CN102973988B - Absorbable vessel ligature clamp and preparation method thereof - Google Patents
Absorbable vessel ligature clamp and preparation method thereof Download PDFInfo
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- CN102973988B CN102973988B CN201210556673.6A CN201210556673A CN102973988B CN 102973988 B CN102973988 B CN 102973988B CN 201210556673 A CN201210556673 A CN 201210556673A CN 102973988 B CN102973988 B CN 102973988B
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Abstract
The invention provides an absorbable vessel ligature clamp for surgical operation and a preparation method thereof. The vessel ligature clamp is prepared from a biodegradable aliphatic polyester material, wherein the biodegradable aliphatic polyester material is a homopolymer of any one of monomers or a copolymer of any two type of monomers, namely dioxanone, glycolide, lactide, caprolactone and trimethylene carbonate, and the vessel ligature clamp can be prepared by virtue of the modification and injection molding of amino acid. The vessel ligature clamp is good in biocompatibility, adjustable in degradation time, and capable of being matched with the vessel healing period after the surgical operation.
Description
Technical field
The present invention relates to the biological absorbable vascular ligation that a kind of surgical operation being prepared from by the raw material that comprises biodegradable aliphatic polyester material uses presss from both sides.Specifically, relate to biocompatibility excellence, the adjustable biodegradable aliphatic polyester material of degradation time in vivo, and thus preparation there is pliability and biological absorbable vascular ligation folder that surgical operation that good folder closes power, structure optimization is used.In addition the invention still further relates to, the preparation method of described vascular ligation folder.
Background technology
Hemostatic technique is one of core of basic operative techniques technology, the surgical procedures at any position of human body almost relates to hemorrhage and hemostasis bar none, and hemostatic technique develops into the perfect technical system including medicine, material, apparatus, anesthesia etc. under modern surgery condition by simple apparatus hemostasis measure of past.And find bleeding part, hemorrhage blood vessel is processed to the real key that is only hemostasis.Ligation, sew up, tamp, the traditional method such as thermal hemostasis still playing a significant role so far, on the other hand, the vascular clamp that grows up on this basis, hemostatic gauze, anastomat, high frequency electric knife (radio knife), ultrasound knife (ultracision-harmonic scalpel), ligation bundle vessel sealing system (electothermal bipolar vessel sealer) etc. are also just being widely used in operation, it is sealing blood vessels effectively, and prevention and minimizing visual area are hemorrhage.
Vascular ligation folder is a kind of surgical hemostasis consumptive material for the medium and small angiorrbagia in deep occurring in recent years, for example, for blocking blood flow or clamp occluding vascular, the aneurysm clamp using in aneurysm surgery, the gall duct clamp in biliary surgery etc.Its material mostly is silver or alloy, is secondly medical plastic, common are silver brain clip, titanium folder, tantalum folder, hem-o-lok folder etc.The vascular ligation of these types presss from both sides due to its nonabsorable, is retained in the most at last in patient body, is organized parcel, becomes foreign body.The ligation clip being retained in patient body can cause tissue to produce foreign body reaction or stimulate tissue to produce the complication such as inflammation, pain; Simultaneously metal ligation clip also can affect the inspections such as X ray after operation in patients, CT, MRI.Therefore the vascular ligation folder of, being made by biodegradable or absorbable material is the good way addressing this problem.
The experimentation of surgery absorbability vascular ligation folder starts from the phase early 1980s.Patent documentation 1 discloses a kind of preparation method of high molecular PPDO, but do not carry out the research for the biocompatibility of the medical material of being prepared by PPDO, with and the research of the machine-shaping technology produced in batches while preparing medical treatment consumptive materials.Existing known PPDO texture material is pliable and tough, and the medical treatment consumptive materials insufficient strength that material is made thus need to be done further to optimize to its moulding process.The ligation clip material therefor that patent documentation 2,3 is made is the blend of polylactic acid and polyglycolic acid, although these materials have acceptable biocompatibility, the degradation time of this ligation clip is unadjustable.
Although through years of researches in industry, the performance of vascular ligation folder has obtained significantly promoting, but being centered around between degradable aliphatic polyester homopolymerization or copolymer always, the improvement of vascular ligation folder carries out, and very few about the bibliographical information of modulating vascular ligation clip degradation time.Urgently develop at present a kind of can be for implant site difference and degradation time adjustable, the Biodegradable material with good biocompatibility, and can be applied to thus blood vessel, there is the vascular ligation folder of the new structure that can avoid operation technique to cause surrounding tissue damage.
Patent documentation 1: the Chinese patent that publication number is CN101186686A
Patent documentation 2: the United States Patent (USP) that publication number is US4741337
Patent documentation 3: the United States Patent (USP) that publication number is US4889119
Summary of the invention
the problem that invention will solve
The inventor, in order to solve the deficiency of prior art medium vessels ligation clip, studies assiduously from material selection, preparation technology, the shape design three aspects: of vascular ligation folder.Found that the raw material that comprises biodegradable aliphatic polyester material by use, the method of injection mo(u)lding in certain melting injection molding process, mould at given shape, thereby can obtain not only to have pliability but also have good folder, close power, the monolayer that degradation time can regulate and control (0.5-24 month) can absorb vascular ligation folder; This vascular ligation fixture has good biocompatibility; This vascular ligation folder finally can be absorbed by the body completely, and tissue is not had to zest.
for the scheme of dealing with problems
Can realize above-mentioned purpose of the present invention by following scheme.
[1] one can absorb vascular ligation folder, it is characterized in that: described vascular ligation folder is prepared from by the raw material that comprises biodegradable aliphatic polyester material, and described ligation clip has good biocompatibility.
[2] according to the absorbed vascular ligation folder [1] Suo Shu, wherein, described biodegradable aliphatic polyester is that its viscosity-average molecular weight is 100,000 ~ 800,000 to any homopolymer or copolymer of any two above monomer in them in dioxy Ketohexamethylene (PDO), Acetic acid, hydroxy-, bimol. cyclic ester (GA), lactide (LA), caprolactone (CL), trimethylene carbonate (TMC).
[3], according to the absorbed vascular ligation folder [2] Suo Shu, wherein, described biodegradable aliphatic polyester is to dioxy Ketohexamethylene and one or more the copolymer being selected from Acetic acid, hydroxy-, bimol. cyclic ester, lactide, caprolactone, trimethylene carbonate.
[4] according to the absorbed vascular ligation folder described in any one in [1]～[3], wherein, described biodegradable aliphatic polyester can be through amino-acid modified, and described aminoacid is for being selected from one or more in glutamic acid (Glu), aspartic acid (Asp).
[5] according to the absorbed vascular ligation folder [4] Suo Shu, wherein, in described biodegradable aliphatic polyester material, aliphatic poly ester units and amino acid whose unit mol ratio are aliphatic polyester: aminoacid=95:5～60:40, and described properties of materials viscosity number is 1.0 ~ 6.0dL/g.
[6] according to the absorbed vascular ligation folder described in [1]～[5] any one, wherein, described biodegradable aliphatic polyester properties of materials viscosity number is 0.5 ~ 8.0dL/g.
