CN102784015A - Artificial blood vessel loaded with pseudo-ginseng medicines, and preparation method and application for artificial blood vessel - Google Patents
Artificial blood vessel loaded with pseudo-ginseng medicines, and preparation method and application for artificial blood vessel Download PDFInfo
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Abstract
The invention provides an artificial blood vessel loaded with pseudo-ginseng medicines, and a preparation method and application for the artificial blood vessel. The artificial blood vessel sequentially consists of an inner layer, a middle layer and an outer layer which are closely connected with one another; the outer layer consists of nondegradable polymer materials; the middle layer consists of degradable high polymer materials and pseudo-ginseng powder distributed on the surface and/or the inside of the middle layer; the inner layer consists of degradable natural biological materials and pseudo-ginseng powder distributed on the surface and/or the inside of the inner layer; the mass percent of the pseudo-ginseng powder in the inner layer is larger than 5%; the content of the pseudo-ginseng powder in the middle layer is higher than that of the pseudo-ginseng powder in the inner layer; the outer layer is a nondegradable layer and is mainly used for protecting and replacing a blood vessel for a long time; the middle layer is a long-acting antithrombosis layer, can degrade high polymers, and can slowly release medicines so as to realize a long-acting antithrombosis effect; and the inner layer is a quick degrading layer, when the blood vessel is punctured and injured by a foreign object, the pseudo-ginseng medicines wrapped in the blood vessel are directly exposed on a wound, blood is stopped quickly, and the artificial blood vessel is particularly suitable for application to products such as hematodialysis.
Description
Technical field
The invention belongs to medical instruments field, particularly a kind of artificial blood vessel who is loaded with the Radix Notoginseng medicine and preparation method thereof and application.
Background technology
Present global cardiovascular and cerebrovascular disease death toll occupies all disease umber ones, and relapse rate is the highest, and disability rate is the highest.Cardiovascular and cerebrovascular disease has become the first healthy killer of harm humans.Along with economic development; Living standard improves, the life style of Chinese population and dietary structure generation significant change, the food Excessive Intake of higher fatty acid, high protein, high heat; Hypokinesia and aged tendency of population aggravation, cardiovascular disease increases rapidly at the sickness rate of China.
The artificial blood vessel has important use to be worth in the treatment of cardiovascular disease as the succedaneum of many serious narrow or occlusive blood vessels.Ideal artificial blood vessel should keep persistent intensity in vivo, has good biocompatibility again, can be closely affine with in-vivo tissue, and most important is that blood vessel inner layer has repair, reaches good antithrombotic property.Be out at present in the section operation, the artificial blood vessel is mainly used in temporary or nonvolatil damaged tremulous pulse or vein displacement, or as the bypass channel of obstructing arterial, and patients with renal failure required arteriovenous bridging path when carrying out hemodialysis.Only heavy caliber artificial blood vessel (internal diameter is greater than 6mm) is widely used in the reconstructing blood vessel operation at present.This is because 6 months patency rate of small-caliber artificial blood vessel (internal diameter is less than 6mm) postoperative is lower than 40%, in the effect that the satisfaction of not obtaining aspect alternative human body small artery or the vein always.Its main cause is owing to thrombosis and new intima thickens, the blood resistance blocks than the ambassador artificial blood vessel.Therefore, prevent after the artificial blood vessel implants that the research narrow, particularly small-caliber artificial blood vessel endothelialization of its caliber from having become the focus and the difficult point of artificial blood vessel's research.Research at present mainly concentrates on modification and coating and artificial blood vessel's endothelialization three aspects in material selection, the blood vessel.
Artificial blood vessel's material surface hydrophilic improves, and its interfacial free energy is reduced, and reduces plasma protein absorption; It is thin and even that the interior pseudomembrane of artificial blood vessel is formed; Avoiding thrombosis, as connecting PEO (PEO) side chain at surface of polymer material, is exactly a kind of up-and-coming process.At artificial blood vessel's material surface coupling heparin, also can improve artificial blood vessel's anticoagulating active, but can heparin keep permanent biological activity further to study.Through some specific coatings material, can reduce platelet aggregation as adopting the carbon coating artificial blood vessel, but long-term patency rates is not seen obvious improvement in addition.The compound polymer artificial blood vessel who also has a kind of employing phospholipid polymer (MPC) coating to process; Do not find at animal model that thrombosis and pseudomembrane formed in 1 month; But can suppress neointimal hyperplasia for a long time still doubtful, though because MPC has similar cell membrane appearance structure of phospholipid, have anti-thrombosis function; But poly-compounds still exists in the effect of body internal adsorption plasma protein, and the self assembly effect of adhesion protein may influence its secular antithrombotic acitivity.In actual use, the coating bracket inner surface medicine layer that it is found that present artificial blood vessel only can area coverage 5%～12%, and drug loading is limited, can't accomplish the long time release.In actual therapeutic, still have the restenosis incidence rate (seeing " research of Prevention of Cardiovascular restenosis nano-particle drug-carried coat support ", " Southeast China University's journal (natural science edition) " 06 phase in 2004) about 10%.
The endothelial cell seeding experiment is widely used in the clinical very big technology barrier that still has.Subject matter comprises endotheliocyte source, cell culture scale and treats ageing etc.In the established blood vessel of ripe organ, endotheliocyte keeps a kind of static, nonproliferative state.The formation of neovascularity receives strict control, but under many pathological conditions such as wound, ischemia, inflammation, wound healing, tumor growth, diabetic retinopathy, rheumatic arthritis, psoriasis, new vascularization (neo-vascularization) also can take place.Angiogenesis comprises following process: the degraded of 1. little blood vessel (usually being the blood capillary posterior vein) basement membrane and substrate; Participate in this process have collagenase, urokinase type plasminogen activator (urokinase-type plasminogen activator, uPA) etc.; 2. endotheliocyte moves under the effect of chemotactic factor; Basic fibroblast growth factor (basic fibroblast growth factor; BFGF), VEGF (vascular endothelial growth factor, VEGF), interleukin (interleukin) 8 and uPA etc. all have facilitation to this process; 3. endothelial cell proliferation; 4. on the basis of endothelium blastogenesis (sprouting), form tube chamber (canalization); 5. blastogenic tube chamber is fused into annular vessel branch each other, forms three-dimensional tubular structure, allows blood flow to pass through; 6. perivascular cell (pericytes) further makes up blood vessel structure; 7. the formation of basement membrane around the blood vessel.
