CN104861177B - Hydrogel material with thrombin-responsive thrombolysis capacity and preparation method thereof - Google Patents
Hydrogel material with thrombin-responsive thrombolysis capacity and preparation method thereof Download PDFInfo
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- CN104861177B CN104861177B CN201510204456.4A CN201510204456A CN104861177B CN 104861177 B CN104861177 B CN 104861177B CN 201510204456 A CN201510204456 A CN 201510204456A CN 104861177 B CN104861177 B CN 104861177B
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 34
- 230000002537 thrombolytic effect Effects 0.000 title claims abstract description 33
- 239000000463 material Substances 0.000 title claims abstract description 29
- 108090000190 Thrombin Proteins 0.000 title claims abstract description 19
- 229960004072 thrombin Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 102000009123 Fibrin Human genes 0.000 claims description 37
- 108010073385 Fibrin Proteins 0.000 claims description 37
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 claims description 37
- 229950003499 fibrin Drugs 0.000 claims description 37
- 230000000694 effects Effects 0.000 claims description 24
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 18
- 229920001184 polypeptide Polymers 0.000 claims description 17
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 17
- 239000003431 cross linking reagent Substances 0.000 claims description 15
- 238000004132 cross linking Methods 0.000 claims description 13
- 230000004044 response Effects 0.000 claims description 13
- 239000000758 substrate Substances 0.000 claims description 13
- 239000000178 monomer Substances 0.000 claims description 11
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000003999 initiator Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 238000010526 radical polymerization reaction Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 239000008363 phosphate buffer Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- -1 aliphatic diamine Chemical class 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- 239000012190 activator Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 abstract description 13
- 210000004369 blood Anatomy 0.000 abstract description 3
- 239000008280 blood Substances 0.000 abstract description 3
- 230000007774 longterm Effects 0.000 abstract description 2
- 230000004043 responsiveness Effects 0.000 abstract 2
- 230000007547 defect Effects 0.000 abstract 1
- 230000015271 coagulation Effects 0.000 description 6
- 238000005345 coagulation Methods 0.000 description 6
- 230000002785 anti-thrombosis Effects 0.000 description 5
- 239000003146 anticoagulant agent Substances 0.000 description 5
- 102100033571 Tissue-type plasminogen activator Human genes 0.000 description 4
- 108050006955 Tissue-type plasminogen activator Proteins 0.000 description 4
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical group [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical group CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 3
- 102000019400 Tissue-type plasminogen activator Human genes 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011435 rock Substances 0.000 description 2
- 229960000103 thrombolytic agent Drugs 0.000 description 2
- 108091023037 Aptamer Proteins 0.000 description 1
- XUUXCWCKKCZEAW-YFKPBYRVSA-N Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](N)CCCN=C(N)N XUUXCWCKKCZEAW-YFKPBYRVSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 1
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 102000013566 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000003114 blood coagulation factor Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 210000005096 hematological system Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 230000001453 nonthrombogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention discloses a hydrogel material with thrombin-responsive thrombolysis capability and a preparation method thereof. The material has thrombolysis capacity with thrombin responsiveness (thrombus responsiveness), avoids the defect that a series of complications are caused by long-term exposure of active molecules in the traditional thrombolysis material, and has application prospect in the aspect of implanting blood contact materials into human bodies.
Description
Technical field
The present invention relates to biological medical polymer material and chemical field, and in particular to one kind has response molten
The material of bolt function with and preparation method thereof.
Background technology
Material triggers the generation of thrombus to be the one of the main reasons for causing human body to be implanted into blood contacting devices application failure, mesh
The preceding main approach for solving the problem is to introduce antithrombotic acitivity molecule in the material, such as heparin and plasminogen, and then
Realize dissolving of the material to the suppression of Coagulation test or to thrombus of coming into being.However, the long-term exposure of antithrombotic acitivity molecule is inevitable
The dysfunction of hematological system can be triggered, with serious complication, such as tissue bleeding.Preferable antithrombotic acitivity material should
With thrombus response, i.e., only start antithrombotic mechanism when Coagulation test occurs, this also more meets human body itself function point analysis
The operating mode of mechanism.
The generation of the adjoint significant fibrin ferment of generation of thrombus.The ii factor swashs during fibrin ferment reacts as coagulation cascade
Form living, is the shared product of different coagulation pathways, and its enzymolysis to fibrinogen promotes fibrin aggregation（Just
Level thrombus）Generation.In addition fibrin ferment can also feed back the clotting factor of activation coagulation cascade process upstream, cause Coagulation test
Autoacceleration.In a word, the generation of fibrin ferment is thrombotic key character event.
