole degraded.After support was implanted a period of time, the timbering material degraded produced the fritter fragment.If this moment, support still exposed in blood vessel, the degraded fragment just may be along with blood circulation, flows to cause little blood vessel embolism in the littler blood vessel.In order to prevent this danger, before degraded produces fragment, just support need be wrapped in the tunica intima the inside, i.e. the complete endothelialization of support.How guaranteeing in time timbering material to be wrapping among the tunica intima is a very important problem.
Yet, the material of Biodegradable scaffold such as degradable polymer etc., the developing performance under X-ray is all bad, and is invisible under the X-ray even.In order to determine backing positions by X-ray in operation process, the developing performance that improves support also is a problem of needing solution badly.
In addition, also there is certain limitation in prior art, when solving a problem, usually brings otherwise danger.With the visualization way is example, and prior art mainly adopts the mode of adding development point (ring) on support, perhaps developing material is added directly in the rack body.Yet development point (ring) and developing material all are nondegradable materials.Degraded along with support, development point (ring) remains in the human body, might be in free state and cause thrombosis then, even support is being covered by the newborn endotheliocyte of one deck before the degraded fully, the development point (ring) of rack surface or inside and developing material are surrounded by vascular endothelial cell and do not dissociate, but the biocompatibility of developing material and vascular endothelial cell is a problem that merits attention.And development point (ring) and developing material long-term existence also can cause interference to later x-ray in the middle of blood vessel endothelium.
U.S. Pat 20080288057 discloses at the aglucon of stent surface coated one layer of polymeric with the link biologically active, and these aglucons can be caught the CFU-GM of endotheliocyte in blood, urge the into growth of vascular endothelial cell on support.
U.S. Pat 20080103584 discloses and x-ray contrast agent is coated in rack surface as coating has made support have the method for X-ray observability.But this patent is emphasized is outer surface with support, just carries out coating near the one side of blood vessel wall.The used material of coating is a contrast agent itself, perhaps the simple mixed blend of contrast agent and polymer.
U.S. Pat 5443458 discloses a kind of mounting system of overbrushing layer.Rack body is a Biodegradable material, and the coating material of rack surface is the degradable coating that contains medicine, and the medicine of external surface coating is for suppressing the medicine of neointimal hyperplasia, and the medicine of coating on inner surface is a thrombolytic drug.
United States Patent (USP) 20090204203 discloses by add the method that the point that develops develops support to support.
As mentioned above, development all is the major issue that the Biodegradable scaffold system must solve under support blood vessels, anti-restenosis, short interior membranization and the X-ray.The problem of some aspects that prior art may exist at Biodegradable scaffold provides solution, but the neither one mounting system can systematically solve above-mentioned all problems.
Summary of the invention
The invention provides a kind of Biodegradable scaffold, comprise the rack body of making by Biodegradable material, it is characterized in that containing medication coat at least, promote two-layer in endothelial cell growth layer and the development key-course at rack surface with laminated coating.
The Biodegradable scaffold main body is to be made by biodegradable metal material or macromolecular material, and the biodegradable metals material comprises magnesium metal, ferrum etc.; The copolymer of degradable high polymer material such as polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid, polycaprolactone, polydioxanone, poly-anhydride, polytyrosine, poe, Merlon or the like.According to the difference of material, support degradation cycle in vivo can be selected arbitrarily from one month by 3 years.
Medication coat is a carrier by biodegradable polymer, is loaded with to suppress inner membrance and the outgrowth medicine of smooth muscle cell.The shared percentage by weight of medication coat Chinese medicine is 10%-60%.Biodegradable polymer as carrier comprises: the copolymer of polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid, polycaprolactone, polydioxanone, poly-anhydride, tyrosine Merlon etc.Preferentially select the degradable polymer of superficial degradations such as poly-anhydride, tyrosine Merlon for use.Suppress inner membrance and the outgrowth medicine of smooth muscle cell and comprise rapamycin, paclitaxel and derivant thereof etc.
