CN107537056A - A kind of endocranium sealing gel and preparation method and application - Google Patents
A kind of endocranium sealing gel and preparation method and application Download PDFInfo
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- CN107537056A CN107537056A CN201710811387.2A CN201710811387A CN107537056A CN 107537056 A CN107537056 A CN 107537056A CN 201710811387 A CN201710811387 A CN 201710811387A CN 107537056 A CN107537056 A CN 107537056A
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Abstract
The invention discloses a kind of biodegradable albumin hydrogel.The hydrogel gelation time is less than 20 seconds, and swellbility is 50 200%, and BURSTING STRENGTH is not less than 10kPa, and degradation time in vitro is less than 30 days.Preparing the raw material of the hydrogel includes the second component of the first component albumin containing nucleophilic functional group, the hydrophilic polymer containing multiple electrophilic functional groups and visualizing agent mixture, and two kinds of components covalent cross-linking in situ after double-component injection device physical mixed forms hydrogel.The physical property of subject hydrogel, biodegradability can be adjusted by changing the second component, and hydrogel macroscopic is good, is closed available for the internal different tissues position surface of a wound, such as the closure of endocranium otch.
Description
Technical field
The present invention relates to medical instruments field, and in particular to a kind of albumin sealing gel and preparation method and application.
Background technology
Hydrogel is a kind of three-dimensional net structure polymer with hydrophilic radical as a kind of biocompatible materials,
Because the physical crosslinking between polymer chain and chemical crosslinking act on, hydrogel can be water-swellable but not soluble in water and keep certain
Shape.Medically, hydrogel can be used for Wound dressing, Post operation to prevent adhesion, perform the operation in hemostasis, tissue filling, prevent tissue
Liquid seepage or gas leakage etc..
According to formation basic theory, hydrogel is divided into chemically crosslinked aquagel and the major class of physical cross-linking hydrogel two.Physical crosslinking
The type such as temperature-sensitive hydrogel and molecular self-assembling hydrogel can be divided into.Physical hydrogel is combined by physical force,
Such as winding of electrostatic interaction, hydrogen bond, chain.Chemical hydrogel is the three-dimensional network polymer being cross-linked to form by chemical bond, can
It is divided into the types such as cross-linking agents hydrogel, radiation crosslinking hydrogel, photo-initiated crosslinking hydrogel.
The species of hydrogel is relatively more, can be divided into external gel and internal in-situ gel according to gel formats.It is former in vivo
Position gel has the advantages of syringeability, and cannot be only used for open operation can be used for Minimally Invasive Surgery.Aquagel tissue seals
Mixture can be by the way that two kinds of aqueous solution be mixed to be formed, and each aqueous solution includes a kind of crosslinkable component, required using
Before site, two kinds of solution are premixed using mixing arrangement, sprayed in biological tissue.
Sealing agent of performing the operation has many potential medical applications, including closes wound, suture is aided in surgical operation
Or suturing nail, as barrier for preventing post-operation adhesion and as hemostasis sealing agent etc..
Fibrin gel（Also referred to as Fibrin Glue）It is a kind of clinical widely used blood derivative composition,
It is developed as surgical operation styptic, tissue adhesive and sealing agent.Typical commercially available fibrin gel kit is by freezing
Dry concentration human fibrinogen bottle composition, the also plasminogen containing fibronectin, FXIII and decrement, are used
It is preceding to be reconstructed with solution and be heated to 37 DEG C.Second component of adhesive composition is lyophilized thrombin of beef solution, and it uses calcium chloride
Solution reconstructs.Preparation can also contain extra component, such as fibrinolysis inhibitor.As a kind of two-component adhesive,
Rapid reaction forms gel after mixing.The gel formed can adhere to tissue, hemostasis, the bridge joint tissue surface of a wound etc. until more
It is combined into only.But the most important shortcoming of Fibrin Glue is that fibrinogenolysis speed is slower, when gel strength is low and degrades
Between it is too fast.
