CN110215542A - A method of forming the interim obturator of blood vessel - Google Patents
A method of forming the interim obturator of blood vessel Download PDFInfo
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- CN110215542A CN110215542A CN201810174354.6A CN201810174354A CN110215542A CN 110215542 A CN110215542 A CN 110215542A CN 201810174354 A CN201810174354 A CN 201810174354A CN 110215542 A CN110215542 A CN 110215542A
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- blood vessel
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- obturator
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/005—Ingredients of undetermined constitution or reaction products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/041—Mixtures of macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
Abstract
A method of the interim obturator of blood vessel is formed, is related to field of medical materials, by the dissolution under non-electroneutrality condition, biomaterial is enable to dissolve more abundant, obtain the biomaterial solution of stable uniform.Again at low ambient temperatures, biomaterial solution is adjusted to molecule is electroneutral.Low temperature environment ensure that biomaterial solution during recalling to electroneutral, remains solution state, avoids biomaterial and is precipitated and destroys stability of solution.It is eventually adding pH stable agent, the pH range of the interim obturator precursor of blood vessel is accurately controlled, interim obturator precursor is obtained.The interim obturator precursor is free fluid state under cryogenic, by in-situ injection or can imported into blood vessel, and rapid phase transition is the interim obturator of blood vessel of gel state in the blood vessels, achievees the purpose that block blood vessel.Meanwhile the interim obturator of the blood vessel is by low-temperature treatment, can rapid phase transition be free fluid state, it is convenient so that restoration of blood flow is unimpeded to remove.
Description
Technical field
The present invention relates to field of medical materials, in particular to a kind of method for forming the interim obturator of blood vessel.
Background technique
Tubular structure may need to carry out temporary plug in actual application such as blood vessel or urethra.Such as blood vessel seam
It closes in operation, in order to facilitate surgical procedure, it usually needs interim hemostasis processing first is carried out to the vascular ports of disconnection, is then sutured
Blood vessel fracture realizes that blood flow is unimpeded.Clinically used interim hemostatic fashion is to clamp blood vessel fracture using haemostatic clamp (or hemostatic clamp)
Cause blood flow to stop, to carry out vascular suture operation, it is unimpeded that haemostatic clamp recovery blood flow is unclamped again after the connection of the blood vessel of fracture.
For the haemostatic clamp of vascular surgery, although the tooth of tooth socket is thinner, shallower, elasticity preferably, but still can squeeze tissue to normal blood
Tube wall and endangium cause to damage, or even can cause angiorrhoxis due to the improper use in clamping, are unable to reach interim stop
The effect of blood and the progress for influencing vascular suture operation, and may cause different degrees of bleeding, influencing operation goes on smoothly, even
Jeopardize patient vitals.Even if vascular suture operation can be completed, the blood vessel at impaired place still has rupture or thrombosed hidden danger.
Summary of the invention
The purpose of the present invention is to provide a kind of method for forming the interim obturator of blood vessel, it is easy to operate efficiently, can be with
The temporary plug object with certain mechanical strength is formed in the blood vessels, achievees the purpose that occluding vascular.Meanwhile it can according to need
Facilitated by way of low-temperature treatment and removes the interim obturator of the blood vessel so that restoration of blood flow is unimpeded.
The embodiment of the present invention is achieved in that
A method of forming the interim obturator of blood vessel comprising:
Biomaterial is sufficiently dissolved in the case where molecule is non-electroneutrality condition, obtains biomaterial solution；In -10~10 DEG C
Under, the pH of biomaterial solution is adjusted, making molecule in biomaterial is in electroneutral；Keeping temperature is -10~10 DEG C, and pH value is added
Stabilizer makes the pH stable of biomaterial solution in the range of 6~8, obtains the interim obturator precursor of blood vessel；Blood vessel is faced
When the injection of obturator precursor or import intravascular is formationed hydrogel and block blood vessel.
The beneficial effect of the embodiment of the present invention is:
The present invention provides a kind of methods for forming the interim obturator of blood vessel, are first in non-electrical in molecule by biomaterial
It is sufficiently dissolved under conditions of property, obtains biomaterial solution.By the dissolution under non-electroneutrality condition, enable biomaterial
It dissolves more abundant, obtains the biomaterial solution of stable uniform.Again at low ambient temperatures, biomaterial solution is adjusted to
Molecule is electroneutral.Low temperature environment ensure that biomaterial solution during recalling to electroneutral, remains solution state,
Biomaterial is avoided to be precipitated and destroy stability of solution.It is eventually adding pH stable agent, to the pH model of blood vessel occlusion precursor
It encloses and is accurately controlled, obtain interim obturator precursor.The interim obturator precursor is free fluid state under cryogenic,
By in-situ injection or it can be imported into blood vessel, and rapid phase transition is the interim obturator of blood vessel of gel state in the blood vessels, is reached
Block the purpose of blood vessel.Meanwhile the blood vessel occlusion quickly can mutually become free fluid state by low-temperature treatment, move
Except convenient so that restoration of blood flow is unimpeded.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
A kind of method of interim obturator of formation blood vessel of the embodiment of the present invention is specifically described below.