Promote the endothelial cell growth layer to be loaded with the factor or the aglucon of biologically active.This coating can be caught the endothelial progenitor cells in the blood or be promoted the growth of endotheliocyte at rack surface.The factor or the aglucon of this one deck comprise: CD34 antibody, CD133 antibody, cell divising regulatory gene, actin, endothelial cell growth factor (ECGF) etc.
The development key-course is mainly made by the polymer that contains the X-ray developing cell.The polymer that contains the X-ray developing cell comprises: the degradable high polymer material that contains x-ray contrast agent with polymerization or blend form, perhaps, perhaps contain the degradable high polymer material of metal nanoparticle and derivant thereof for containing the degradable high polymer material of iodine atomic radical.X-ray contrast agent can be the contrast agent that is used for the blood radiography, comprising: one or more in amidotrizoic acid, bis-conray, the general glucose of first, iotrolan, Iopromide, iohexol, iodixanol and the ioversol.The development key-course can decompose in 3 months and finishes, and was discharged in the blood metabolism then to external.
When the outside of development key-course at medication coat, medicine must just can be discharged in the blood vessel by the development key-course and go, and the key-course that therefore develops can play the effect of control drug release speed in the early stage simultaneously.By regulating the thickness and the coating material of development key-course, speed that can control drug release.
The present invention has medication coat and development key-course simultaneously on the surface of Biodegradable scaffold.This Biodegradable scaffold is after implanting lesion locations, and support force is strong, can play the effect of supporting lesion vessels in a short time.Position and expansion concordance thereof that the development key-course of rack surface can help the doctor accurately to observe support in operation prevent displacement, the generation of adverse events such as subside at once.Rack surface has the degradable coating that one deck contains medicine simultaneously, and the medicine of the inhibition neointimal hyperplasia in the coating can prevent the support implantation restenosis of blood vessel generation in a short time later on.When the development key-course is coated in outside the medication coat, the speed that the development key-course can control drug release, guarantee anti-proliferative drug in a period of time near at the uniform velocity discharging, effectively prevent vascular restenosis in a short time.Implant after a period of time, the degraded of development key-course excretes fully, and medicine also discharges and finishes.Because developing material is very fast to be gone out externally by metabolism, can not contact with the endotheliocyte of blood vessel, also increased the biological safety of support when having improved the support developing performance.
Support for the whole degraded of material of main part, has the endothelial cell growth of promotion layer simultaneously on the surface of Biodegradable scaffold, the coating of the promotion endothelial cell growth function on the support can promote the growth of endotheliocyte at rack surface, and support was wrapped up by blood vessel endothelium in six months.Though this moment, the rack body material began quick degraded, may be degraded into fractionlet, yet because support is surrounded by internal film tissue, the degraded fragment can not be shed to and remove to cause thromboembolism in the blood.But in blood vessel wall, further being degraded into small-molecule substance, the metabolism that is absorbed by the body is fallen.Support has good biological safety, has reduced the probability of degraded fragment initiation thromboembolism.
Description of drawings
In order to be illustrated more clearly in the application's technical scheme, accompanying drawing is done to introduce simply below in conjunction with embodiment.Apparently, the accompanying drawing in describing below only is some embodiment that put down in writing among the application, for those of ordinary skills, under the prerequisite of not paying creative work, can also obtain other accompanying drawing according to these accompanying drawings.
Fig. 1, Biodegradable scaffold structural representation.
Fig. 2, support and coating combination 1, the surfaces externally and internally of rack body all are covered with anti-narrow medicament slow release layer of one deck and development key-course from inside to outside successively.
Fig. 3, support and coating combination 2 are coated with the development key-course at the inner surface of support, and its outer surface distributing successively from inside to outside anti-restenosis medicament slow release layer and development key-course.
