CN103480045A - Fully degradable high molecular material cardiovascular stent - Google Patents
Fully degradable high molecular material cardiovascular stent Download PDFInfo
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- CN103480045A CN103480045A CN201310407004.7A CN201310407004A CN103480045A CN 103480045 A CN103480045 A CN 103480045A CN 201310407004 A CN201310407004 A CN 201310407004A CN 103480045 A CN103480045 A CN 103480045A
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Abstract
All coronary stents used on the current market are made of a metallic material, cannot be degraded and are remained in the coronaries of human bodies permanently once implanted. The new stent technology is developed towards the degradable high molecular material. The stent is made by melt-mixing PLLA (Poly L-Lactic Acid) and PLGA (Poly(Lactic-co-Glycolic Acid)) high molecules, so that sufficient mechanical support can be provided and the in-vivo degradation time is also much less than that of the pure PLLA stent. According to the stent, an original tube is injection molded, is annularly plasticized into a precursor tube and is laser-engraved into the stent; the stent has specific internal diameter and external diameter and is annularly coupled and clamped on a balloon when being implanted into the human body. The stent has sufficient strength and plasticity and good degradability and biocompatibility. The optimal ratio for melt mixing of PLLA and PLGA high molecules is discovered. According to the brand new technology, the annular distribution of a polymer molecular chain is effectively controlled and induced, and the damage to the polymer molecular chain is reduced as much as possible. The integral performance of the stent is affected through preferable structural design of the tube.
Description
Technical field
The invention belongs to three class medical instruments fields.Relate to extensible implantation class prosthese, relate more specifically to a kind of macromolecule angiocarpy bracket, after this polymeric stent implantable intravascular, launch with sacculus.Support is that the fully-degradable polymer material is made.The macromolecular material that the invention still further relates to this property support forms and preparation technology.
Background technology
One " implanting the class prosthese ", corresponding to a device that can be used for implanting body interior, within being placed on the dissection cavity, more particularly, " cavity " refers to the pipe of a cavity, as blood vessel.Support is an example of prosthese.Support is all generally cylindrical device, and its function is for enlarging vessel segment or other anatomical cavity, as urethra and bile duct.Support is often used in treating atherosclerotic angiostenosis.
How the treatment of disease sites carries and placing rack if relating to." conveying " refers to that the stent delivery system of introducing arrives the position that needs treatment by the pathological changes anatomical cavity; " placement " expanded corresponding to the endoluminal stent in top processing region.Carry and placing rack by an end of locating support conduit, by skin, insert the end of conduit, enter anatomical cavity, be advanced to desirable treatment position at the conduit of anatomical cavity, prop up support on the position for the treatment of, then take out the tube chamber of conduit.
The normal conditions menisectomy is all used sacculus to prop up support.This support is installed on the conduit by air bag.Mounting bracket is usually directed to the hoop compression or is crimped on the sacculus of support, then to inflated, props up support, and last sacculus is exitted and withdraws from conduit.
Support must meet certain mechanical performance.At first, at support, must can bear structural loads, can bear the blood vessel compression stress on support that is applied to of hoop, thereby the support to blood vessel wall is provided.Support must possess enough hoop intensity.Hoop intensity refers to the ability of stent support hoop compression stress and the ability that hoop launches, and is the strength and stiffness of the support on the circumferencial direction around it.Therefore, also can be described to hoop strength and rigidity.
The second, once support struts, it must fully keep its size and shape in its whole service life in process, comprises the heartbeat that cyclic loading causes.This cyclic loading can not cause the plastic deformation of support hoop direction, otherwise can reduce Clinical efficacy.
In addition, support must have intensity and the toughness that enough CYCLIC LOADING for after clinical crimping, placement and placement are born.Support vertically can extend flexibly and shrink is very important, and in addition, support must have good biocompatibility, in order to do not trigger any bad reaction.
The tubulose that the structural design of support normally is complementary with blood vessel, tube wall is carved with penetrating pattern, and pattern often is designed to network structure.The reasonable mechanical structure design of pattern and the key property of material are to guarantee that support can bear hoop compression (being installed on sacculus allowing) and circumferential expansion (permission placement).
Existing coronary artery bracket is all metal material, comprises rustless steel, cochrome, platinum evanohm etc.What most patients installed is to scribble the coating stent of medicine of medicine in metal surface, once insert, will forever remain in the arteria coronaria of human body.In order to improve the safety of drug stent, new support technology is constantly towards the future development of degradable macromolecule and better biocompatibility macromolecule.Up-to-date noticeable support is exactly Biodegradable scaffold (Bioabsorbable stent).The biodegradable intravascular stent (BVS, Bioresorbable Vascular Scaffold) only used in the listing of global minority hospital at present.
