CN103480045B - Fully-degradable polymer material cardiovascular stent - Google Patents
Fully-degradable polymer material cardiovascular stent Download PDFInfo
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- CN103480045B CN103480045B CN201310407004.7A CN201310407004A CN103480045B CN 103480045 B CN103480045 B CN 103480045B CN 201310407004 A CN201310407004 A CN 201310407004A CN 103480045 B CN103480045 B CN 103480045B
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Abstract
Coronary artery bracket used is all metal material in the market, can not degrade, and will forever remain in the arteria coronaria of human body once insert.New support technology is constantly towards degradable high polymer material future development.The present invention adopts PLLA and PLGA macromolecule melting mixing to make support, not only can provide enough mechanical support, and degradation time in vivo also can be significantly less than pure PLLA support.The present invention is the original pipe of employing injection moulding, hoop plasticising becomes precursor tube, laser engraving becomes support, and it has a specific internal diameter and external diameter, is installed on sacculus during implant into body by hoop coupling.Support of the present invention has enough intensity and plasticity, has good degradability and biocompatibility.The present invention have found the optimum proportioning of PLLA and PLGA macromolecule melting mixing.Brand-new technique controls to distribute with the hoop of induced polymer strand effectively, and reduces the destruction of macromolecular chain as much as possible.Designed by the preferred structure of pipe, thus affect the overall performance of support.
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 fully-degradable polymer material is made.The invention still further relates to macromolecular material composition and the preparation technology of this property support.
Background technology
One " implanting class prosthese " can be used for corresponding to one the device implanting body interior, and be placed on and dissect within 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, its function for expanding 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 the stent delivery system of introducing by pathological changes anatomical cavity to the position needing treatment; " placement " corresponds to the endoluminal stent expansion in processing region above.Conveying and placing rack, by one end of locating support conduit, by skin, insert the end of conduit, enter anatomical cavity, be advanced to desired treatment position at the conduit of anatomical cavity, support is propped up in the position for the treatment of, then takes out the tube chamber of conduit.
Normal conditions menisectomy all uses sacculus to prop up support.This support is installed on the conduit by air bag.Mounting bracket is usually directed to hoop compression or is crimped on the sacculus of support, and then prop up support to inflated, last Deflation also withdraws from conduit.
Support must meet certain mechanical performance.First, must can bear structural loads at support, the blood vessel compression stress be applied on support of hoop can be born, thus the support to blood vessel wall is provided.Support must possess enough hoop intensity.Hoop intensity refers to the ability of support support ring to compression stress and the ability of hoop expansion, is the strength and stiffness of the support circumferentially around it.Therefore, also hoop strength and rigidity can be described to.
The second, support is once strut, and 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 direction plastic deformation of support hoop, otherwise can reduce Clinical efficacy.
In addition, support must have enough intensity of bearing for the CYCLIC LOADING after clinical crimping, placement and placement and toughness.Support longitudinally can extend flexibly and shrink is very important, and in addition, support must have good biocompatibility, not trigger any bad reaction.
The tubulose that the structural design of support normally matches with blood vessel, tube wall is carved with penetrating pattern, and pattern is often designed to network structure.The reasonable mechanical structure design of pattern and the key property of material ensure that support can bear hoop compression (to allow to be installed on sacculus) and circumferential expansion (allowing to place).
Existing coronary artery bracket is all metal material, comprises rustless steel, cochrome, platinum evanohm etc.What most patient installed is the coating stent of medicine scribbling medicine in metal surface, will forever remain in the arteria coronaria of human body once insert.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).At present only in the Biodegradable vascular scaffold (BVS, Bioresorbable Vascular Scaffold) that the listing of global minority hospital uses.
Art-recognized affect polymeric stent holding structure performance integrity because have: external load, as coupling and inflation power.The influencing mechanism of these interactive factors to support still imperfectly understands.
Traditional support is Metal Drugs support.Some analyses of generally acknowledging or empirical method/model are for predicting that the behavior of metal rack is not often suitable for polymeric stent, and existing model can not predict the implantation performance of polymeric stent usually.
The present invention adopts the macromolecular material of degradable to make support, and material therefor is the macromolecular material of PLLA and PLGA melting mixing.And macromolecular material and metallographic phase ratio, there is lower strength-weight ratio, thus polymeric stent generally than metal rack do thicker wider, reached mechanical property and the metallic equivalent of polymeric stent.In addition, polymeric stent fragility often.So the design of polymeric stent, be installed mode, and the techniques such as sterilization method can not indiscriminately imitate metal rack, thus all need again to grope.