Seralbumin is the very high globular protein of the water solubility being present in blood plasma.Seralbumin accounts for the total egg of blood plasma
White 40%-60%, 80% osmotic pressure is undertaken by albumin in blood.Plasma albumin is a critically important albumen again
Matter warehouse, amino acid is decomposed into when body needs synthesizes other various protein for tissue and be used.Lack blood in blood
Slurry albumin can cause oedema.Contribute to low albumen caused by alleviating liver, kidney illness and burning using plasma albumin preparation
Mass formed by blood stasis.Seralbumin is a kind of important component in blood, main to act the normal osmotic pressure for maintaining blood and hydrophilic point of conveying
The effect of son, albumin, which also has, in addition detoxifies, participates in the transport of slightly soluble material in lipid metabolism and blood plasma, maintains blood soda acid to put down
The effect such as weighing apparatus, has a wide range of applications in clinical medicine and biological field.Seralbumin contains a large amount of amino acid residues.Aldehyde radical
Imide bond can be produced with the amino coupled of exposure on protein.In the 90's of 20th century, CryoLife companies of the U.S. are by long-term
Research, develops a kind of new medical soft tissue sealing agent, i.e. BioGlue.Bioglue be it is a kind of based on bovine albumin solution with
Situ-gel sealing agent inside glutaraldehyde solution, utilize the amino of bovine serum albumin(BSA) and the aldehyde radical reaction generation west of glutaraldehyde
Not alkali is widely used for cardiovascular and big vascular surgery seepage place and mechanically sealed abroad so as to produce crosslinking.Should
Sealing agent has obtained the state such as the U.S., European Union, Canada and Australia food and medicine approved by management.But Bioglue
Residual glutaraldehyde can cause cytotoxicity, or even can trigger nervous tissue degeneration.In recent years, for using being produced after BioGlue
The case report of postoperative complications is of common occurrence, and sustainer occurs using patient after BioGlue as Gabrijelcic reports
Postoperative complications [Gabrijelcic T, the Blockage of a mechanical aortic valve of valve insufficiency
leaflet with Bioglue: a case report. Heart Surg Forum, 2012, 15 (6):E310-
312.]；Luk etc. then find using some patientss after BioGlue occur false aneurysm [Luk A, David TE,
Butanv J. Complications of Bioglue postsurgery for dissect ions and aortic
valve replacement. J Clin Pathol, 2012, 65(11):1008-1012]。
Cerebrospinal fluid seepage is the most common complication of all neurosurgery operations of opening cranium.Due to being opened in neurosurgery
Endocranium and arachnoid, therefore cerebrospinal fluid is in open state in surgical procedure.Lacked flexibility because meninx quality is tougher,
Often a small amount of bleeding when cutting off dura mater, stopped blooding easily shrinkage using bipolar coagulation, so terminated before operation terminates, the close nothing of meninx
Seepage suture is often " can not possibly complete ", so the postoperative different degrees of cerebrospinal fluid seepage of generation is also relatively conventional shows
As.Cerebrospinal fluid seepage is the most common complication of operation of opening cranium, can cause intracranial infection, operative region infection, hypohydropses,
Situations such as wound seepage, cause Wound healing slowly, extended hospital stay, or even need again operation wound clearing treat.At present, face
Conventional treatment method is autologous meninx repairing, the repairing of exogenous meninx patching material, Epidural cavity catheter drainage on bed.
Due to the most water white transparency of sealing agent gel（Such as hundred special company Coseal surgeries blood vessel sealing agents）, spray to group
After knitting the surface of a wound, visually it is not easy to observe, therefore does not allow the position of gel spraying easy to identify and form the thickness of gel.For endocranium
For sealing agent, gel thicknesses are bigger than normal, may result in and brain tissue is oppressed, gel coating thickness is less than normal, is likely to result in envelope
BURSTING STRENGTH after conjunction is relatively low, does not reach the purpose of the closure surface of a wound.Visualizing agent with the perceptible wavelength reflection of human eye or
Light is sent, so that gel can be observed in the user of sealing gel.Macroscopic reagent is added in gel is sealed can be with
Reference is provided for sealing gel spraying position and the thickness identification for sealing gel.
Therefore, develop that a kind of macroscopic is good, plastic speed is fast, degradation speed is moderate and can effectively close endocranium cuts
The sealing gel for mouthful preventing cerebrospinal fluid seepage be neurosurgery it is clinical there is an urgent need to.