Fibrin ferment response performance is introduced in the design of some antithrombotic reagents and pharmaceutical carrier, is allowed medicament in thrombus
The position of generation plays a role.For example, S. Absar et al. white eggs thrombolytics surface is polypeptide grafted by thrombin substrate
In vain, so as to temporarily shelter its fibrinolytic, and activity can be discharged by the enzymolysis of polypeptide at the position that fibrin ferment is produced
Thrombolytics（Journal of Controlled Release, 177, 42-50, 2014).In another example M. A. Nakatsuka
Et al. be prepared for microbubble as fibrin ferment response acoustic contrast agent by the use of the aptamer of fibrin ferment for crosslinking points
（Biomaterials, 34, 9559-9565, 2013）.
The content of the invention
Instant invention overcomes the deficiencies in the prior art, fibrin ferment response performance is applied to the design of nonthrombogenic material.By
In the generation of the i.e. adjoint primary thrombus of the generation of fibrin ferment, therefore, fibrin ferment response is combined by we with thrombolysis activity, system
For the hydrogel material with thrombus response corroded rock mass.
To reach above-mentioned purpose, a kind of technical scheme that the present invention is used for：One kind has fibrin ferment response thrombolysis energy
The hydrogel material of power, it is characterised in that：Using organic molecule as monomer, using thrombin substrate polypeptide as crosslinking agent, pass through
Polymerization wraps up thrombolysis activity molecule while forming hydrogel, and the thrombolysis activity molecule is cut in fibrin ferment to crosslinking agent chemical bond
It can be fast released under disconnected effect.
In a preferred embodiment of the present invention, the chopping speed of the crosslinking points and the concentration positive correlation of fibrin ferment are described
Chopping speed positive correlation of the ratio between the amount of material of monomer and the crosslinking agent with the crosslinking points.
In a preferred embodiment of the present invention, the organic molecule monomer can be water soluble vinyl molecule monomer.
In a preferred embodiment of the present invention, the crosslinking agent is the thrombin substrate polypeptide of two terminal modified double bonds.
In a preferred embodiment of the present invention, the sequence of the thrombin substrate polypeptide is methacrylic acid-Gly-dPhe-
Pro-Arg-Gly-Phe-Pro-Ala-Gly-Gly-Lys (methacrylic acid)
In a preferred embodiment of the present invention, it can be tissue-type plasminogen activator that the thrombolysis activity molecule, which is,.
In a preferred embodiment of the present invention, the reaction condition of radical polymerization is pH=6 ~ 8,0 ~ 37 DEG C of temperature range.
In a preferred embodiment of the present invention, the reaction condition of radical polymerization is pH=7.4,25 DEG C of temperature range.
Another technical scheme that the present invention is used for：A kind of method prepared such as hydrogel material, it is characterised in that bag
Include following steps：By water-soluble vinyl monomer solution, the thrombin substrate polypeptide solution of two terminal modified double bonds, thrombolysis activity point
Son and the mixing of initiator system, carry out Raolical polymerizable.
In a preferred embodiment of the present invention, the water-soluble vinyl monomer solution is specially acrylamide solution.
In a preferred embodiment of the present invention, the initiator system is water-soluble redox system, the oxidant
For persulfate, the reducing agent is fatty amine or aliphatic diamine.
In a preferred embodiment of the present invention, the solution, the initiator and the bioactive molecule solution use phosphoric acid
Salt buffer is prepared.
In a preferred embodiment of the present invention, it can be tissue-type plasminogen activator that the thrombolysis activity molecule, which is,.
In a preferred embodiment of the present invention, in the redox system, the oxidant is ammonium persulfate, described to go back
Former agent is N, N, N ', N '-tetramethylethylenediamine.
In a preferred embodiment of the present invention, the Raolical polymerizable can also carry out following operation after terminating：Will
Reaction gained hydrogel cleans a period of time by phosphate buffer, produces.
Brief description of the drawings
Fig. 1 is t-PA release profiles of the hydrogel material in the presence of having fibrin ferment and athrombia；
Fig. 2 is thrombolysis power curve of the hydrogel material in the presence of having fibrin ferment and athrombia；
Thrombolysis activity molecule release rate curve of the hydrogel of Fig. 3 difference degrees of cross linking in 20U/mL concentration fibrin ferments；
Thrombolysis activity molecule release rate curve of Fig. 4 hydrogels in various concentrations fibrin ferment；
Fig. 5 thrombolysis activities molecule discharges the relation curve of Mean Speed and concentration of thrombin.