The embodiment of the invention provides a kind of methods for forming the interim obturator of blood vessel comprising:
S1. biomaterial is sufficiently dissolved in the case where molecule is non-electroneutrality condition, obtains biomaterial solution.
Wherein, biomaterial includes at least one of natural biologic material and synthesising biological material.Natural biologic material
Including alginic acid, alginate, hyaluronic acid, fish glue, chitosan, chitosan/phosphoglycerol disodium mixture, collagen, gelatin
At least one of with clupeine.Synthesising biological material include polyvinyl alcohol, polyethylene glycol, acrylic acid, acrylic acid derivative,
At least one of Block copolymer.Acrylic acid derivative includes polyacrylic acid, polymethylacrylic acid, polyacrylamide, gathers
At least one of n-isopropyl acrylamide.Block copolymer includes poloxamer.
Dissolubility of biomaterial in the environment of its molecule is in electroneutral is poor, and in the environment of non-electroneutral, due to
Molecule is easier to be dissolved in water to form solution per se with positive and negative charge.In order to reach better solute effect, the present invention
The method that embodiment uses exactly allows the molecule of biomaterial to be detached from its electroneutral environment, and carries out in the environment of non-electroneutral
Dissolution, to form the biomaterial solution of stable uniform.
By biomaterial, in the case where molecule is non-electroneutrality condition, the method that dissolves is: by biomaterial cosolvent auxiliary
Under be dissolved in the water, cosolvent includes any one of acid reagent and alkaline reagent.Acid reagent and alkaline reagent can be with
Biomaterial molecule is set to deviate electroneutral environment and take positive and negative charge, to preferably be dissolved in water.
Acid reagent includes at least one of organic acid and inorganic acid.For example, it may be the nothings such as hydrochloric acid, sulfuric acid, phosphoric acid
At least one of machine acid.It is also possible to one of organic acids such as tartaric acid, citric acid, oxalic acid, acetic acid, formic acid.It considers
The interim obturator precursor of the blood vessel is likely to be used for bio-medical material, in the preparation method, it is preferred to use harm to the human body
Lesser organic acid reagent, wherein but it is preferable with the effect of citric acid.
Alkaline reagent includes at least one of organic base and inorganic base.For example, it may be triethylamine, tetramethyl second two
At least one of organic bases such as amine, pyridine are also possible to sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, phosphoric acid hydrogen two
At least one of inorganic bases such as sodium, sodium bicarbonate.Similarly, it is contemplated that the interim obturator precursor of the blood vessel is likely to be used for giving birth to
Object medical material, in the preparation method, the alkaline reagent used is with the sodium and the corresponding alkali compounds of potassium contained by human body
Based on, injury of the reduction blood vessel occlusion precursor to human body as far as possible guarantees it with preferable biocompatibility.
The content of biomaterial is 0.1wt%~20wt% in biomaterial solution.Preferably, the content of biomaterial is
0.5wt%~10wt%；Preferably, the content of the biomaterial is 5wt%~8wt%.It is worth noting that, above-mentioned concentration
Range is directed to the entire scope for the biomaterial that all possible applications are arrived in embodiment of the present invention, specific implementation process
In, for the solubility property of different biomaterials, there is biggish differences for concentration range.For example, preferable for solubility
The substances such as hyaluronic acid, the content of biomaterial can achieve 10wt%~20wt% in biomaterial solution.And it is poly- for shell
The poor biomaterial of the solubility such as sugar, concentration range may be in 0.1wt%~10wt%.Meanwhile it is interim for the blood vessel
For obturator precursor, when the content of biomaterial is down to 0.1wt% in biomaterial solution, concentration is very low, though
So still it can achieve the effect that Rapid gelation occluding vascular, the gel of formation also has enough stability, but its mechanics is strong
It spends poor.
Further, the process of above-mentioned dissolution can also carry out at low temperature, be advisable with -10~10 DEG C.Biomaterial exists
Solubility under room temperature is lower, on the contrary, but can preferably dissolve at low temperature.Inventor sends out by itself creative work
It is existing, while dissolution under non-neutral environment, using low temperature environment, the dissolution of biomaterial can be made more abundant.
A kind of method forming the interim obturator of blood vessel provided by embodiment of the present invention, further includes:
S2. at -10~10 DEG C, the pH for adjusting biomaterial solution makes molecule in biomaterial be in electroneutral.