The content of the invention
Present invention aims to overcome that the deficiencies in the prior art, there is provided a kind of degradation speed matches with tissue repair speed
, the albumin that macroscopic is good sealing gel.
Albumin of the present invention seals gel, including following component：
（1）, the first liquid component, the liquid component contains that to be dissolved in pH scopes be that the concentration in 6.0-10.0 cushioning liquid is
5%-45%（w/v）Albumin；
（2）, the second solid constituent, the solid constituent be the hydrophilic polymer containing multiple electrophilic functional groups and visualization try
The mixture of agent.
When in use, the cushioning liquid dissolving second for being first 6.0-10.0 with pH scopes is solid for above-mentioned albumin sealing gel
Body component, preparation obtain concentration as 5% ~ 45%（w/v）Second component solution；Then by the first liquid component and the second component solution
Mixing, is cross-linked to form albumin gel.Albumin solution and the second component solution volume ratio are from 30:70 to 70:30, be preferably
40:60 to 60:40, more preferably 45:55 to 55:45.
Above-mentioned albumin sealing gel, the source of albumin can be that the serum of the animals such as people, ox, horse, sheep, mouse is white
Albumen, preferably human serum albumins.Seralbumin can be recombinantly expressed by genetic engineering and produced, either can from people or
Extracted in animal blood plasma.
Above-mentioned albumin seals gel, and the buffer solution for being used to dissolve albumin in the first liquid component is to be able to maintain that
PH values are 6.0-10.0 any buffer solution under aqueous solution state, can be optionally from phosphate buffer, boric acid salt buffer
Liquid, histidine buffering liquid, sodium bicarbonate-carbonate buffer solution, Tris-HCl buffer solutions, diethanolamine buffer or above-mentioned slow
Rush combination of salt etc., preferably phosphate buffer solution.Buffer solution pH value for dissolving albumin is 6.0-10.0, preferable ph
For 7.0-9.0；Concentration range is 1-500mM, preferably 10-300mM, more preferably 50-200mM.Albumen after albumin dissolving is dense
Spend for 5%-45%（w/v）, preferable concentration range is 10% ~ 40%（w/v）, more preferably 20%-30%（w/v）.
In the second solid constituent in above-mentioned albumin sealing gel, in described solid constituent and the first liquid component
The mass ratio of albumin be 0.3-2, preferably 0.5-1.5, more preferably 0.75-1.
In the second solid constituent in above-mentioned albumin sealing gel, described electrophilic functional group is selected from succinimide
Glutaric acid ester group（-SG）, succinimide decanedioic acid ester group（-SSeb）, succinimidyl succinate base（-SS）, succinyl
Imines propionic acid ester group（-SPA）, succinimide acetate groups（-SCM）, succinimdyl carbonate base（-SC）, maleimide
Amido（-Mal）With propionic aldehyde base（-ALD）It it is more than 3 Deng, electrophilic functional group's number.
In the second solid constituent in above-mentioned albumin sealing gel, described hydrophilic polymer main body is selected from poly- second two
Alcohol, PEO, ethylene oxide-propylene oxide block copolymer, polyvinyl alcohol and PVP.
It is furthermore preferred that described hydrophilic polymer can be selected from 4 arm polyethylene glycol Succinimidyl glutarates（4-
arm-PEG-SG）, 4 arm polyethylene glycol succinimide succinates（4-arm-PEG-SS）, 4 arm polyethylene glycol succinimides
Sebacate（4-arm-PEG-SSeb）In one or more, molecular weight be 1000 ~ 100000, preferably 2000-50000.
In the second solid constituent in above-mentioned albumin sealing gel, described visualizing agent be FD ＆ C bluenesss #1,
One or more in FD ＆ C blueness #2, FD ＆ C blueness #3, D ＆ C greens #6, methylene blue and Fox Green.Described is visual
It is 0.1 ~ 1% to change mass fraction of the reagent in solid constituent.
Buffer solution for dissolving the second solid constituent is to be able to maintain that under aqueous solution state pH values are 6.0-10.0's
Any buffer solution, can be optionally from phosphate buffer, borate buffer solution, histidine buffering liquid, sodium bicarbonate-carbonate
The combination etc. of buffer solution, Tris-HCl buffer solutions, diethanolamine buffer or above-mentioned buffer salt, preferably phosphate buffer solution.It is slow
The pH of fliud flushing is preferably 6.0-8.0；The concentration range of buffer solution is 1-500mM, preferably 10-300mM, more preferably 50-200mM.