New vessels also can form through second kind of approach: the column stroma of in the former vessel lumen that pre-exists, growing into, along with the continued growth of these column stromas with stable, caused the separation of lumen of vessels and the reconstruction of local vascular net.If new vessels is greater than blood capillary, then VSMC is also divided a word with a hyphen at the end of a line, and adheres on the substrate of new formation.
Can know that from above angiogenic process remove outside the participation of hormone and enzyme of human body self, the migration of relevant cell and propagation have guiding pivotal role (comprising endotheliocyte and smooth muscle cell), also can run through the whole process of angiogenesis simultaneously.At present, exist in the prior art more fibrous framework to be applied among the artificial blood vessel, this micro/nano fiber structure is beneficial to migration, attaching, growth and the propagation of cell very much.Thereby can promote endotheliocyte and smooth muscle cell migration to increase and realize self-regeneration.
Yet; Under physiological status, the thrombin in the blood constantly is activated, and can produce thrombin; Form micro-fibrin; Calm on tunica intima, but the fibrinolytic system that these micro-fibrins constantly have been activated again dissolves, and the thrombin that is activated is simultaneously also constantly engulfed by mononuclear phagocyte system.The dynamic equilibrium of above-mentioned blood coagulation system and fibrinolytic system; At the blood vessel repair process,, do not have normal anticoagulation function because the angiogenesis inner membrance does not form as yet; Under the factor effect of coagulation process; Break dynamic equilibrium, trigger coagulation process, before not forming self-regeneration, formed serious thrombosis.Therefore, preparation antithrombotic artificial blood vessel is the focus and the difficult point of research at present.
Radix Notoginseng has promoting blood circulation to remove blood stasis and wound hemostasia effect concurrently, can antiplatelet aggregation and antithrombotic, again can be in the angiorrhexis place quick-acting haemostatic powder.Its effective ingredient is an arasaponin, mainly is panaxatriol's glycosides Rg1.Radix Notoginseng total arasaponins (PNS) all can significantly suppress collagen, the inductive platelet aggregation of ADP in rats in vitro or rabbit body.The rat vein administration can suppress the formation of experimental thrombosis.At rat disseminated inravascular coagulation (DIC) model that thrombin brings out, intravenous injection Rg1 can significantly suppress the increase of hematoblastic minimizing and fibrin degradation product (FDP) (FDP), shows to have anti-DIC, reduces the effect of consumption of coagulation factors.High sticky blood or (with) patient of hyperlipemia takes the content that the raw sangqi ginseng powder can significantly reduce plasma fibrinogen.The Radix Notoginseng Trombin inhibiting inductive from fibrin as far as fibrinous conversion, and can activate urokinase, promote fibrinous dissolving.Radix Notoginseng antithrombotic and anti-disseminated inravascular coagulation (DIC) effect are main relevant with platelet.Its antithrombotic mechanism possibly be to synthesize and the former little being of secretory tissue fibrinolytic protein through improving vascular endothelial cell, and works through suppressing hematoblastic gathering.Radix Notoginseng total arasaponins (PNS) can significantly suppress rat platelet aggregation external, and platelet cAMP content is obviously increased, and also suppresses the release of 5-HT simultaneously, and its anticoagulant degree is parallel with 5-HT release inhibition degree.
At present, not about Radix Notoginseng being used for artificial blood vessel's report.
Summary of the invention
The shortcoming that primary and foremost purpose of the present invention is to overcome prior art provides a kind of artificial blood vessel who is loaded with the Radix Notoginseng medicine with not enough.
Another object of the present invention is to provide the method for preparing that is loaded with the artificial blood vessel of Radix Notoginseng medicine through said.
A purpose more of the present invention is to provide the described application that is loaded with the artificial blood vessel of Radix Notoginseng medicine.
Above-mentioned purpose of the present invention realizes through following technical proposals: a kind of artificial blood vessel who is loaded with the Radix Notoginseng medicine, constitute by close-connected internal layer, intermediate layer and skin successively, and skin is made up of nondegradable polymeric material; The intermediate layer by degradable high polymer material and be distributed in its surface and/or inner Notoginseng Root form; Internal layer by the degradable natural biomaterial and be distributed in its surface and/or inner Notoginseng Root form; Notoginseng Root content mass percent is greater than 5% in the internal layer; The content of Notoginseng Root is higher than the content of Notoginseng Root in the internal layer in the intermediate layer;
Described Notoginseng Root is the Notoginseng Root granule, and its particle diameter is preferably 100～500nm;
The supporting role adjustment thickness that described outer field wall thickness can provide as required wherein is preferably 0.2～0.4mm;
Described nondegradable polymeric material is preferably the mixture of a kind of in polyurethane, PET, Merlon, expanded PTFE, Kynoar, polyether-ether-ketone, polyether-ketone, PEO, polysulfones or the polyformaldehyde or at least two kinds;
Notoginseng Root content preferred mass percentage ratio is 38～60% in the described intermediate layer, and all the other are degradable high polymer material;
The intermediate layer of described tube wall is nanofiber layer or thin layer;
Described nanofiber layer is for being that the cellosilk of 200～2000nm constitutes by diameter, and wherein the Notoginseng Root granule is included in the inner sheath cored structure that forms of cellosilk;
Described thin layer is to have the two-layer at least rete structure that is coated with, and is coated with rete and is degradable macromolecule and be coated with the alternating structure that rete and Notoginseng Root are coated with rete; Wherein degradable macromolecule is coated with rete near internal layer, and thickness is 50～100 μ m; Notoginseng Root is coated with rete near skin, and thickness is 200～500 μ m, and said Notoginseng Root is coated with and contains degradable macromolecule in the rete, plays adhesive effect, can prevent that Notoginseng Root from coming off;
Described intermediate layer preferably obtains through coaxial electrically spun method or coating method, and coaxial electrical spinning method is wrapped in degradable macromolecule with the Notoginseng Root granule and forms cellosilk inside, forms the sheath cored structure; Utilize coating method molding successively, realize that degradable macromolecule is coated with the alternating structure that rete and Notoginseng Root are coated with rete; The intermediate layer can slowly discharge medicine, and plays long-acting antithrombotic effect; Simultaneously, the existence in intermediate layer and unique design are also utilized the another one haemostatic properties of Notoginseng Root; When blood vessel during by the foreign object penetration damage; The Radix Notoginseng medicine of its internal package will directly be exposed to wound, reach the effect of quick-acting haemostatic powder, and this is particularly useful for the application of products such as hemodialysis; After quick release of internal layer and degraded, the existence in intermediate layer can effectively help the reparation of blood vessel inner layer, forms normally functioning blood vessel inner layer.
