CN201200505Y - Intravascular stent for treating coronary heart disease - Google Patents
Intravascular stent for treating coronary heart disease Download PDFInfo
- Publication number
- CN201200505Y CN201200505Y CNU2008200798045U CN200820079804U CN201200505Y CN 201200505 Y CN201200505 Y CN 201200505Y CN U2008200798045 U CNU2008200798045 U CN U2008200798045U CN 200820079804 U CN200820079804 U CN 200820079804U CN 201200505 Y CN201200505 Y CN 201200505Y
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- Prior art keywords
- blood vessel
- support
- scaffold
- intravascular stent
- vessel wall
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- Materials For Medical Uses (AREA)
Abstract
The utility model discloses a vessel scaffold for curing coronary heart disease. The scaffold comprises a bare metal scaffold and a coat at one side of the bare metal scaffold contacting with the vessel wall. The utility model is characterized in that the vessel scaffold also comprises a coat at one side of the bare metal scaffold contacting with the vessel cavity. The bare metal scaffold is a stainless steel vessel scaffold or a cobalt-chromium alloy vessel scaffold. The thickness of the coat at one side of the bare metal scaffold contacting with the vessel wall or the coat at one side of the bare metal scaffold contacting with the vessel cavity is 5 mm to 10 mm. The scaffold of the utility model is made by two layers of coats, so that the scaffold synchronously solves a series of problems of smooth muscle cell multiplication and vessel endothelium degree delay.
Description
Technical field
This utility model relates to a kind of intravascular stent for the treatment of coronary heart disease.
Background technology
The support that is used for the treatment of coronary heart disease at present has naked metal rack (BMS) and bracket for eluting medicament (DES) two classes.The material of naked metal rack mainly contains two kinds of 316L rustless steel and cochromes.DES is support that naked metal rack, polymer and anti-restenosis medicaments are combined (this polymer is that medicine is carried to carrier on the naked metal rack), and be divided into according to the anti-restenosis medicaments that support carried: rapamycin and derivant FirebirdTM thereof are (as Cypher produced in USA
TMAnd Endeaver
TMThe Firebird that China produces
TM, Partner
TMAnd EXCEL
TMDeng) and the paclitaxel FirebirdTM (as TAXUS produced in USA
TMSeries stent) two kind; Whether degradable is divided into the polymer that uses according to support: polymer non-degradable bracket for eluting medicament is (as Cypher
TM, Endeaver
TM, Firebird
TM, Partner
TMAnd TAXUS
TMSeries stent) and polymer degradable medicaments FirebirdTM (as EXCEL
TM).Restenosis rate caused patient's postoperative heart condition events incidence to increase up to 20%～30% (research thinks that the main cause of naked metal rack postoperative restenosis is a vascular smooth muscle cell proliferation) after coronary artery was implanted into naked metal rack; In order to overcome these shortcomings of naked metal rack, people have at first developed the nondegradable DES of polymer, and restenosis rate was reduced in 10% after it can make stenting, so DES is described as the 3rd milestone on the coronary heart disease interventional therapy history.
But, remove EXCEL
TMOutside the support, other DES all is the comprehensive coating brackets (being called symmetrical coating) that scribble polymer and anti-restenosis medicaments coating at the support all sites, the anti-restenosis medicaments that support contact blood vessel wall one side is carried is by suppressing the effect that vascular smooth muscle cell proliferation plays anti-restenosis, the anti-restenosis medicaments that support contact lumen of vessels one side is carried then suppresses the growth of endotheliocyte, make the vascular endothelial cell reparation postpone, cause the brace sections blood vessel endotheliumization incomplete, thereby, increased thrombosis in the support even caused the danger of death; On the other hand, use the DES of non-degradable polymer because its polymer is forever residual, cause the blood vessel wall reaction that is inflamed, even serious allergy, therefore, the blood vessel endothelium reparation is delayed more, but also have the generation that causes support in late period adherent bad (LSM) and the aneurysm formation of support place etc. dangerous.
Does this patent utility model people (have faulty wording at the above-mentioned shortcoming of the comprehensive coating DES of non-degradable polymer?) Wang Jicheng developed the polymer degradable (this polymer finally is degraded to CO in vivo
2And H
2O), the bracket for eluting medicament-EXCEL of single face coating (promptly only scribble polymer and medication coat, be called asymmetric coating) in support contact blood vessel wall one side
TMPreliminary clinical studies show: it can effectively prevent the generation (Zhang Yuxiao of thrombosis incident in in-stent restenosis and the support, Lu Caiyi, Xue Qiao, etc. carry the clinical observation of rapamycin degradable polymer coating bracket treatment coronary heart disease. Chinese cardiovascular diseases's magazine .2006; 34 (11): 971-974.); Zoopery shows: the Cypher of the endothelialization time ratio bibliographical information of brace sections blood vessel
TMSupport is short, the local inflammation response light, similar to naked metal rack (Zhang Yuxiao, Lu Caiyi. carry the clinical and experimentation of rapamycin degradable polymer coating bracket treatment coronary heart disease. the thesis for the doctorate .2006. of Military Surgeon Further Education College, PLA).The also EXCEL of instruction book finishing coat
TMSupport is not better than naked metal rack aspect blood vessel endotheliumization, still exist because the brace sections blood vessel endotheliumization not exclusively causes thrombotic danger in the support.
Present zoopery and clinical research think that the permanent residual local vessel wall inflammatory reaction that causes of vascular smooth muscle cell proliferation, the delay of brace sections blood vessel endothelium and non-degradable polymer is the main cause that restenosis and the interior thrombosis of support in late period take place behind the implantation DES.Therefore, have only to solve the permanent residual problem of vascular smooth muscle cell proliferation, the delay of brace sections blood vessel endothelium and non-degradable polymer simultaneously, could fundamentally solve in-stent restenosis and because the interior thrombotic problem of the infull support that causes of brace sections blood vessel endotheliumization.
At delay of brace sections blood vessel endothelium and the infull problem of endothelialization, people such as Dirk doctor H have developed a kind of gene FirebirdTM---and be will promote the outgrowth phVEGF-2 of blood vessel endothelium to be carried to the support of making on the naked metal rack with polymer, zoopery proves that this support has the effect of significant promotion brace sections blood vessel endotheliumization, but, do not carry the medicine that suppresses vascular smooth muscle cell proliferation on this support, in theory, it can not stop because the restenosis that causes of vascular smooth muscle cell proliferation takes place, so whether it possesses certainly and effective anti-restenosis effect remains further experiment and confirms.