[7] according to the absorbed vascular ligation folder described in [1]～[6] any one, wherein, the degradation time of described ligation clip can regulate in the time range of 0.5 ~ 24 month.
[8] according to the absorbed vascular ligation folder described in any one in [1]～[7], wherein, it is 0 ~ 1 grade that described ligation clip has according to mtt assay evaluation cytotoxicity, and 24 hour cell adhesion rates reach more than 60% good biocompatibility.
[9] a kind of preparation method that absorbs vascular ligation folder, wherein, described ligation clip is prepared from by the raw material that comprises biodegradable aliphatic polyester material is carried out to melting injection moulding with following condition, mold preheating temperature is 25 ~ 60 ℃, injection temperature is 100 ~ 120 ℃, the pressure that shoots material is 25 ~ 55 bar, and briquetting pressure remains 20 ~ 50 bar, and the dwell time is 5 ~ 15 seconds.
the effect of invention
Accompanying drawing explanation
Fig. 1 is schematic diagram of the present invention.In figure, 1 is folder hook, and 2 is folder hook groove, and 3 is upper clip arm, and 4 is lower clip arm, and 5 is localizer, 6 be " indulging " to anti-slip veins, 7 be " horizontal stroke " to anti-slip veins, 8 is arc groove.
The specific embodiment
Provide to achieve the object of the present invention one can absorb vascular ligation folder and preparation method thereof, this can absorb vascular ligation, and to press from both sides to comprise biodegradable aliphatic polyester material be that raw material is prepared from, through melting, be injected in the mould cavity of given shape, obtain the vascular ligation folder of molding.The vascular ligation folder of above-mentioned molding is packed after sterilization treatment can be in clinical use.
In a specific embodiment of the present invention, degradable aliphatic polyester of the present invention is homopolymer or the copolymer of the homopolymer of the homopolymer of the homopolymer of homopolymer to dioxy Ketohexamethylene or copolymer, Acetic acid, hydroxy-, bimol. cyclic ester or copolymer, lactide or copolymer, caprolactone or copolymer, trimethylene carbonate, or by these homopolymer or the above-mentioned amino-acid modified copolymer obtaining for copolymer, the viscosity-average molecular weight of described degradable aliphatic polyester is 100,000 ~ 800,000.
In the present invention, if no special instructions, described viscosity-average molecular weight is all according to Mark-Houwink equation
calculate.Wherein, η represents the intrinsic viscosity of polymer, α, K value can be referring to " the 2687th page of < < Macromolecular Chemistry and Physics > the 201st the 18th phase of volume of >; 2000 ", for example, for PPDO, its α=0.63, K=79 × 10
-3cm
3/ g.In this content by the document, introduce the present invention.
In another specific embodiment of the present invention, the vascular ligation fixture that absorbs of the present invention has good biocompatibility; It is 0 ~ 1 grade that described ligation clip has according to mtt assay evaluation cytotoxicity, and 24 hour cell adhesion rates reach more than 60% good biocompatibility; Preferably having according to mtt assay evaluation cytotoxicity is 0 grade, and 24 hour cell adhesion rates reach more than 70% good biocompatibility; More preferably having according to mtt assay evaluation cytotoxicity is 0 grade, and 24 hour cell adhesion rates reach more than 80% good biocompatibility.
In another specific embodiment of the present invention, the degradation time that absorbs vascular ligation folder of the present invention is regulatable.Described degradation time can be adjustable in the time range of 0.5 ~ 24 month; Preferably can be adjustable in the time range of 1 ~ 13 month; More preferably can be adjustable in the time range of 6 ~ 10 months.It should be noted that, for degradable high polymer material, biodegradation than biological absorbing again, the implication of biological absorbable, bio-absorbable and bioerosion is wider, because the degradation mechanism occurring is in vivo difficult to distinguish, often adopt that biodegradation explains that biodegradation, biology absorb again, biological absorbable, bio-absorbable and bioerosion, and do not add differentiation.Indication " degradation time " all refers to that described vascular clamp product starts in actual implantable bioartificial body herein, until the time interval being absorbed by organism completely.
In another specific embodiment of the present invention, ligation clip of the present invention has following coagulant blood effect: PT prothrombin time, TT thrombin time, APTT activated partial thromboplastin time are all less than the PT prothrombin time, TT thrombin time and the APTT activated partial thromboplastin time that contrast healthy blood plasma.
In another specific embodiment of the present invention, in amino-acid modified biodegradable aliphatic polyester material used in the present invention, aliphatic poly ester units and amino acid whose unit mol ratio are aliphatic polyester: aminoacid=95:5～60:40, and described properties of materials viscosity number is 1.0 ~ 6.0dL/g.In the present invention, if no special instructions, described intrinsic viscosity is all by take phenol/sym-tetrachloroethane (volume ratio is as 2:3) mixed solution as solvent, with Ubbelohde viscometer, in 25 ℃ of waters bath with thermostatic control, records.
In another specific embodiment of the present invention, the vascular ligation folder that absorbs of the present invention is prepared from by melting Shooting Technique, mold preheating temperature 25-60 ℃, preferably 35-45 ℃; Injection temperature 100-120 ℃, preferably 105-115 ℃; The pressure 25-55 that shoots material bar, preferably 40-50 bar (Bar); Briquetting pressure remains 20-50 bar (Bar), preferably 35-45 bar (Bar); Dwell time 5-15 second (s), preferably 9-11 second (s).
In another specific embodiment of the present invention, of the present inventionly absorb vascular ligation folder is monolayer, V-structure.Particularly, described V-structure comprises upper clip arm, lower clip arm, one end of described upper clip arm and lower clip arm interconnects, the other end of described upper clip arm and lower clip arm is sealed port part, and it is by forming for the sealed folder hook groove structure of described latch hook on the free end of the latch hook structure on the free end of upper clip arm and lower clip arm.
In another specific embodiment of the present invention, the upper clip arm that absorbs vascular ligation folder V-structure of the present invention is provided with the bolt that horizontal two row " protruding " rise, lower clip arm is provided with the bolt that longitudinal string " protruding " rises, and the setting of this bolt is clamped condition after can making lower clip arm sealed.
In a preferred specific embodiment of the present invention, the junction that absorbs vascular ligation folder V-structure upper clip arm and lower clip arm of the present invention is provided with the groove of an arc.Further, described arc groove is crescent shape.Concrete shape can be referring to accompanying drawing 1.
The vascular ligation folder that absorbs of the present invention is for single layer structure, and outward appearance is V-shaped.The sealed mouthful place of V-structure is provided with the structure of latch hook, once ligation clip cannot be opened formation locking state after sealed again, can only disposablely use.The opening angle of vascular ligation folder V-structure is 0 ~ 60 °.This folder is compared with double-decker, the most outstanding advantage is to have designed latch hook at sealed mouthful of place, ligation clip can be firmly locked in together after closure, make ligation clip can sustain larger tube chamber pressure, expanded the range of application of ligation clip, make ligation clip can not only be applied to bile duct ligation, can also be applied to the ligation of the relatively large blood vessel of tube chamber pressure.
