CN101618236A - Injectable myocardial tissue engineering product used for treating myocardial infarction - Google Patents
Injectable myocardial tissue engineering product used for treating myocardial infarction Download PDFInfo
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Abstract
The invention discloses an injectable myocardial tissue engineering product used for treating myocardial infarction, in particular, the product applies OPF hydrogel as a scaffold and carries one or more different angiogenic growth factors such as bFGF, PDGF-BB, VEGF and the like, and the repair effect of the product on myocardial infarction regions is observed after the product is injected and transplanted into the certain regions of an animal myocardial infarction model. The product built by the scaffold can promote generation of myocardial capillary and arteriola, enhance generation of myofibroblast, promote regeneration of the myocardial tissues, increase the ventricular wall thickness of the infarction regions, reshape the original ventricle and improve the cardiac function. The invention is simple in operating process and mild in implementation conditions, provides a new product for the myocardial tissue engineering and is of great significance in the development of clinically treating heart diseases by tissue-engineered myocardium.
Description
Technical field
The invention belongs to organizational project and regenerative medicine field, relate to a kind of cardiac muscle tissue engineering products based on OPF hydrogel and angiogenic growth factor, particularly relating to a kind of is that carrier carries gelatin corpuscle that loads angiogenic growth factor and the product that can be used for treating myocardial infarction with low Polyethylene Glycol fumarate (OPF) hydrogel.
Background of invention
The coronary artery disease that causes of atherosclerosis is the main cause of M ﹠ M in the world, wherein takes place the most serious with heart infarction.Although people are obtaining remarkable progress aspect the heart infarction treatment, myocardial cell can not regeneration behind the heart infarction, the infringement of left ventricular remodeling and cardiac function remains the main cause of heart failure.
Angiogenic growth factor comprises family and their hypotypes such as VEGF, FGF, PDGF, promotes angiogenesis by specific receptor.VEGF mainly acts on endotheliocyte.BFGF is the strong regulator gene of hyperplasia, vigor, differentiation and survival, comprises that in conciliation the growth of the target cell of endotheliocyte has great role.BFGF selects vasostimulant generation in vivo.PDFG mainly acts on the perivascular cell that comprises pericyte and vascular smooth muscle cell, and PDGF-BB plays stable rebirth blood vessel function.
Angiogenic growth factor can promote to be in the tissue regeneration of the different phase of hyperplasia and differentiation, promote the generation of blood vessel, thereby reparation and regeneration to damage location have great role, but this effect does not always reach in vivo, to be somatomedin have the very short half-life and spread faster and can not keep its biological activity at body one of its reason, therefore, must solve somatomedin slow release problem in vivo to strengthen its effect.
Based on material make angiogenic growth factor in vivo the method for slow release be a kind of very promising method.The previous research various carriers of report such as gelatin hydrogel, fibrin hydrogel and Matrigel etc. carry angiogenic growth factor and are applied to the ischemia body and promote the ischemia local vascular to generate and improve the ischemia local function cut much ice.
Low Polyethylene Glycol fumarate (oligo (poly (ethylene glycol) fumarate) hydrogels (OPF)) is a kind of novel biomaterial with good biocompatibility and biodegradable ability.OPF is the big monomer of a kind of water solublity, alternately is made up of Polyethylene Glycol and fumarate, has good hydrophilic.The OPF hydrogel can carry multiple different biomolecule, is a kind of good syringeability carrier.The delivery vector that has research report, OPF hydrogel can be used as bioactie agent promotes the regeneration of cartilage.The gelatin corpuscle toleration in the OPF hydrogel that contains TGF-β 1 is good, in 14 all rabbits, shows fabulous osteochondral defect repairing effect.In other experiments, the gelatin corpuscle in the OPF hydrogel has loaded more than a kind of somatomedin and has kept spatiotemporal sustained release.The gelatin corpuscle effect of oppositely charged in charged bioactive molecule and the OPF hydrogel, the main mechanism that bioactive molecule discharges are that gelatin corpuscle is degraded by the excretory enzyme of peripheral cell, make and finish required local delivery in repair process.12 weeks of postoperative, observe the degraded fully of OPF at Os Leporis seu Oryctolagi cartilage defect position, the more simple OPF hydrogel of OPF hydrogel that carries insulin-like growth factor I GF-1 has better bone repair of cartilage effect.At present the OPF hydrogel is mainly used in cartilage and bone tissue engineer, but with it as bio-carrier, the product that carries the growth factor for treating heart infarction does not appear in the newspapers so far as yet.