For part biological material, when molecule is in electroneutral, biomaterial solution may be acid.And for
For other biomaterials, when molecule is in electroneutral, biomaterial solution is also likely to be alkalinity.Meanwhile for a kind of life
For object material, in certain pH value range, molecule can be rendered as electroneutral.For example, for fish glue, point
When son is in electroneutral namely the isoelectric point of fish glue, corresponding pH range are 4.8~5.2, and in the range, fish glue molecule is main
Exist in the form of neutral molecule；For clupeine, molecule be in electroneutral when namely clupeine isoelectric point,
Corresponding pH range is 12.0~12.2, and in the range, clupeine molecule mainly exists in the form of neutral molecule.
Meanwhile from the foregoing, it can be understood that biomaterial solubility in the case where molecule is in electroneutral is poor, in order to prevent in general
The molecular regulation of biomaterial is wired back during neutrality, and biomaterial will not be precipitated since solubility reduces, to destroy
The stabilization of biomaterial solution, the process of adjusting needs to carry out at low temperature, best with -10~10 DEG C of effects.Adjust biological material
The pH value of material solution makes molecule in biomaterial be in that the method for electroneutral is, by biomaterial solution and alkaline reagent and/or acid
Property reagent mixing.Which kind of reagent specifically used, need according to the reagent that uses when making biomaterial solution deviate electroneutral and
It is fixed.For example, when making biomaterial solution deviate electroneutral, using acid reagent, then by the molecule of biomaterial
Alkaline reagent is then used when recalling to electroneutral, vice versa.It, can be using dropwise addition when adding acid reagent and/or alkaline reagent
Mode be slowly added, cause temperature to increase to prevent due to acid-base neutralization reaction heat release too fast, and then influence solution
Stability.
A kind of method forming the interim obturator of blood vessel provided by embodiment of the present invention, further includes:
S3. keeping temperature is -10~10 DEG C, and pH stable agent is added, makes the pH stable of the biomaterial 6~8
In the range of, obtain interim obturator precursor.
6~8 pH value range is endovascular pH range under normal circumstances, can maintain blood as far as possible using the pH range
Microenvironment in pipe reduces rejection.
The pH stable agent of meaning of the embodiment of the present invention refers to can be by the examination of the pH stable of solution in a certain range
Agent, range that can be stable can be adjusted according to its specific ingredient.The pH value of pH stable agent itself is 4~10,
Preferably, the pH value of pH stable agent is 6~8.Depending on specific pH range can according to need stable range, and by changing
Become its specific ingredient to be adjusted.
PH stable agent includes specific ion/molecule pair to stablize pH value, and specific ion/molecule is to including Tris-H+, Tris- lysine hydrochloride, Tris- lysine hydrochloride-ethylenediaminetetraacetic acid radical ion, methenamine-NH4 +, barbital sodium-H+, barbital-barbital sodium, barbital-Na+-Cl-, citric acid radical ion-OH-, citric acid radical ion-HPO4 2-, citric acid radical
Ion-H2PO4 -、NH4 +-NH3, borax-Ca2+, borax-CO3 2-, borax-HCO3 -, borax-PO4 3-, borax-HPO4 2-, borax-
H2PO4 -, borax-Ac-, borax-Cl-, borax-SO4 2-, borax-HSO4 -、Ac--H+-NH4 +、HAc-Ac-、HAc-Ac--NH4 +、
PO4 3--H+Triethylamine, HPO4 2--H+Triethylamine, H2PO4 --H+Triethylamine, PO4 3--HPO4 2-、PO4 3--H2PO4 -、HPO4 2--
H2PO4 -、HPO4 2--NH4 +、H2PO4 --HCO3 -、H2PO4 --CO3 2-、Tris-HAc、Tris-H2PO4 -、Tris-NH4 +、HPO4 2-Lemon
Lemon acid, HCO3 -Citric acid, CO3 2-Citric acid, H2PO4 -Citric acid, PO4 3-Citric acid, Ac-At least one of citric acid.
In other words, in actual use, specific ion/molecule in pH stable agent is to can be above-mentioned ion/molecular pair
Any one of, it is also possible to the mixed system of a variety of compositions of above-mentioned ion/molecular centering.In most cases, it usually adopts
With the mixed system of a variety of compositions of above-mentioned ion/molecular centering, better stablizing effect can be obtained.