In a preferred specific embodiment of the present invention, the amino-acid modified biodegradable aliphatic polyester material of use is the PPDO polymeric material through glutamic acid modification.Wherein preferably, to the unit mol ratio of dioxy Ketohexamethylene-glutamic, be 95:5～60:40, intrinsic viscosity 2.0～5.0dL/g, more preferably, to the unit mol ratio of dioxy Ketohexamethylene-glutamic, be 90:10～70:30, intrinsic viscosity 3.0～4.0dL/g, viscosity-average molecular weight 40～800,000.
In the present invention, polymer raw material is used the graininess pellet that diameter is 1-8mm.Pellet melt injection is carried out to injection molding in mould cavity, mold preheating temperature 25-60 ℃, preferably 35-45 ℃; Injection temperature 100-120 ℃, preferably 105-115 ℃; The pressure 25-55 that shoots material bar, preferably 40-50 bar; Briquetting pressure remains 20-50 bar, preferably 35-45 bar; Dwell time 5-15 second, preferably 9-11 second.
In the raw materials of vascular ligation of the present invention folder, except above-mentioned biodegradable aliphatic polyester material, can contain the conventional auxiliary agent of other harmless its biological degradabilities, the medical pigments such as such as No. 2, D & C purple.
The present invention preparing after vascular ligation folder, further studied its degradation behavior in the buffer solution of simulated body fluid environment, studied its cytotoxicity, studied its cell compatibility and detected its blood coagulation effect with PT prothrombin time, TT thrombin time and APTT activated partial thromboplastin time with extracorporeal culture-ing with mtt assay.
In the present invention, vascular ligation folder is carried out to simulated body fluid Degrading experiment, found that, make vascular ligation fixture have longer degradation time, when reducing amino acid ratio, the molecular weight of polymer is also wanted corresponding raising.Make thus the requirement of the synthetic factors (monomer purity, catalyst amount, response time etc.) that has facilitation to heavy polymer harsher, these factors have brought difficulty all to the preparation of ligation clip, and have increased manufacturing cost.With merely by control molecular weight regulate degradation time comparison, in the molecular weight ranges of certain easy preparation, by regulating copolymer ratio to regulate and control the degradation time of polymer, from product, preparing aspect says the material benefit more economically of such mode, more has an operability, from sufferer use, say that reduce ligation clip is deposited in time in patient, can effectively alleviates the postoperative Psychological inadaptability sense of sufferer and foreign body sensation as far as possible, is convenient to the mental recovery of sufferer.After a large amount of research, we finds, the unit mol ratio of aliphatic polyester-amino acid copolymer is in the scope of 100:0～40:60, can be 1 to 18 months by degradation time control, this be preferred for taking into account manufacturing cost and applicable degradation time.More preferably aliphatic polyester-amino acid copolymer unit mol ratio is 70:30～90:10, intrinsic viscosity 3.0-4.0dL/g, degradation time 6-10 month.
The inventor has also carried out biocompatibility test to vascular ligation folder.Found that, vascular ligation fixture of the present invention has good cell compatibility, and it is 0 ~ 1 grade that mtt assay is evaluated cytotoxicity, and 24 hour cell adhesion rates reach more than 60%.Preferably mtt assay evaluation cytotoxicity is 0 grade, and 24 hour cell adhesion rates reach more than 70%.This vascular ligation fixture has certain coagulant blood effect, and PT prothrombin time, TT thrombin time, APTT activated partial thromboplastin time are all less than the PT prothrombin time, TT thrombin time and the APTT activated partial thromboplastin time that contrast healthy blood plasma.The PT prothrombin time of the healthy blood plasma of the contrast measured in the application is that 36.64 seconds, TT thrombin time are that 16.21 seconds, APTT activated partial thromboplastin time are 93.82 seconds.
As the sterilization method of product, in the present invention, can select the modes such as ethanol for disinfection, oxirane, ultraviolet, gamma-rays to carry out sterilization treatment to molding ligation clip.Its concrete sterilising conditions is respectively: (1) ethanol for disinfection sterilizing: adopt 75% alcohol-pickled ligation clip 30min, then with 10mL aseptic bottle, pack.(2) ethylene oxide sterilizing: adopt the oxirane that concentration is 500mg/L, 55 ℃ of temperature, relative humidity is controlled at 30%-40%, sterilizing 12 hours; After sterilizing standing 1 day, to remove residual oxirane.(3) ultraviolet disinfection: under the condition that is 50%-70% at relative humidity, with radiation value>=100 μ W/cm
230W Burdick lamp, in superclean bench internal radiation, more than 2 hours, aseptic packaging is stand-by.(4) γ ray sterilization: adopt the gamma-ray irradiation device sterilizing with microcomputer automatic control and REVOLVING IRRADIATION STAGE, dosage is 20kGy, irradiation field temperature 15-25 ℃.
In these sterilization methods, optimization ethylene oxide, γ ray sterilization.Can further optimize sterilization method and sterilizing parameter according to needs of production.
Embodiment
Below, illustrate that embodiment and comparative example are specifically described embodiments of the present invention.But the present invention is not limited to following embodiment.
(synthesizing of aliphatic poly ester material)
The preparation of synthesis example 1 to dioxy Ketohexamethylene-glutamic 1
Will be to dioxy Ketohexamethylene and two kinds of monomers of glutamic acid, with the mol ratio proportioning of 70:30, the 300g that weighs adds in reactor, to the stannous octoate catalyst that adds 0.02% in reactor.Sealed reaction system, passes into nitrogen protection reaction.Controlling response system temperature is 120 ℃, reacts 10 hours.Reactant chopping is made to the pellet of 1-8mm particle diameter, weigh and obtain pellet 191g, yield 95.5%.Above-mentioned pellet is dissolved in phenol/sym-tetrachloroethane (2:3/V:V) mixed solution, and the intrinsic viscosity that records copolymer with Ubbelohde viscometer in 25 ℃ of waters bath with thermostatic control is 3.28dL/g.
The preparation of synthesis example 2 to dioxy Ketohexamethylene-glutamic 2
Will be to dioxy Ketohexamethylene and two kinds of monomers of glutamic acid, with the mol ratio proportioning of 80:20, the 500g that weighs adds in reactor, to the stannous octoate catalyst that adds 0.01% in reactor.Sealed reaction system, passes into argon shield reaction.Controlling response system temperature is 130 ℃, reacts 10 hours.Reactant chopping is made to the pellet of 1-6mm particle diameter, weigh and obtain pellet 491g, yield 98.2%.Above-mentioned pellet is dissolved in phenol/sym-tetrachloroethane (2:3/V:V) mixed solution, and the intrinsic viscosity that records copolymer with Ubbelohde viscometer in 25 ℃ of waters bath with thermostatic control is 3.34dL/g.