It is a further object of the present invention to provide a kind of preparation method of albumin sealing gel.Albumin provided by the invention
The preparation method of gel is sealed, is comprised the following steps：
（1）, prepare the first liquid component：It is to prepare to obtain concentration and be in 6.0-10.0 cushioning liquid that albumin is dissolved in into pH scopes
5%-45%（w/v）Albumin solution；
（2）, prepare second liquid component：By the hydrophilic polymer containing multiple electrophilic functional groups and the solid of visualizing agent
Component is dissolved in the cushioning liquid that pH scopes are 6.0-10.0, and preparation obtains concentration as 5% ~ 45%（w/v）Contain electrophilic function
The hydrophilic polymer components solution of group, wherein described solid constituent and the mass ratio of the albumin in the first liquid component are
0.3-2；
（3）, the first liquid component mixed with second liquid component, be cross-linked to form albumin sealing gel.
The albumin sealing gel that the above method is prepared, its matrix components are albumin, contain multiple electrophilic functions
The polymer and micro visualizing agent of group.Albumin can be recombinantly expressed by genetic engineering and produced, either can from people or
Extracted in animal blood plasma.
In the above method, the buffer solution for preparing the first liquid component and second liquid component is to be able to maintain that in aqueous solution
PH values are 6.0-10.0 any buffer solution under state, can be optionally from phosphate buffer, borate buffer solution, histidine
Buffer solution, sodium bicarbonate-carbonate buffer solution, Tris-HCl buffer solutions or diethanolamine buffer etc., preferably phosphate buffering
Liquid.Wherein, the buffer solution pH value for dissolving albumin is 6.0-10.0, preferable ph 7.0-9.0；Concentration range is 1-
500mM, preferably 10-300mM, more preferably 50-200mM.For dissolving the preferred pH of buffer solution containing electrophilic functional components
It is worth for 6.0-10.0, preferably 6.0-8.0；Concentration range is 1-500mM, preferably 10-300mM, more preferably 50-200mM.
Solid constituent in the above method is the hydrophilic polymer containing multiple electrophilic functional groups and visualizing agent
Mixture.Described hydrophilic polymer main body is selected from polyethylene glycol, PEO, epoxy ethane-epoxy propane block copolymerization
Thing, polyvinyl alcohol and PVP.Preferable electrophilic functional group is selected from Succinimidyl glutarate base（-SG）,
Succinimide decanedioic acid ester group（-SSeb）, succinimidyl succinate base（-SS）, succinimidyl propionate base（-
SPA）, succinimide acetate groups（-SCM）, succinimdyl carbonate base（-SC）, dimaleoyl imino（-Mal）With third
Aldehyde radical（-ALD）It it is more than 3 Deng, electrophilic functional group's number.
It is furthermore preferred that described hydrophilic polymer can be selected from 4 arm polyethylene glycol Succinimidyl glutarates（4-
arm-PEG-SG）, 4 arm polyethylene glycol succinimide succinates（4-arm-PEG-SS）, 4 arm polyethylene glycol succinimides
Sebacate（4-arm-PEG-SSeb）In one or more, molecular weight be 1000 ~ 100000, preferably 2000-50000.
In the above method, described visualizing agent is FD ＆ C blueness #1, FD ＆ C blueness #2, FD ＆ C blueness #3, D ＆ C
One or more in green #6, methylene blue and Fox Green.Mass fraction of the described visualizing agent in solid constituent
For 0.1 ~ 1%.
In the above method, albumin solution is from 30 with the polymer solution volume ratio containing electrophilic functional group：70 to 70：
30, preferably 40：60 to 60：40, more preferably 45：55 to 55：45.Albumin solution and polymerizeing containing electrophilic functional group
Gelation time is that gel swelling 50-200%, BURSTING STRENGTH was not less than 10kPa less than 20 seconds after the mixing of thing solution, external drop
The time is solved less than 30 days.
