CN105288601A - Application of hydrogel microspheres embedded with blood coagulation related enzyme - Google Patents
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Abstract
The invention discloses application of hydrogel microspheres embedded with blood coagulation related enzyme. Grain size of the prepared microspheres is 100-1000 micrometers and is uniform (CV is smaller than 20%), the blood coagulation related enzyme is uniformly distributed in the hydrogel microspheres, a mass ratio of the blood coagulation related enzyme to sodium alginate in the microspheres is 1:3-4:1, drug loading rate of the dewatered blood coagulation related enzyme is 25-80%, and the hydrogel microspheres carrying the blood coagulation related enzyme are used for coagulation of blood and plasma.
Description
Technical field
The present invention relates to a kind of application of hydrogel microsphere, particularly a kind of application of hydrogel microsphere in blood coagulation being embedded with blood coagulation relevant enzyme.
Background technology
Disclosed method of solidifying for blood (or blood plasma) is all adopt directly solidifying of blood coagulation relevant enzyme at present, and this method is only applicable to the condensation of a small amount of static sample or more tiny pipeline.But if the tube chamber system that diameter is very large, and when having malleation to advance, be difficult to the rapid solidification of blood (or blood plasma) and the effective shutoff of target tube chamber that realize flowable state at short notice.
Summary of the invention
For the problems referred to above, the biochemical procoagulant activity of thrombin combines with the blocking action of hydrogel microsphere by the present invention, proposes a kind of application of hydrogel microsphere at coagulation process being embedded with blood coagulation relevant enzyme.It is characterized in that: the main component of hydrogel microsphere is alginate material, microspherulite diameter 100-1000 micron, uniform particle diameter (CV<20%), the mass ratio 1:3-4:1 of blood coagulation relevant enzyme and sodium alginate in Sodium Alginate Hydrogel Films microsphere containing blood coagulation relevant enzyme, after dewatering, the drug loading of blood coagulation relevant enzyme is at 25%-80%, is loaded with the hydrogel microsphere of blood coagulation relevant enzyme for one of following three kinds of situations or more than two kinds;
A, pipe blocking containing fibrin primary liquid flow process in pipeline;
Or, B, containing fibrin primary liquid in pipeline one of flow process or two close with upper pipeline opening;
Or, C, condensation containing fibrin primary liquid.
Wherein, describedly in vitro blood or blood plasma is comprised containing fibrinogenic liquid.
Described flowing close containing the obstruction of Fibrinogen liquid line, opening and liquid condensation comprises the synergy of physical-chemical;
Physical action is strengthened blocking sealing process after comprising the mechanical blockage of microsphere and the rapid imbibition of hydrogel; Chemical action refers to that blood coagulation relevant enzyme acts on the obstruction brought after Fibrinogen initiation liquid solidifies and closes and condensation effects.
Described hydrogel microsphere is particularly useful for one of the situation of closing containing the pipe blocking of fibrinogenic working fluid, pipeline opening of existing of certain pressure (60-150mmHg) or liquid condensation or more than two kinds.
Blood coagulation relevant enzyme in described hydrogel microsphere, comprise in thrombin or hemocoagulase one or both.
In described alginate hydrogel microsphere, alginate molecular weight 10kDa-2000kDa, described alginate comprises one in alginic acid calcium salt or alginic acid barium salt or two kinds, the one that also can comprise simultaneously or not comprise in alginic acid sodium salt or potassium salt or two kinds.
The preparation method of described hydrogel microsphere comprises the steps:
A, compound concentration 10-30g/L sodium alginate soln;
B, blood coagulation relevant enzyme to be dissolved in sodium alginate soln prepared by steps A, the concentration of blood coagulation relevant enzyme is 10-40g/L, obtains the sodium alginate soln containing blood coagulation relevant enzyme;
C, preparation coagulation bath aqueous solution, containing one or both of total concentration 5-30g/L calcium chloride or barium chloride in coagulation bath, coagulation bath aqueous solution is also containing the one in total concentration 1-20g/L sodium chloride or potassium chloride or two kinds; Coagulation bath aqueous solution is also containing one or two or more kinds in total concentration 0.5-20g/L sodium citrate or sodium phosphate or sodium hydrogen phosphate or sodium dihydrogen phosphate; Coagulation bath aqueous solution is also containing the one in total concentration 1-30g/L tween or F68 or two kinds;
D, at high-pressure electrostatic after the match, the sodium alginate soln containing blood coagulation relevant enzyme prepared by step B forms uniform jet droplets, drop enters in the coagulation bath solution of step C preparation, gelation reaction occurs, must be embedded with the alginate hydrogel microsphere of blood coagulation relevant enzyme.