Further, in pH stable agent specific ion/molecule pair concentration range can according to specific needs depending on.By
After adding pH stable agent in biomaterial solution, the pH value and concentration of biomaterial solution can also change.Especially
When pH stable agent is solution state, biomaterial solution is actually diluted after addition, i.e. biomaterial solution concentration
It reduces, this may will affect the gelatinization results of the interim obturator precursor of blood vessel, as gelation temperature, gelling time, gelling are reversible
Property, gelation stability etc..Therefore, when pH stable agent is solution state, wherein specific ion/molecule pair concentration is 0.1
~50M；Preferably, wherein specific ion/molecule pair concentration is 0.2~20M；Preferably, wherein specific ion/molecule pair
Concentration is 1~10M.In order to reduce influence of the addition pH stable agent to biomaterial solution concentration as far as possible, it might even be possible to
PH stable agent fractions are added with solid state, i.e., the solid powder of pH stable agent fractions are added directly into life
In object material solution.
Further, specific ion/molecule is 0.05~8M to the concentration in the interim obturator precursor of the blood vessel；It is excellent
Selection of land, specific ion/molecule are 0.1~5M to the concentration in the interim obturator precursor of the blood vessel；Preferably, it is specific from
Son/molecule is 2~4M to the concentration in the interim obturator precursor of the blood vessel.It is worth noting that, above-mentioned concentration range needle
Pair be all possible applications are arrived in embodiment of the present invention specific ion/molecule pair entire scope, specific implementation process
In, for different specific ion/molecules pair, there is biggish differences for concentration range.For example, lesser for molecular weight
Tris-H+Plasma/molecule pair, concentration range need to reach 5~8M, are just able to satisfy stablizing effect required for the application.
And HPO biggish for molecular weight4 2--H2PO4 -Plasma/molecule pair, concentration range may be within 2M, or even in 0.05M
Low concentration under can also reach required stabilization.Meanwhile mixed system of the various ionic/molecular to composition is come
It says, specific ion/molecule refers to all specific ion/molecules pair in the solution in the concentration in blood vessel occlusion precursor
Concentration summation, respective ion/molecule therein is to possibly lower than above-mentioned concentration range.
Meanwhile other lewis' acids for not having stablizing effect, including Cl are further comprised in pH stabilizer-、
Na+、K+、SO4 2-、Ca2+Deng although to the stabilization of the interim obturator precursor pH value of blood vessel, it is same for directly participation for these ions
Sample has a degree of influence to the overall stability of the interim obturator precursor of blood vessel.Therefore, before the interim obturator of blood vessel
Total ion concentration in body is 0.1~10M；Preferably, the total ion concentration of the interim obturator precursor of blood vessel is 0.5~8M；It is excellent
Selection of land, the total ion concentration of the interim obturator precursor of blood vessel are 2~5M.It is worth noting that, above-mentioned concentration range is directed to
The lewis' acid that all possible applications are arrived in embodiment of the present invention, in specific implementation process, for different ion or point
Son, since there is biggish differences for concentration range, total ion concentration is possibly lower than above-mentioned concentration range.Total ion concentration packet
Specific ion/molecule pair concentration is contained, therefore, the size of total ion concentration will receive specific ion/molecule to the shadow of concentration
It rings, on ordinary meaning, when specific ion/molecule pair concentration is higher, total ion concentration is higher.
Further, dissolution of the pH stable agent in mixed solution is poor, is especially using high concentration pH stable
In the case where agent, such case is become apparent.In order to dissolve pH stable agent preferably, obtains uniform blood vessel and temporarily block
Object precursor, to guarantee the uniformity and mechanical strength of gel, embodiment of the present invention uses and is slowly added pH stable agent
Mode into mixed solution is added pH stable agent.Preferably, the speed of addition is that pH stable is added per minute
5wt%~10wt% of agent；Preferably, 6wt%~8wt% of pH stable agent is added per minute.Meanwhile during addition
The low temperature for being kept for -10~10 DEG C allows biomaterial to keep adequately dissolution, more preferably more uniformly to mix with pH stable agent.
It should be noted that the mixed dissolution of pH stable agent, biomaterial is the process of a dynamic equilibrium, it is desirable to keep solution whole
The homogeneity of body, the adding rate for keeping low temperature environment to control pH stable agent simultaneously play a very important role, and make biology
Material is in the state being completely dissolved, and pH stable agent is allowed slowly to be combined with biomaterial, and the moment keeps the balance of system, ability
Realize the effect of embodiment of the present invention occluding vascular to be achieved.
It is worth noting that, in the other preferred embodiments of the present invention, it is understood that there may be after having added pH stable agent, blood vessel
The case where pH value of interim obturator precursor still exceeds 6~8, at this point it is possible to by further adding acid reagent or alkalinity
Reagent more accurately regulates and controls pH value, falls into the pH value of the interim obturator precursor of blood vessel in the range of 6~8.
A kind of method forming the interim obturator of blood vessel provided by embodiment of the present invention, further includes:
S4. the interim obturator precursor of blood vessel is injected or is imported intravascular.