Present invention also offers a kind of medicine equipment external member for delivering albumin sealing gel, including：
（1）, the first liquid component in the first container of sealing, the liquid component contains that to be dissolved in pH scopes be 6.0-10.0
Concentration in cushioning liquid is 5%-45%（w/v）Albumin；
（2）, the second solid constituent in the second container of sealing, the solid constituent is the parent containing multiple electrophilic functional groups
The mixture of waterborne polymeric and visualizing agent, described hydrophilic polymer main body be selected from polyethylene glycol, PEO,
Ethylene oxide-propylene oxide block copolymer, polyvinyl alcohol and PVP；Described visualizing agent is selected from
FD ＆ C blueness #1, FD ＆ C blueness #2, FD ＆ C blueness #3, D ＆ C greens #6, methylene blue and one kind or more in Fox Green
Kind；Wherein described solid constituent and the mass ratio of the albumin in the first liquid component are 0.3-2.
（3）, independent packaging second solid constituent that is used to dissolve be able to maintain that under aqueous solution state that pH values are 6.0-
10.0 buffer solution, it is added to when in use in the second sealing container and dissolves the second solid constituent.
In the medicine equipment external member of delivering albumin sealing gel, albumin solution can be encapsulated in double-component injection
In first syringe cavity of device, and the solid constituent of hydrophilic polymer and visualizing agent containing multiple electrophilic functional groups
It is encapsulated in the second syringe cavity.During actual use, extracting suitable buffer solution and being added in the second syringe cavity makes
Solid constituent dissolves, and applying pressure by push rod makes the liquid component in the first syringe and the second syringe in batch mixing head cavity body
Middle mixing, sprayed to finally by shower nozzle on the wound of the various surgical operations of human body, be cross-linked to form albumin sealing gel, play
Bonding, hemostasis, antiseep and the effect of preventing adhesion etc..
The sealing gel of the present invention can use following methods to detect.
Gelation time detects：The speed that gel solidification time response gel is molded in the original location, directly affecting clinical gel makes
Carried out with what rear lower step was performed the operation.Using the inverted method detection gelation time of test tube.By albumin solution and contain multiple electrophilic officials
It can roll into a ball and the component solution of visualizing agent is filled into double-component injection device respectively, be expelled in centrifuge tube, be put in 37 DEG C of constant temperature
In water-bath, using manual time-keeping, the time that solution is flowed to after centrifuge tube is inverted in centrifuge tube between not flowing is plastic
Time.
Swellbility detects：Swellbility refers to that swelling reaches quality increase percentage after balance in physiological saline after gel cross-linkage
Than.Detection method is as follows：Albumin solution and the component solution containing multiple electrophilic functional groups and visualizing agent are filled respectively
To double-component injection device, it is expelled in template, after gel, weighs.Gel is moved on in centrifuge tube, physiological saline is added, after 4 hours
Sample is taken out, surface moisture is sucked with filter paper, is weighed.Quality × 100% before quality/swelling after swellbility=swelling.
The detection of BURSTING STRENGTH：In addition to gelation time and swellbility, the BURSTING STRENGTH of gel is equally critically important, and it reflects
The mechanical property of gel in use.Detection method is：Take and the hole that a diameter is about 0.2cm made a call on fresh hog intestine,
Two-component is filled into respectively with the albumin solution and the component solution containing multiple electrophilic functional groups and visualizing agent of the present invention
In syringe, spray on this hole and form gel, amount of gel about 2mL, pressurizeed with physiological saline, until gel is damaged, record
Maximum number pressure on the digitizer being connected with sensor.
Degradation time in vitro detects：By albumin solution with distinguishing containing the component solution of multiple electrophilic functional groups and visualizing agent
Double-component injection device is filled into, is expelled in template, is transferred to after gel in centrifuge tube, adds physiological saline, daily observation is extremely
Untill visually invisible, gel degradation time in vitro is designated as.