The art-recognized polymeric stent that affects keeps the factor of structural behaviour integrity to have: external load, and as coupling and inflation power.These interactive factors still imperfectly understand the mechanism that affects of support.
Traditional support is the Metal Drugs support.The analysis that some are generally acknowledged or empirical method/model are for predicting that the behavior of metal rack often is not suitable for polymeric stent, and existing model can not be predicted the implantation performance of polymeric stent usually.
The present invention adopts the macromolecular material of degradable to make support, the macromolecular material that material therefor is PLLA and PLGA melting mixing.And macromolecular material and metallographic phase ratio have lower strength-weight ratio, therefore that polymeric stent is generally done than metal rack is thicker wider, reached mechanical property and the metallic equivalent of polymeric stent.In addition, polymeric stent fragility often.So the design of polymeric stent, the mode that is installed, the techniques such as sterilization method can not be indiscriminately imitated metal rack, thereby all need again to grope.
Existing BVS support is because component is PLLA, so about 3～4 years of its vivo degradation time.And the present invention adopts macromolecule melting mixing composition, can not only provide enough mechanics to support as support, and the vivo degradation time also can be significantly less than pure PLLA support.
Summary of the invention
First aspect of the present invention provides a kind of fully-degradable polymer material angiocarpy bracket of being made by polylactic acid and polyglycolic acid.
But the macromolecular material of employing bio-absorbable of the present invention.The biological absorbable polymer material comprises poly-(lactic acid-ethanol) (PLGA), PLLA (PLLA).PLLA and PLGA are of a sort macromolecules, and wherein the proportioning of glycolic (GA), can change within the specific limits.PLLA and PLGA are the macromolecules of hemicrystalline, their form, comprise crystallization and amorphous domain, by changing degree of crystallinity, to provide support required mechanical performance, for example extend, after contraction, crimping, implantation and the rigid support after anatomical tissue laminating on every side.Other suitable macromolecule includes but not limited to gather (L-lactide-co-D-lactide) (PLLA-co-PDLA) copolymer, PLLA/poly-(D-ALPHA-Hydroxypropionic acid) be blend etc. (PLLA/PDLA), it based on polylactic acid derivative, is the polyester block copolymer that contains rigid chain segment and soft chain segment, rigid section PLLA or PLGA, poly-(6-caprolactone) of soft chain segment (PCL) or PTMC (PTMC), poly-to dioxanone (PPDO).The substrate macromolecule that other of PLLA and PLGA are suitable and specific compositions also can be manufactured support, and suitable component and processing technique can be made angiocarpy bracket.The interpolation of PGA component can be shortened degradation time, and this is the improvement of a very important aspect of performance.
A second aspect of the present invention provides the preparation method of fully-degradable polymer material angiocarpy bracket.The tubing that this support is made by polylactic acid and polyglycolic acid, adopt hoop to strut technology and make tubing reach suitable diameter and mechanical property, adopts laser engraving to become support.
Step 1: the selection of macromolecular material
The macromolecular material that PLLA and PLGA are matrix, with specific proportioning components, timbering material is manufactured in blend, the support of making in conjunction with special processing technique, every instructions for use that can reach the intravascular stent implantation process and implant after-poppet.The interpolation of PGA component can be shortened degradation time, and this is the improvement of a very important aspect of performance.
The PLLA of blend of the present invention and PLGA, its proportioning components is 95/5～50/50.The PLLA composition adopts high molecular, and generally at intrinsic viscosity more than 4, preferably, intrinsic viscosity is more than 5.PLGA adopts LA/GA=95/5～50/50; Preferably, LA/GA=90/10～70/30.
Step 2: the macromolecule original tube is extruded
The macromolecule original tube is to form by extrusion.In extrusion, substrate macromolecule material is admitted in extruder.At a certain temperature, melt polymer material, apply the macromolecular material that certain pressure is extruded melting, then by a ring mould (head), forms extruding pipe.Extrusion carries out in a Small-size Twin-Screw Extruders extruder, macromolecular material is that PLLA and PLGA are with 90/10 blend, manual feeding, macromolecular material is dry under 60 ℃ in advance, extrude the captain and the diameter ratio is 24:1, compression ratio is 3.3:1, screw rod is selected speed 5～15rpm, Temperature Setting is at 210 ℃, and pressure is from 2000 to 5000psi, at extrusion, need to use a mould, the mould that different size is arranged, the diameter dimension of mould commonly used is 1～3mm, extrudes approximately 230 ℃ of head temperatures, pressure 500～800psi.