By the injection of blood vessel interim obturator precursor or speed when importing intravascular formation hydrogel blocking blood vessel be 0.5~
The total amount of 12mL/min, injection or the interim obturator precursor of the blood vessel imported is 0.05~10mL.In the invention, blood vessel
Though interim obturator precursor is using the material with biocompatibility, slight rejection is still difficult to avoid that.Meanwhile by
It is lower in the interim obturator precursor self-temperature of blood vessel, introduce blood vessel after caused by low temperature stimulation it is also very important.Based on above-mentioned
Reason, inventor carry out the speed and dosage of injecting or import the interim obturator precursor of blood vessel after creative work
It is further to limit, while meeting obturator and possessing enough intensity and reach blockage effect, reduce the thorn to blood vessel to the greatest extent
Swash.
The interim obturator precursor of the blood vessel is free fluid state, after injecting or importing blood vessel, can 0.5~
In 5min, rapid phase transition forms the blood vessel occlusion with the gel state of certain mechanical strength, reaches the mesh of interim occluding vascular
's.Preferably, the time injected or imported is 5~300s, within preferably 1min, by the blood for collecting sufficient amount in the short time
Interim obturator precursor is managed, being conducive to it, quickly solidification forms blocking.
Preferably, the interim obturator precursor of blood vessel could preferably maintain its mobility at low temperature, guarantee injection or lead
Enter smoothly completing for blood vessel, therefore, blocks blood injecting or importing intravascular formation hydrogel for the interim obturator precursor of blood vessel
Guan Shi, need to keep the temperature of the interim obturator precursor of part blood vessel that is to be injected or importing is -10~10 DEG C.Further, may be used
1~5min is first pre-chilled in the interim obturator precursor of blood vessel at -10~10 DEG C before being injected or being imported, make it sufficiently
It is cooling, preferably maintain free fluid state.
Further, the interim obturator of vascularization can remove.When needing to remove, interim obturator is subjected to low temperature
Processing.The temperature of low-temperature treatment is -10~10 DEG C, it is preferable that temperature is 0~4 DEG C.The mode of low-temperature treatment includes cold water
Flushing material, cold PBS solution flushing material, cold saline flushing material, ice cube coolant, dry ice coolant, low temperature
At least one of probe or metal bar coolant.
The feature of embodiment of the present invention and performance are described in further detail with reference to embodiments.
Embodiment 1
The present embodiment provides a kind of interim obturator precursor of blood vessel, preparation method is as follows:
S1. fish glue and hydrochloric acid solution are uniformly mixed at 8 DEG C, it is molten is configured to the fish glue that fish glue content is 1wt%
Liquid.
S2. stirring is maintained at -1 DEG C, NaOH solution is slowly added dropwise in Xiang Shangshu fish gelatin solution, by the pH value of fish gelatin solution
It is adjusted to 6.1.
S3. continue to stir at 1 DEG C, and be slowly added pH stable agent into above-mentioned fish gelatin solution, addition manner is every
Minute 6wt%, adds, obtains the interim obturator precursor of blood vessel for 20 minutes.
Specific ion/the molecule for including in the pH stable agent is to for Tris-H+, after addition, Tris-H in solution+
Concentration be 5M.For accuracy controlling solution ph, NaOH solution is further added dropwise, guarantees that the pH range of solution is 6.5 ± 1.
Embodiment 2
The present embodiment provides a kind of interim obturator precursor of blood vessel, preparation method is as follows:
S1. chitosan, sodium alginate and ammonia spirit are uniformly mixed, being configured to chitosan content is 10wt%,
Sodium alginate content is the solution of 0.1wt%.
S2. stirring is maintained at 4 DEG C, and citric acid solution is slowly added dropwise in Xiang Shangshu solution, the pH value of solution is adjusted to
8.0。
S3. continue to stir at -2 DEG C, and be slowly added pH stable agent into above-mentioned solution, addition manner is per minute
10wt% is added for 5 minutes, obtains the interim obturator precursor of blood vessel.
Specific ion/the molecule for including in the pH stable agent is to for NH4 +-NH3And HPO4 2--H+Triethylamine has added
Bi Hou, NH in solution4 +-NH3Concentration be 5M, HPO in solution4 2--H+The concentration of triethylamine is 0.01M.The pH range of solution
It is 6.8 ± 1.
Embodiment 3
The present embodiment provides a kind of interim obturator precursor of blood vessel, preparation method is as follows:
S1. hyaluronic acid, collagen and oxalic acid, acetic acid solution are uniformly mixed, being configured to hyaluronic acid contents is
18wt%, collagen content are the solution of 0.25wt%.
S2. stirring is maintained at 2 DEG C, and KOH solution is slowly added dropwise in Xiang Shangshu solution, the pH value of solution is adjusted to 6.8.