Described degradable high polymer material be preferably polylactic acid, pla-pcl, polyglycolic acid, PET, polyhydroxy-alkanoate (Polyhydroxyalkanoates, PHA), the mixture of a kind of in Merlon, Polyethylene Glycol, poly butyric valerate (PHBV), poly butyric alkyl caproate, poly phosphate, polyvinyl alcohol, polyoxy ethane, collagen protein, gelatin, chitosan, modification of chitosan, starch, cellulose, modified cellulose, fibrin, fibroin, alginic acid, chondroitin sulfate, agar, glucosan or the alginic acid or at least two kinds;
The internal layer of described tube wall is the fibrous framework structure, and the nanofiber surface area is bigger, has quick degradation characteristic, and Notoginseng Root is evenly distributed in the said fibrous framework, can be included in cellosilk inside, also can be on filametntary surface; Along with the quick degraded of fibrous framework, Notoginseng Root ability rapid release plays quick antithrombotic effect;
The cellosilk diameter of described formation tube wall internal layer is 200～600nm;
Described internal layer preferably adopts electrospinning process preparation, will evenly be mixed with the particulate degradable natural biomaterial of Notoginseng Root and carry out electricity and spin, and obtains cellosilk; Adopt degradable natural biologic material to combine Radix Notoginseng,, discharge medicine, play quick antithrombotic effect at the operation initial stage;
Said degradable natural biomaterial is preferably a kind of or at least two kinds of mixture in chitosan, collagen protein, fibroin albumen, gelatin, modification of chitosan, starch, cellulose, modified cellulose, fibrin, fibroin, silkworm silk, alginic acid, hyaluronic acid, chondroitin sulfate, agar, polylactic acid-glycolic guanidine-acetic acid copolymer, glucosan or the sodium alginate;
Notoginseng Root content mass percent is greater than 5% in the described internal layer, and mass content is not obvious less than 5% internal layer anti-thrombogenic capacity; Notoginseng Root content preferred mass percentage ratio is 11.8～50% in the internal layer, and all the other are degradable natural biologic material;
Said internal layer internal diameter is less than 6mm, and preferred 4～5mm most preferably is 5mm;
A kind of method for preparing that is loaded with the artificial blood vessel of Radix Notoginseng medicine may further comprise the steps:
(1) outer field preparation:, obtain artificial blood vessel's skin after the cooling with nondegradable polymeric material oven dry back extrusion molding; Or with after the nondegradable polymeric material fusion, join in the mould, cool off the back demoulding, obtain artificial blood vessel's skin;
(2) preparation of internal layer: the method through electrostatic spinning prepares internal layer;
The method of electrostatic spinning is following: degradable natural biologic material and Notoginseng Root are dissolved in the solvent respectively; Obtain spinning solution and Radix Notoginseng drug solution; Wherein the final concentration of degradable natural biologic material is a mass volume ratio 10～20%, and the final concentration of Notoginseng Root is a mass volume ratio 1～10%; Spinning solution is carried out coaxial electrostatic spinning and is collected in cylindrical receptor surface; Control voltage is 2～8mL/h at 15～25kV, fltting speed, and rotating speed is that per minute 50～300 changes, and cylindrical diameter is 5～10mm; Internal layer obtains the fibrous framework internal layer from the receptor surface isolation; Fibre diameter in the fibrous framework internal layer is 200～600nm.
(3) be wrapped in the preparation in the intermediate layer on internal layer surface, prepare the intermediate layer through electrospinning process or coating method:
1. use dissolution with solvents degradable high polymer material and Notoginseng Root, obtain spinning solution, wherein the final concentration of degradable high polymer material is a mass volume ratio 10～20%, and the final concentration of Notoginseng Root is a mass volume ratio 10～20%; Spinning solution is carried out coaxial electrically spun; The fiber that obtains is received on the cylinder that is coated with internal layer of step (2) preparation; Control voltage is that 10～30kV, fltting speed are 2～6mL/h, and the demoulding behind the removal residual solvent obtains being wrapped in the surperficial nanofiber intermediate layer of internal layer; The diameter of fiber is 200～2000nm in the nanofiber intermediate layer;
2. use dissolution with solvents degradable high polymer material and Notoginseng Root, obtain spinning solution, wherein the final concentration of degradable high polymer material is a mass volume ratio 10～20%, and the final concentration of Notoginseng Root is a mass volume ratio 10～20%; Spinning solution is carried out electrostatic spinning, and the fiber that obtains is received on the cylinder, and control voltage is that 10～30kV, fltting speed are 2～6mL/h, and the demoulding behind the removal residual solvent obtains the nanofiber intermediate layer; The diameter of fiber is 200～2000nm in the nanofiber intermediate layer; The intermediate layer is enclosed within the internal layer outside that step (2) prepares, and connects, and obtains being wrapped in the intermediate layer on internal layer surface;
3. degradable high polymer material is dissolved in solvent and obtains solution A, wherein the final concentration of degradable high polymer material is that mass volume ratio is 10～20%; Notoginseng Root is dissolved in solvent, and adds degradable high polymer material and obtain mixed liquid B, wherein the final concentration of Notoginseng Root is a mass volume ratio 10～20%, and the degradable high polymer material final concentration is a mass volume ratio 2～10%; Then, solution A is filmed at the cylindrical metal tube outer surface, the reuse mixed liquid B is then filmed after 37～50 ℃ of held to partial desiccations, reuses solution A again and mixes that B alternately films 0 time or at least once, film forming; Separate from cylinder in 37～50 ℃ of dry backs, obtain the intermediate layer; The intermediate layer is enclosed within the internal layer outside that step (2) prepares, and connects, and obtains being wrapped in the intermediate layer on internal layer surface;
(4) be loaded with the artificial blood vessel's of Radix Notoginseng medicine preparation: the skin of step (1) preparation is enclosed within the outside, intermediate layer that is wrapped in the internal layer surface of step (3) gained,, obtains being loaded with the artificial blood vessel of Radix Notoginseng medicine with each layer connection.