Embodiment
Presently in connection with drawings and examples, the present invention is further detailed explanation.
The technical problems to be solved by the invention are：A kind of water-setting glue material with fibrin ferment response thrombolysis ability is provided
Material and preparation method thereof.The hydrogel can occur to degrade and discharge molten when in the presence of fibrin ferment being thrombus generation
Thrombus activity molecule, realizes the dissolving to thrombus.
As Figure 1-5：
Fibrin ferment causes the mechanism of blood coagulation to be just turned off soluble fibrinogen in vivo（That is Fg albumen）Arg-
Gly keys（Key i.e. between arginine and glycine）By the insoluble fibrin of conversion.
Fibrin ferment cuts off crosslinking points（Chemical bond）The mechanism of action be：Peptide sequence used in the present invention for metering system-
Arg-Gly in the middle of Gly-dPhe-Pro-Arg-Gly-Phe-Pro-Ala-Gly-Gly-Lys (methacrylic acid), the polypeptide
Key can be by fibrin ferment digestion, so in the presence of fibrin ferment, crosslinking agent can be broken, cross-linked structure is destroyed, and then is released
Put thrombolysis activity molecule.
The regulation of the hydrogel degree of cross linking：The degree of cross linking is adjusted by changing the amount of addition crosslinking agent（I.e. crosslinking agent is being matched somebody with somebody
Concentration in solution processed）, cross-linked dosage is more, and the degree of cross linking is bigger, and the bigger gel protein rate of release of the degree of cross linking is slower.
Concentration of thrombin is higher, and thrombolysis activity molecule is faster from the rate of release in hydrogel.
The present invention realizes its function by following proposal：
Vinyl monomer, thrombin substrate polypeptide crosslinking agent, thrombolysis activity molecule, catalyst system and catalyzing are mixed, by freedom
Base polymerisation, obtains being enclosed with the hydrogel of thrombolysis activity molecule.The crosslinking agent of the hydrogel --- thrombin substrate polypeptide,
Polypeptide is long chain, and its chemical bond can be broken in the presence of fibrin ferment, so that hydrogel is degraded and discharged
Thrombolysis activity molecule.
Compared with prior art, the characteristics of present invention has following prominent：
1. using thrombin substrate polypeptide as crosslinking agent, hydrogel is prepared by radical polymerization, hydrogel is in fibrin ferment
Effect is lower to degrade.
2. hydrogel contains thrombolysis activity molecule, the molecule is only released in the presence of fibrin ferment, and then dissolves blood
Bolt.
The method that what the present invention was provided prepare fibrin ferment response thrombolysis material, is using water soluble vinyl molecule to be single
Body, the thrombin substrate polypeptide using two terminal modified double bonds forms hydrogel as crosslinking agent by radical polymerization.
With reference to instantiation, the invention will be further described, but does not limit the present invention.
Embodiment 1
It is the polypeptide that 150 mg/mL acrylamide solution, 5 μ L concentration are 50mg/mL by 25 μ L concentration（Sequence is methyl
Acrylic acid-Gly-dPhe-Pro-Arg-Gly-Phe-Pro-Ala-Gly-Gly-Lys (methacrylic acid)）Solution, 2.5 μ L are dense
Spend for 1 mg/mL tissue-type plasminogen activator（t-PA）Solution, 0.5 μ L N, N, N ', N '-tetramethylethylenediamine
（TEMED）, and the ammonium persulfate solution that 2 μ L concentration are 500 mg/mL（Solution uses the phosphate buffer of PH=7.4
（PBS）Prepare）Mixing, in carrying out after Raolical polymerizable, 20 min cleaning gained soak into PBS at 25 DEG C
3h, that is, obtain the hydrogel material of fibrin ferment response corroded rock mass.
The process that hydrogel discharges t-PA in the presence of fibrin ferment is tested by isotope-labelling method.As shown in figure 1,
T-PA can significantly be discharged only in the presence of fibrin ferment, and rate of release can be adjusted by changing the degree of cross linking.
Solution after release is tested for blood plasma thrombolysis, as shown in Fig. 2 occurring to degrade and discharge only under thrombin action
Going out t-PA hydrogel can again be dissolved after thrombus generation.
In wherein Fig. 3, the degree of cross linking magnitude relationship of hydrogel is：A>B>C>D；
Fig. 5 is drawn in Fig. 4 data basis.