Summary of the invention
This product adopts the OPF hydrogel to carry the gelatin substrate that loads angiogenic growth factor as bio-carrier first and makes up syringeability organizational project cardiac muscle product, it is expelled in the dancing heart ischemic injuries cardiac muscle, slowly discharge in vivo to reach angiogenic growth factor, and keep better biological activity, promote heart infarction position capillary network and arteriolar generation, and promote into myofibrillar generation, improve the blood flow of ischemic tissue, repair large tracts of land heart infarction cicatrix and improve the purpose of cardiac function.
Therefore, first goal of the invention of the present invention is for the heart infarction treatment provides a kind of new product, specifically, provides a kind of syringeability tissue engineering product of angiogenic growth factor.
In a specific embodiments, the hydrogel composites that described syringeability tissue engineering product is made up of angiogenic growth factor, gelatin corpuscle and OPF; Wherein, the angiogenic growth factor of charged gelatin corpuscle elder generation and oppositely charged forms ionic complex, and then is cross-linked to form injectable OPF hydrogel with OPF, thereby after making the OPF hydrogel be injected in the body, is condensed into solid-state in the short time.Gelatin corpuscle can be alkaline gelatin corpuscle or acid gelatin corpuscle.
In another embodiment, angiogenic growth factor can be existing any angiogenic growth factor, for example, comprises all angiogenic growth factors of FGF, VGEF, PDGF.Wherein, FGF comprises aFGF, bFGF etc. in interior FGF family; VEGF is the VEGF family that comprises VEGF-A, VEGF-B etc.; PDGF comprises the PDGF family of PDFG-AA, PDGF-AB, PDGF-BB etc.Also in another embodiment, both can use single angiogenic growth factor and gelatin corpuscle and OPF to prepare the syringeability tissue engineering product, and also can unite and use above-mentioned two or more angiogenic growth factors arbitrarily to prepare the syringeability tissue engineering product with gelatin corpuscle and OPF.
Second goal of the invention of the present invention provides the method for the syringeability tissue engineering product of the above-mentioned angiogenic growth factor of preparation, comprising:
(1) gelatin corpuscle packing angiogenic growth factor
To be immersed in pH be in 7.4 the angiogenic growth factor solution and hatched under 4 ℃ 15 hours with gelatin corpuscle, and under this pH, electrically charged gelatin can form ionic complex with the angiogenic growth factor of oppositely charged;
(2) OPF and ionic complex are cross-linked to form hydrogel
OPF and cross-linking agent Polyethylene Glycol-diacrylate (PEG-DA) weight ratio with 2: 1 is mixed in the PBS buffer, and mix with the PBS that contains the gelatin corpuscle that has loaded angiogenic growth factor, after adding the gentle mixing of heat radical initiator, form the syringeability OPF hydrogel that can be used for treating myocardial infarction.
Should be understood that, the concrete injection rate of angiogenic growth factor should be decided according to different animals kind and its myocardial infarction damaged area size, in view of different manufacturers with the source angiogenic growth factor purity different with effectiveness, the Different Individual case is different with sensitivity to the dependency of medicine, and the injection rate of angiogenic growth factor should according to circumstances be decided.Among the present invention, the scope of selecting for use usually is 250ng-50 μ g.