Described Notoginseng Root is the Notoginseng Root granule, and its particle diameter is preferably 100～500nm;
Nondegradable polymeric material described in the step (1) is preferably the mixture of a kind of in polyurethane, PET, Merlon, expanded PTFE, Kynoar, polyether-ether-ketone, polyether-ketone, PEO, polysulfones or the polyformaldehyde or at least two kinds;
The temperature of the oven dry described in the step (1) is preferably 60～100 ℃;
The condition optimization of the extrusion molding described in the step (1) is: shear rate 50～120r/min; First section temperature is 150～175 ℃, and second section temperature is 160～180 ℃, and the 3rd section temperature is 175～200 ℃; Die temperature is 180～190 ℃, obtains different tube wall thicknesses through an adjustment mouthful mould size;
Solvent described in step (2) and (3) is preferably the mixed liquor of a kind of in formic acid, acetic acid, ethanol, acetone, dimethyl formamide, dimethyl acetylamide, oxolane, dimethyl sulfoxide, hexafluoroisopropanol, trifluoroethanol, dichloromethane, methanol, chloroform 、 diox, HFC-143a, trifluoroacetic acid or the water or at least two kinds;
Degradable natural biologic material described in the step (2) is preferably a kind of in collagen protein, fibroin albumen, gelatin, chitosan, modification of chitosan, starch, cellulose, modified cellulose, fibrin, fibroin, silkworm silk, alginic acid, hyaluronic acid, chondroitin sulfate, agar, polylactic acid-glycolic guanidine-acetic acid copolymer, glucosan or the sodium alginate or at least two kinds;
Described modification of chitosan comprises the chitosan of chemical modification and the chitosan of physical modification; Chemical modification is divided into acidylate, carboxylated, alkylation, etherificate, graft reaction etc. again, and it is compound inorganics filled etc. with micromolecule that physical modification is divided into polyelectrolyte;
Degradable high polymer material described in the step (3) be preferably polylactic acid, pla-pcl, polyglycolic acid, PET, polyhydroxy-alkanoate (Polyhydroxyalkanoates, PHA), a kind of in Merlon, Polyethylene Glycol, poly butyric valerate (PHBV), poly butyric alkyl caproate, poly phosphate, polyvinyl alcohol, collagen protein, gelatin, chitosan, modification of chitosan, starch, cellulose, modified cellulose, fibrin, fibroin, alginic acid, chondroitin sulfate, agar, glucosan or the alginic acid or at least two kinds;
The thickness that the 3. middle degradable macromolecule that uses described solution A to obtain of step (3) is coated with rete is 50～100 μ m; It is 200～500 μ m that the Notoginseng Root that uses described solution B to obtain is coated with thicknesses of layers;
Step (3) 2., 3. and the connected mode described in the step (4) is preferably ultrasonic fusion, use the non-degradable suture to sew up or use behind the two-layer slit of non-degradable colloidal sol filling crosslinked;
The power of described ultrasonic fusion is preferably 20000～30000Hz;
Described crosslinked mode is the crosslinked or heat cross-linking of UV.
A kind of artificial blood vessel who is loaded with the Radix Notoginseng medicine obtains through above-mentioned method for preparing;
The described artificial blood vessel who is loaded with the Radix Notoginseng medicine uses in clinical as the implant into body medical apparatus and instruments.
The present invention has following advantage and effect with respect to prior art:
(1) the present invention is through being compound to the medicine Radix Notoginseng among the artificial blood vessel; Make up three-decker, comprise compacted zone, long-acting antithrombotic and quick degraded layer; The different phase that realizes medicine discharges (short-term and long-acting combining), to reach good and lasting antithrombotic effect.
(2) the artificial blood vessel of the present invention is realized direct, the efficient application of Radix Notoginseng medicine aspect antithrombotic therapy.
(3) artificial blood vessel provided by the invention, the cellosilk or the drug of intermediate layer nuclear sheath structure are filmed, and all can fast the Radix Notoginseng drug release that inside comprises be come out in the blood vessel breakage, reach the effect of quick-acting haemostatic powder.Be particularly useful for using the artificial blood vessel as hemodialysis.
(4) artificial blood vessel who is loaded with the Radix Notoginseng medicine provided by the invention reduces the using dosage of Radix Notoginseng medicine, and toxic and side effects is low; Need not oral, injection etc., effect is continual and steady.
(5) activity of method for preparing protection core substance provided by the invention avoids electricity to spin the activity influence of solution system to medicine, somatomedin; Wherein electro spinning nano fiber support biomimetic features helps tissue repair, can adsorb better and the blood of growing in stem cell, endotheliocyte.
(6) electricity spins migration and the growth that structure is beneficial to the angiogenic growth relevant cell very much, and reparation has good effect for blood vessel, plays natural antithrombotic effect.
(7) electricity spins the effect that structure and Radix Notoginseng binding energy are implemented in blood vessel in-situ accomplishes anticoagulant, reaches good antithrombotic effect.
Description of drawings
Fig. 1 is artificial blood vessel's a schematic perspective view; Wherein 1 is outer, and 2 is the intermediate layer, and 3 is internal layer.