The described alginate hydrogel microsphere being embedded with blood coagulation relevant enzyme can further with said polycation solution cross-linking reaction, form polyelectrolyte complex film at microsphere surface, form the alginate-polycation microsphere being embedded with blood coagulation relevant enzyme, concrete steps are:
1) the alginate hydrogel microsphere being embedded with blood coagulation relevant enzyme is put in said polycation solution, the volume ratio of microsphere and said polycation solution is 1:2-1:10, rotate concussion, allow microsphere be in even suspension state in the solution, carry out polyelectrolyte complex reaction 2-60 minute;
2) microsphere is separated with polycation reactant liquor, collects microsphere, namely obtains the alginate-polycation microsphere being embedded with blood coagulation relevant enzyme after normal saline cleaning;
Wherein, polycation comprises Chitosan-phospholipid complex, α or ε polylysine, poly ornithine, poly arginine, polyamine and derivant, polyamide and derivant thereof, polyimides and derivant thereof, and one or two or more kinds in the copolymer of above-mentioned any or more than two kinds polycations, the molecular weight of polycation molecules at 1kDa-500kDa, said polycation solution concentration 0.2-20g/L.
The described hydrogel microsphere being embedded with blood coagulation relevant enzyme according to application demand, can realize the slow controlled release of blood coagulation relevant enzyme at applied environment.
Advantage of the present invention:
1. the alginate hydrogel microsphere of year thrombin is for closing and liquid condensation containing the obstruction of Fibrinogen liquid line, opening of flowing.The action effect of more simple gel micro-ball or simple thrombin is compared, the effect that the chemical effect of physical effect and thrombin that the present invention has played hydrogel microsphere is combined.Wherein, physical effect is strengthened blocking sealing process after comprising the mechanical blockage of microsphere and the rapid imbibition of hydrogel; Chemical action refers to that blood coagulation relevant enzyme acts on the obstruction brought after Fibrinogen initiation liquid solidifies and closes and condensation effects.Therefore, the alginate hydrogel microsphere being loaded with thrombin in the present invention can give full play to closing containing the obstruction of Fibrinogen liquid line, opening and the effect of liquid condensation flowing.
2. due to external slow release can be realized.Therefore, the biochemistry of thrombin is urged coagulation function to combine with the physical blockage effect of alginate hydrogel microsphere, what realize existing at certain pressure (60-150mmHg) closes and liquid condensation containing the pipe blocking of fibrinogenic working fluid, opening.
3. technique preparation process mild condition of the present invention, is easy to the bioactive maintenance of blood coagulation relevant enzyme.
4. the blood coagulation relevant enzyme embedding process of the present invention's employing, is directly embed into microsphere by blood coagulation relevant enzyme in alginate hydrogel microsphere preparation process, and the envelop rate of blood coagulation relevant enzyme is up to more than 90%, and the drug loading height after dewatering is to 25%-80%.
Accompanying drawing explanation
Accompanying drawing 1: the modeling of new zealand white rabbit renal artery and microsphere thromboembolism image;
A: normal kidney image;
B: image (red arrow is hemorrhage after being depicted as damage) after renal blood vessels damage modeling;
C: utilize image after microsphere thromboembolism damaged arteries, display stopped bleeding;
D: after thromboembolism, 10min checks angiography display without hemorrhage, and thrombin microsphere thromboembolism stops blooding successfully.