Human vascular endothelial growth factor (hVEGF, GeneID:7422,
Http:// www.ncbi.nlm.nih.gov/Entrez/) the dimer glycoprotein formed with disulfide bond by two identical polypeptide chains, molecular weight be 46kD (Connolly DT, Heuvelman DM, Nelson R, et al.[J] .J ClinInvest, 1989; 84 (5): 1470-1478) can promote vascular endothelial proliferation, its encoding gene is positioned at chromosomal 6q21.3, total length 14kb, 8 exons and 7 intron (Wei MH of comprising alternately montage, Popescu NC, Lerman MI, et al.Localization of the human vascular endothelial growth factor gene, VEGF, at chromosome 6q12[J] .Hum Genet, 1996,97 (1): 794-797), can form human vascular endothelial growth factor 121 (hVEGF121), human vascular endothelial growth factor 165 (hVEGF165), human vascular endothelial growth factor 189 (hVEGF189), human vascular endothelial growth factor 206 (hVEGF206) and human vascular endothelial growth factor 145 at least 5 kinds of albumen isomer (Mingqing S such as (hVEGF145), Sreemathy R, SumathiR, et al.Angiogenic role for glycodelin in tumorigenesis[J] .Medical Sciences, 2001,98 (16): 9265-9270.).These a few type human vascular endothelial growth factor biological activitys are close, and they are by being spliced to form differently with a kind of primary transcript, and VEGF121 and VEGF165 are main isomeric forms in the human cell.And most emiocytosis VEGF are based on VEGF165, and this also is the principal mode that VEGF plays a role.At present, people utilize the technology of cellular expression VEGF and various hypotypes thereof ripe.
Fibroblast growth factor (FGF) is the cell growth factor that a kind of cell to the mesoderm source has strong short propagation and differentiation, and the cell in this mesoderm source has comprised 3 kinds of main vascular cells: fibroblast, endotheliocyte and smooth muscle cell.FGF have 7 kinds of family's series (Schott RJ, Morrow LA.[J] .Cardiovascres, 1993; 27 (7): 1155-1161), studying more is acid fibroblast mother cell growth factor (aFGF) and basic fibroblast mother cell growth factor (bFGF), aFGF is made up of 140 aminoacid, bFGF then is made up of 146 aminoacid, both sequence of amino acid about 53% are identical, and bFGF's is distributed more widely general, see blood vessel endothelium, vascular smooth muscle, myocardial cell and are rich in the histoorgan of blood vessel, aFGF distributes and limits to relatively, does not see the report that it distributes at blood vessel endothelium.Two factors extensively exist in many organs such as brain, heart, and participate in the differentiation and the reparation of tissue.FGF plays a role by its specific receptor, there are two kinds of receptors in FGF effector lymphocyte surface: high-affinity and low-affinity receptor, the molecule gram petition of surrender of high-affinity receptor is bright, they are respectively FGFR1, FGFR2, FGFR3 and FGFR4 (Jaye M, Schlessinger J, Dionne CA, et al.[J] .Biochim BiophysActa, 1992; 1135 (2): 185-199).In vitro study is found to add FGF in blood capillary, not only can promote cell proliferation, division and growth, but also can induce blood capillary sample tube chamber to form.Find simultaneously to vascular endothelial cell have intensive chemotaxis (Thomas KA.Rios CM, Gimenez GG, et al.[J] .Proc Natl Acad SciUSA, 1985; 82 (19): 6409-6419).Discover in the body FGF have intensive short vascularization effect (ClarkeMSF, Khakee R, McNeil PL.[J] .J Cell sci 1993,106 (1): 121-123; Unger EF, Banai S, ShouM, et al.[J] .Am J physiol, 1994; 266 (4pt2): H1588-1595).FGF promotes angiopoietic effect to mainly contain: the propagation that 1. promotes vascular endothelial cell; 2. promote the migration of endotheliocyte; 3. promotion has the release of the protein kinase of degraded basement membrane effect; 4. promote endotheliocyte to form tube chamber.
The utility model content
At the deficiency that naked metal rack, the comprehensive coating DES of non-degradable polymer, degradable polymer single face coating bracket for eluting medicament and simple phVEGF gene FirebirdTM exist, this utility model provide have asymmetric coating can anti-simultaneously restenosis, promote the intravascular stent of the treatment coronary heart disease of vascular endothelial growth.
The intravascular stent of treatment coronary heart disease provided by the utility model, but contain the degradable polymer coating of asymmetrical year anti-restenosis medicaments and carry the expressing human VEGF and/or the intravascular stent of the degradable polymer coating of the recombinant expression carrier of human desmocyte somatomedin; Be to contact lumen of vessels one side coating with naked metal rack and constitute by naked metal rack, naked metal rack contact blood vessel wall one side coating; Described naked metal rack contact blood vessel wall one side coating is the mixture of anti-restenosis medicaments and degradable polymer; But described naked metal rack contact lumen of vessels one side coating is the recombinant expression carrier of expressing human VEGF and/or human desmocyte somatomedin and the mixture of degradable polymer.Described anti-restenosis medicaments is rapamycin and/or rapamycin derivative and/or paclitaxel; Described rapamycin derivative can be Biolimus A
9, ABT578, Everolimus or Tacrolimus.
Described human vascular endothelial growth factor can be human vascular endothelial growth factor 165 (hVEGF165) and/or human vascular endothelial growth factor 121 (hVEGF 121) and/or human vascular endothelial growth factor 2 (hVEGF2).
But but the recombinant expression carrier of described expressing human VEGF and/or human desmocyte somatomedin is preferably the recombinant expression carrier of expressing human VEGF; But but the recombinant expression carrier of described expressing human VEGF is preferably the recombinant expression carrier of expressing human VEGF-165.
But but the recombinant expression carrier of described expressing human VEGF-165 is the recombinant expression carrier that the encoding gene of human vascular endothelial growth factor 165 is inserted into the expressing human VEGF-165 that obtains in the carrier for expression of eukaryon.But the recombinant expression carrier of described expressing human VEGF-165 is preferably pcDNA3-VEGF165.
Described naked metal rack is rustless steel intravascular stent or cochrome intravascular stent, can be the naked metal rack of commercially available any treatment coronary heart disease, and its structure is a tubulose, and tube wall has hollow out, and outward appearance is the webmaster shape.Described naked metal rack specification (diameter * length) scope is 2.5mm～4.0mm * 14mm～33mm.
Described degradable polymer is a polylactic acid.Described polylactic acid be preferably poly-dl-lactide (D, L-PLA).
The thickness of described naked metal rack contact blood vessel wall one side coating or described naked metal rack contact lumen of vessels one side coating is 5 microns～10 microns.
, make the function of support obtain optimization because but support of the present utility model has adopted the recombinant vector of anti-restenosis medicaments and expressing human VEGF and/or human desmocyte somatomedin to be applied to the asymmetric coated designs of support blood vessel wall and lumen of vessels one side respectively.On the one hand, in blood vessel wall one side coating, anti-restenosis medicaments is arranged, and in lumen of vessels one side coating not anti-restenosis medicaments, both played and suppressed the effect that smooth muscle cell proliferation prevents restenosis, vascular endothelial cell reparation delay and the infull adverse consequences (inhibitory action of promptly having avoided anti-restenosis medicaments that vascular endothelial cell is repaired) of brace sections blood vessel endotheliumization of having avoided anti-restenosis medicaments that the inhibitory action of vascular endothelial cell is caused again; On the other hand, the human vascular endothelial growth factor in the support contact lumen of vessels one side coating and/or the recombinant expression carrier of human desmocyte somatomedin rise and promote the brace sections blood vessel endotheliumization, avoid thrombotic effect in the support; The recombinant expression carrier of nobody's VEGF and/or human desmocyte somatomedin has been avoided the influence to the blood vessel wall one side cell of support contact of human vascular endothelial growth factor and/or human desmocyte somatomedin in support contact blood vessel wall one side coating.