Select original pipe sizing also very important.Original tube can enlarge its internal diameter and external diameter by the special process hoop.At present, preferred original pipe diameter, as shown in Figure 1.The size of general tubing is from external diameter 1～3mm, and internal diameter is from 0.05～2.5mm.
Step 3: circumferential deformation is toughness reinforcing
After original tube is extruded, the internal-and external diameter and the wall thickness that need further processing tube to become to need, and make the tubing hoop reach intensity and the toughness needed.Adopt the single face hard mold, the technique of another side blowing (soft mold).Make pipe with rustless steel, internal diameter is equal to the external diameter that macromolecule tubing needs the hoop expansion.Original tube is put into to stainless steel tube, heat pressurization (blowing) in backward original tube and there is required size and the precursor tube of mechanical performance with formation.The blowing process is induced the macromolecular material chain orientation.For the wall thickness of control valve, can extend by the preheating of original pipe the wall thickness of the original pipe of attenuate before blowing, then blowing in stainless steel tube, can obtain the thicker precursor tube of thin-walled.Water-cooled or air-cooled after blowing, polymer tube exits from stainless steel tube afterwards, obtains required precursor tube.A kind of relation of above-mentioned external diameter of preferred size as shown in Figure 3.Precursor tubing after toughness reinforcing, the general external diameter of size is from 3～5mm, and internal diameter is from 2.5～4.5mm.
Rustless steel tubulose mould, need to have high-precision internal diameter and require the above roughness of specular light, and the internal diameter of stainless steel tube is the mould numerical value that forms the precursor tube external diameter, and the requirement of roughness is to be easy to exit from stainless steel tube for precursor tube.Precursor tube external diameter numerical value is according to human vas diameter design, and it directly determines that pipe ring in the blowing process, to swell increment, also affects the mechanical property of macromolecular material and the differently-oriented directivity of strand, thereby affects the overall performance of support.Tubing is the hoop orientation of induced polymer strand in the blowing process in a circumferential direction, and macromolecular chain hoop orientation can strengthen with toughness reinforcing.If strengthen toughness reinforcing deficiency, support can after placement, collapse fully or part is collapsed, and does not reach the support purpose.If excessively toughness reinforcing, also may cause the intensity excessive descent, cause the collapse of timbering material and collapse.
Step 4: be engraved as support
The design of support is directly connected to the last mechanics support force of support, the ability that whole plasticity and support can be installed.Optimal design of the present invention as shown in Figure 4.By the design to depiction, reach the structure optimization of intravascular stent, can provide enough support strength, compliance and even dilatancy for support, be beneficial to support and be installed on balloon catheter, place rear distraction and fix.
The accompanying drawing explanation
Fig. 1: the original tube of polymer material extrusion
Fig. 2: the tubing flow chart that hoop is toughness reinforcing
Fig. 3: the precursor tube that blowing is toughness reinforcing
Fig. 4: depiction design sketch
Fig. 5: depiction design drawing
Fig. 6: depiction partial enlarged drawing
Fig. 7: mechanical performance compare (after toughness reinforcing and before toughness reinforcing)
Fig. 8: in-vitro simulated degraded comparison diagram
The specific embodiment
The preparation of fully-degradable polymer material angiocarpy bracket
Step 1: blend PLLA and PLGA, its proportioning components is 70/30.PLLA composition viscosity is 4.The PLGA composition is PL/GA=90/10.
Step 2: the polymer material extrusion original tube, as shown in Figure 1.The macromolecule original tube is to form by extrusion, extrusion carries out in a Small-size Twin-Screw Extruders extruder, extrude the captain and the diameter ratio is 24:1, compression ratio is 3.3:1, and screw rod is selected speed 10rpm, Temperature Setting is at 210 ℃, pressure is from 3000psi, at extrusion, need to use a mould, and diameter dimension is 3mm, extruding head temperature is 230 ℃, and pressure is 600psi.Macromolecular material is dry under 60 ℃ in advance, and at a certain temperature, melt polymer material, apply the macromolecular material that certain pressure is extruded melting, then by a ring mould (head), extrudes original tube.The external diameter of original tube is 2mm, and internal diameter is 1.5mm.
Step 3: step as shown in Figure 2, be processed into precursor tube by original tube.First manufacture a stainless steel tube, internal diameter size is 4mm, and roughness is 0.6.Original tube is put into to stainless steel tube, heat in backward original tube pressurize (blowing) to form precursor tube, as shown in Figure 3, precursor tube external diameter 4mm, internal diameter 3mm.