Detailed description of the invention
Embodiment 1
[1] sodium alginate soln (concentration 15g/L) is prepared;
[2] be dissolved into by thrombin (100mg) in sodium alginate soln prepared by step [1], concentration is 10g/L, obtains the sodium alginate soln containing thrombin;
[3] coagulation bath solution is prepared, containing calcium chloride (concentration 30g/L) in coagulation bath, sodium chloride (concentration 5g/L), sodium dihydrogen phosphate (concentration 1g/L), tween 5g/L;
[4] at high-pressure electrostatic after the match, the sodium alginate soln containing thrombin step [2] prepared forms uniform jet droplets, drop enters in the coagulation bath solution that step [3] prepares, there is gelation reaction, react and after 30 minutes, namely obtain the alginate hydrogel microsphere being embedded with thrombin, microspherulite diameter 500 ± 100 microns.
[5] the alginate hydrogel microsphere being embedded with thrombin prepared by step [4], film formation reaction is carried out 10 minutes with under chitosan solution (concentration 5g/L) room temperature, brine 3 times, namely obtains the alginate-chitosan microball being embedded with thrombin.
[6] prepare fibrinogen solution: get Fibrinogen, add 0.9% sodium chloride solution and be prepared into solution containing 1g/L.
[7] prepare one-to-two, the pipeline of three grades of branches of two point four by micro-processing technology, afterbody forms long 1cm, diameter
4 parallel pipelines, line end is open, is connected with liquid storage tank, and by peristaltic pump by one-level pipeline application of sample entrance in liquid storage tank liquid again blowback three grades of branching pipe roads, formation closed circuit.The fibrinogen solution that step [6] is prepared is placed in liquid storage tank, namely under peristaltic pump effect, with the flow speed stability of 10ml/s by three grades of flow lines.
[8] alginate-chitosan microball being embedded with thrombin step [5] prepared imports three grades of flow line afterbody distance opening 5mm places by capillary vessel (internal diameter is 1mm), 0.2ml microsphere is put in flow line, take out conduit, namely plasma fluid is there is and solidifies in the conduit finding to be placed with microsphere after 30 seconds, and do not place the pipeline of microsphere, still keep normal flow regime.
Comparative example 1
[1] prepare fibrinogen solution: get Fibrinogen, add 0.9% sodium chloride solution and be prepared into solution containing 1g/L.
[2] three grades of identical branching pipe roads are processed into embodiment 1 same procedure.
[3] thrombin solution with embodiment 1 equivalent is imported three grades of flow line afterbody distance opening 5mm places by capillary vessel (internal diameter is 1mm), take out conduit, after finding for 30 seconds all there is not Hirschfeld-Klinger reaction in each conduit, still normal flow regime is kept, after 5 minutes, at the solidification phenomenon of reservoir generating portion fluid.
Comparative example 2
[1] three grades of identical branching pipe roads are processed into embodiment 1 same procedure.
[2] the blank sodium alginate-chitosan microsphere identical with embodiment 1 particle diameter is imported three grades of flow line afterbody distance opening 5mm places by capillary vessel (internal diameter is 1mm), 0.2ml microsphere is put in flow line, take out conduit, find that namely microsphere is gone out in liquid storage tank by the liquid flowed in the catheter very soon, and do not place the pipeline of microsphere, also still keep normal flow regime.
Embodiment 2
[1] sodium alginate soln (concentration 20g/L) is prepared;
[2] be dissolved into by thrombin (50mg) in sodium alginate soln prepared by step [1], concentration is 10g/L, obtains the sodium alginate soln containing thrombin;
[3] coagulation bath solution is prepared, containing barium chloride (concentration 20g/L) in coagulation bath, sodium chloride (concentration 1g/L), sodium dihydrogen phosphate (concentration 1g/L), tween 10g/L;
[4] at high-pressure electrostatic after the match, the sodium alginate soln containing thrombin step 2 prepared forms uniform jet droplets, drop enters in the coagulation bath solution that step [3] prepares, there is gelation reaction, react and after 30 minutes, namely obtain the alginate hydrogel microsphere being embedded with hemocoagulase, microspherulite diameter 300 ± 100 microns.