Fig. 2 is artificial blood vessel's a generalized section; Wherein, 1 is outer, and 2 is the intermediate layer, and 3 is internal layer.
The specific embodiment
Below in conjunction with embodiment and accompanying drawing the present invention is described in further detail, but embodiment of the present invention is not limited thereto.
Embodiment
(1) outer field preparation:
1. with polyurethane (BASF, 1180A EU) freeze-day with constant temperature 4h in 70 ℃, join in the extruder barrel having dried the polyurethane material; Set processing conditions: shear rate: 60r/min, first section temperature: 155 ℃, second section temperature: 165 ℃; The 3rd section temperature: 180 ℃, die temperature: 180 ℃, shear melting is extruded the postcooling molding; Obtain artificial blood vessel's skin, control mouthful mould size and pulling speed obtain the tubing that wall thickness is 0.2mm, are artificial blood vessel's skin.
2. (Arkema, Kynar740) freeze-day with constant temperature 4h in 90 ℃ join in the extruder barrel having dried the Kynoar material with Kynoar; Set processing conditions: shear rate: 110r/min, first section temperature: 175 ℃, second section temperature: 180 ℃; The 3rd section temperature: 190 ℃; Die temperature: 185 ℃, shear melting is extruded the postcooling molding, obtains artificial blood vessel's skin; Control mouthful mould size and pulling speed obtain the tubing that wall thickness is 0.4mm, are artificial blood vessel's skin.
3. with polyurethane (BASF, 1190A EU) freeze-day with constant temperature 4h in 80 ℃, join in the extruder barrel having dried the polyurethane material; Set processing conditions: shear rate: 80r/min, first section temperature: 165 ℃, second section temperature: 170 ℃; The 3rd section temperature: 186 ℃, die temperature: 183 ℃, shear melting is extruded the postcooling molding; Obtain artificial blood vessel's skin, control mouthful mould size and pulling speed obtain the tubing that wall thickness is 0.4mm, are artificial blood vessel's skin.
4. or with Merlon (Bayer, model 2858) granule 10g under nitrogen protection, be warmed up to 200 ℃ of fusions.Use rustless steel to prepare two-layer cylindrical sleeve, spacing 0.3mm.Merlon after the fusion is joined in the outer wall centre of cast mould, and keep 200 ℃ of following 10min to treat Merlon uniform distribution in tube wall.Slowly cool to room temperature with 10 ℃/min, polymer solidifies the back demoulding, obtains artificial blood vessel's skin, and this skin wall thickness is 0.3mm.
(2) preparation of internal layer:
1. the method for electrostatic spinning is following: successively with gelatin (sigma; The pharmacopeia level) and Notoginseng Root (Yunnan mountain of papers Radix Notoginseng academy) (particle diameter 100nm) be dissolved in the hexafluoroisopropanol; The concentration of gelatin is mass volume ratio 10%; The mass volume ratio of Notoginseng Root is 10%, obtains spinning solution.With the rustless steel cylinder is receptor, external diameter 5mm, rotating speed 100rpm.Draw spinning solution with glass syringe, through teflon catheter spinning solution is passed to the spinning needle point from micro-injection pump, injection speed is 2mL/h.The spinning needle point is apart from receptor 20cm, and needle point moves back and forth about vertically along receiving roller, and slew rate is 1cm/s.Add 15kV voltage at needle point, the beginning electricity spins.Electricity takes off receptor after spinning end, under 40 ℃, is kept in the vacuum drying oven 4 days, removes residual solvent in the fiber, and layer thickness is 0.1mm in the fibrous framework that obtains, and said inner fiber filament diameter is 600nm.Internal layer takes out or still overlays on rustless steel cylinder outer surface.
2. the method for electrostatic spinning is following: successively with carboxymethyl modified chitosan (Heppe Medical Chitosan; 70% modification) and Notoginseng Root (500nm) be dissolved in the hexafluoroisopropanol; The concentration of modification of chitosan is mass volume ratio 15%; The concentration of Radix Notoginseng is mass volume ratio 2%, obtains spinning solution.With the rustless steel cylinder is receptor, external diameter 5mm, rotating speed 280rpm.Draw spinning solution with glass syringe, through teflon catheter spinning solution is passed to the spinning needle point from micro-injection pump, injection speed is 8mL/h.The spinning needle point is apart from receptor 20cm, and needle point moves back and forth about vertically along receiving roller, and slew rate is 1cm/s.Add 25kV voltage at needle point, the beginning electricity spins.Electricity takes off conduit after spinning end, under 40 ℃, is kept in the vacuum drying oven 4 days, removes residual solvent in the fiber, and the thickness of the fibrous framework internal layer that obtains is 0.1mm, and said inner fiber filament diameter is 200nm.Internal layer takes out or still overlays on rustless steel cylinder outer surface.
3. the method for electrostatic spinning is following: successively with sodium carboxymethyl cellulose (Sigma; Molecular weight 90,000) and Notoginseng Root (particle diameter 300nm) be dissolved in the hexafluoroisopropanol; Cellulosic concentration is mass volume ratio 20%, and the concentration of Radix Notoginseng is mass volume ratio 6%, obtains spinning solution.With the rustless steel cylinder is receptor, external diameter 8mm, rotating speed 150rpm.Draw spinning solution with glass syringe, through teflon catheter spinning solution is passed to the spinning needle point from micro-injection pump, injection speed is 4mL/h.The spinning needle point is apart from receptor 20cm, and needle point moves back and forth about vertically along receiving roller, and slew rate is 1cm/s.Add 20kV voltage at needle point, the beginning electricity spins.Electricity takes off conduit after spinning end, under 40 ℃, is kept in the vacuum drying oven 4 days, removes residual solvent in the fiber, and the thickness of the fibrous framework internal layer that obtains is 0.1mm, and said inner fiber filament diameter is 400nm.Internal layer takes out or still overlays on rustless steel cylinder outer surface.