Step 4: precursor tube is enclosed within on the stainless steel tube that an external diameter is 3mm, is carved by laser, depiction is as shown in Fig. 4-6.In the present embodiment, striped length a=2.0mm, width of fringe b=1.5mm, striped thickness h=0.2mm, gap c=1.0mm.
Mechanical performance compare
Macromolecule tubing is made tubing from extruding, hoop is toughness reinforcing and be engraved as support, and its molecular weight of each link can change to some extent.This directly has influence on the mechanical property of final finished, and toughness reinforcing front and back stress/strain curves as shown in Figure 7.The pipe processing technique that we adopt can make the macromolecule long-chain not be damaged as far as possible, and the change of molecular weight as shown in Table 1.
The change of molecular weight of material in form 1 course of processing
| Title | IV(dl／g) |
| Extruding pipe | 3.06 |
| Precursor tube | 2.98 |
| Support | 3.23 |
The external degradation test
Support and PLA stitching thread are placed in external macromolecule decomposition apparatus, and, in 37 ℃ of water-baths, the pH value that detects whole buffer changes, the palliating degradation degree of known material after converting, as shown in Figure 8.External degradation evidence support is degraded faster than PLA stitching thread in testing in vitro.
Claims (11)
1. a fully-degradable polymer material angiocarpy bracket, is characterized in that this support is by PLLA and PLGA melting mixing processing procedure.Wherein, PLLA/PLGA=50/50～90/10, the LA/GA=90/10 of PLGA～50/50.Mixture components is from PLLA:PLGA50/50 to 90/10.Wherein PLGA is LA/GA=90/10～50/50.
2. a kind of fully-degradable polymer material angiocarpy bracket according to claim 1, is characterized in that preferably PLLA/PLGA=80/20～60/40, LA/GA=90/10 in PLGA～70/30.
3. a kind of fully-degradable polymer material angiocarpy bracket according to claim 1, is characterized in that the preparation method of this support is for extruding original tube, and then toughness reinforcing one-tenth precursor tube, be reprocessed into support.
4. fully-degradable polymer material angiocarpy bracket preparation method according to claim 3, is characterized in that the original tube size is from 1 to 3 millimeter of external diameter, from 0.05 to 2.5 millimeter of internal diameter.
5. fully-degradable polymer material angiocarpy bracket preparation method according to claim 4, is characterized in that original tube is by toughness reinforcing one-tenth precursor tube, from 3 to 5 millimeters of the final external diameters of precursor tube, from 2.5 to 4.5 millimeters of internal diameters.
6. fully-degradable polymer material angiocarpy bracket preparation method according to claim 4, is characterized in that toughing ways comprises: the typing of pipe external diameter employing hard mold, the blowing of bore employing soft mold.
7. fully-degradable polymer material angiocarpy bracket preparation method according to claim 6, is characterized in that hard mold makes pipe with the 316L rustless steel, and the concrete numerical value of internal diameter is equal to the external diameter of claim 5 described precursor tube.Roughness R
a<0.8.
8. fully-degradable polymer material angiocarpy bracket preparation method according to claim 6, it is characterized in that original tube is put into to stainless steel tube, heat pressurization 8～16MPa in backward original tube and there is required size and the precursor tube of mechanical performance with formation.
9. fully-degradable polymer material angiocarpy bracket preparation method according to claim 6, it is characterized in that for controlling the precursor tube internal diameter, blowing is front by the preheating of original pipe, 60～100 ℃ of wall thickness with the original pipe of extension attenuate of preheat temperature, arrive again blowing in stainless steel tube, can obtain the thicker precursor tube of thin-walled.
10. tubing according to claim 5, is characterized in that this tubing is engraved as the support of various patterns.Striped length 1～2mm, width of fringe 1～2mm, striped thickness 0.1～0.3mm, gap 1～2mm.
11. support according to claim 10, is characterized in that this support is installed on sacculus when placing.
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Cited By (2)
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| CN104511058A (en) * | 2014-12-29 | 2015-04-15 | 复旦大学 | Fully bio-absorbable polymer stent and production method thereof |
| CN104983484A (en) * | 2015-05-26 | 2015-10-21 | 中国人民解放军第一0一医院 | Degradable bioprosthetic valve system which is implanted in high elasticity external stent through conduit, preparation thereof and application thereof |
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| CN104983484A (en) * | 2015-05-26 | 2015-10-21 | 中国人民解放军第一0一医院 | Degradable bioprosthetic valve system which is implanted in high elasticity external stent through conduit, preparation thereof and application thereof |
| CN104983484B (en) * | 2015-05-26 | 2018-07-24 | 无锡市第二人民医院 | It is a kind of to be implanted into high resiliency support arm degradable biological valve system and preparation and application through conduit |
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