The polylactic acid that support of the present utility model uses can be degraded to the CO harmless to the people as the carrier of anti-restenosis medicaments and promotion endothelialization gene fully in human body
2And H
2O, not residual in vivo, contact the recombinant expression plasmid that lumen of vessels one side is coated with the expressing human VEGF with promotion brace sections blood vessel endotheliumization with support be safe and effective but zoopery result proof is coated with the rapamycin with anti-restenosis effect same piece of naked metal rack contact blood vessel wall one side, points out in the clinical intervene operation that support of the present utility model can be applied to coronary heart disease.
Description of drawings
Fig. 1 is an intravascular stent sectional view of the present utility model.
Fig. 2 is that intravascular stent of the present utility model launches back front view (plane graph).
Fig. 3 is that intravascular stent of the present utility model launches the back axonometric chart.
Fig. 4 is the vascular endothelial cell stereoscan photograph around 24 hours supports and the scaffold pole after the intravascular stent implantation of the present utility model.A is the stereoscan photograph of scaffold pole surface modification among Fig. 4; B is the stereoscan photograph that endotheliocyte changes around the scaffold pole among Fig. 4.
Fig. 5 is the stereoscan photograph of 1 month brace sections blood vessel endothelium situation and scaffold pole different parts vascular endothelial cell form and arrangement thereof behind the Stent of embodiment 1 preparation; A for the Stent of embodiment 1 preparation after 1 month support strut surfaces 100% covered by new intima; B is the form and the arrangement of scaffold pole different parts endotheliocyte; C is that the newborn endotheliocyte in scaffold pole position is " paving stone " sample form; D is for being " fusiformis " away from the newborn endotheliocyte in scaffold pole position, and its major axis is consistent with blood flow direction; E arranges for be " whirlpool sample " at scaffold pole camber line traveling position endotheliocyte.
Fig. 6 is behind the Stent of embodiment 1 preparation 1 month, the transmission electron microscope photo of synthetic attitude vascular smooth muscle cell of brace sections blood vessel wall and contracted state vascular smooth muscle cell; A is synthetic attitude vascular smooth muscle cell among the figure; B is the contracted state vascular smooth muscle cell.
Fig. 7 is the result of 1 month brace sections blood vessel om observation behind the Stent of embodiment 1 preparation; A is the light microscopic photo of brace sections blood vessel wall three-decker, new intima hypertrophy and middle film and adventitia pressurized situation among the figure, and B is the light microscopic photo (HE dyeing, * 1000) of brace sections vessel wall inflammation reaction.
The specific embodiment
As Fig. 1～shown in Figure 3, be a kind of intravascular stent provided by the utility model, it includes:
, make the function of support obtain optimization because but support of the present utility model has adopted the recombinant vector of anti-restenosis medicaments and expressing human VEGF and/or human desmocyte somatomedin to be applied to the asymmetric coated designs of support blood vessel wall and lumen of vessels one side respectively.On the one hand, in blood vessel wall one side coating, anti-restenosis medicaments is arranged, and in lumen of vessels one side coating not anti-restenosis medicaments, both played and suppressed the effect that smooth muscle cell proliferation prevents restenosis, vascular endothelial cell reparation delay and the infull adverse consequences (inhibitory action of promptly having avoided anti-restenosis medicaments that vascular endothelial cell is repaired) of brace sections blood vessel endotheliumization of having avoided anti-restenosis medicaments that the inhibitory action of vascular endothelial cell is caused again; On the other hand, but the recombinant expression plasmid carrier of expressing human VEGF in the support contact lumen of vessels one side coating and/or human desmocyte somatomedin rise and promote the brace sections blood vessel endotheliumization, avoid thrombotic effect in the support; But in support contact blood vessel wall one side coating, do not have the recombinant expression carrier of expressing human VEGF and/or human desmocyte somatomedin, avoided the influence of human vascular endothelial growth factor and/or human desmocyte somatomedin the blood vessel wall one side cell of support contact.
With following embodiment 1-4 is that example prepares intravascular stent of the present utility model, and carries out the effect experiment.
The preparation of embodiment 1, intravascular stent of the present utility model
With 2.5mm * 14mm support is processing technology and the major parameter that example is introduced this support:
With 10.0g viscosity is polylactic acid (poly-dl-lactide) the adding 4.5g rapamycin of 0.9dl/g, place in the beaker of a cleaning, the ethyl acetate that adds 100ml was mixed 10 minutes at 0-60 ℃ following 500 rev/mins, under 20KHZ ultrasonic 20 minutes then, gained solution is coating liquid, promptly naked metal rack contact blood vessel wall one side coating liquid.
10.0g viscosity is added 1.0g pcDNA3-VEGF165 plasmid (available from the limited company of Beijing hundred million Li Gaoke biotechnology research by the polylactic acid (poly-dl-lactide) of 0.9dl/g, pcDNA3-VEGF165 is the plasmid that sets out with pcDNA3.1, but the recombiant plasmid of the expressing human VEGF165 that the encoding gene fragment of inserting people VEGF165 obtains), the ethyl acetate that adds 100ml was mixed 10 minutes at 0-60 ℃ following 500 rev/mins, under 20KHZ ultrasonic 20 minutes then, make naked metal rack contact lumen of vessels one side coating liquid.
With naked metal rack (the S support that Singapore Parkson company produces, the model of support (diameter * length) is 2.5mm * 14mm) be soaked in the water, ultrasonic clean is not up to rack surface contamination-free (the support cleaning solution should have macroscopic granule in the highlight inspection).
Coat the above-mentioned naked metal rack contact lumen of vessels one side coating liquid that makes with contact lumen of vessels one side of being stained with the naked metal rack that the method for being coated with will clean, coating layer thickness is 7 microns; Coat the above-mentioned naked metal rack contact blood vessel wall one side coating liquid that makes in naked metal rack contact blood vessel wall one side with being stained with the method for being coated with, coating layer thickness is 7 microns.
Being placed in the container of a cleaning after the coating will be finished, maintenance vacuum is 0.1-0.07MPa, under the 0-60 ℃ of temperature, make solvent evaporates, promptly obtain support contact blood vessel wall one side and scribble polylactic acid and rapamycin, support contact lumen of vessels one side scribbles the intravascular stent of polylactic acid and pcDNA3-VEGF165 plasmid.