In the specific embodiments of a step (2), OPF and cross-linking agent Polyethylene Glycol-diacrylate (PEG-DA) weight ratio with 2: 1 is mixed among the 300 μ lPBS, and mixes with PBS that 100 μ l contain the gelatin corpuscle that has loaded one or more angiogenic growth factors of 250ng-50 μ g.The heat radical initiator that adds isopyknic (50 μ l), i.e. 25mM Ammonium persulfate. (APS) and 25mMN, N, N ', the PBS solution of N '-tetramethylethylenediamine (TEMED).Behind the gentle mixing, what be liquid state treats the heart infarction product based on OPF hydrogel and angiogenic growth factor.Suspension is expelled to the heart infarction position can becomes glue in 5-10 minute.
In the specific embodiments of another step (2), the gelatin corpuscle and the OPF that load one or more angiogenic growth factors is crosslinked, form hydrogel; The heat radical initiator is 25mM Ammonium persulfate. (APS) and 25mMN, N, N ', the PBS solution of N '-tetramethylethylenediamine (TEMED).
In addition, in the specific embodiments of a step (1), if a. angiogenic growth factor is that isoelectric point, IP is that 9.6 bFGF, isoelectric point, IP are that 8.5 VEGF or isoelectric point, IP are 9.8 PDGF, be that 5.0 acid gelatin is made electronegative gelatin corpuscle then with isoelectric point, IP; Perhaps, b. then is 9.0 the positively charged gelatin corpuscle of alkaline gelatin making with isoelectric point, IP if angiogenic growth factor is an isoelectric point, IP is 5.6 aFGF; Perhaps c. is if other charged angiogenic growth factor, then according to the acid gelatin or the alkaline gelatin of the corresponding zone of preference opposite charges of its isoelectric point, IP.
Should be understood that, OPF (low Polyethylene Glycol fumarate, oligo (poly (ethylene glycol) fumarate) hydrogels) and gelatin corpuscle be a kind of novel biomaterial with good biocompatibility and biodegradable ability, their preparation method (has for example extensively obtained report, Seongbong Jo, Heungsoo Shin, Antonios G.Mikos.Synthesis andCharacterization of Oligo (poly (ethylene glycol) fumarate) Macromer.Macromolecules 2001,34,2839-2844).Therefore, the present invention both can use prior preparation method, also can use following preparation method:
(1) preparation of OPF
By Polyethylene Glycol (PEG), fumaryl chloride and triethylamine (mol ratio 1: 0.9: 0.9) one-step method prepared in reaction.Behind the azeotropic distillation, PEG is dissolved in dichloromethane and fumaryl chloride and triethylamine and is dropwise added in several hrs, and reaction flask maintains 0 ℃ simultaneously.Stir 1-2 days then under the room temperature to guarantee maximum conversion.
For the purification oligomer, remove by rotary evaporation and to desolvate, afterwards lysate in ethyl acetate.Solution removes by filter the salt that chloride ion and triethylamine generate in the reaction, oligomer twice in recrystallization in ethyl acetate.Last pure OPF is precipitated out in ether, and vacuum drying (＜1mmHg) obtain powder solid.
The OPF of purification is stored in-20 ℃ and sterilize by being exposed in the oxirane 16 hours before use.