The preparation of synthesis example 3 to dioxy Ketohexamethylene-glutamic 3
Will be to dioxy Ketohexamethylene and two kinds of monomers of glutamic acid, with the mol ratio proportioning of 90:10, the 300g that weighs adds in reactor, to the stannous octoate catalyst that adds 0.01% in reactor.Sealed reaction system, passes into nitrogen protection reaction.Controlling response system temperature is 140 ℃, reacts 10 hours.Reactant chopping is made to the pellet of 1-4mm particle diameter, weigh and obtain pellet 292.5g, yield 97.5%.Above-mentioned pellet is dissolved in phenol/sym-tetrachloroethane (2:3/V:V) mixed solution, and the intrinsic viscosity that records copolymer with Ubbelohde viscometer in 25 ℃ of waters bath with thermostatic control is 3.51dL/g.
The preparation of synthesis example 4 to dioxy Ketohexamethylene-glutamic 4
According to the method for synthesis example 1, except dioxy Ketohexamethylene and glutamic acid mol ratio are become to 0:100, synthetic obtaining dioxy Ketohexamethylene-glutamic 4, the intrinsic viscosity that its method according to synthesis example 1 is measured is 1.61dL/g.
The preparation of synthesis example 5 to dioxy Ketohexamethylene-glutamic 5
According to the method for synthesis example 1, except dioxy Ketohexamethylene and glutamic acid mol ratio are become to 10:90, synthetic obtaining dioxy Ketohexamethylene-glutamic 5, the intrinsic viscosity that its method according to synthesis example 1 is measured is 2.31dL/g.
The preparation of synthesis example 6 to dioxy Ketohexamethylene-glutamic 6
According to the method for synthesis example 1, except dioxy Ketohexamethylene and glutamic acid mol ratio are become to 20:80, synthetic obtaining dioxy Ketohexamethylene-glutamic 6, the intrinsic viscosity that its method according to synthesis example 1 is measured is 2.34dL/g.
The preparation of synthesis example 7 to dioxy Ketohexamethylene-glutamic 7
According to the method for synthesis example 1, except dioxy Ketohexamethylene and glutamic acid mol ratio are become to 30:70, synthetic obtaining dioxy Ketohexamethylene-glutamic 7, the intrinsic viscosity that its method according to synthesis example 1 is measured is 3.32dL/g.
The preparation of synthesis example 8 to dioxy Ketohexamethylene-glutamic 8
According to the method for synthesis example 1, except dioxy Ketohexamethylene and glutamic acid mol ratio are become to 40:60, synthetic obtaining dioxy Ketohexamethylene-glutamic 8, the intrinsic viscosity that its method according to synthesis example 1 is measured is 3.61dL/g.
The preparation of synthesis example 9 to dioxy Ketohexamethylene-glutamic 9
According to the method for synthesis example 1, except dioxy Ketohexamethylene and glutamic acid mol ratio are become to 50:50, synthetic obtaining dioxy Ketohexamethylene-glutamic 9, the intrinsic viscosity that its method according to synthesis example 1 is measured is 3.78dL/g.
The preparation of synthesis example 10 to dioxy Ketohexamethylene-glutamic 10
According to the method for synthesis example 1, except dioxy Ketohexamethylene and glutamic acid mol ratio are become to 60:40, synthetic obtaining dioxy Ketohexamethylene-glutamic 10, the intrinsic viscosity that its method according to synthesis example 1 is measured is 3.82dL/g.
The preparation of synthesis example 11 to dioxy Ketohexamethylene-glutamic 11
According to the method for synthesis example 1, except dioxy Ketohexamethylene and glutamic acid mol ratio are become to 95:5, synthetic obtaining dioxy Ketohexamethylene-glutamic 11, the intrinsic viscosity that its method according to synthesis example 1 is measured is 3.27dL/g.
The preparation of synthesis example 12 to dioxy Ketohexamethylene homopolymer 1
According to the method for synthesis example 1, except dioxy Ketohexamethylene and glutamic acid mol ratio are become to 100:0, synthetic obtaining dioxy Ketohexamethylene homopolymer 1, the intrinsic viscosity that its method according to synthesis example 1 is measured is 3.48dL/g.
The intrinsic viscosity of the product of synthesis example 1 ~ 12 is summarized in following table 1 ~ 3.To dioxy Ketohexamethylene and glutamic acid mol ratio, be wherein that 0:100,10:90,20:80,30:70 are difficult to stable prepare full-bodied polymer, the polymer intrinsic viscosity 1.0 ~ 3.0dL/g preparing; To dioxy Ketohexamethylene and glutamic acid mol ratio, be polymer intrinsic viscosity 3.0 ~ 4.0dL/g that 40:60,50:50,60:40,70:30,80:20,90:10,95:5,100:0 prepare.
The preparation of synthesis example 13 to dioxy Ketohexamethylene homopolymer 2
To add in reactor dioxy Ketohexamethylene 200g, to the stannous octoate catalyst that adds 0.02% in reactor.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 120 ℃, reacts 48 hours.Reactant chopping is made to the pellet of 1-8mm particle diameter, weigh and obtain pellet 192g, yield 96%.The intrinsic viscosity that records PPDO according to the method for synthesis example 1 is 5.66dL/g.
The preparation of synthesis example 14 to dioxy Ketohexamethylene-aspartic acid copolymer 1
Will be to dioxy Ketohexamethylene and two kinds of monomers of aspartic acid, with the mol ratio proportioning of 70:30, the 200g that weighs adds in reactor, to the stannous octoate catalyst that adds 0.01% in reactor.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 120 ℃, reacts 10 hours.Reactant chopping is made to the pellet of 1-8mm particle diameter, weigh and obtain pellet 197.4g, yield 98.7%.According to the method for synthesis example 1, recording the intrinsic viscosity of dioxy Ketohexamethylene-aspartic acid copolymer is 3.36dL/g.
The preparation of synthesis example 15 to dioxy Ketohexamethylene-aspartic acid copolymer 2
Except by the mol ratio proportioning with 80:20 to dioxy Ketohexamethylene and two kinds of monomers of aspartic acid, according to the conditioned response of synthesis example 14 10 hours.Reactant chopping is made to the pellet of 1-6mm particle diameter, weigh and obtain pellet 193.6g, yield 96.8%.According to the method for synthesis example 1, recording the intrinsic viscosity of dioxy Ketohexamethylene-aspartic acid copolymer is 3.25dL/g.
The preparation of synthesis example 16 PGAs
Acetic acid, hydroxy-, bimol. cyclic ester 300g is added in reactor, to the stannous octoate catalyst that adds 0.01% in reactor.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 120 ℃, reacts 36 hours.Reactant chopping is made to the pellet of 1-4mm particle diameter, weigh and obtain pellet 293.5g, yield 97.8%.The intrinsic viscosity that records PGA according to the method for synthesis example 1 is 4.61dL/g.
The preparation of synthesis example 17 polylactides
Lactide 200g is added in reactor, to the stannous octoate catalyst that adds 0.01% in reactor.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 130 ℃, reacts 28 hours.Reactant chopping is made to the pellet of 2-6mm particle diameter, weigh and obtain pellet 196.3g, yield 98.2%.The intrinsic viscosity that records polylactide according to the method for synthesis example 1 is 4.37dL/g.