(3) intermediate layer or be wrapped in the preparation in the intermediate layer on internal layer surface:
1. dissolve polylactic acid (Purac with hexafluoroisopropanol; Molecular weight 240,000), Radix Notoginseng medicine and gelatin (Sigma); Wherein the concentration of polylactic acid is mass volume ratio 10%, and the Radix Notoginseng drug concentrations is a mass volume ratio 20%, and the concentration of gelatin is mass volume ratio 4%.With the rustless steel cylinder is receptor, external diameter 5mm, and rotating speed 100rpm, injection speed are 2mL/h.The spinning needle point is apart from receptor 20cm, and needle point moves back and forth about vertically along receiving roller, and slew rate is 1cm/s.Add 12kV voltage at needle point, the beginning electricity spins.Electricity takes off conduit after spinning end, under 40 ℃, is kept in the vacuum drying oven 4 days, removes residual solvent in the fiber, obtains the nanofiber intermediate layer, and said nanofiber diameter is 2000nm.
2. dissolve polycaprolactone (Sigma, molecular weight 80,000) with hexafluoroisopropanol and the Radix Notoginseng medicine obtains spinning solution, wherein the concentration of polycaprolactone is mass volume ratio 16%, and the Radix Notoginseng drug concentrations is a mass volume ratio 15%.The cylinder that is coated with internal layer with step (2) preparation is a receptor, external diameter 5mm, and rotating speed 200rpm, injection speed are 4mL/h.The spinning needle point is apart from receptor 20cm, and needle point moves back and forth about vertically along receiving roller, and slew rate is 1cm/s.Add 30kV voltage at needle point, the beginning electricity spins, and condition is the same, and the demoulding behind the removal residual solvent obtains being wrapped in the surperficial nanofiber intermediate layer of internal layer, and said nanofiber diameter is 600nm.
3. dissolve polylactic acid, Radix Notoginseng medicine and gelatin with hexafluoroisopropanol, obtain spinning solution, wherein the concentration of polylactic acid is mass volume ratio 10%, and the Radix Notoginseng drug concentrations is a mass volume ratio 10%, and the concentration of gelatin is mass volume ratio 6%.The cylinder that is coated with internal layer with step (2) preparation is a receptor, external diameter 5mm, and rotating speed 200rpm, injection speed are 6mL/h.The spinning needle point is apart from receptor 20cm, and needle point moves back and forth about vertically along receiving roller, and slew rate is 1cm/s.Add 20kV voltage at needle point, the beginning electricity spins, and condition is the same, and the demoulding behind the removal residual solvent obtains being wrapped in the surperficial nanofiber intermediate layer of internal layer, and said nanofiber diameter is 1000nm.
4. Polyethylene Glycol (Sigma, molecular weight 35000) is dissolved in hexafluoroisopropanol separately, concentration is 16%, obtains polyglycol solution; Notoginseng Root and Polyethylene Glycol are dissolved in hexafluoroisopropanol solvent formation mixed solution, and wherein the final concentration of Notoginseng Root is a mass volume ratio 15%, and the final concentration of Polyethylene Glycol is a mass volume ratio 5%.With the periphery of polyglycol solution uniform coating at external diameter 5mm, 40 ℃ of held 2h are to the partial desiccation state, and uniform coating mixed solution on this rete forms the second layer again.50 ℃ of down dry 5h molding separate promptly to obtain the intermediate layer from cylinder, wherein to be coated with thicknesses of layers be 100 μ m to Polyethylene Glycol, and it is 300 μ m that Notoginseng Root is coated with rete.
5. step in pressing 4. is behind the second layer that obtains filming, behind 40 ℃ of following dry 2h; Uniform coating polyglycol solution on this rete forms the 3rd layer again, behind 40 ℃ of following dry 3h; Uniform coating mixed solution on the 3rd layer forms the 4th layer again, 50 ℃ of following dry 5h aftershapings; Promptly obtain the intermediate layer from the cylinder separation, wherein Polyethylene Glycol is coated with thicknesses of layers and is 100 μ m, and Notoginseng Root is coated with thicknesses of layers and is 200 μ m.
(4) intermediate layer that step (3) 1., 4. or is 5. got is enclosed within the internal layer surface that step (2) obtains, and uses the ultrasonic fusion of 20000Hz frequency.Every at a distance from the mode of 10cm distance through a fusion with interior, in two-layer linking together.
(5) be loaded with the artificial blood vessel's of Radix Notoginseng medicine preparation: with the skin of step (1) preparation be enclosed within the step (3) 2., 3. or outside the internal layer that obtains in the step (4) and the pipeline that the intermediate layer has been connected; Use the ultrasonic fusion of 30000Hz frequency; Every separated 10cm distance is carried out a fusion, obtains being loaded with the artificial blood vessel of Radix Notoginseng medicine.
(6) under in-vitro simulated condition, adopt the artificial blood vessel of step (5) preparation, testing drug degraded situation.With clip 5cm artificial blood vessel, be immersed in the 0.01M phosphate-buffered behind the ethylene oxide sterilizing and dissolve in (PBS solution) (pH about 7.4), at 37 ℃, 5%CO
2Place in the cell culture incubator.Whenever used the ultraviolet light absorption appearance to detect free medicament contg in the solution at a distance from 7 days.The result shows that medicine began to continue to discharge from soaking in second day.When observing six month, the medicine total amount discharges 30% approximately, explains that the artificial blood vessel is very obvious to the slow release effect of medicine.
Radix Notoginseng medicinal application HPLC (HPLC) method to the artificial blood vessel discharges is measured total saponin content in the Radix Notoginseng medicine, and is consistent with total saponin content in the pure Radix Notoginseng medicine, on average is about 11%.It is thus clear that the artificial blood vessel is fine to the reservation of pharmaceutically active.