(2) gelatin corpuscle preparation
Gelatin corpuscle is selected to be prepared by acid gelatin or alkaline gelatin according to the isoelectric point, IP of the angiogenic growth factor that its needs load, and its product is respectively the acid gelatin corpuscle of isoelectric point, IP 5.0 or 9.0 alkaline gelatin corpuscle.Specifically, the 5g gelatin is dissolved in 45ml60 ℃ the middle preparation of distillation deionized water (ddH2O) gel solution.To stir in the gelatin solution olive oil that joins the 250ml pre-cooling dropwise and with 500rpm then.After 30 minutes, the acetone (4 ℃) of 100ml pre-cooling is joined in the emulsion.After 60 minutes, the filtered and recycled microsphere is also used acetone rinsing.These gelatin corpuscles carry out crosslinkedly in 0.1wt%Tween 80 solution that added 10mM glutaraldehyde (GA) afterwards, and in 15 ℃, 500rpm stirs down.After 15 hours, the gelatin corpuscle that filtered and recycled is crosslinked made the GA inactivation that does not have reaction in 1 hour with after the ddH2O flushing its stirring being joined in the 25mM glycine solution.These gelatin corpuscles of filtered and recycled, with the ddH2O flushing, lyophilized is spent the night afterwards.At last, the gelatin corpuscle of drying is crossed screen cloth and is obtained the granule of diameter 50-100mm and sterilize by being exposed in the oxirane 16 hours.
The 3rd goal of the invention of the present invention provides described syringeability tissue engineering product, or the product of described method preparation, is used to the purposes of the medicine of preparation treatment treatment myocardial infarction.Wherein, myocardial infarction is an acute myocardial infarction, or old myocardial infarction.
Beneficial effect
This product, carries the gelatin corpuscle that has loaded one or more angiogenic growth factors and carries out the site of myocardial infarction injection for curing as bio-carrier with the OPF hydrogel.In vivo, angiogenic growth factor can slowly discharge along with the degraded of gelatin corpuscle and OPF, thereby efficiently solve it in vivo because of spreading too fast and the too fast problems such as activity reduction that cause of degraded, promoted the vascularization of heart infarction district, increasing blood supplies, increase ventricle wall volume and infarcted region chamber wall thickness, reinvent original ventricle shape, improve cardiac function.This product has the feature of syringeability, and invasive is little, has directionality, is convenient to the treatment operation, can avoid the risks that operation brought such as cardiac arrest, extracorporeal circulation.Operating procedure of the present invention is simple, implementation condition is gentle, for cardiac muscle tissue engineering provides a kind of new product, engineered cardiac muscle treatment cardiac disorder clinical is carried out significant.
Description of drawings
Fig. 1. the OPF of solid powdery
The histocompatibility of Fig. 2 .OPF hydrogel detects (HE dyeing)
A.1 all, * 40; B.2 all, * 40; C.3 all, * 40; D.4 all, * 40;
Fig. 3. carry the OPF hydrogel of the gelatin corpuscle that loads angiogenic growth factor
Fig. 4. rat heart infarction Preparation of model
A. rat coronary artery anterior descending branch ligation;
B. electrocardio diagram ST section is raised the formation of prompting heart infarction;
Back infarction middle part ventricle wall thickness situation (HE dyeing) around injection of Fig. 5 .OPF hydrogel and the simple heart infarction
The injection of A.OPF hydrogel, * 4; B. simple heart infarction, * 4;
Fig. 6 .OPF gel carries gelatin corpuscle injection, the injection of OPF hydrogel and the infarction middle part angiogenesis situation (VIII factor immunohistochemical staining) after 4 weeks of having loaded angiogenic growth factor
The A.OPF gel carries the gelatin corpuscle injection of having loaded angiogenic growth factor, * 10; B.OPF hydrogel injection * 10;
C.PBS injection * 10;
The specific embodiment
Only further describe the present invention now with mode with reference to following non-restrictive example.But should be appreciated that the following examples only as illustration, should be by any way when doing the restriction overall to the invention described above.Unless other explanation is arranged, the traditional molecular biology in embodiments of the invention use this area, cytobiology, tissue engineering or the like.These technology are that the technical staff knows, and detailed explanation is arranged in the literature.Referring to, for example, Lanza, Langer and Vacanti " Principlesof Tissue Engineering " (2006); Atala and Lanza " Methods of Tissue Engineering " (2006).