S3. continue to stir at -2 DEG C, and be slowly added pH stable agent into above-mentioned solution, addition manner is per minute
8wt% is added for 30 minutes, obtains the interim obturator precursor of blood vessel.
Specific ion/the molecule for including in the pH stable agent is to for borax-Ac-And CO3 2-Citric acid, addition finish
Afterwards, borax-Ac in solution-Concentration be 0.02M, CO in solution3 2-The concentration of citric acid is 0.02M, and the pH range of solution is
7.2±1.Total ion concentration is 0.1M.
Embodiment 4
The present embodiment provides a kind of interim obturator precursor of blood vessel, preparation method is as follows:
S1. clupeine, polyvinyl alcohol and triethylamine, NaOH solution are uniformly mixed, are configured to clupeine and contain
Amount is 1.2wt%, and polyvinyl alcohol content is the solution of 20wt%.
S2. stirring is maintained at -3 DEG C, and formic acid solution is slowly added dropwise in Xiang Shangshu solution, the pH value of solution is adjusted to
8.1。
S3. continue to stir at 5 DEG C, and be slowly added pH stable agent into above-mentioned solution, addition manner is per minute
7wt% is added for 45 minutes, obtains the interim obturator precursor of blood vessel.Specific ion/the molecule for including in the pH stable agent to for
Citric acid radical ion-OH-, after addition, citric acid radical ion-OH in solution-Concentration be 5M, the pH range of solution is 7.2
±1.Total ion concentration is 10M.
For the hydrogel that the interim obturator precursor of the blood vessel is formed, its stability, including mechanical strength and water-setting are tested
Two aspect of plastic structure.Wherein, hydrogel compression modulus can reach 10kPa, hydrogel structure impregnate in water 30 days there is no
Significant change, structural integrity.Thus it proves, hydrogel has good stability.
Embodiment 5
The present embodiment provides a kind of interim obturator precursor of blood vessel, preparation method is as follows:
S1. polyacrylamide and tartaric acid, phosphoric acid solution are uniformly mixed, being configured to polyacrylamide amine content is
The solution of 15wt%.
S2. stirring is maintained at 7 DEG C, tetramethylethylenediamine solution is slowly added dropwise in Xiang Shangshu solution, by the pH value of solution
It is adjusted to 6.2.
S3. continue to stir at 0 DEG C, and be slowly added pH stable agent into above-mentioned solution, addition manner is per minute
6wt% is added for 28 minutes, obtains the interim obturator precursor of blood vessel.
Specific ion/the molecule for including in the pH stable agent to for Tris- lysine hydrochloride-ethylenediaminetetraacetic acid root from
Son and barbital sodium-H+, after addition, Tris- lysine hydrochloride-ethylenediaminetetraacetic acid radical ion concentration is in solution
0.17M, barbital sodium-H+Concentration be 5M, the pH range of solution is 6.3 ± 1.Total ion concentration is 10M.
Embodiment 6
The present embodiment provides a kind of interim obturator precursor of blood vessel, preparation method is as follows:
S1. poloxamer, alginic acid and acetic acid solution are uniformly mixed, being configured to poloxamer content is
17wt%, seaweed acid content are the solution of 0.03wt%.
S2. stirring is maintained at 8 DEG C, and NaOH solution is slowly added dropwise in Xiang Shangshu solution, the pH value of solution is adjusted to
7.2。
S3. continue to stir at 2 DEG C, and be slowly added pH stable agent into above-mentioned solution, addition manner is per minute
8.4wt% is added for 60 minutes.
Specific ion/the molecule for including in the pH stable agent is to for borax-PO4 3-, after addition, borax-in solution
PO4 3-Concentration be 1M, the pH range of solution is 6.5 ± 1.
Test example 1
It using blood vessel occlusion precursor provided by embodiment 1, is injected into rat aorta, tests its obstruction effect
Fruit, specific operation process are as follows:
The aorta on the inside of rat back leg is cut open with sharp weapon, will be injected into the blood vessel occlusion precursor of free fluid state
At blood vessel cut.Injection parameters are as follows: speed under the conditions of 4 DEG C with the 2mL/min in-situ injection in 0.5min enters rat aorta, infuses
The amount of penetrating about 1mL.It is observed after 30s, which is mutually deformed into the gel state with certain mechanical strength
Blood vessel occlusion, blood stop outflow, successfully reach the purpose for blocking blood vessel.Using ice bag at blood vessel cut carry out ice compress,
After 30s, which mutually becomes free fluid state, restores mobility, and be discharged with the outflow again of blood.