Fig. 4, support and coating combination 3 are covered with anti-restenosis medicament slow release layer and development key-course at the outer surface of support, apply short endothelial cell growth layer at the inner surface of support.
Fig. 5, support and coating combination 4 are covered with anti-restenosis medicament slow release layer at the outer surface of support, at the inner surface of support distributing successively from inside to outside short endothelial cell growth layer and development key-course.
Fig. 6, support and coating combination 5 are covered with anti-restenosis medicament slow release layer at the outer surface of support, are covered with the development key-course at the inner surface of support.
The specific embodiment
In order to make those skilled in the art person understand technical scheme among the application better, will the technical scheme in the embodiment of the present application be clearly and completely described below.Obviously, described embodiment only is the application's part embodiment, rather than whole embodiment.Based on the embodiment among the application, those of ordinary skills are not making the every other embodiment that is obtained under the creative work prerequisite, all should belong to the scope of the application's protection.
Embodiment one
As shown in Figure 2, the material of the rack body that provides of the embodiment of the present application is selected biodegradable macromolecular material polysalicylates anhydride.By the method for extruding, the polysalicylates anhydride is extruded into external diameter 3mm, the tubing of wall thickness 0.25mm.Utilize femto-second laser that tubing is cut into the support of length 12mm, supporting structure as shown in Figure 1.This rack body intensity is higher, effective support blood vessels, and can disappearing in degraded in the implantable intravascular 2 years, and material of main part is superficial degradation, can not produce the degraded fragment.
The mixed solution of rapamycin and polylactic acid is sprayed to the surfaces externally and internally of support by the method for spraying.Because support is an engraved structure, spray solution can attach the surfaces externally and internally at support uniformly.By the control spray time, the thickness that can control rapamycin medication coat (medicine proportion in coating is 20wt%) changes from 0.5-10 μ m.After treating that coating parches, again the solution of developing material is sprayed to the surfaces externally and internally of medication coat by the method for spraying.By the control spray time, the thickness that can regulate the development key-course changes from 10 μ m-100 μ m.Wherein the structure of developing material iohexol-lactic acid polymer is as follows:
M wherein, n, p represent the number of lactic acid units in the polymeric material, m, n, p 〉=0 and be not 0 simultaneously.By regulation and control m, n, the value of p, degradation speed that can telomerized polymer, and the mass percent 3%-46% of iodine in polymer.
Finish after these a series of operations, can obtain satisfactory multilamellar support, the bracket coating order as shown in Figure 2.
This multilamellar support pressure is held on the suitable sacculus, be transported to the narrow positions of blood vessel then, fill sacculus with expandable stent, thereby strut narrow blood vessel.In the whole surgery process, can see support profile clearly by X-ray machine.After support was implanted 3 months, by the state of radiography check support, find that support does not develop under X-ray, illustrate that coating material has decomposed to finish.The membranization process begins in observing simultaneously.Membranization was finished in intravascular ultrasound after 6 months was observed, and support is wrapped up by blood vessel endothelium fully.Clinical Follow-up after 2 years can't see support, illustrates that the rack body material degrades fully.Restenosis and other inflammation do not appear in whole implantation process medium vessels.
Embodiment two
As shown in Figure 3, the material of the rack body that provides of the embodiment of the present application is selected biodegradable macromolecular material poe.By the method for extruding, poe is extruded into external diameter 2.5mm, the tubing of wall thickness 0.15mm.Utilize femto-second laser that tubing is cut into the support of length 15mm, supporting structure as shown in Figure 1.This rack body intensity is higher, effective support blood vessels, and can disappearing in degraded in the implantable intravascular 3 years, and material of main part is superficial degradation, can not produce the degraded fragment.
Rapamycin and 1: 1 mixed solution of polysalicylates anhydride are sprayed to the outer surface of support by the method for spraying.Place an obstructing tube at internal stent during spraying, spray solution can't be attached at the support inner surface, thereby medication coat only is present in rack outer surface.By the control spray time, the thickness that can control the rapamycin medication coat changes from 0.5-10 μ m.