The preparation of embodiment 1:OPF
With the 30g molecular weight is that 1000 Polyethylene Glycol is dissolved in the 250ml toluene, behind the azeotropic distillation, exsiccant Polyethylene Glycol is dissolved in the anhydrous dichloromethane of 250ml.In 5 hours fumaryl chloride (0.3mol) and triethylamine are dropwise joined in the polyglycol solution then, reaction flask maintains 0 ℃ simultaneously, stirs 1-2 days under the room temperature to guarantee maximum conversion.After the reaction, remove by rotary evaporation and to desolvate, afterwards lysate in the 500ml ethyl acetate.Solution removes by filter the salt that chloride ion and triethylamine generate in the reaction, oligomer twice in recrystallization in ethyl acetate.Last pure OPF is precipitated out in ether, and vacuum drying (＜1mmHg) obtain powder solid (Fig. 1).
The OPF of purification is stored in-20 ℃ and sterilize by being exposed in the oxirane 16 hours before use.
The histocompatibility of embodiment 2:OPF hydrogel detects
OPF hydrogel 0.1ml injection is implanted in the cardiac muscle of S-D rat, respectively at putting to death in 1,2,4 weeks, gets 2 at every turn, carries out paraffin section after the taking-up specimen, makes the situation that inflammatory reaction is observed in HE dyeing.The visible OPF hydrogel of postoperative 1 week section extensively is distributed in the cardiac muscular tissue gap, a little inflammatory cell that mixes (Fig. 2 A) therebetween; The visible OPF hydrogel of postoperative 2 week group is partly degraded, and has inflammatory cell infiltration (Fig. 2 B) on every side; 4 weeks of postoperative are organized and fail to see tangible OPF hydrogel, visible a small amount of inflammatory cell infiltration (Fig. 2 C).
Embodiment 3 carries the preparation of the OPF hydrogel of the gelatin corpuscle that loads angiogenic growth factor
To be immersed in pH be in 7.4 the angiogenic growth factor solution and hatched under 4 ℃ 15 hours with gelatin corpuscle, forms the ionic complex of gelatin and angiogenic growth factor.Subsequently, OPF and cross-linking agent Polyethylene Glycol-diacrylate (PEG-DA) are mixed among the 300 μ lPBS with the weight ratio of 2:1, and mix with PBS that 100 μ l contain the gelatin corpuscle that has loaded one or more angiogenic growth factors of 300ng.The heat radical initiator that adds isopyknic (50 μ l), i.e. 25mM Ammonium persulfate. (APS) and 25mMN, N, N ', the PBS solution of N '-tetramethylethylenediamine (TEMED).Behind the gentle mixing, promptly liquid treats heart infarction product (Fig. 3) based on OPF hydrogel and angiogenic growth factor.Suspension is expelled to the heart infarction position can becomes glue in 5-10 minute.
Embodiment 4: the selection of animal and the preparation of heart infarction
S-D rat (about 225-300g) is used in experiment, and pentobarbital sodium (40mg/kg body weight) carries out intraperitoneal anesthesia, is connected with animal trace respirator.The row thoracotomy is cut off pericardium, fully exposes heart.At left auricle lower edge 2mm place, prick with 0-7 silk thread seam.Left locular wall loses color after the ligation, and ventricular wall motion weakens (Fig. 4 A).Cardiac monitoring sees that the ST section that I, II lead obviously raises, and shows that coronary artery infarction animal model prepares successfully (Fig. 4 B).
The detection that the short cardiac structure of embodiment 5:OPF hydrogel improves
20 of S-D rats about 240g are divided into OPF hydrogel injection group, simple myocardial infarction model group at random.8 of picked at random S-D rats, male and female are not limit, pentobarbital sodium 35mg/kg body weight intraperitoneal injection of anesthesia.By the rat coronary artery ligation, cause myocardial infarction after 30 minutes, myocardial ischemia place injection OPF hydrogel.In 1,2,4 weeks of postoperative, put to death respectively and carry out histology, immunohistochemical detection.The experimental group that as seen result injects the OPF hydrogel has improved the ventricle wall thickness (Fig. 5) at heart infarction position than matched group, and the myocardium quantity of survival increases, and fibrosis alleviates, and the vessel density at infarction position increases.