Test example 2
It using blood vessel occlusion precursor provided by embodiment 1, is injected into rat aorta, tests its obstruction effect
Fruit, the specific operation process is as follows:
The specified injection region on the aorta on the inside of rat back leg will be in the blood vessel occlusion precursor of free fluid state
It is injected into specified injection region, injection parameters are as follows: speed under the conditions of 4 DEG C with the 2mL/min in-situ injection in 0.5min enters greatly
Mouse blood vessel, injection volume about 1mL.It is observed after 30s, which has mutually been deformed into certain mechanical strength
The blood vessel occlusion of gel state, the blood vessel occlusion can be felt by being touched with hand.The specified injection region is carried out using ice bag
Ice compress, after 30s, which mutually becomes free fluid state, restores mobility, and with blood flow, with hand touch less than
Any obturator.
Test example 3
It using blood vessel occlusion precursor provided by embodiment 1, is injected into rat aorta, tests its obstruction effect
Fruit, the specific operation process is as follows:
The specified injection region on the aorta on the inside of rat back leg will be in the blood vessel occlusion precursor of free fluid state
It is injected into specified injection region, injection parameters are as follows: speed under the conditions of 4 DEG C with the 2mL/min in-situ injection in 0.5min enters greatly
Mouse blood vessel, injection volume about 1mL.It is observed after 30s, which has mutually been deformed into certain mechanical strength
The blood vessel occlusion of gel state.The blood vessel positioned at specified injection region far from heart one end is cut open with sharp weapon, only a small amount of blood
Outflow, illustrates that the blood vessel occlusion successfully blocks the aorta.Ice is carried out to the specified injection region using ice bag
It applies, after 30s, which mutually becomes free fluid state, restores mobility, and flow out in vitro with blood.
It, can be fast in 30s using blood vessel occlusion precursor provided by embodiment 1 it can be seen from test example 1~3
Speed realizes the closure to blood vessel, and the urgent closure hemostasis after being not only suitable for angiorrhoxis is also applied for before surgery to Surgery
The pretreatment of position reduces blood volume loss when operation.And during the test of test example 1~3, every physiology of rat refers to
It marks normal.After the test, every physical signs of rat is normal for test example 2, wherein and blood vessel various functions are normal,
Blood vessel pH value is 7.2 ± 0.2.Accordingly confirm using it is provided by the present invention formed the interim obturator of blood vessel method to blood vessel into
The safety and effectiveness of row temporary plug.
In conclusion the present invention provides a kind of methods for forming the interim obturator of blood vessel, first biomaterial is being divided
Son obtains biomaterial solution sufficiently to dissolve under conditions of non-electroneutral.By the dissolution under non-electroneutrality condition, make to give birth to
Object material can dissolve more abundant, obtain the biomaterial solution of stable uniform.Again at low ambient temperatures, by biomaterial
It is electroneutral that solution, which is adjusted to molecule,.Low temperature environment ensure that biomaterial solution during recalling to electroneutral, is protected always
Solution state is held, biomaterial is avoided and is precipitated and destroys stability of solution.It is eventually adding pH stable agent, to blood vessel occlusion
The pH range of precursor is accurately controlled, and interim obturator precursor is obtained.The interim obturator precursor is free fluid state, can
To pass through in-situ injection or imported into blood vessel, and rapid phase transition is the interim obturator of blood vessel of gel state in the blood vessels, reaches envelope
The purpose of stifled blood vessel.Meanwhile the blood vessel occlusion quickly can mutually become free fluid state by low-temperature treatment, remove
Conveniently so that restoration of blood flow is unimpeded.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of method for forming the interim obturator of blood vessel characterized by comprising
Biomaterial is sufficiently dissolved in the case where molecule is non-electroneutrality condition, obtains biomaterial solution；At -10~10 DEG C,
The pH for adjusting the biomaterial solution, making molecule in the biomaterial is in electroneutral；Keeping temperature is -10~10 DEG C, is added
Enter pH stable agent, make the pH stable of the biomaterial solution in the range of 6~8, before obtaining the interim obturator of blood vessel
Body；By the interim obturator precursor injection of the blood vessel or import intravascular formation hydrogel blocking blood vessel.
2. the method according to claim 1 for forming the interim obturator of blood vessel, which is characterized in that the biomaterial includes
At least one of natural biologic material and synthesising biological material；Preferably, the natural biologic material includes alginic acid, seaweed
In hydrochlorate, hyaluronic acid, fish glue, chitosan, chitosan/phosphoglycerol disodium mixture, collagen, gelatin and clupeine extremely
Few one kind；Preferably, the synthesising biological material includes polyvinyl alcohol, polyethylene glycol, acrylic acid, acrylic acid derivative, block
At least one of formula polymer；Preferably, the acrylic acid derivative includes polyacrylic acid, polymethylacrylic acid, polypropylene
At least one of amide, poly-N-isopropyl acrylamide；Preferably, the Block copolymer includes poloxamer.