The desirable embodiment according to the present invention is enlightenment above, by above-mentioned description, and related personnel completely can be with
Without departing from the scope of the technological thought of the present invention', various changes and amendments are carried out.The technical scope of this invention
It is not limited to the content on specification, it is necessary to determine the technical scope according to the scope of the claims.
Claims (9)
1. a kind of hydrogel material with fibrin ferment response thrombolysis ability, it is characterised in that：With water soluble vinyl molecule
As monomer, using thrombin substrate polypeptide as crosslinking agent, thrombolysis activity is wrapped up while by polymerisation formation hydrogel
Molecule, the thrombolysis activity molecule can be fast released under cutting action of the fibrin ferment to crosslinking agent chemical bond.
2. hydrogel material according to claim 1, it is characterised in that：The chopping speeds of the crosslinking points and fibrin ferment
Chopping speed positive correlation of the ratio between the amount of material of concentration positive correlation, the monomer and the crosslinking agent with the crosslinking points.
3. hydrogel material according to claim 1 or 2, it is characterised in that：The crosslinking agent is two terminal modified double bonds
Thrombin substrate polypeptide.
4. hydrogel material according to claim 1 or 2, it is characterised in that：The thrombolysis activity molecule is that tectotype is fine
Dissolved preferment activator.
5. hydrogel material according to claim 1, it is characterised in that：The polymerisation is Raolical polymerizable,
The reaction condition of the radical polymerization is pH=6~8,0~37 DEG C of temperature range.
6. a kind of method for preparing hydrogel material as claimed in claim 1, it is characterised in that comprise the following steps：Will be water-soluble
Sex ethylene base monomer solution, the thrombin substrate polypeptide solution of two terminal modified double bonds, thrombolysis activity molecular solution and initiator
System is mixed, and carries out Raolical polymerizable.
7. preparation method according to claim 6, it is characterised in that：The initiator system is water soluble, redox body
System, wherein oxidant are persulfate, and reducing agent is fatty amine or aliphatic diamine.
8. preparation method according to claim 6, it is characterised in that：The water-soluble vinyl monomer solution, described two
The thrombin substrate polypeptide solution of terminal modified double bond, the initiator system and the thrombolysis activity molecular solution use phosphate
Buffer.
9. preparation method according to claim 6, it is characterised in that：The Raolical polymerizable also needed to after terminating into
Row is following to be operated：Reaction gained hydrogel is cleaned into a period of time by phosphate buffer, produced.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107519543B (en) * | 2017-08-22 | 2020-10-30 | 苏州大学 | Fibrinolytic coating with thrombin responsiveness and application thereof |
| WO2022021363A1 (en) * | 2020-07-31 | 2022-02-03 | 苏州大学 | Coating composition, hydrogel coating and preparation method therefor, and coated product |
| CN111870698B (en) * | 2020-08-26 | 2022-03-11 | 中国药科大学 | Thrombin-responsive network polymers and uses thereof |
| CN114099694B (en) * | 2021-11-25 | 2022-05-13 | 南京邮电大学 | Thrombin-responsive DNA nano machine and preparation method and application thereof |
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| CN101583348A (en) * | 2006-10-13 | 2009-11-18 | 梅达佛股份有限公司 | Formation of medically useful gels comprising microporous particles and methods of use |
| CN101629162A (en) * | 2009-08-26 | 2010-01-20 | 暨南大学 | Cell sheet engineering and preparation method thereof |
| CN102124346A (en) * | 2008-07-16 | 2011-07-13 | 雷迪奥米特医学公司 | Thrombin substrate and assay for determining the level of bioactive thrombin in a sample |
| CN103037845A (en) * | 2010-06-01 | 2013-04-10 | 巴克斯特国际公司 | Process for making dry and stable hemostatic compositions |
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2015
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101583348A (en) * | 2006-10-13 | 2009-11-18 | 梅达佛股份有限公司 | Formation of medically useful gels comprising microporous particles and methods of use |
| CN102124346A (en) * | 2008-07-16 | 2011-07-13 | 雷迪奥米特医学公司 | Thrombin substrate and assay for determining the level of bioactive thrombin in a sample |
| CN101629162A (en) * | 2009-08-26 | 2010-01-20 | 暨南大学 | Cell sheet engineering and preparation method thereof |
| CN103037845A (en) * | 2010-06-01 | 2013-04-10 | 巴克斯特国际公司 | Process for making dry and stable hemostatic compositions |
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