Embodiment 6:OPF hydrogel carries somatomedin and promotes angiogenesis of cardiac muscle and improve the cardiac function detection
18 of S-D rats about 240g are divided at random the OPF hydrogel carries somatomedin injection group, PBS carries somatomedin injection group, PBS injection group.6 of picked at random S-D rats, male and female are not limit, pentobarbital sodium 35mg/kg body weight intraperitoneal injection of anesthesia.By the rat coronary artery ligation, cause myocardial infarction 30min after, somatomedin (as 1 μ g) OPF hydrogel is carried in myocardial ischemia place injection.Carry out the ultrasoundcardiogram monitoring after the injection two days later.In 4 weeks of postoperative, carry out putting to death animal after ultrasoundcardiogram and hemodynamics detect respectively and carry out histology, immunohistochemical detection.As seen the result injects experimental group that the OPF hydrogel carries somatomedin and obviously improves than the cardiac function of other two matched groups, heart infarction position ventricle wall thickness obviously improves, the vessel density at infarction position obviously increases (Fig. 6), and the myocardium quantity of survival increases, and fibrosis alleviates.
Claims (10)
1. a syringeability tissue engineering product that is used for the treatment of myocardial infarction is characterized in that the hydrogel composites that described product is made up of angiogenic growth factor, gelatin corpuscle and OPF; Wherein, the angiogenic growth factor of charged gelatin corpuscle elder generation and oppositely charged forms ionic complex, and then is cross-linked to form injectable OPF hydrogel with OPF, thereby after making the OPF hydrogel be injected in the body, is condensed into solid-state in the short time.
2. by the syringeability tissue engineering product described in the claim 1, wherein gelatin corpuscle is alkaline gelatin corpuscle or acid gelatin corpuscle.
3. by the syringeability tissue engineering product described in the claim 1, wherein angiogenic growth factor is selected from FGF, VGEF or PDGF, perhaps is selected from the combination in any among FGF, VGEF or the PDGF.
4. by the syringeability tissue engineering product described in the claim 3, wherein FGF comprises aFGF, bFGF etc. in interior FGF family; VEGF is the VEGF family that comprises VEGF-A, VEGF-B etc.; PDGF is the PDGF family that comprises PDFG-AA, PDGF-AB, PDGF-BB etc.
5. prepare the method for arbitrary described syringeability tissue engineering product among the claim 1-4, comprise step:
(1) gelatin corpuscle packing angiogenic growth factor
To be immersed in pH be in 7.4 the angiogenic growth factor solution and hatched under 4 ℃ 15 hours with gelatin corpuscle, and under this pH, electrically charged gelatin can form ionic complex with the angiogenic growth factor of oppositely charged;
(2) OPF and ionic complex are cross-linked to form hydrogel
OPF and cross-linking agent Polyethylene Glycol-diacrylate (PEG-DA) weight ratio with 2: 1 is mixed in the PBS buffer, and mix with the PBS that contains the gelatin corpuscle that has loaded angiogenic growth factor, after adding the gentle mixing of heat radical initiator, form the syringeability OPF hydrogel that can be used for treating myocardial infarction.
6. the described method of claim 5, wherein in step (2):
The gelatin corpuscle and the OPF that load one or more angiogenic growth factors is crosslinked, form hydrogel; The heat radical initiator is 25mM Ammonium persulfate. (APS) and 25mMN, N, N ', the PBS solution of N '-tetramethylethylenediamine (TEMED).
7. claim 5 or 6 described methods wherein add the angiogenic growth factor of 250ng-50 μ g.