3. the method according to claim 1 for forming the interim obturator of blood vessel, which is characterized in that the biomaterial solution
Described in biomaterial content be 0.1wt%~20wt%；Preferably, the content of the biomaterial be 0.5wt%~
10wt%；Preferably, the content of the biomaterial is 5wt%~8wt%.
4. the method according to claim 1 for forming the interim obturator of blood vessel, which is characterized in that the biomaterial exists
Molecule is that the method dissolved under non-electroneutrality condition is: the biomaterial is dissolved in the water under the auxiliary of cosolvent, institute
Stating cosolvent includes any one of acid reagent and alkaline reagent；Preferably, the acid reagent includes organic acid and inorganic
At least one of acid；Preferably, the inorganic acid includes at least one of hydrochloric acid, sulfuric acid and phosphoric acid；Preferably, described to have
Machine acid includes at least one of tartaric acid, citric acid, oxalic acid, acetic acid and formic acid；Preferably, the alkaline reagent includes organic
At least one of alkali and inorganic base；Preferably, the organic base include in triethylamine, tetramethylethylenediamine and pyridine at least
It is a kind of；Preferably, the inorganic base includes sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, disodium hydrogen phosphate and bicarbonate
At least one of sodium.
5. the method according to claim 4 for forming the interim obturator of blood vessel, which is characterized in that adjust the biomaterial
The pH value of solution makes molecule in the biomaterial be to try the biomaterial solution and the alkalinity in the method for electroneutral
Agent and/or acid reagent mixing.
6. the method according to claim 1 for forming the interim obturator of blood vessel, which is characterized in that the pH stable agent packet
Specific ion/molecule pair to stablize pH value is included, the specific ion/molecule is to including Tris-H+, Tris- hydrochloric acid rely ammonia
Acid, Tris- lysine hydrochloride-ethylenediaminetetraacetic acid radical ion, methenamine-NH4 +, barbital sodium-H+, barbital-barbital
Sodium, barbital-Na+-Cl-, citric acid radical ion-OH-, citric acid radical ion-HPO4 2-, citric acid radical ion-H2PO4 -、NH4 +-
NH3, borax-Ca2+, borax-CO3 2-, borax-HCO3 -, borax-PO4 3-, borax-HPO4 2-, borax-H2PO4 -, borax-Ac-, boron
Sand-Cl-, borax-SO4 2-, borax-HSO4 -、Ac--H+-NH4 +、HAc-Ac-、HAc-Ac--NH4 +、PO4 3--H+Triethylamine,
HPO4 2--H+Triethylamine, H2PO4 --H+Triethylamine, PO4 3--HPO4 2-、PO4 3--H2PO4 -、HPO4 2--H2PO4 -、HPO4 2--NH4 +、
H2PO4 --HCO3 -、H2PO4 --CO3 2-、Tris-HAc、Tris-H2PO4 -、Tris-NH4 +、HPO4 2-Citric acid, HCO3 -Citric acid,
CO3 2-Citric acid, H2PO4 -Citric acid, PO4 3-Citric acid, Ac-At least one of citric acid.
7. the method according to claim 6 for forming the interim obturator of blood vessel, which is characterized in that the specific ion/point
Son is 0.05~8M to the concentration in the blood vessel occlusion precursor；Preferably, the specific ion/molecule is in the blood
Concentration in pipe choking object precursor is 0.1~5M；Preferably, the specific ion/molecule is in the blood vessel occlusion precursor
In concentration be 2~4M.
8. the method according to claim 7 for forming the interim obturator of blood vessel, which is characterized in that before the blood vessel occlusion
The total ion concentration of body is 0.1~10M；Preferably, the total ion concentration of the blood vessel occlusion precursor is 0.5~8M；It is preferred that
Ground, the total ion concentration of the blood vessel occlusion precursor are 2~5M.
9. the method according to claim 1 for forming the interim obturator of blood vessel, which is characterized in that temporarily hinder the blood vessel
The speed that plug thing precursor is injected or imported when intravascular formation hydrogel blocks blood vessel is 0.5~12mL/min, injects or imports
The interim obturator precursor of the blood vessel total amount be 0.05~10mL；Preferably, the time injected or imported is 5~300s.
10. the method according to claim 9 for forming the interim obturator of blood vessel, which is characterized in that the blood vessel is interim
When intravascular formation hydrogel blocking blood vessel is injected or imported to obturator precursor, the part blood vessel that is to be injected or importing is kept
The temperature of interim obturator precursor is -10~10 DEG C；Preferably, before being injected or being imported, first the blood vessel is temporarily hindered
1~5min is pre-chilled in plug thing precursor at -10~10 DEG C.
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