After treating that coating parches, the obstructing tube of inside is carefully extracted out, and then the mixed solution of iohexol and polylactic acid is sprayed to the surface of medication coat by the method for spraying.This moment, spray solution can attach the surfaces externally and internally at support uniformly by the hollow out place of support because the lining rod is extracted out.By the control spray time, the thickness that can regulate the development key-course changes from 10 μ m-100 μ m.
Finish after these a series of operations, can obtain satisfactory multilamellar support, the bracket coating order as shown in Figure 3.
The mode of this multilamellar support by balloon expandable strutted at diseased region.In the whole surgery process, the developing performance of support under X-ray is good.Implant in 1 month,, find support development variation, illustrate that the development key-course has begun degraded by the state of radiography check support.When implanting 6 months, radiography check does not observe support, illustrates that the development key-course has been degraded to finish.The membranization process began in intravascular ultrasound was observed.After 8 months, membranization was finished in intravascular ultrasound was found, support is wrapped up by blood vessel endothelium fully.After 3 years, Clinical Follow-up can't see support, illustrates that the rack body material degrades fully.Restenosis and other inflammation do not appear in whole implantation process medium vessels.
Embodiment three
As shown in Figure 4, the material of the rack body that provides of the embodiment of the present application is selected biodegradable macromolecular material polylactic acid.By the method for extruding, polylactic acid is extruded into external diameter 3mm, the tubing of wall thickness 0.16mm.Utilize femto-second laser that tubing is cut into the support of length 15mm, supporting structure as shown in Figure 1.This rack body intensity is higher, effective support blood vessels, and can disappear in degraded in the implantable intravascular 2 years.
Paclitaxel and 1: 2 mixed solution of polylactic acid are sprayed to the outer surface of support by the method for spraying.Place an obstructing tube at internal stent during spraying, spray solution can't be attached at the support inner surface, thereby medication coat only is present in rack outer surface.By the control spray time, the thickness that can control the taxol drug coating changes from 0.5-10 μ m.After treating that this coating parches, the mixture of ioversol-polysalicylates anhydride is sprayed to the outer surface of support.By the control spray time, the thickness that can regulate the development key-course changes from 10-100 μ m.After treating that coating parches, obstructing tube is extracted out from support carefully.
Then above-mentioned rack outer surface is covered with polytetrafluoroethylene film, carry out dip-coating in the mixed solution of immersion hyaluronate sodium and CD133 antibody, the support endosexine is coated one deck CD133 antibody.After the dip-coating, to support wash, dehumidify, drying, the thin film with rack outer surface carefully peels off then.
Can obtain satisfactory multilamellar support by aforesaid operations, rack outer surface is covered with two-layer uniform coating, is followed successively by anti-restenosis medicament slow release layer and development key-course, and inner surface is short endothelial cell growth layer, as shown in Figure 4.
The multilamellar support that preparation is finished is discharged into diseased region by the mode of balloon expandable.In the implantation process, can observe complete support overall structure by X-ray machine.Support can well play the effect of support blood vessels.After 1 month, radiography check finds that the developing performance of support disappears, and illustrates that the development key-course degrades.After 5 months, intravascular ultrasound finds that support is wrapped up uniformly by internal film tissue.After 2 years, follow up a case by regular visits to and find that support disappears, and illustrates that scaffold degradation finishes.The situation of restenosis and blood vessel embolism does not take place during this time.
Embodiment four
As shown in Figure 5, the material of the rack body that provides of the embodiment of the present application is selected biodegradable macromolecular material polylactic acid-glycolic guanidine-acetic acid copolymer.By the method for extruding, the polylactic acid-glycolic guanidine-acetic acid is extruded into external diameter 2.5mm, the tubing of wall thickness 0.17mm.Utilize femto-second laser that tubing is cut into the support of length 18mm, supporting structure as shown in Figure 1.This rack body intensity is higher, effectively support blood vessels, and the disappearance of can degrading in implantable intravascular 1-2.