Effect embodiment
Employing is the artificial blood vessel of embodiment step (5) method preparation, uses experiment wolf dog (Zhongshan University's Experimental Animal Center) to carry out experiment in the body.The artificial blood vessel is outer, in, internal layer carries out testing in the animal body with the artificial blood vessel that above-mentioned each layer preparation embodiment obtains respectively: 1. 3. 2. (being that 3. skin+step (3) that embodiment step (1) 1. prepare prepares the internal layer that intermediate layer+step (2) 2. prepares), 2. 4. 3. (being the internal layer that intermediate layer+step (2) that skin+step (3) that embodiment step (1) 2. prepares 4. prepares 3. prepares), 4. 5. 1. (being the internal layer that intermediate layer+step (2) that skin+step (3) that embodiment step (1) 4. prepares 5. prepares 1. prepares), 3. 1. 2. (being the internal layer that intermediate layer+step (2) that skin+step (3) that embodiment step (1) 3. prepares 1. prepares 2. prepares), 1. 4. 2. (being the internal layer that intermediate layer+step (2) that skin+step (3) that embodiment step (1) 1. prepares 4. prepares 2. prepares), 3. 5. 1. (being the internal layer that intermediate layer+step (2) that skin+step (3) that embodiment step (1) 3. prepares 5. prepares 1. prepares), 2. 3. (being the internal layer that intermediate layer+step (2) that skin+step (3) that embodiment step (1) 2. prepares 2. prepares is 3. Zhi Beied) Zu He; And with 2.-3. (being the internal layer that skin+step (2) that embodiment 1 step (1) 2. prepares 3. prepares) ,-2. 1. (being the internal layer that intermediate layer+step (2) that embodiment 1 step (3) 2. prepares 1. prepares), 4.-(being the intermediate layer that skin+step (3) that embodiment 1 step (1) 4. prepares 4. prepares), choose 3 experiment wolf dogs for every group and carry out following processing as matched group.Under the sterile working, back leg muscle strip off is exposed large artery trunks.Choose one section part that about 15cm is long, two ends are used mosquito forceps to clamp the back and are clipped 5cm from the centre.The method that adopts the end position to sew up with the degradable suture is sewn onto defect with aseptic artificial blood vessel.Observe the stitching situation, layer-by-layer suture wound behind the ne-leakage after decontroling mosquito forceps.Take different time points to observe whether the artificial blood vessel has the thromboembolism phenomenon in the body.Simulate the puncture experiment February.Operative site is cleaned out, under the sterile working, back leg muscle strip off is exposed the artificial blood vessel.The use front end is sharp-pointed, and the stainless pin of 1.0mm diameter punctures with 30 ° of oblique angles, pokes the firm intravasation of blood vessel wall with syringe needle and exceeds.Extract syringe needle then, observe the hemostasis situation.Get an experimental dogs anatomic observation respectively for every group.Experiment effect is as shown in table 1:
Table 1:
The foregoing description is a preferred implementation of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (14)
1. artificial blood vessel who is loaded with the Radix Notoginseng medicine, it is characterized in that: said artificial blood vessel is made up of close-connected internal layer, intermediate layer and skin successively; Skin is made up of nondegradable polymeric material; The intermediate layer by degradable high polymer material and be distributed in its surface and/or inner Notoginseng Root form; Internal layer by the degradable natural biomaterial and be distributed in its surface and/or inner Notoginseng Root form; The mass percent of Notoginseng Root content is greater than 5% in the internal layer; The content of Notoginseng Root is higher than the content of Notoginseng Root in the internal layer in the intermediate layer.
2. the artificial blood vessel who is loaded with the Radix Notoginseng medicine according to claim 1 is characterized in that:
Described nondegradable polymeric material is the mixture of a kind of in polyurethane, PET, Merlon, expanded PTFE, Kynoar, polyether-ether-ketone, polyether-ketone, PEO, polysulfones or the polyformaldehyde or at least two kinds;
Described degradable high polymer material is a polylactic acid; Pla-pcl; Polyglycolic acid; PET; Polyhydroxy-alkanoate; Merlon; Polyethylene Glycol; The poly butyric valerate; The poly butyric alkyl caproate; Poly phosphate; Polyvinyl alcohol; Polyoxy ethane; Collagen protein; Gelatin; Chitosan; Modification of chitosan; Starch; Cellulose; Modified cellulose; Fibrin; Fibroin; Alginic acid; Chondroitin sulfate; Agar; The mixture of a kind of in glucosan or the alginic acid or at least two kinds;
Described degradable natural biologic material is a kind of or at least two kinds of mixture in collagen protein, fibroin albumen, gelatin, chitosan, modification of chitosan, starch, cellulose, modified cellulose, fibrin, fibroin, silkworm silk, alginic acid, hyaluronic acid, chondroitin sulfate, agar, polylactic acid-glycolic guanidine-acetic acid copolymer, glucosan or the sodium alginate.
3. the artificial blood vessel who is loaded with the Radix Notoginseng medicine according to claim 1 is characterized in that:
Described intermediate layer is nanofiber layer or thin layer; Nanofiber layer is that the cellosilk of 200～2000nm constitutes by diameter, and wherein the Notoginseng Root granule is included in the inner sheath cored structure that forms of cellosilk; Thin layer is to have the two-layer at least rete structure that is coated with, and is coated with rete and is degradable macromolecule and be coated with the alternating structure that rete and Notoginseng Root are coated with rete; Wherein degradable macromolecule is coated with rete near internal layer, and thickness is 50～200 μ m; Notoginseng Root is coated with rete near skin, and thickness is 200～500 μ m.
4. according to claim 1 or the 3 described artificial blood vessels that are loaded with the Radix Notoginseng medicine, it is characterized in that: described internal layer is the fibrous framework structure, and wherein the cellosilk diameter is 200～600nm, and Notoginseng Root is evenly distributed on filametntary inside or surface.
5. the artificial blood vessel who is loaded with the Radix Notoginseng medicine according to claim 1 is characterized in that: described outer field wall thickness is 0.2～0.4mm.
6. the artificial blood vessel who is loaded with the Radix Notoginseng medicine according to claim 1 is characterized in that: said internal layer internal diameter is less than 6mm.
7. the artificial blood vessel who is loaded with the Radix Notoginseng medicine according to claim 1 is characterized in that: said internal layer internal diameter is 4～5mm.
8. the artificial blood vessel who is loaded with the Radix Notoginseng medicine according to claim 1 is characterized in that: said Notoginseng Root is the Notoginseng Root granule, and grain diameter is 100～500nm.