[5] the alginate hydrogel microsphere being embedded with thrombin prepared by step [4], film formation reaction is carried out 10 minutes with under polylysin solution (concentration 0.5g/L) room temperature, brine 3 times, namely obtains the alginate-polylysine microsphere being embedded with hemocoagulase.
[6] accurately measure the sodium alginate-polylysine microsphere containing thrombin weigh (0.543g) prepared by 0.5ml step [5], microsphere is immersed the test tube that 10ml0.9% normal saline solution is housed.Test tube is placed in 37 DEG C of shaking tables, rotating speed is 50rpm.From test tube, 0.5ml sample solution is taken out respectively, 4 DEG C of preservations at the interval point (1h, 12h, 24h, 38h, 48h, 60h, 72h) preset; Fresh 0.9% normal saline solution of 0.5ml of equivalent is in vitro added after every sub-sampling.
[7] according to the titration method of the thrombin lyophilized powder in Chinese Pharmacopoeia 2010 editions two, draw presetting period-thrombin activity unit norm curve.
[8] get internal diameter 1cm, long 10cm test tube some, add fibrinogen solution 0.9ml respectively, put in 37 DEG C of water-baths and be incubated 5 minutes, measure the testing sample solution 0.1ml that step [6] is preserved, add rapidly in each test tube, timing immediately, to shake up in juxtaposition 37 DEG C of water-baths, observe the fibrinous presetting period.According to step [7] presetting period-thrombin activity unit norm curve, calculate the thrombin activity unit in variant time point sample.Result shows, and in the dispose procedure of 72h, thrombin activity still remains on more than 20u/ml.
Embodiment 3
[1] the alginate hydrogel microsphere of thrombin is embedded with according to step [1-4] preparation of embodiment 1.
[2] animal model prepares: new zealand white rabbit, intraperitoneal injection of anesthesia, groin preserved skin, implants arterial sheath, uses angiography catheter to arrive renal artery branch (target artery) through femoral artery, ventral aorta.
[3] open abdomen and expose kidney, make hemorrhage damage model.
[4] alginate microsphere (thrombin alginate microsphere: contrast agent: 0.9% normal saline=1:1:1) being embedded with thrombin is slowly injected after angiography catheter being sent to the thromboembolism site of injured blood vessel proximal part.
[5] observe the bleeding change of kidney injury region after thromboembolism, to find after thromboembolism 5 second stopped bleeding, until stopping blooding completely and confirming to withdraw from conduit after the success of injured blood vessel thromboembolism, extract arterial sheath, ligation femoral artery through radiography.Utilize image display stopped bleeding after microsphere thromboembolism damaged arteries, and after thromboembolism, 10min checks angiography display without hemorrhage, thrombin microsphere thromboembolism stops blooding successfully (see accompanying drawing 1).
[6] kidney is taken out after putting to death animal, make renal tissue sections observation, find that thrombin microsphere mainly concentrates on the nearly section of the initial position of renal artery branch (namely drafting thromboembolism site), can see after amplifying the mixed thrombus sectioning image formed, thrombosis composition includes the microsphere, hemocyte and the fibrin that are interweaved together.
Claims (10)
1. be embedded with an application for the hydrogel microsphere of blood coagulation relevant enzyme, it is characterized in that: be loaded with the hydrogel microsphere of blood coagulation relevant enzyme for one of following three kinds of situations or more than two kinds;
A, pipe blocking containing fibrin primary liquid flow process in pipeline;
Or, B, containing fibrin primary liquid in pipeline one of flow process or two close with upper pipeline opening;
Or, C, condensation containing fibrin primary liquid.
2., according to application according to claim 1, it is characterized in that:
The main component of described hydrogel microsphere is alginate material, microspherulite diameter 100-1000 micron, uniform particle diameter (CV<20%), the mass ratio 1:3-4:1 of blood coagulation relevant enzyme and sodium alginate in Sodium Alginate Hydrogel Films microsphere containing blood coagulation relevant enzyme, after dewatering, the drug loading of blood coagulation relevant enzyme is at 25%-80%.
3. according to application according to claim 1, it is characterized in that: describedly comprise in vitro blood or blood plasma containing fibrinogenic liquid.