Support is through after the above-mentioned processing, on the production line support is being preloaded onto on the sacculus, give the full sacculus of pressure of this sacculus burst pressure, problem such as evenly whether the perusal support stretch, whether coating has explosion and come off is observed whether explosion or come off of coating afterwards under Electronic Speculum.The result shows, the intravascular stent of above-mentioned preparation does not have phenomenons such as stretching inhomogeneous, coating explosion and coating shedding to be taken place in the full fully back of sacculus.
Show that with metallurgical microscope mensuration the coating layer thickness of this support contact blood vessel wall one side is 7 microns, the coating layer thickness of contact lumen of vessels one side is 7 microns.Show that with HPLC mensuration the rapamycin content of this support contact blood vessel wall one side coating is 140 μ g/cm
2The pcDNA3-VEGF165 plasmid content of contact lumen of vessels one side coating is 110 μ g/cm
2The structure chart of this intravascular stent such as Fig. 1, Fig. 2 and shown in Figure 3, Fig. 1 is an intravascular stent sectional view of the present utility model, Fig. 2 is that intravascular stent of the present utility model launches back figure, and from blood vessel wall one side front view, Fig. 3 is that intravascular stent of the present utility model launches the back axonometric chart; 1 for support contacts blood vessel wall one side coating among Fig. 1, Fig. 2 and Fig. 3, and 2 is the metal part of support, and 3 is support contact lumen of vessels one side coating.
The preparation of embodiment 2, intravascular stent of the present utility model
With 2.75mm * 14mm support is processing technology and the major parameter that example is introduced this support:
With 10.0g viscosity is the middle 2.5g of adding of polylactic acid (poly-dl-lactide) rapamycin of 0.2dl/g, place in the beaker of a cleaning, the acetone that adds 100ml mixed 10 minutes at 0-60 ℃ following 500 rev/mins, under 20KHZ ultrasonic 20 minutes then, gained solution is coating liquid, promptly makes naked metal rack contact blood vessel wall one side coating liquid.
Add 0.03g pcDNA3-VEGF165 plasmid (available from the limited company of Beijing hundred million Li Gaoke biotechnology research in 10.0g viscosity in by the polylactic acid of 0.2dl/g, pcDNA3-VEGF165 is the plasmid that sets out with pcDNA3.1, but the recombiant plasmid of the expressing human VEGF165 that the encoding gene fragment of inserting people VEGF165 obtains), the acetone that adds 100ml mixed 10 minutes at 0-60 ℃ following 500 rev/mins, ultrasonic 20 minutes mixings under 20KHZ make naked metal rack contact lumen of vessels one side coating liquid then.
With naked metal rack (the S support that Singapore Parkson company produces, the model of support (diameter * length) is 2.75mm * 14mm) be soaked in the aqueous slkali (concentration is the NaOH solution of 0.5M), ultrasonic clean is not up to rack surface contamination-free (the support cleaning solution should have macroscopic granule in the highlight inspection).
Coat the above-mentioned naked metal rack contact lumen of vessels one side coating liquid that makes with being stained with naked metal rack contact lumen of vessels one side that the method for being coated with will clean, coating layer thickness is 10 microns; Coat the above-mentioned naked metal rack contact blood vessel wall one side coating liquid that makes in support contact blood vessel wall one side with being stained with the method for being coated with, coating layer thickness is 10 microns.
Being placed in the container of a cleaning after the coating will be finished, maintenance vacuum is 0.1-0.07MPa, under the 0-60 ℃ of temperature, make solvent evaporates, promptly obtain support contact blood vessel wall one side and scribble polylactic acid and rapamycin, support contact lumen of vessels one side scribbles the intravascular stent of polylactic acid and pcDNA3-VEGF165 plasmid.
Support is through after the above-mentioned processing, on the production line support is being preloaded onto on the sacculus, give the full sacculus of pressure of this sacculus burst pressure, problem such as evenly whether the perusal support stretch, whether coating has explosion and come off is observed whether explosion or come off of coating afterwards under Electronic Speculum.The result shows, the intravascular stent of above-mentioned preparation does not have phenomenons such as stretching inhomogeneous, coating explosion and coating shedding to be taken place in the full fully back of sacculus.
Show that with metallurgical microscope mensuration the contact blood vessel wall one side coating layer thickness of this support is 10 microns, contact lumen of vessels one side coating is 10 microns.Show that with HPLC mensuration the rapamycin concentrations of the contact blood vessel wall one side coating of this support is 110 μ g/cm
2The pcDNA3-VEGF165 plasmid concentration of contact lumen of vessels one side coating is 72 μ g/cm
2The structure chart of this intravascular stent such as Fig. 1, Fig. 2 and shown in Figure 3, Fig. 1 is an intravascular stent sectional view of the present utility model, Fig. 2 is after intravascular stent of the present utility model launches, and from blood vessel wall one side front view, Fig. 3 is that intravascular stent of the present utility model launches the back axonometric chart; 1 for contacting blood vessel wall one side coating among Fig. 1, Fig. 2 and Fig. 3, and 2 is the metal part of support, and 3 are contact lumen of vessels one side coating.
The preparation of embodiment 3, intravascular stent of the present utility model
With 3.0mm * 14mm support is processing technology and the major parameter that example is introduced this support:
With 10.0g viscosity is the polylactic acid adding 15g rapamycin of 1.2dl/g, place in the beaker of a cleaning, the chloroform that adds 100ml mixed 10 minutes at 0-60 ℃ following 500 rev/mins, under 20KHZ ultrasonic 20 minutes then, gained solution is coating liquid, the coating liquid of promptly naked metal rack contact blood vessel wall one side.
10.0g viscosity is added 10.0g pcDNA3-VEGF165 plasmid (available from the limited company of Beijing hundred million Li Gaoke biotechnology research by 1.0 polylactic acid, pcDNA3-VEGF165 is the plasmid that sets out with pcDNA3.1, but the recombiant plasmid of the expressing human VEGF165 that the encoding gene fragment of inserting people VEGF165 obtains), the chloroform that adds 100ml mixed 10 minutes at 0-60 ℃ following 500 rev/mins, ultrasonic 20 minutes mixings under 20KHZ make naked metal rack contact lumen of vessels one side coating liquid then.
With naked metal rack (the S support that Singapore Parkson company produces, the model of support (diameter * length) is 3.0mm * 14mm), be soaked in the 20g acetone, the vibration cleaning is not up to rack surface contamination-free (the support cleaning solution should have macroscopic granule in the highlight inspection).
Coat the above-mentioned naked metal rack contact lumen of vessels one side coating liquid that makes with being stained with naked metal rack contact lumen of vessels one side that the method for being coated with will clean, coating layer thickness is 5 microns; Coat the above-mentioned naked metal rack contact blood vessel wall one side coating liquid that makes in support contact blood vessel wall one side with being stained with the method for being coated with, coating layer thickness is 5 microns.