Polyethylene glycol has the hydrophily of height, and does not have immunogenicity.By the oxidation of cytochrome p450 system
Effect, PEG resolves into the PEG of small molecule, through bile excretion.PEG products safe disposal can absorb in vivo, and it is anti-not produce rejection
Should, by medical polyethylene glycol（PEG）Medical device product prepared by product can be widely applied in the various surgical operations of human body
In the bonding of wound, hemostasis, antiseep and the material such as prevent adhesion.The present invention, which uses, contains multiple electrophilic functional groups（More than 3）'s
Compound is as crosslinking agent, the compound phase ratio with parents' electricity functional group, can improve the reaction speed of electrophilic compound and albumin
The mechanical property of degree, further lifting sealing gel.
Visualizing agent can be added in present invention sealing gel, visualizing agent is with the perceptible wavelength reflection of human eye or hair
Light extraction, so that gel can be observed in the user of sealing gel.Visualizing agent may be selected from having good biocompatibility
Implantable any nontoxic colored material, such as FD ＆ C blueness #1, FD ＆ C blueness #2, FD ＆ C blueness #3, D ＆ C greens #6,
Methylene blue and Fox Green etc..It is present in concentration 0.02-3.0mg/ml concentration in final sealing gel.Visualization examination
Agent assigns sealing gel color, but not hinders plastic reaction.
Therefore, it is a further object of the present invention to provide described albumin sealing gel or medicine equipment external member are each in human body
The bonding of wound in kind of surgical operation, hemostasis, antiseep or the application in preventing adhesion.The hydrogel of the present invention medically can use
Defective tissue is sealed during neurosurgery, angiocarpy, department of general surgery, department of plastic surgery, ophthalmology or bone surgery.Tissue can be reduced
Blood oozing from the wound surface and veinlet bleeding, promote Wound healing, prevent tissue adhesion, seal defective tissue, promote chronic ulcer face
Healing, such as in neurosurgery（In head, spinal operation）For the sealing of Broken dura remedy, less postoperative brain spinal fluid oozes
Leakage；Cornea seals after ophthalmology is used for cataract operation, lens injury, eyelid surgery, lachrymal gland and the sealing of conjunctiva reparation；In the heart
The sealing being used in vascular surgery at reconstructing blood vessel；It is used for gas after less lung tissue fiber sutures in thoracic surgery pneumonectomy operation
The leakage of body；It is used for postoperative prevent adhesion in surgical operation；It can be additionally used in the fixation of hernia paster；And Surgical healing Post operation
The sealing of previous anastomotic.
Brief description of the drawings
Fig. 1 is double-component injection device schematic diagram.10 be shower nozzle, and 11 be batch mixing head, and 12 be push rod, and 13 be double-component injection device
The syringe cavity of component 1,14 be the syringe cavity of double-component injection device component 2, and 15 be syringe rack.
Fig. 2 is 4 arm polyethylene glycol Succinimidyl glutarate molecular structures（4-arm-PEG-SG）.
Fig. 3 is 4 arm polyethylene glycol succinimide sebacate molecular structures（4-arm-PEG-SSeb）.
Embodiment
Embodiment 1
Cerebrospinal fluid seepage is the common complication after head and spinal operation.Because the nerve near head and backbone is for tissue
Inflammation or operation implantation material（Such as artificial pachymeninx）Oppressed caused by swelling very sensitive, it is therefore desirable to which swellbility is relatively low
Hydrogel, it is preferably minimized the compressing to tissue.The present invention is used for the preparation method for the sealing hydrogel for preventing cerebrospinal fluid seepage
It is as follows：
Weigh 2.5 grams of human serum albumins（25%, w/v）, it is dissolved in the 10mL phosphate buffers prepared by deionized water
（10mM, pH=9.2）.37 DEG C of occasional agitations 1 hour, make its dissolving, after after albumen, thoroughly dissolving turns into transparence liquid, with true
Empty pumping gas causes that bubble quickly eliminates in solution for 30 minutes.
Weigh 4 arm polyethylene glycol Succinimidyl glutarates（4-arm-PEG-SG, molecular weight 10000Da）2g and
FD ＆ C blueness #1 visualizing agent 5mg, the 10mL phosphate buffers (10mM, pH=7.4) prepared by deionized water are dissolved in,
Vortex makes its dissolving turn into transparence mixture liquid.
Human serum albumin solution and 4-arm-PEG-SG and FD ＆ C blueness #1 mixed solutions are filled into two-component respectively
In syringe, spraying post-crosslinking forms albumin sealing gel.Gelation time is 3 seconds after mixing, and the seralbumin of preparation coagulates
Peptization expansibility is 115%, and BURSTING STRENGTH reaches 23.7kPa, degradation time in vitro 19 days.