4., according to the application described in claim 1,2 or 3, it is characterized in that: described flowing close containing the pipe blocking of Fibrinogen liquid line, opening or liquid condensation comprises the synergy of physical-chemical;
Wherein, physical action is strengthened blocking sealing process after comprising the mechanical blockage of microsphere and the rapid imbibition of hydrogel; Chemical action refers to that blood coagulation relevant enzyme acts on the obstruction brought after Fibrinogen initiation liquid solidifies and closes and condensation effects.
5. according to the application described in claim 1,2 or 3, it is characterized in that: described hydrogel microsphere is particularly useful for one of the situation of closing containing the pipe blocking of fibrinogenic working fluid, pipeline opening of existing of certain pressure (60-150mmHg) or liquid condensation or more than two kinds.
6. according to the application described in claim 1 or 2, it is characterized in that: the blood coagulation relevant enzyme in described hydrogel microsphere, comprise in thrombin or hemocoagulase one or both.
7. according to the application described in claim 1 or 2, it is characterized in that: in described alginate hydrogel microsphere, alginate molecular weight 10kDa-2000kDa, described alginate comprises one in alginic acid calcium salt or alginic acid barium salt or two kinds, the one that also can comprise simultaneously or not comprise in alginic acid sodium salt or potassium salt or two kinds.
8. according to application according to claim 1, it is characterized in that: the preparation method of described hydrogel microsphere comprises the steps:
A, compound concentration 10-30g/L sodium alginate soln;
B, blood coagulation relevant enzyme to be dissolved in sodium alginate soln prepared by steps A, the concentration of blood coagulation relevant enzyme is 10-40g/L, obtains the sodium alginate soln containing blood coagulation relevant enzyme;
C, preparation coagulation bath aqueous solution, containing one or both of total concentration 5-30g/L calcium chloride or barium chloride in coagulation bath, coagulation bath aqueous solution is also containing the one in total concentration 1-20g/L sodium chloride or potassium chloride or two kinds; Coagulation bath aqueous solution is also containing one or two or more kinds in total concentration 0.5-20g/L sodium citrate or sodium phosphate or sodium hydrogen phosphate or sodium dihydrogen phosphate; Coagulation bath aqueous solution is also containing the one in total concentration 1-30g/L tween or F68 or two kinds;
D, at high-pressure electrostatic after the match, the sodium alginate soln containing blood coagulation relevant enzyme prepared by step B forms uniform jet droplets, drop enters in the coagulation bath solution of step C preparation, gelation reaction occurs, must be embedded with the alginate hydrogel microsphere of blood coagulation relevant enzyme.
9. according to the application described in claim 1 or 8, it is characterized in that: described in be embedded with blood coagulation relevant enzyme alginate hydrogel microsphere can further with said polycation solution cross-linking reaction, polyelectrolyte complex film is formed at microsphere surface, form the alginate-polycation microsphere being embedded with blood coagulation relevant enzyme, concrete steps are:
1) the alginate hydrogel microsphere being embedded with blood coagulation relevant enzyme is put in said polycation solution, the volume ratio of microsphere and said polycation solution is 1:2-1:10, rotate concussion, allow microsphere be in even suspension state in the solution, carry out polyelectrolyte complex reaction 2-60 minute;
2) microsphere is separated with polycation reactant liquor, collects microsphere, namely obtains the alginate-polycation microsphere being embedded with blood coagulation relevant enzyme after normal saline cleaning;
Wherein, polycation comprises Chitosan-phospholipid complex, α or ε polylysine, poly ornithine, poly arginine, polyamine and derivant, polyamide and derivant thereof, polyimides and derivant thereof, and one or two or more kinds in the copolymer of above-mentioned any or more than two kinds polycations, the molecular weight of polycation molecules at 1kDa-500kDa, said polycation solution concentration 0.2-20g/L.
10., according to application according to claim 1, it is characterized in that: described in be embedded with blood coagulation relevant enzyme hydrogel microsphere according to application demand, the slow controlled release of blood coagulation relevant enzyme at applied environment can be realized.
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