Being placed in the container of a cleaning after the coating will be finished, maintenance vacuum is 0.1-0.07MPa, under the 0-60 ℃ of temperature, make solvent evaporates, promptly obtain support contact blood vessel wall one side and scribble polylactic acid and rapamycin, support contact lumen of vessels one side scribbles the intravascular stent of polylactic acid and pcDNA3-VEGF165 plasmid.
Support is through after the above-mentioned processing, on the production line support is being preloaded onto on the sacculus, give the full sacculus of pressure of this sacculus burst pressure, problem such as evenly whether the perusal support stretch, whether coating has explosion and come off is observed whether explosion or come off of coating afterwards under Electronic Speculum.The result shows, the intravascular stent of above-mentioned preparation does not have phenomenons such as stretching inhomogeneous, coating explosion and coating shedding to be taken place in the full fully back of sacculus.
Show that with metallurgical microscope mensuration the coating layer thickness of this support contact blood vessel wall one side is 5 microns, contact lumen of vessels one side coating is 5 microns.Show that with HPLC mensuration the rapamycin concentrations of the contact blood vessel wall one side coating of this support is 180 μ g/cm
2The pcDNA3-VEGF165 plasmid concentration of contact lumen of vessels one side coating is 140 μ g/cm
2The structure chart of this intravascular stent such as Fig. 1, Fig. 2 and shown in Figure 3, Fig. 1 is an intravascular stent sectional view of the present utility model, Fig. 2 is after intravascular stent of the present utility model launches, and from blood vessel wall one side front view, Fig. 3 is that intravascular stent of the present utility model launches the back axonometric chart; 1 for contacting blood vessel wall one side coating among Fig. 1, Fig. 2 and Fig. 3, and 2 is the naked metal rack of metal, and 3 are contact lumen of vessels one side coating.
The preparation of embodiment 4, intravascular stent of the present utility model
With 4.0mm * 14mm support is processing technology and the major parameter that example is introduced this support:
With 10.0g viscosity is the polylactic acid of 1.5dl/g, the 15g rapamycin places in the beaker of a cleaning, and the chloroform that adds 100ml mixed 10 minutes at 0-60 ℃ following 500 rev/mins, under 20KHZ ultrasonic 20 minutes then, promptly make naked metal rack contact blood vessel wall one side coating liquid.
Add 10.0g pcDNA3-VEGF165 plasmid (available from the limited company of Beijing hundred million Li Gaoke biotechnology research in 10.0g viscosity in by the polylactic acid of 1.0dl/g, pcDNA3-VEGF165 is the plasmid that sets out with pcDNA3.1, but the recombiant plasmid of the expressing human VEGF165 that the encoding gene fragment of inserting people VEGF165 obtains), the chloroform that adds 100ml mixed 10 minutes at 0-60 ℃ following 500 rev/mins, ultrasonic 20 minutes mixings under 20KHZ make naked metal rack contact lumen of vessels one side coating liquid then.
With naked metallic blood vessel bracket (the S support that Singapore Parkson company produces, the model of support (diameter * length) is 4.0mm * 14mm) be soaked in the 20g acetone, the vibration cleaning is not up to rack surface contamination-free (the support cleaning solution should have macroscopic granule in the highlight inspection).
Coat the above-mentioned naked metal rack contact lumen of vessels one side coating liquid that makes with being stained with naked metal rack contact lumen of vessels one side that the method for being coated with will clean, coating layer thickness is 5 microns; Coat the above-mentioned naked metal rack contact blood vessel wall one side coating liquid that makes in support contact blood vessel wall one side with being stained with the method for being coated with, coating layer thickness is 5 microns.
Being placed in the container of a cleaning after the coating will be finished, maintenance vacuum is 0.1-0.07MPa, under the 0-60 ℃ of temperature, make solvent evaporates, promptly obtain support contact blood vessel wall one side and scribble polylactic acid and rapamycin, support contact lumen of vessels one side scribbles the intravascular stent of polylactic acid and pcDNA3-VEGF165 plasmid.
Support is through after the above-mentioned processing, on the production line support is being preloaded onto on the sacculus, give the full sacculus of pressure of this sacculus burst pressure, problem such as evenly whether the perusal support stretch, whether coating has explosion and come off is observed whether explosion or come off of coating afterwards under Electronic Speculum.The result shows, the intravascular stent of above-mentioned preparation does not have phenomenons such as stretching inhomogeneous, coating explosion and coating shedding to be taken place in the full fully back of sacculus.
Show that with metallurgical microscope mensuration the contact blood vessel wall one side coating layer thickness of this support is 5 microns, contact lumen of vessels one side coating is 5 microns.Show that with HPLC mensuration the rapamycin concentrations of the contact blood vessel wall one side coating of this support is 110 μ g/cm
2The pcDNA3-VEGF165 plasmid concentration of contact lumen of vessels one side coating is 140 μ g/cm
2The structure chart of this intravascular stent such as Fig. 1, Fig. 2 and shown in Figure 3, Fig. 1 is an intravascular stent sectional view of the present utility model, Fig. 2 is after intravascular stent of the present utility model launches, and from blood vessel wall one side front view, Fig. 3 is that intravascular stent of the present utility model launches the back axonometric chart; 1 for contacting blood vessel wall one side coating among Fig. 1, Fig. 2 and Fig. 3, and 2 is the naked metal rack of metal, and 3 are contact lumen of vessels one side coating.
The implantation effect detection of embodiment 5, intravascular stent of the present utility model
One, the animal blood vessels support is implanted
1, animal origin
Healthy 6 of dogs of hybrid (being provided by Chinese People's Liberation Army General Hospital zoopery center) are implanted into the intravascular stent (every dog implanted 1 piece of support) that embodiment 1 prepares in its coronary artery; The parameter of support (diameter * length) is 2.5mm * 14mm, selects the vessel segment implant frame of support balloon diameter/blood vessel diameter=1.1～1.3:1 in the art.
2, the processing of animal in the experimentation
The described experimental dog of step 1 is carried out following experiment (having 1 dog to implant the death of quivering of back generation chamber in support in the support implantation process):
1) gets the execution in 24 hours behind Stent of 1 dog at random;
2) all the other dogs execution in 1 month behind Stent.
All experimental dogs are all in preceding 12 hours fasting water of Stent; Art was fed Aspirin Enteric-coated Tablets 300mg in preceding 24 hours, and postoperative 150mg/ days, until sacrifice of animal; Use anticoagulant heparin in the Stent.
Carrying out coronarography (CAG) before the execution observes: have or not in the support and bracket edge restenosis and crown aneurysmal expansion generation;
The brace sections blood vessel is carried out scanning electron microscopic observation: brace sections blood vessel endothelium situation;
Transmission electron microscope observing: the quantity of new intima vascular smooth muscle cell and phenotype change;
Om observation: brace sections blood vessel wall structure; Middle film, the pressurized degree of adventitia and neointimal hyperplasia degree, new intima thickness and the area of corresponding site; The cell component of tube chamber area and new intima.