The preparation of synthesis example 18 polycaprolactones
Caprolactone 100g is added in reactor, to the stannous octoate catalyst that adds 0.02% in reactor.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 130 ℃, reacts 10 hours.Reactant chopping is made to the pellet of 2-8mm particle diameter, weigh and obtain pellet 95.6g, yield 95.6%.The intrinsic viscosity that records polycaprolactone according to the method for synthesis example 1 is 3.81dL/g.
The preparation of synthesis example 19 PTMC
Trimethylene carbonate 100g is added in reactor, to the stannous octoate catalyst that adds 0.01% in reactor.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 120 ℃, reacts 12 hours.Reactant chopping is made to the pellet of 1-4mm particle diameter, weigh and obtain pellet 96.1g, yield 96.1%.The intrinsic viscosity that records PTMC according to the method for synthesis example 1 is 3.65dL/g.
The preparation of synthesis example 20 to dioxy Ketohexamethylene-glycolide copolymer
Will be to dioxy Ketohexamethylene and two kinds of monomers of Acetic acid, hydroxy-, bimol. cyclic ester, with the mol ratio proportioning of 70:30, the 200g that weighs adds in reactor, to the stannous octoate catalyst that adds 0.01% in reactor.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 120 ℃, reacts 16 hours.Reactant chopping is made to the pellet of 1-4mm particle diameter, weigh and obtain pellet 194.4g, yield 97.2%.According to the method for synthesis example 1, recording the intrinsic viscosity of dioxy Ketohexamethylene-glycolide copolymer is 4.15dL/g.
The preparation of synthesis example 21 to dioxy Ketohexamethylene-lactide copolymer
Will be to dioxy Ketohexamethylene and two kinds of monomers of lactide, with the mol ratio proportioning of 70:30, the 200g that weighs adds in reactor, to the stannous octoate catalyst that adds 0.01% in reactor, adds 0.01% D & C purple No. 2.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 120 ℃, reacts 14 hours.Reactant chopping is made to the pellet of 2-6mm particle diameter, weigh and obtain pellet 193g, yield 96.5%.According to the method for synthesis example 1, recording the intrinsic viscosity of dioxy Ketohexamethylene-lactide copolymer is 3.92dL/g.
The preparation of synthesis example 22 to dioxy Ketohexamethylene-caprolactone copolymer
Will be to dioxy Ketohexamethylene and two kinds of monomers of caprolactone, with the mol ratio proportioning of 70:30, the 200g that weighs adds in reactor, to the stannous octoate catalyst that adds 0.01% in reactor.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 120 ℃, reacts 12 hours.Reactant chopping is made to the pellet of 2-8mm particle diameter, weigh and obtain pellet 196.8g, yield 98.4%.According to the method for synthesis example 1, recording the intrinsic viscosity of dioxy Ketohexamethylene-caprolactone copolymer is 3.47dL/g.
The preparation of synthesis example 23 to dioxy Ketohexamethylene-trimethylene carbonate copolymer
Will be to dioxy Ketohexamethylene and two kinds of monomers of trimethylene carbonate, with the mol ratio proportioning of 70:30, the 200g that weighs adds in reactor, to the stannous octoate catalyst that adds 0.01% in reactor.Sealed reaction system, opens agitating device, keeps vacuum condition reaction, and controlling response system temperature is 120 ℃, reacts 14 hours.Reactant chopping is made to the pellet of 1-4mm particle diameter, weigh and obtain pellet 195.6g, yield 97.8%.According to the method for synthesis example 1, recording the intrinsic viscosity of dioxy Ketohexamethylene-trimethylene carbonate copolymer is 3.68dL/g.
The preparation of synthesis example 24 to dioxy Ketohexamethylene-Acetic acid, hydroxy-, bimol. cyclic ester-glutamic acid terpolymer
According to the method for synthesis example 1, except dioxy Ketohexamethylene, Acetic acid, hydroxy-, bimol. cyclic ester, glutamic acid mol ratio are become to 70:20:10, synthetic obtaining dioxy Ketohexamethylene-Acetic acid, hydroxy-, bimol. cyclic ester-glutamic acid random copolymer 24, the intrinsic viscosity that its method according to synthesis example 1 is measured is 3.43dL/g.
(can absorb the injection mo(u)lding of vascular ligation folder)
According to melting Shooting Technique of the present invention, the aliphatic poly ester material of synthesis example 1 ~ 24 is carried out to injection mo(u)lding.Concrete process conditions are listed in the table below in 1 ~ 5.The mould using in injection mo(u)lding meets following requirement: make the structure shown in vascular ligation fixture drawings attached 1 that injection mo(u)lding obtains.
(test of the closing force that vascular ligation folder product is sealed mouthful)
The vascular ligation that adopts 1 ~ 24 injection mo(u)lding of Taiwan high ferro measurer for pulling force GT-AI-3000 test synthesis example to obtain presss from both sides the closing force of sealed mouthful.Experimental results is listed in following table 1 ~ 5.
(can absorb the simulated body fluid Degrading experiment of vascular ligation folder)
The vascular ligation that above-mentioned synthesis example 1 ~ 24 injection moulding is prepared presss from both sides every group gets 500 samples, puts into the centrifuge tube (10 ligation clip/centrifuge tubes) of 50 50mL, the phosphate buffer solution that the pH that adds 35mL is 7.4 after accurately weighing.The water bath with thermostatic control shaking table of putting into 37 ℃ with masking foil sealing centrifuge tube is degraded, and within every 2 weeks, changes one time phosphate buffer solution.After certain degradation time, remove by filter buffer solution, after vacuum drying, measure the weight of ligation clip.Calculated weight conservation rate (ratio of the weight of the weight of ligation clip and the front ligation clip of degraded after degraded a period of time).Repeat to change the step of a phosphate buffer solution in every 2 weeks, until the weight conservation rate that the vascular ligation recording is clipped in after above-mentioned degradation step is 0, now elapsed time is as the degradation time of described vascular ligation folder sample.Experimental results is listed in following table 1 ~ 5.
Table 1 injection mo(u)lding test
*: because described material cannot molding, therefore do not carry out simulated body fluid Degrading experiment.
Table 2 injection mo(u)lding test
Table 3 injection mo(u)lding test
Above-mentioned synthesis example 13 is compared synthesis example 12, and because the response time extends, gained is increased to 5.66 to the intrinsic viscosity of dioxy Ketohexamethylene copolymer, and its degradation time is also extended accordingly.
From result shown in table 1 ~ 3, to the mol ratio of dioxy Ketohexamethylene and glutamic acid be 0:100,10:90,20:80,30:70 to dioxy Ketohexamethylene-glutamic, cannot injection mo(u)lding obtain vascular ligation folder.To the mol ratio of dioxy Ketohexamethylene and glutamic acid be 40:60,50:50,60:40,70:30,80:20,90:10,95:5,100:0 to dioxy Ketohexamethylene-glutamic, can prepare the vascular ligation folder that closing force is greater than 23N through injection molding technology.The closing force of ligation clip prepared by existing PPDO material is 25N.From table 1 ~ 3, can see, the closing force that is the ligation clip prepared by dioxy Ketohexamethylene-glutamic of 70:30,80:20,90:10,95:5 to the mol ratio of dioxy Ketohexamethylene and glutamic acid is all greater than 25N.Especially, the closing force that is the ligation clip prepared by dioxy Ketohexamethylene-glutamic of 70:30,80:20,90:10 to the mol ratio of dioxy Ketohexamethylene and glutamic acid is greater than 30N.