9. the artificial blood vessel who is loaded with the Radix Notoginseng medicine according to claim 1 is characterized in that: the Notoginseng Root content in the described intermediate layer is mass percent 38～60%; Notoginseng Root content in the described internal layer is mass percent 11.8～50%.
10. each described method for preparing that is loaded with the artificial blood vessel of Radix Notoginseng medicine of claim 1～9 is characterized in that may further comprise the steps:
(1) outer field preparation:, obtain artificial blood vessel's skin after the cooling with nondegradable polymeric material oven dry back extrusion molding; Or with after the nondegradable polymeric material fusion, join in the mould, cool off the back demoulding, obtain artificial blood vessel's skin;
(2) preparation of internal layer: the method through electrostatic spinning prepares internal layer;
The method of electrostatic spinning is following: degradable natural biologic material and Notoginseng Root are dissolved in the solvent respectively; Obtain spinning solution and Radix Notoginseng drug solution; Wherein the final concentration of degradable natural biologic material is a mass volume ratio 10～20%, and the final concentration of Notoginseng Root is a mass volume ratio 1～10%; Spinning solution is carried out coaxial electrostatic spinning and is collected in cylindrical receptor surface; Control voltage is 2～8mL/h at 15～25kV, fltting speed, and rotating speed is that per minute 50～300 changes, and cylindrical diameter is 5～10mm; Internal layer obtains the fibrous framework internal layer from the receptor surface isolation;
(3) be wrapped in the preparation in the intermediate layer on internal layer surface, prepare the intermediate layer through electrospinning process or coating method:
1. use dissolution with solvents degradable high polymer material and Notoginseng Root, obtain spinning solution, wherein the final concentration of degradable high polymer material is a mass volume ratio 10～20%, and the final concentration of Notoginseng Root is a mass volume ratio 10～20%; Spinning solution is carried out coaxial electrically spun; The fiber that obtains is received on the cylinder that is coated with internal layer of step (2) preparation; Control voltage is that 10～30kV, fltting speed are 2～6m L/h, and the demoulding behind the removal residual solvent obtains being wrapped in the surperficial nanofiber intermediate layer of internal layer;
2. use dissolution with solvents degradable high polymer material and Notoginseng Root, obtain spinning solution, wherein the final concentration of degradable high polymer material is a mass volume ratio 10～20%, and the final concentration of Notoginseng Root is a mass volume ratio 10～20%; Spinning solution is carried out electrostatic spinning, and the fiber that obtains is received on the cylinder, and control voltage is that 10～30kV, fltting speed are 2～6mL/h, and the demoulding behind the removal residual solvent obtains the nanofiber intermediate layer; The intermediate layer is enclosed within the internal layer outside that step (2) prepares, and connects, and obtains being wrapped in the intermediate layer on internal layer surface;
3. degradable high polymer material is dissolved in solvent and obtains solution A, wherein the final concentration of degradable high polymer material is that mass volume ratio is 10～20%; Notoginseng Root is dissolved in solvent, and adds degradable high polymer material and obtain mixed liquid B, wherein the final concentration of Notoginseng Root is a mass volume ratio 10～20%, and the degradable high polymer material final concentration is a mass volume ratio 2～10%; Then, solution A is filmed at the cylindrical metal tube outer surface, the reuse mixed liquid B is then filmed after 37～50 ℃ of held to partial desiccations, reuses solution A again and mixes that B alternately films 0 time or at least once, film forming; Separate from cylinder in 37～50 ℃ of dry backs, obtain the intermediate layer; The intermediate layer is enclosed within the internal layer outside that step (2) prepares, and connects, and obtains being wrapped in the intermediate layer on internal layer surface;
(4) be loaded with the artificial blood vessel's of Radix Notoginseng medicine preparation: the skin of step (1) preparation is enclosed within the outside, intermediate layer that is wrapped in the internal layer surface of step (3) gained,, obtains being loaded with the artificial blood vessel of Radix Notoginseng medicine with each layer connection.
11. the method for preparing that is loaded with the artificial blood vessel of Radix Notoginseng medicine according to claim 10 is characterized in that:
Solvent described in step (2) and (3) is the mixed liquor of a kind of in formic acid, acetic acid, ethanol, acetone, dimethyl formamide, dimethyl acetylamide, oxolane, dimethyl sulfoxide, hexafluoroisopropanol, trifluoroethanol, dichloromethane, methanol, chloroform 、 diox, HFC-143a, trifluoroacetic acid or the water or at least two kinds.
12. the method for preparing that is loaded with the artificial blood vessel of Radix Notoginseng medicine according to claim 10 is characterized in that:
The temperature of the oven dry described in the step (1) is 60～100 ℃;
The condition of the extrusion molding described in the step (1) is: shear rate 50～120r/min; First section temperature is 150～175 ℃, and second section temperature is 160～180 ℃, and the 3rd section temperature is 175～200 ℃; Die temperature is 180～190 ℃.
13. the method for preparing that is loaded with the artificial blood vessel of Radix Notoginseng medicine according to claim 10 is characterized in that:
Step (3) 2., 3. and the connected mode described in the step (4) be ultrasonic fusion, use the non-degradable suture to sew up or use behind the two-layer slit of non-degradable colloidal sol filling crosslinked; The power of described ultrasonic fusion is 20000～30000Hz; Described crosslinked mode is the crosslinked or heat cross-linking of UV.
14. each described artificial blood vessel who is loaded with the Radix Notoginseng medicine of claim 1～9 is as the application of implant into body medical apparatus and instruments in clinical.
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Address after: 510663 Guangzhou District, Guangdong, new high tech Industrial Development Zone, Science City, 80 E third district. Co-patentee after: Shenzhen Medprin Regenerative Medical Technologies Co., Ltd. Patentee after: Guangzhou Maple regenerative medicine Polytron Technologies Inc Address before: 510663 Guangzhou, Guangdong, Guangzhou hi tech Industrial Development Zone, Science City, 80 E third district. Co-patentee before: Shenzhen Medprin Regenerative Medical Technologies Co., Ltd. Patentee before: Medprin Regenerative Medical Technologies Co., Ltd. |