In the definition blood vessel wall film pressurized degree be divided into slightly, three grades of moderate and severes; Compare with the middle film of adjacent not pressurized, slight pressurized is that thickness reduces≤30%; Moderate is that thickness reduces〉30%≤60%; Severe is that thickness reduces〉60%; Blood vessel wall adventitia pressurized degree is divided into slightly, three grades of moderate and severes; Compare with the adventitia of adjacent not pressurized, slight pressurized is that thickness reduces≤30%; Moderate is that thickness reduces〉30%≤60%; Severe is that thickness reduces〉60%.
The method of the various inspections of in whole process experimental dog being carried out is as described below:
(1) coronary angiography inspection
Guard in Animal Anesthesia and the art: give the sodium intravenous anesthesia of 3% pentobarbital by 20～25mg/kg, keep trocar venous transfusion and append pentobarbital sodium to keep the appropriate anaesthetization degree of depth; After anaesthetizing successfully, animal is fixed on the enterprising circulation of qi promoting cannula of special-purpose operation frame, electrocardiogram and monitoring of blood pressure and recording ecg and blood pressure.
Coronarography: cut dog right side skin of neck earlier, separate subcutaneous tissue, expose common carotid artery, direct-view with Seldinger method puncture right carotid, is inserted fixedly sheath pipe of 7F arterial sheath and ligation down, the common carotid artery of ligation simultaneously distal end; Give heparin 300IU/kg in the sheath pipe, heparin 500IU was appended in the every increase of art journey in 1 hour; Directly select the big chamber in 7F/JR3.5～4.0 or 6F/JR3.5～4.0 guiding catheter in 40 °～45 ° capable coronarographies of left anterior oblique position.
(2) support implant surgery
The intracoronary stent implantation: before the implant frame through conduit to intracoronary injection nitroglycerin 50 μ g, adopt support balloon diameter/blood vessel diameter=1.1～1.3:1 that the target phase blood vessel is carried out direct implant frame after 5-10 minute, expansion pressure is 14～18 atmospheric pressure, and the expansion time is 10～15 seconds.
Post surgery treatment: pull out the arterial sheath pipe when operation finishes, ligation common carotid artery proximal part, layer-by-layer suture muscle, subcutaneous tissue and skin and with the compound iodine wound of sterilizing; The continuous intramuscular injection penicillin of postoperative 4,000,000 units/d, totally 3 days.
(3) put to death preceding coronarography
Take to implant identical modus operandi and carry out the coronarography inspection, observe to have or not in the support and take place with bracket edge restenosis and the expansion of crown aneurysmal through the left carotid approach with support.
(4) sacrifice of animal, draw materials and the making of coherence check specimen
1. sacrifice of animal: after the coronarography inspection finished, the sacrificed by exsanguination animal opened breast afterwards immediately and takes out heart (reservation ascending aorta).
2. the flushing of brace sections blood vessel: each specimen is all near at support, respectively get about 1mm between the support mesh of far-end
31 in tissue, it is fixing to put into 3% glutaraldehyde, in order to make the diaphotoscope specimen.
3. it is fixing to draw materials: with the brace sections blood vessel pressure flush of step in 2., isolate that brace sections and support are near, the vessel segment of each 5mm of far-end, earlier non-brace sections vascular tissue is cut that to put into 4% neutral formalin respectively fixing in order to making light microscopy specimen; According to the principle of handled easily, cut off from an end along the blood vessel major axis brace sections length of vessel 1/2 after, cut this section blood vessel along vertical blood vessel long axis direction again, it is fixing in order to making the scanning electron microscope specimen to put into 3% glutaraldehyde after careful the expansion; Second half puts into 4% the fixing making light microscopy specimen of preparing against of neutral formalin.
(5) scanning electron microscope preparation of specimen
1. the cleaning of sample: the sample that is used to make the scanning electron microscope specimen that the step in the step (4) is fixed in 3., with isoosmotic normal saline clean surface.
2. fixing: that the sample that 1. step obtains is two fixing with glutaraldehyde and osmic acid.
3. dehydration: the sample ethanol dehydration that 2. step is obtained.
4. dry: that the sample that 3. step obtains is dry in HMDS.
5. metal coating: give the specimen surface gold-plating according to a conventional method with the sample that 4. step obtains.
6. take a picture, record and interpretation of result: the sample that 5. step obtains is taken a picture under professional and technical personnel and cardiovascular pathology doctor's guidance, is write down and analysis result.
(6) transmission electron microscope preparation of specimen
Carry out preparation of specimen and interpretation of result according to following step:
1. sample dehydration: it is that 70%～100% acetone soln carries out the gradient dehydration that the specimen that is used to make diaphotoscope after the step of step (4) handled in 2. adopts concentration expressed in percentage by volume routinely.
2. soak into: the sample with 1. step obtains, soak into 812 embedding mediums, DMP-30 and acetone routinely.
3. embedding: with the sample that 2. step obtains, routine is embedded in the expanded rubber embedding template, and oven dry then, polymerization sclerosis form embedded block.
4. semithin section and location:, make semithin section with ultramicrotome with the sample that 3. step obtains; Under light microscopic, observe the location.
5. carry net and supporting film:, be fixed in the 200 purpose copper mesh and make supporting film and cover tissue slice with the sample that 4. step obtains.
6. dyeing: the sample with 5. step obtains, dye with leaded dye liquor.
7. take a picture, record and interpretation of result: under professional and technical personnel and cardiovascular pathology doctor's guidance, take a picture, record and analysis result.
(7) contain the making of the light microscopy specimen of framework
1. the basic step of organization embedding
A: fixing dehydration: the specimen that fixes successively is soaked in following steps dehydrations (this process is all carried out) with the tap water flushing back of spending the night in 4 ℃ of environment: with volumn concentration is 40% alcohol solution dipping 1～2 day, be 70% alcohol solution dipping 1～2 day with volumn concentration then, be 95% alcohol solution dipping 2 days with volumn concentration then, use 100% soak with ethanol 1 day then, soaked 1 day with dimethylbenzene at last.
B: soak into embedding: at first prepare immersion, the tissue to fixing dehydration carries out embedding afterwards.
The preparation of immersion:
Solution I: methyl methacrylate 75ml and dibutyl phthalate 25ml stirring and evenly mixing 3 hours.
Solution II: methyl methacrylate 75ml, dibutyl phthalate 25ml, benzoyl peroxide 2.5g stirring and evenly mixing 3 hours.
Solution III: methyl methacrylate 75ml, dibutyl phthalate 25ml, benzoyl peroxide 62.5g stirring and evenly mixing 4～6 hours.
Program is soaked in immersion: soaked 2 days with solution I, soaked 2 days with solution II then, soaked 1～2 day with solution III at last.
Embedding program: add the freshly prepared solution III of 5ml in clean 25ml vial, add a cover the back ambient temperature overnight, put into 42 ℃ of baking boxs again, 1～3 aggregates into solid.The specimen of immersion is put into above-mentioned ready vial, set the position, refill full fresh solution III, add a cover the back ambient temperature overnight, put into 42 ℃ of baking box polymerizations afterwards again and solidify, embedded specimen is at room temperature deposited.