Embodiment 2
Weigh 2 grams of human serum albumins（20%, w/v）, it is dissolved in the 10mL phosphate buffers prepared by deionized water（10mM,
pH=9.2）.37 DEG C of occasional agitations 1 hour, make its dissolving, after after albumen, thoroughly dissolving turns into transparence liquid, with vacuum pumping
Gas causes that bubble quickly eliminates in solution for 30 minutes.
Weigh 4 arm polyethylene glycol Succinimidyl glutarates（4-arm-PEG-SG, molecular weight 20000Da）2g and
FD ＆ C blueness #2 visualizing agent 10mg, be dissolved in by deionized water prepare 10mL phosphate buffers (10mM, pH=
7.4), being vortexed makes its dissolving turn into transparence mixture liquid.
Human serum albumin solution and 4-arm-PEG-SG and FD ＆ C blueness #2 visualizing agents mixture solution are distinguished
It is filled into double-component injection device, spraying post-crosslinking forms albumin sealing gel.Gelation time is 2 seconds after mixing, preparation
Seralbumin gel swelling is 138%, and BURSTING STRENGTH reaches 22.5kPa, degradation time in vitro 12 days.
Embodiment 3
Weigh 2.5 grams of the human serum albumins in blood plasma source（25%, w/v）, it is dissolved in the 10ml borates prepared by deionized water
Buffer solution（10mM, pH 9.0）.37 DEG C of occasional agitations 1 hour, make its dissolving, treat that thoroughly dissolving turns into transparence liquid to albumen
Afterwards, it is evacuated with vavuum pump and make it that within 30 minutes that bubble quickly eliminates in solution.
Weigh the succinimide sebacate of 4 arm polyglycol ether four（4-arm-PEG-SSeb, molecular weight 12000D）
2g and methylene blue visualizing agent 15mg, it is dissolved in the 10ml phosphate buffers prepared by deionized water（10mM, pH=
6.0）, being vortexed makes its dissolving turn into transparence mixture liquid.
The human serum albumin solution in blood plasma source is mixed with 4-arm-PEG-SSeb and methylene blue visualizing agent
Thing solution is filled into double-component injection device respectively, and spraying post-crosslinking forms seralbumin gel.Gelation time is after mixing
18 seconds, the seralbumin gel swelling of preparation was 105%, and BURSTING STRENGTH reaches 35.3kPa, and degradation time in vitro is 29 days.
Claims (9)
1. a kind of albumin seals gel, including following component：
（1）, the first liquid component, the liquid component contains that to be dissolved in pH scopes be that the concentration in 6.0-10.0 cushioning liquid is
5%-45%（w/v）Albumin；
（2）, the second solid constituent, the solid constituent be the hydrophilic polymer containing multiple electrophilic functional groups and visualization try
The mixture of agent.
2. albumin according to claim 1 seals gel, it is characterised in that：Described albumin sealing gel is configuring
When, the cushioning liquid for being first 6.0-10.0 with pH scopes dissolves the second solid constituent, and preparation obtains concentration as 5% ~ 45%（w/v）The
Two component solutions；Then the first liquid component is mixed with the second component solution, is cross-linked to form albumin sealing gel.
3. albumin according to claim 1 seals gel, it is characterised in that：Described hydrophilic polymer main body is poly-
Ethylene glycol, PEO, ethylene oxide-propylene oxide block copolymer, polyvinyl alcohol and PVP.
4. albumin according to claim 1 seals gel, it is characterised in that：Described electrophilic functional group is selected from succinyl
Imines glutaric acid ester group（-SG）, succinimide decanedioic acid ester group（-SSeb）, succinimidyl succinate base（-SS）, amber
Amber propionates base（-SPA）, succinimide acetate groups（-SCM）, succinimdyl carbonate base（-SC）, Malaysia
Imide（-Mal）With propionic aldehyde base（-ALD）It it is more than 3 Deng, electrophilic functional group's number.