Existing BVS support due to component be PLLA, so about 3 ~ 4 years of its degradation time in vivo.And the present invention adopts macromolecule melting mixing composition, can not only provide enough mechanical support as support, and degradation time in vivo 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 cardiovascular stent be made up of polylactic acid and polyglycolic acid.
The present invention adopts can the macromolecular material of bio-absorbable.Biological absorbable polymer material comprises poly-(lactic acid-ethanol) (PLGA), PLLA (PLLA).PLLA and PLGA is of a sort macromolecule, and wherein the proportioning of glycolic (GA), can change within the specific limits.PLLA and PLGA is the macromolecule of hemicrystalline, their form, comprises crystallization and amorphous domain, by changing degree of crystallinity, to provide the mechanical performance needed for support, such as extend, shrink, crimp, implant after and surrounding anatomical laminating after rigid support.Other suitable macromolecule includes but not limited to gather (L-lactide-co-D-lactide) (PLLA-co-PDLA) copolymer, PLLA/poly-(D-ALPHA-Hydroxypropionic acid) (PLLA/PDLA) blend etc., based on the polyester block copolymer that polylactic acid derivative is containing rigid chain segment and soft chain segment, rigid section PLLA or PLGA, poly-(6-caprolactone) (PCL) of soft chain segment or PTMC (PTMC), poly-to dioxanone (PPDO).Other suitable substrate macromolecules of PLLA and PLGA and specific compositions also can manufacture support, and suitable component and processing technique can make angiocarpy bracket.The interpolation of PGA component can shorten 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 cardiovascular stent.The tubing that this support is made up of polylactic acid and polyglycolic acid, adopts hoop to strut technology and makes tubing reach suitable diameter and mechanical property, adopts laser engraving to become support.
Step 1: the selection of macromolecular material
PLLA and PLGA is the macromolecular material of matrix, and with specific proportioning components, blended manufacture timbering material, in conjunction with the support that special processing technique is made, can reach every instructions for use of intravascular stent implantation process and implantation after-poppet.The interpolation of PGA component can shorten degradation time, and this is the improvement of a very important aspect of performance.
PLLA and PLGA that the present invention is blended, its proportioning components is 95/5 ~ 50/50.PLLA composition adopts high molecular, generally at intrinsic viscosity more than 4, preferably, and intrinsic viscosity more than 5.PLGA adopts LA/GA=95/5 ~ 50/50; Preferably, LA/GA=90/10 ~ 70/30.
Step 2: macromolecule original tube is extruded
Macromolecule original tube is formed by extrusion.In extrusion, substrate macromolecule material is admitted in extruder.At a certain temperature, melt polymer material, applies the macromolecular material that certain pressure extrudes melting, then forms extruding pipe by a ring mould (head).Extrusion carries out in a Small-size Twin-Screw Extruders extruder, macromolecular material is that PLLA and PLGA is blended with 90/10, manual feeding, macromolecular material is dry at 60 DEG C in advance, extrude captain and diameter ratio is 24:1, compression ratio is 3.3:1, screw rod selects speed 5 ~ 15rpm, temperature is set in 210 DEG C, and pressure is from 2000 to 5000psi, needs use mould at extrusion, there is the mould of different size, the diameter dimension of conventional mould is 1 ~ 3mm, extrudes head temperature about 230 DEG C, pressure 500 ~ 800psi.
Select original pipe sizing also very important.Original tube can expand its internal diameter and external diameter by 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, need further processing tube to become internal-and external diameter and the wall thickness of needs, and make tubing hoop reach intensity and the toughness of needs.Adopt one side 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 hoop to expand.Original tube is put into stainless steel tube, heats pressurization (blowing) in backward original tube, to be formed, there is required size and the precursor tube of mechanical performance.Blow-molding process induction macromolecular material chain orientation.For the wall thickness of control valve, before blowing, extend the wall thickness of thinning original pipe by the preheating of original pipe, then blowing in stainless steel tube, the precursor tube that more thin-walled is thick can be obtained.Water-cooled or air-cooled after blowing, polymer tube exits from stainless steel tube afterwards, namely 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 tubular die, needs high-precision internal diameter and the roughness requiring more than specular light, and the internal diameter of stainless steel tube is the mould numerical value forming precursor tube external diameter, and the requirement of roughness is in order to precursor tube is easy to exit from stainless steel tube.Precursor tube external diameter numerical value is according to human vas diameter design, and it directly determines that pipe ring in blow-molding process is to swell increment, also affects the mechanical property of macromolecular material and the differently-oriented directivity of strand, thus affects the overall performance of support.Tubing is the hoop orientation of induced polymer strand in blow-molding process in a circumferential direction, and macromolecular chain hoop orientation can strengthen with toughness reinforcing.If activeness and quietness is not enough, support can collapse or partial collapse after placement completely, does not reach support object.If excessively toughness reinforcing, also may cause 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 mechanical support power of support, and overall plasticity and support can by the abilities 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, enough support strength, compliance and even inflation can be provided for support, be beneficial to support and be installed on balloon catheter, place rear distraction and fix.