2. tissue slice
It is moments later freezing that the vial that embedded piece of tissue is housed is put into refrigerator, with hammer shattered glass bottle, takes out embedded block, is trimmed to suitable size and shape (will remain to the minority millimeter around the specimen) so that fix during section with specific purpose tool; By every 10～15 vertical tube chamber long axis direction section of μ m thickness, each specimen is cut 6 continuously with the special-purpose microtome of orthopaedics (tungsten carbide steel knife), and after process was taken off and moulded processing, optional three were dyeed.
3. dyeing, mounting, photograph
The specimen of handling well is fixed on through on the pretreated microscope slide Giemsa-Yihong and HE dyeing back mounting; Purpose is chosen the different parts photograph according to the observation under light microscopic; Adopt new intima thickness, area, the tube chamber area of Image-Pro Plus 5.0 little image analysis software mensuration brace sections blood vessels and comprise that the vessel cross-sections of new intima is long-pending; Each parameter of each specimen is all got the meansigma methods of 3 section measured values.
(8) light microscopy specimen that does not contain framework is made
1. organization embedding
A: dewater: the specimen that fixes is used from gradient ethanol dewatered according to a conventional method.
B: transparent: successively use the dimethylbenzene transparent processing 2 times.
C: waxdip: waxdip 3 times repeatedly in 62 ℃～65 ℃ liquid wax.
D: embedding: the specimen paraffin embedding that will finish waxdip
2. cut into slices, dye, photograph and graphical analysis: the dicing method of paraffin-embedded tissue is cut 6 continuously to each specimen routinely, and optional three are dyeed; Observe the interior membrane structure of non-brace sections blood vessel and cell composition and compare with the brace sections blood vessel.
Two, the testing result of support effect
1, implants the coronarography result of the intravascular stent of embodiment 1 preparation
Put to death 1 of experimental dog after the intravascular stent implantation of embodiment 1 preparation in 24 hours; Postoperative was put to death 4 of experimental dogs in 1 month.
The experimental dog that postoperative 1 month is put to death, in the execution coronarography inspection that moves ahead: 4 dogs all do not have in-stent restenosis, bracket edge restenosis and the expansion of brace sections hemangioma sample and take place.
2, implant the endothelialization situation of the intravascular stent after-poppet section blood vessel of embodiment 1 preparation
(1) see substantially: put to death 1 of experimental dog in 24 hours after the intravascular stent implantation of embodiment 1 preparation, its support portions does not have endothelium and covers; 4 of the experimental dogs of putting to death in 1 month, its support portions is all covered by translucent new intima.
(2) scanning electron microscopic observation result
1. 1 dog of putting to death in 24 hours after the intravascular stent implantation of embodiment 1 preparation, on scaffold pole, be coated with fibrin, platelet and a small amount of hemocyte, near the scaffold pole endotheliocyte quantity is few, and the arrangement of endotheliocyte and structure all destroyed (A among Fig. 4, B).A is the stereoscan photograph of scaffold pole surface modification among Fig. 4; B is the stereoscan photograph that endotheliocyte changes around the scaffold pole among Fig. 4.
2. postoperative 1 month 4 dogs of putting to death, the common feature of its newborn endotheliocyte is: scaffold pole surface 100% is covered by new intima, but newborn endotheliocyte is different with arrangement in the different parts shape of scaffold pole, scaffold pole surface and near endotheliocyte be " paving stone " sample, the microvillus structure of visible cell nuclear position projection and cell surface, gap between the cell increases, major axis at the straight line traveling position of scaffold pole endotheliocyte is arranged along blood flow direction, be " whirlpool sample " at camber line traveling position endotheliocyte and arrange, the relation of the major axis of cell and blood vessel major axis is unfixing; Endotheliocyte away from the scaffold pole position is " fusiformis ", the microvillus structure of visible cell nuclear position projection and cell surface, and cell is arranged comparatively dense, major axis consistent with blood flow direction (A among Fig. 5, B, C, D and E).Among Fig. 5, A for the Stent of embodiment 1 preparation after 1 month support strut surfaces 100% covered by new intima; B is the form and the arrangement of scaffold pole different parts endotheliocyte; C is that the newborn endotheliocyte in scaffold pole position is " paving stone " sample form; D is for being " fusiformis " away from the newborn endotheliocyte in scaffold pole position, and its major axis is consistent with blood flow direction; E arranges for be " whirlpool sample " at scaffold pole camber line traveling position endotheliocyte.
3, implant the intravascular stent after-poppet section vascular smooth muscle cell of embodiment 1 preparation and the variation of new intima:
(1) transmission electron microscope observing result
(2) om observation result
1. the change of blood vessel wall structure and pressurized degree: postoperative 1 month, blood vessel wall three-decker clear (being inner membrance, middle film and adventitia), the interior elastic force film at non-scaffold pole position is complete, and the interior elastic force film fracture at part scaffold pole position there is no the adherent bad phenomenon of scaffold pole.At the scaffold pole place of different parts, the pressurized degree of middle film and outside is different, the slight pressurized of film in 85%～90% the scaffold pole position, and adventitia does not have the pressurized change, the new intima hyperplasia degree of corresponding site is lighter; Arrive the severe pressurized in 10%～15% the scaffold pole position in the film, the adventitia of corresponding site shows as light to moderate pressurized, the position that the new intima hyperplasia degree at this position is light than the pressurized degree is obvious, and general trend is heavy more then this position new intima hypertrophy of the pressurized degree of middle film and adventitia obvious more (seeing A among Fig. 7).
2. the new intima thickness of brace sections blood vessel: the average new intima thickness of brace sections blood vessel is (0.04 ± 0.03) mm.
3. new intima area: the average new intima area of brace sections blood vessel is (0.46 ± 0.21) mm
2
4. tube chamber area: the average tube cavity area of brace sections blood vessel is (2.70 ± 0.15) mm
2
5. the cell component of new intima: the new intima main component of brace sections blood vessel is smooth muscle cell and extracellular matrix; Cell composition away from the cell composition at scaffold pole position and scaffold pole position is basic identical.Visible a small amount of lymphocyte, neutrophilic granulocyte around the scaffold pole, accidental macrophage is not seen eosinophilic granulocyte's (seeing B among Fig. 7).A is the light microscopic photo of brace sections blood vessel wall three-decker, new intima hypertrophy and middle film and adventitia pressurized situation among Fig. 7; B is the light microscopic photo (HE dyeing, * 1000) of brace sections vessel wall inflammation reaction
The effect of the support that embodiment 6, embodiment 2-4 are prepared
1) gets 1 execution in 24 hours behind Stent at random;
2) all the other dogs execution in 1 month behind Stent.
All experimental dogs are all in preceding 12 hours fasting water of Stent; Art was fed Aspirin Enteric-coated Tablets 300mg in preceding 24 hours, and postoperative 150mg/ days, until sacrifice of animal; Use anticoagulant heparin in the Stent.