Table 4 injection mo(u)lding test
Table 5 injection mo(u)lding test
From table 1 ~ 5, biodegradable aliphatic polyester material of the present invention all can be prepared molding according to melting Shooting Technique of the present invention, and the V-type vascular ligation fixture of molding has good folder to close power.
According to the result of simulated body fluid Degrading experiment, the present invention is preferably to dioxy Ketohexamethylene: the unit mol ratio of glutamic acid/aspartic acid is 90:10～70:30, to dioxy Ketohexamethylene: the unit mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester/lactide/caprolactone/trimethylene carbonate is 90:10～70:30, and polylactide, can guarantee that like this degradation time of vascular ligation folder is controlled at 6 ~ 10 months.
(the MTT cell toxicity test of vascular ligation folder)
To pass eugonic l cell (L929 cell) after two generations, being mixed with concentration is 10 × 10
4the cell suspension of individual/mL, is inoculated in 3 96 orifice plates, every group of 3 holes, every hole 100 μ L.At 37 ℃, 5%CO
2and in the incubator of saturated humidity, cultivate 24 hours, make cell attachment.Original fluid in every hole is absorbed, and adding through aperture is the vascular clamp lixiviating solution 100 μ L that 0.2 μ m water filter filters, and blank group adds the culture fluid 100 μ L of new preparation.At 37 ℃, 5%CO
2and in the incubator of saturated humidity, cultivate after 48 hours and take out, the MTT liquid that absorption sample lixiviating solution adds 10 μ L/ holes continues to cultivate 4 hours, then absorbs.Add again the dimethyl sulfoxide in 100 μ L/ holes, shake 10 minutes.In immune microplate reader, 570nm place surveys absorption value.By following formula, calculate the relative rate of increase of cell (RGR), RGR=experimental group light absorption value/matched group light absorption value × 100%.
According to the method described above, the ligation clip to dioxy Ketohexamethylene-glutamic (intrinsic viscosity 3.0 ~ 4.0dL/g) and synthesis example 16 ~ 23 preparations of synthesis example 1 ~ 3,8 ~ 12 is carried out to MTT test.
According to American Pharmacopeia, GB/T16886.12-1996, GB/T16886.5-1997 rate of increase evaluation criterion relative to ISO10993-5:1992 cell:
The classification of table 6 cytotoxicity and cell appreciation rate
| Grade | 0 | 1 | 2 | 3 | 4 | 5 |
| RGR | ≥100 | 75-99 | 50-74 | 25-49 | 1-25 | 0 |
Generally, as biomaterial, require cell appreciation rate to reach more than 1 grade.We have selected and have built the l cell L929 that is, use mtt assay to evaluate, and concrete outcome is as shown in table 7 below:
Table 7 cell appreciation rate
As shown in Table 7, vascular ligation prepared by biodegradable aliphatic polyester material of the present invention presss from both sides with reference to the relative rate of increase evaluation criterion of cell, and its toxicity is 0 ~ 1 grade.Experimental result shows, vascular ligation fixture prepared by biodegradable aliphatic polyester material of the present invention has lower cytotoxicity, small on the growth and breeding impact of cell.
(to the cell compatibility test of dioxy Ketohexamethylene-glutamic)
To dioxy Ketohexamethylene-glutamic be hot pressed into the thin film that average thickness is 100 μ m with compression molding bed under 115 ℃ and 10MPa, then dense film is cut into the sequin that diameter is 15mm with card punch, with tap water, tri-distilled water (referring to the tap water through three distillations), wash and insert later in medical alcohol container 24 hours, after taking out, with sterilizing tri-distilled water, rinse three times, with air surface, be fixed on the bottom, hole of 24 hole tissue culturing plates upward, through irradiation under ultraviolet ray sterilizing in 6 hours.The 24 every holes of hole tissue culturing plate after sterilizing add 1mL cell suspension (1 × 10
5individual/mL), at 37 ℃, 5%CO
2and cultivate after certain hour in the incubator of saturated humidity, by fluorescence inverted microscope observation of cell form, then with micropipettor, remove culture fluid, and wash away and do not attach cell with buffer solution, finally add pancreatin by the counting that gets off of the cell dissociation on polymeric film, calculate cell attaching rate.
To make thin film to dioxy Ketohexamethylene-glutamic and be divided into five groups: sample sets is (to dioxy Ketohexamethylene: glutamic acid=70:30,3.28dL/g) 1., sample sets is (to dioxy Ketohexamethylene: glutamic acid=80:20,3.34dL/g) 2., sample sets is (to dioxy Ketohexamethylene: glutamic acid=90:10,3.51dL/g) 3., sample sets is (to dioxy Ketohexamethylene: glutamic acid=95:5,3.27dL/g) 4., and sample sets is (to dioxy Ketohexamethylene homopolymer, 3.48dL/g) 5..Sample sets 1., sample sets 2., sample sets 3., sample sets 4. and the sample sets 4 hour cell attaching rates of 5. cultivating be respectively 41%, 34%, 29%, 27%, 25%, 24 hour cell attaching rates are respectively 88%, 72%, 67%, 65%, 66%, cell quantity obviously increases, cell, at material surface division growth, increases rapidly.In vitro culture shows that the PPDO material after glutamic acid modification reveals better cell compatibility than simple to dioxy Ketohexamethylene material list.
(thrombotest of vascular ligation folder)
PT prothrombin time: blood plasma to be measured adds excessive calcic tissue thromboplastin, again the blood plasma of calcification activates Stuart factor when tissue factor exists becomes Xa, the latter makes thrombinogen change thrombin into, thrombin makes Fibrinogen change not hemolytic fibrin into, mensuration is solidified the required time, is plasma prothrombin time to be measured (PT).
TT thrombin time test: blood plasma to be measured adds appropriate thrombin solution, and Fibrinogen changes insoluble fibrin into, measures and solidifies required time, is thrombin time of blood plasma to be measured (TT).
APTT APTT: blood plasma to be measured adds partial thromboplastin solution, under calcium ion participates in, Fibrinogen changes insoluble fibrin into, measures and solidifies required time, is blood plasma activated partial thromboplastin time to be measured (APTT).
Vascular ligation to be measured folder sample is cut into small pieces inserts plastics and detects in box, at COATRON TECOIV PLUS(TECO Inc., German) in detection.