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 (toughness reinforcing after and toughness reinforcing before)
Fig. 8: in-vitro simulated degraded comparison diagram
Detailed description of the invention
The preparation of fully-degradable polymer material cardiovascular stent
Step 1: blended PLLA and PLGA, its proportioning components is 70/30.PLLA composition viscosity is 4.PLGA composition is PL/GA=90/10.
Step 2: polymer material extrusion original tube, as shown in Figure 1.Macromolecule original tube is formed by extrusion, extrusion carries out in a Small-size Twin-Screw Extruders extruder, extrude captain and diameter ratio is 24:1, compression ratio is 3.3:1, and screw rod selects speed 10rpm, temperature is set in 210 DEG C, pressure is from 3000psi, and need use mould at extrusion, diameter dimension is 3mm, extruding head temperature is 230 DEG C, and pressure is 600psi.Macromolecular material is dry at 60 DEG C in advance, and at a certain temperature, melt polymer material, applies the macromolecular material that certain pressure extrudes melting, then extrudes original tube by a ring mould (head).The external diameter of original tube is 2mm, and internal diameter is 1.5mm.
Step 3: step as shown in Figure 2, is 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 stainless steel tube, heats 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 being enclosed within an external diameter is on the stainless steel tube of 3mm, and carved by laser, depiction as Figure 4-Figure 6.In the present embodiment, strip length a=2.0mm, width of fringe b=1.5mm, striation thickness h=0.2mm, gap c=1.0mm.
Mechanical performance compare
Macromolecule tubing makes 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, high polymer long chain can be made not to be damaged, and the change of molecular weight as shown in Table 1 as far as possible.
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 |
External degradation is tested
Support and PLA stitching thread are placed in external macromolecule decomposition apparatus, namely in 37 DEG C of water-baths, detect the pH value change of whole buffer, the palliating degradation degree of known material after converting, as shown in Figure 8.External degradation test proof support is degraded faster than PLA stitching thread in testing in vitro.
Claims (5)
1. a preparation method for fully-degradable polymer material cardiovascular stent, is characterized in that, comprises the following steps:
1) PLLA and PLGA melting mixing is made substrate macromolecule material; Wherein PLLA/PLGA=70/30 ~ 90/10, LA/GA=90/10 ~ 70/30 of PLGA,
pLLAintrinsic viscosity more than 4;
2) by described substrate macromolecule material by extruding formation original tube; This original tube diameter is from 1 to 3 millimeters, and internal diameter is from 0.05 to 2.5 millimeters;
3) by toughness reinforcing for described original tube one-tenth precursor tube; Wherein, pipe external diameter adopts hard mold sizing, and bore adopts soft mold blowing; Particularly, by the preheating of original tube before blowing, preheat temperature 60 ~ 100 DEG C is to extend the wall thickness control precursor tube internal diameter of thinning original tube, again original tube is put into stainless steel tube, heat pressurization 8 ~ 16MPa in backward original tube, to be formed, there is required size and the precursor tube of mechanical performance; The final external diameter of this precursor tube is from 3 to 5 millimeters, and internal diameter is from 2.5 to 4.5 millimeters;
4) described precursor tube is carved, form the figuratum support of tool.
2. the preparation method of fully-degradable polymer material cardiovascular stent according to claim 1, it is characterized in that, pipe made by described hard mold 316L rustless steel, and the concrete numerical value of internal diameter is equal to the external diameter of described precursor tube, roughness Ra < 0.8.
3. the fully-degradable polymer material cardiovascular stent prepared of method according to claim 1, it is characterized in that, this support is made up of PLLA and PLGA melting mixing, wherein, PLLA/PLGA=70/30 ~ 90/10, LA/GA=90/10 ~ 70/30 of PLGA.
4. fully-degradable polymer material cardiovascular stent according to claim 3, is characterized in that this support is engraved as various pattern; Wherein strip length 1 ~ 2mm, width of fringe 1 ~ 2mm, striation thickness 0.1 ~ 0.3mm, gap 1 ~ 2mm.
5. fully-degradable polymer material cardiovascular stent according to claim 3, is characterized in that this support is installed on sacculus when placing.
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| CN201310407004.7A CN103480045B (en) | 2013-09-10 | 2013-09-10 | Fully-degradable polymer material cardiovascular stent |
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| CN201310407004.7A CN103480045B (en) | 2013-09-10 | 2013-09-10 | Fully-degradable polymer material cardiovascular stent |
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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 |
| 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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