Carrying out coronarography (CAG) before the execution observes: have or not in the support and bracket edge restenosis and crown aneurysmal expansion generation;
The brace sections blood vessel is carried out scanning electron microscopic observation: brace sections blood vessel endothelium situation;
Transmission electron microscope observing: the quantity of new intima vascular smooth muscle cell and phenotype change;
Om observation: brace sections blood vessel wall structure; Middle film, the pressurized degree of adventitia and neointimal hyperplasia degree, new intima thickness and the area of corresponding site; The cell component of tube chamber area and new intima.
Experimental result is as described below
1, implants the coronarography result of the intravascular stent of embodiment 1 preparation
To the experimental dog of putting to death in 1 month behind the prepared Stent of embodiment 2,3,4, in the execution coronarography inspection that moves ahead: all do not have in-stent restenosis, bracket edge restenosis and the expansion of brace sections hemangioma sample and take place.
2, implant the endothelialization situation of the intravascular stent after-poppet section blood vessel of embodiment 1 preparation
(1) see substantially: all put to death 1 of experimental dog in 24 hours behind the prepared Stent of embodiment 2,3,4, its support portions does not all have endothelium and covers; The experimental dog of putting to death in 1 month behind the prepared Stent of embodiment 2,3,4, its support portions is all covered by translucent new intima.
(2) scanning electron microscopic observation result
1. 1 dog of putting to death in 24 hours behind the prepared Stent of embodiment 2,3,4, on scaffold pole, be coated with fibrin, platelet and a small amount of hemocyte, near the scaffold pole endotheliocyte quantity is few, and the arrangement of endotheliocyte and structure are all destroyed.
2. embodiment 2,3, the dog of putting to death in 1 month behind the 4 prepared Stents, the common feature of its newborn endotheliocyte is: scaffold pole surface 100% is covered by new intima, but newborn endotheliocyte is different with arrangement in the different parts shape of scaffold pole, scaffold pole surface and near endotheliocyte be " paving stone " sample, the microvillus structure of visible cell nuclear position projection and cell surface, gap between the cell increases, major axis at the straight line traveling position of scaffold pole endotheliocyte is arranged along blood flow direction, be " whirlpool sample " at camber line traveling position endotheliocyte and arrange, the relation of the major axis of cell and blood vessel major axis is unfixing; Endotheliocyte away from the scaffold pole position is " fusiformis ", the microvillus structure of visible cell nuclear position projection and cell surface, and cell is arranged comparatively dense, and major axis is consistent with blood flow direction.
3, implant the prepared support after-poppet section vascular smooth muscle cell of embodiment 2,3,4 and the variation of new intima:
(1) transmission electron microscope observing result
Implant the dog of putting to death in 1 month behind the prepared support of embodiment 2,3,4, new intima medium vessels number of smooth muscle cells is less relatively, based on collagen and extracellular matrix; Wherein, " synthetic attitude " vascular smooth muscle cell that is in the state of dedifferenting than the differentiation degree preferably " contracted state " vascular smooth muscle cell lack, the cell space of " synthetic attitude " vascular smooth muscle cell is big and fine and close, nucleus increases, mitochondrion and free ribosome increases, rough endoplasmic reticulum is obviously expanded and myofilament content is less in the endochylema, and the vascular smooth muscle cell cell space of " contracted state " and nuclear phase be to less, and rough endoplasmic reticulum, Golgi body in the endochylema, mitochondrion is less, myofilament content is more than " synthetic attitude " vascular smooth muscle cell.
(2) om observation result
Behind the prepared Stent of the change of blood vessel wall structure and pressurized degree: embodiment 2,3,41 month, blood vessel wall three-decker clear (being inner membrance, middle film and adventitia), the interior elastic force film at non-scaffold pole position is complete, the interior elastic force film fracture at part scaffold pole position there is no the adherent bad phenomenon of scaffold pole.At the scaffold pole place of different parts, the pressurized degree of middle film and outside is different, the slight pressurized of film in 85%～90% the scaffold pole position, and adventitia does not have the pressurized change, the new intima hyperplasia degree of corresponding site is lighter; Arrive the severe pressurized in 10%～15% the scaffold pole position in the film, the adventitia of corresponding site shows as light to moderate pressurized, the position that the new intima hyperplasia degree at this position is light than the pressurized degree is obvious, and general trend is that heavy more then this position new intima hypertrophy of the pressurized degree of middle film and adventitia is obvious more.
The cell component of new intima: the new intima main component of brace sections blood vessel is smooth muscle cell and extracellular matrix; Cell composition away from the cell composition at scaffold pole position and scaffold pole position is basic identical.Visible a small amount of lymphocyte, neutrophilic granulocyte around the scaffold pole, accidental macrophage is not seen the eosinophilic granulocyte.
The conclusion that above-mentioned experimental result draws
(1) rapamycins coating of intravascular stent contact blood vessel wall one side of the present utility model has the effect of significant inhibition support postoperative restenosis.
(2) the recombinant vector coating of the expressed hVEGF165 of intravascular stent contact lumen of vessels one side of the present utility model has the effect that promotes the brace sections blood vessel endotheliumization.
(3) inflammatory reaction of the brace sections blood vessel wall that employed degradable poly lactic acid causes in the coating is lighter.
(4) this experimental result proves that also being coated with the rapamycin with anti-restenosis effect same piece of naked metal rack contact blood vessel wall one side contact lumen of vessels one side to be coated with the carrier with the expressed hVEGF165 that promotes the brace sections blood vessel endotheliumization be safe and feasible with support, and can realize that our imagine initial utility model.
In a word, by zoopery, find that intravascular stent of the present utility model has the effect that promotes the brace sections blood vessel endotheliumization when obtaining the effect of ideal inhibition restenosis.
Claims (3)
1, a kind of intravascular stent for the treatment of coronary heart disease comprises that naked metal rack contacts blood vessel wall one side coating with naked metal rack, it is characterized in that, described intravascular stent also comprises naked metal rack contact lumen of vessels one side coating.
2, intravascular stent according to claim 1 is characterized in that: described naked metal rack is rustless steel intravascular stent or cochrome intravascular stent.
3, intravascular stent according to claim 1 and 2 is characterized in that: the thickness of described naked metal rack contact blood vessel wall one side coating or described naked metal rack contact lumen of vessels one side coating is 5 microns～10 microns.
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| CNU2008200798045U CN201200505Y (en) | 2008-04-08 | 2008-04-08 | Intravascular stent for treating coronary heart disease |
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| CNU2008200798045U CN201200505Y (en) | 2008-04-08 | 2008-04-08 | Intravascular stent for treating coronary heart disease |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102711676A (en) * | 2010-03-30 | 2012-10-03 | 泰尔茂株式会社 | Stent |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102711676A (en) * | 2010-03-30 | 2012-10-03 | 泰尔茂株式会社 | Stent |
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