The vascular ligation folder that dioxy Ketohexamethylene-glutamic is prepared is divided into five groups: sample sets is (to dioxy Ketohexamethylene: glutamic acid=70:30,3.28dL/g) 1., sample sets is (to dioxy Ketohexamethylene: glutamic acid=80:20,3.34dL/g) 2., sample sets is (to dioxy Ketohexamethylene: glutamic acid=90:10,3.51dL/g) 3., and sample sets is (to dioxy Ketohexamethylene: glutamic acid=95:5,3.27dL/g) 4..Sample sets is (to dioxy Ketohexamethylene: glutamic acid=100:0,3.48dL/g) 5..Carry out according to the method described above thrombotest, the results are shown in table 8.
Table 8 vascular ligation folder thrombotest
| Sample | PT(second) | TT(second) | APTT(second) |
| Fresh and healthy blood plasma (blank group) | 36.64 | 16.21 | 93.82 |
| Sample sets 1. | 30.43 | 13.26 | 89.03 |
| Sample sets 2. | 31.28 | 14.48 | 91.71 |
| Sample sets 3. | 31.85 | 14.24 | 90.52 |
| Sample sets 4. | 34.57 | 15.62 | 92.84 |
| Sample sets 5. | 36.52 | 16.35 | 93.43 |
As shown in Table 8, PT, TT and the APTT time of healthy blood plasma are respectively 36.64 seconds, 16.21 seconds and 93.82 seconds.PT, TT and APTT time on the vascular ligation folder that blood plasma is prepared dioxy Ketohexamethylene and glutamic acid at different proportion are less than blank plasma substantially, have certain hemostasis effect; Vascular ligation folder prepared by dioxy Ketohexamethylene homopolymer substantially to blood plasma blood coagulation without considerable influence.Because material contacts with blood, material surface will adsorb rapidly protein, and then, by the activation of hematoblastic adhesion and coagulation pathway occurs, finally causes blood coagulation.Surface smoothness, surface wettability and surface charge of material etc. all can have influence on blood coagulation.The vascular ligation folder that dioxy Ketohexamethylene-glutamic is prepared is with compared with dioxy Ketohexamethylene homopolymer vascular ligation folder, not only strengthened the closing force of vascular ligation folder, can more effectively resist vessel lumen inner blood pressure, effectively folder closes blood vessel, and there is certain hemostasis effect, at vascular ligation folder, by mechanical force, press from both sides and close after ends of vessels, this vascular ligation folder material has attraction protein, improve the adhesion of platelet in ends of vessels, promote the effect of solidifying of ends of vessels blood, the sealing blood vessels broken ends of fractured bone quickly, reach the object that shortens bleeding stopping period.
(sterilization effects of different sterilizing methods)
According to above-mentioned injection moulding process, the polyester material of synthesis example 1 is prepared to vascular ligation folder, divide five groups and carry out sterile test (not sterilizing group, ethanol for disinfection group, oxirane group, ultraviolet group, gamma-rays group).Through the ligation clip of sterilizing, with antibacterial culturing detection by quantitative sterilization effect.During detection, in sterile test tube, add the 1mL ordinary broth of sterilization, the ligation clip of the ligation clip through sterilizing and sterilized is respectively got to one and put into respectively test tube, fully mix.Test tube is put into 37 ℃ of incubators to be cultivated 4 hours; Meat soup is evenly coated on MH agar plate, in 37 ℃ of incubators, cultivated 18-24 hour, calculate viable count.The results are shown in table 9.With aseptic meat soup, make negative control, test each group after sterilizing, each group detects all negative.Simple meat soup is also without bacterial growth.
Each group bacterial population Examined comparison after the sterilizing of table 9 distinct methods (x ± s)
| Sterilizing methods | Sampling observation quantity (n) | Bacterial population (individual/part) | Positive rate (%) |
| Not sterilizing group | 35 | 105±3 | 100 |
| Ethanol for disinfection group | 30 | 0 | 0 |
| Oxirane | 30 | 0 | 0 |
| Ultraviolet group | 30 | 0 | 0 |
| Gamma-rays group | 30 | 0 | 0 |
(impact of different sterilizing methods on vascular ligation folder degradability)
According to above-mentioned injection moulding process, synthesis example 1 is prepared to vascular ligation folder, then divide five groups to carry out degradation property test (not sterilizing group, ethanol for disinfection group, oxirane group, ultraviolet group, gamma-rays group), the impact of more different sterilizing methods on vascular ligation folder degradability.
Ligation clip with not sterilizing group is compared, and ethanol for disinfection sterilizing post polymerization thing intrinsic viscosity declines approximately 5%; After ethylene oxide sterilizing, intrinsic viscosity declines approximately 7%; Ultraviolet radiation 4 hours, intrinsic viscosity declines approximately 21%; After the radiation gamma sterilizing that is 20kGy through radiation dose, intrinsic viscosity declines approximately 16%.Radiation gamma and ultraviolet radiation sterilizing cause the decline of polymer intrinsic viscosity, and difference has significance (P<0.05), and these two kinds of sterilizations make depolymerization obvious; On the contrary, ethanol and ethylene oxide sterilizing decline and there is no significant (P>0.05) the intrinsic viscosity of polymer, not obvious on the impact of depolymerization.But the ligation clip after sterilizing was deposited after 1 week, then carried out the mensuration of intrinsic viscosity, find that the polymer intrinsic viscosity after ethanol sterilizing declines 34%, ultraviolet decline 28%, the decline 8% of oxirane, gamma-ray decline 16%.Preliminary deduction may be after alcohol disinfecting, to remain in moisture on ligation clip to have caused ligation to be clipped in the rapid decline of intrinsic viscosity in the process of depositing, and after ethane via epoxyethane and γ ray sterilization, the intrinsic viscosity of depositing ligation clip in process declines not obvious.
(impact of different sterilizing methods on vascular ligation folder mechanical characteristic)
According to above-mentioned injection moulding process, synthesis example 1 is prepared to vascular ligation folder, then divide five groups to carry out Mechanics Performance Testing (not sterilizing group, ethanol for disinfection group, oxirane group, ultraviolet group, gamma-rays group), the impact of more different sterilizing methods on vascular ligation folder mechanical characteristic.Adopt Taiwan high ferro measurer for pulling force GT-AI-3000 the vascular ligation folder of sterilizing to be carried out to the closing force test of sealed mouthful.The results are shown in table 10.
The mechanical characteristic comparison of table 10 ligation clip after different sterilizing methods are processed
| Sterilizing methods | Sampling observation quantity (n) | Closing force (N) | Closing force (N) after one week |
| Not sterilizing group | 35 | 30.49±1.65 | 30.12±1.54 |
| Ethanol for disinfection group | 30 | 29.87±3.21 | 23.46±4.24 |
| Oxirane group | 30 | 29.65±2.65 | 28.74±2.56 |
| Ultraviolet group | 30 | 24.21±6.15 | 23.61±5.31 |
| Gamma-rays group | 30 | 25.49±2.45 | 24.92±2.62 |
After sterilizing, the maximum pull of ethanol for disinfection group, oxirane group ligation clip declines not obvious compared with not sterilizing group, and ultraviolet group, gamma-rays group decline obviously.But deposit after one week, the maximum pull of ethanol for disinfection group ligation clip declines obviously, has even exceeded ultraviolet group, gamma-rays group.Visible use ethanol for disinfection, to ligation clip sterilizing, is unfavorable for the storage of ligation clip.Optimization ethylene oxide, the sterilizing of gamma-rays group.Can further optimize sterilization method and sterilizing parameter according to needs of production.