Then above-mentioned rack outer surface is covered with polytetrafluoroethylene film, carry out dip-coating in the mixed solution of immersion hyaluronate sodium and CD133 antibody, the support endosexine is coated one deck CD133 antibody.After the dip-coating, to support wash, dehumidify, drying.Then support is immersed dip-coating in the mixed solution of iohexol-polylactic acid.This time time of immersion is unsuitable long, in order to avoid destroy the activity of CD133 antibody.After the dip-coating, support is carried out intensive drying.Then the thin film of support outside is peelled off carefully.
Subsequently rapamycin and 1: 1 mixed solution of poe are sprayed to the outer surface of support by the method for spraying.Place an obstructing tube at internal stent during spraying, spray solution can't be attached at the support inner surface, thereby medication coat only is present in rack outer surface.By the control spray time, the thickness that can control medication coat changes from 0.5-10 μ m.After treating that coating parches, obstructing tube is extracted out from support carefully.
Promptly can obtain multilamellar support in the accompanying drawing 5 by aforesaid operations.
This multilamellar support pressure is held on the corresponding sacculus, is transported to lesion locations, the support expansion is opened, play the purpose of support blood vessels by the method for balloon expandable.In the whole surgery process, support possesses developing performance preferably under X-ray machine.Implant after 1 month, radiography finds that the support developing performance disappears, and illustrates that support development key-course has been degraded to finish.After 3 months, the Vascular Ultrasonography follow-up observation has some internal film tissues to the support inner surface.After 5 months, Vascular Ultrasonography finds that support is wrapped up fully by internal film tissue.1.5 after year, follow up a case by regular visits to and find that support disappears, and illustrates that scaffold degradation finishes.The situation of restenosis and blood vessel embolism does not take place during this time.
Embodiment five
As shown in Figure 6, the material of the rack body that provides of the embodiment of the present application is selected biodegradable macromolecular material poe.By the method for extruding, poe is extruded into external diameter 3.0mm, the tubing of wall thickness 0.17mm.Utilize femto-second laser that tubing is cut into the support of length 16mm, supporting structure as shown in Figure 1.This rack body intensity is higher, effective support blood vessels, and can disappearing in degraded in the implantable intravascular 3 years, and material of main part is superficial degradation, can not produce the degraded fragment.
Then above-mentioned rack outer surface is covered dip-coating in the mixed solution of immersion iohexol-polylactic acid with polytetrafluoroethylene film.By the control time of immersion, can change from 0.5 μ m-30 μ m by control coating thickness.After the dip-coating, support is carried out intensive drying.Then the thin film of support outside is peelled off carefully.
Subsequently rapamycin and 3: 2 mixed solution of poe are sprayed to the outer surface of support by the method for spraying.Place an obstructing tube at internal stent during spraying, spray solution can't be attached at the support inner surface, thereby medication coat only is present in rack outer surface.By the control spray time, the thickness that can control medication coat changes from 0.5-10 μ m.After treating that coating parches, obstructing tube is extracted out from support carefully.
Promptly can obtain multilamellar support in the accompanying drawing 6 by aforesaid operations.
This multilamellar support pressure is held on the corresponding sacculus, is transported to lesion locations, the support expansion is opened, play the purpose of support blood vessels by the method for balloon expandable.In the whole surgery process, support possesses developing performance preferably under X-ray machine.Implant after 1 month, radiography finds that the support developing performance disappears, and illustrates that support development key-course has been degraded to finish.After 6 months, Vascular Ultrasonography is observed the part support and is wrapped up by internal film tissue.After 8 months, Vascular Ultrasonography finds that support is wrapped up fully by internal film tissue.After 3 years, follow up a case by regular visits to and do not observe support, illustrate that scaffold degradation finishes.Restenosis and other inflammation do not take place during this time.