5. albumin according to claim 1 seals gel, it is characterised in that：Described visualizing agent is FD ＆ C blue
One or more in color #1, FD ＆ C blueness #2, FD ＆ C blueness #3, D ＆ C greens #6, methylene blue and Fox Green.
6. albumin according to claim 1 seals gel, it is characterised in that：Examination is visualized in second solid constituent
Agent mass fraction is 0.1 ~ 1%.
7. a kind of preparation method of albumin sealing gel, comprises the following steps：
（1）, prepare the first liquid component：It is to prepare to obtain concentration and be in 6.0-10.0 cushioning liquid that albumin is dissolved in into pH scopes
5%-45%（w/v）Albumin solution；
（2）, prepare second liquid component：Hydrophilic polymer and the second of visualizing agent containing multiple electrophilic functional groups is consolidated
Body component is dissolved in the cushioning liquid that pH scopes are 6.0-10.0, and preparation obtains concentration as 5% ~ 45%（w/v）The second component
Solution, wherein described solid constituent and the mass ratio of the albumin in the first liquid component are 0.3-2；
（3）, the first liquid component mixed with second liquid component, be cross-linked to form albumin sealing gel.
8. a kind of medicine equipment external member for delivering albumin sealing gel, including：
（1）, the first liquid component in the first container of sealing, the liquid component contains that to be dissolved in pH scopes be 6.0-10.0
Concentration in cushioning liquid is 5%-45%（w/v）Albumin；
（2）, the second solid constituent in the second container of sealing, the solid constituent is contains multiple electrophilic functional groups（Greatly
In 3）Hydrophilic polymer and visualizing agent mixture, described hydrophilic polymer main body be selected from polyethylene glycol,
PEO, ethylene oxide-propylene oxide block copolymer, polyvinyl alcohol and PVP；Described is visual
It is one in FD ＆ C blueness #1, FD ＆ C blueness #2, FD ＆ C blueness #3, D ＆ C greens #6, methylene blue and Fox Green to change reagent
Kind is a variety of；Wherein described solid constituent and the mass ratio of the albumin in the first liquid component are 0.3-2；
（3）Independent packaging is able to maintain that under aqueous solution state pH values are 6.0-10.0 for the second solid constituent of dissolving
Buffer solution, be added to when in use in the second sealing container and dissolve the second solid constituent.
9. albumin described in claim any one of 1-6 seal gel in the various surgical operations of human body the antiseep of wound,
Application in bonding, stop blooding or preventing adhesion, or be used for preparing in operation of opening cranium in the medicine equipment of endocranium vascular closure
Purposes.
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| CN201710811387.2A CN107537056A (en) | 2017-09-11 | 2017-09-11 | A kind of endocranium sealing gel and preparation method and application |
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| CN201710811387.2A CN107537056A (en) | 2017-09-11 | 2017-09-11 | A kind of endocranium sealing gel and preparation method and application |
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| CN107537056A true CN107537056A (en) | 2018-01-05 |
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| CN108404199A (en) * | 2018-03-14 | 2018-08-17 | 中国科学院上海硅酸盐研究所 | A kind of multiple trauma dressing and preparation method thereof with tissue adhesive property |
| CN109568641A (en) * | 2018-12-27 | 2019-04-05 | 山东百多安医疗器械有限公司 | A kind of medical closed glue and preparation method thereof can promote wound healing |
| CN110193091A (en) * | 2018-02-27 | 2019-09-03 | 华东理工大学 | Injectable albumen/polyethylene glycol groups hydrogel material and its preparation method and application |
| CN110801528A (en) * | 2019-10-30 | 2020-02-18 | 金路平 | Dura mater spinalis sealing hydrogel and preparation method and application thereof |
| CN111265711A (en) * | 2020-03-09 | 2020-06-12 | 北京爱特康医疗科技有限公司 | Tissue sealant powder, preparation process thereof and tissue sealant |
| CN113491794A (en) * | 2021-04-16 | 2021-10-12 | 中国医学科学院北京协和医院 | Hydrogel patch for repairing dura mater spinalis defect and preparation method and application thereof |
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| CN113491794A (en) * | 2021-04-16 | 2021-10-12 | 中国医学科学院北京协和医院 | Hydrogel patch for repairing dura mater spinalis defect and preparation method and application thereof |
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