Finally, it is also to be noted that, above is only enumerating of several specific embodiments of the present invention.Obviously, the invention is not restricted to above specific embodiment, can also have many modification.All modification that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention, all should think protection scope of the present invention.
Claims (4)
1. a monolayer can absorb vascular ligation folder, it is characterized in that: described vascular ligation folder is prepared from by biodegradable aliphatic polyester material, described ligation clip has good biocompatibility, described biodegradable aliphatic polyester material is served as reasons the homopolymer of dioxy Ketohexamethylene is formed through being selected from the amino-acid modified of glutamic acid or aspartic acid, the described viscosity-average molecular weight to dioxy Ketohexamethylene homopolymer is 100,000～800,000, in described biodegradable aliphatic polyester material, aliphatic poly ester units and amino acid whose unit mol ratio are to dioxy Ketohexamethylene: aminoacid=95:5～60:40, described properties of materials viscosity number is 1.0～6.0dL/g, described vascular ligation presss from both sides V-shaped structure, at sealed mouthful of place, there is latch hook.
2. monolayer according to claim 1 can absorb vascular ligation folder, and wherein, the degradation time of described ligation clip can regulate in the time range of 0.5～24 month.
3. monolayer according to claim 1 and 2 can absorb vascular ligation folder, and wherein, it is 0～1 grade that described ligation clip has according to mtt assay evaluation cytotoxicity, and 24 hour cell adhesion rates reach more than 60% good biocompatibility.
4. one kind can absorb the preparation method of vascular ligation folder according to the monolayer described in any one in claim 1～3, wherein, described ligation clip is prepared from by the raw material that comprises biodegradable aliphatic polyester material is carried out to melting injection moulding with following condition, mold preheating temperature is 25～60 ℃, injection temperature is 100～120 ℃, the pressure that shoots material is 25～55 bar, and briquetting pressure remains 20～50 bar, and the dwell time is 5～15 seconds.
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| CN103549985B (en) * | 2013-10-29 | 2015-07-15 | 杭州铭众生物科技有限公司 | Absorbable ligature clamp and manufacturing method thereof |
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| CN106075543B (en) * | 2016-06-24 | 2021-11-23 | 山东省药学科学院 | Absorbable hemostatic ligation clamp and preparation method thereof |
| CN108236480A (en) * | 2016-12-27 | 2018-07-03 | 江苏风和医疗器材股份有限公司 | Hemostatic clamp |
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| CN107137755A (en) * | 2017-06-07 | 2017-09-08 | 浙江微度医疗器械有限公司 | A kind of hemostatic ligation clip that can quickly absorb |
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| CN107822689A (en) * | 2017-10-23 | 2018-03-23 | 佛山市蓝瑞欧特信息服务有限公司 | The ligation clip of band cutter in a organized way |
| CN107812231B (en) * | 2017-11-20 | 2018-08-24 | 山东省药学科学院 | A kind of enhanced absorbable ligature clamp and preparation method thereof |
| CN107815079B (en) * | 2017-11-20 | 2020-02-28 | 山东省药学科学院 | Medical nano-fiber reinforced composite material and preparation method thereof |
| CN111134761A (en) * | 2020-01-08 | 2020-05-12 | 河北医科大学第一医院 | Ligation clip and preparation method thereof |
| CN112006742A (en) * | 2020-08-20 | 2020-12-01 | 绍兴市人民医院 | Absorbable blood vessel protective sleeve |
| CN112120753B (en) * | 2020-10-21 | 2024-09-17 | 东南大学泰州生物医药与医疗器械研究院 | Absorbable polymer hemostatic clamp |
| CN112843323A (en) * | 2021-01-25 | 2021-05-28 | 北京庆龙科技有限公司 | Hydroxyapatite-added polylactic acid ligation clip and preparation method thereof |
| CN113878895A (en) * | 2021-09-15 | 2022-01-04 | 河北景港橡塑科技有限公司 | Production and manufacturing process of rubber plastic fittings |
| CN114767947B (en) * | 2022-05-05 | 2023-02-14 | 暨南大学 | Absorbable vascular clamp made of polyester composite material and preparation method of absorbable vascular clamp |
| CN116474156A (en) * | 2023-04-10 | 2023-07-25 | 施爱德（厦门）医疗器材有限公司 | Preparation method of absorbable antibacterial material and hemostatic ligature clamp manufactured by same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1041118A2 (en) * | 1999-03-31 | 2000-10-04 | Mitsui Chemicals, Inc. | Resin composition |
| CN101081310A (en) * | 2006-05-29 | 2007-12-05 | 杭州圣石科技有限公司 | Adsorbable hemostatic ligation clip |
-
2012
- 2012-12-19 CN CN201210556673.6A patent/CN102973988B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1041118A2 (en) * | 1999-03-31 | 2000-10-04 | Mitsui Chemicals, Inc. | Resin composition |
| CN101081310A (en) * | 2006-05-29 | 2007-12-05 | 杭州圣石科技有限公司 | Adsorbable hemostatic ligation clip |
Non-Patent Citations (2)
| Title |
|---|
| 白威等.聚对二氧环己酮改性研究进展.《化学进展》.2009,第21卷(第12期),2692-2702. |
| 聚对二氧环己酮改性研究进展;白威等;《化学进展》;20091231;第21卷(第12期);2692-2702 * |
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Free format text: FORMER OWNER: ZHEJIANG MEDZONE BIOMEDICAL MATERIALS AND INSTRUMENT RESEARCH INSTITUTE ZHEJIANG MEDZONE BIOMEDICAL PIONEERING INVESTMENT CO., LTD. Effective date: 20140928 |
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Effective date of registration: 20140928 Address after: 310018, Hangzhou economic and Technological Development Zone, No. 6, No. 2, No. 452, hi tech incubator, building C0101, room No., Zhejiang Patentee after: Hangzhou Medzone Bio-Technology Co., Ltd. Address before: 310018, Hangzhou economic and Technological Development Zone, No. 6, No. 2, No. 452, hi tech incubator, building C0101, room No., Zhejiang Patentee before: Hangzhou Medzone Bio-Technology Co., Ltd. Patentee before: Zhejiang Medzone Biomedical Materials and Equipment Research Institute Patentee before: Zhejiang Medzone Biomedicine Venture Investment Co., Ltd. |
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Address after: 310018 room 2, building 452, No. 6, main street, Hangzhou economic and Technological Development Zone, Zhejiang, Patentee after: Hangzhou Mingshan Biotechnology Co., Ltd Address before: 310018, Hangzhou economic and Technological Development Zone, No. 6, No. 2, No. 452, hi tech incubator, building C0101, room No., Zhejiang Patentee before: Hangzhou Medzone Bio-Technology Co., Ltd. |
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