8. claim 5 or 6 described methods, wherein in step (1):
If a. angiogenic growth factor is that isoelectric point, IP is that 9.6 bFGF, isoelectric point, IP are that 8.5 VEGF or isoelectric point, IP are 9.8 PDGF, be that 5.0 acid gelatin is made electronegative gelatin corpuscle then with isoelectric point, IP;
B. if angiogenic growth factor is an isoelectric point, IP is 5.6 aFGF, then be 9.0 the positively charged gelatin corpuscle of alkaline gelatin making with isoelectric point, IP;
C. if other charged angiogenic growth factor, then according to the acid gelatin or the alkaline gelatin of the corresponding zone of preference opposite charges of its isoelectric point, IP.
9. the product of the described method preparation of described product of claim 1-4 or claim 5-8 is used to prepare the purposes that the medicine of myocardial infarction is treated in treatment.
10. the described purposes of claim 9, wherein myocardial infarction is an acute myocardial infarction, or old myocardial infarction.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102038977A (en) * | 2010-11-29 | 2011-05-04 | 中国人民解放军军事医学科学院基础医学研究所 | Tissue engineered cardiac muscle using OPF (Oligo(Poly(Ethylene Glycol) Fumarate) hydrogel as a carrier and preparation method thereof |
| CN104189958A (en) * | 2014-08-25 | 2014-12-10 | 中国人民解放军总医院 | Method for preparing chitosan-silk fibroin composite nano-fiber multifunctional patch for promoting myocardial tissue regeneration and monitoring stem cells |
| WO2017177480A1 (en) * | 2016-04-15 | 2017-10-19 | 苏州大学张家港工业技术研究院 | Flexible substrate/liquid electrolyte viscous composite material and preparation method therefor |
| CN108066818A (en) * | 2016-11-17 | 2018-05-25 | 中国科学院大连化学物理研究所 | A kind of bionical double-layer sustained release growth factor film and its preparation and application |
| CN111040205A (en) * | 2019-12-06 | 2020-04-21 | 大连理工大学 | Double-network hydrogel based on polyethylene glycol/gelatin particles and preparation method and application thereof |
| CN115887622A (en) * | 2023-01-30 | 2023-04-04 | 东莞市人民医院 | Puerarin composite hydrogel material, and preparation method and application thereof |
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2008
- 2008-07-01 CN CN200810132912A patent/CN101618236A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102038977A (en) * | 2010-11-29 | 2011-05-04 | 中国人民解放军军事医学科学院基础医学研究所 | Tissue engineered cardiac muscle using OPF (Oligo(Poly(Ethylene Glycol) Fumarate) hydrogel as a carrier and preparation method thereof |
| CN104189958A (en) * | 2014-08-25 | 2014-12-10 | 中国人民解放军总医院 | Method for preparing chitosan-silk fibroin composite nano-fiber multifunctional patch for promoting myocardial tissue regeneration and monitoring stem cells |
| CN104189958B (en) * | 2014-08-25 | 2015-12-02 | 中国人民解放军总医院 | For promoting the preparation method of the multi-functional sticking patch of Properties of Chitosan Fibroin Blend albumen composite nano fiber of regenerating heart tissue and stem cell monitoring |
| WO2017177480A1 (en) * | 2016-04-15 | 2017-10-19 | 苏州大学张家港工业技术研究院 | Flexible substrate/liquid electrolyte viscous composite material and preparation method therefor |
| US10500314B2 (en) | 2016-04-15 | 2019-12-10 | Soochow University | Flexible substrate/liquid electrolyte viscous composite material and preparation method therefor |
| CN108066818A (en) * | 2016-11-17 | 2018-05-25 | 中国科学院大连化学物理研究所 | A kind of bionical double-layer sustained release growth factor film and its preparation and application |
| CN111040205A (en) * | 2019-12-06 | 2020-04-21 | 大连理工大学 | Double-network hydrogel based on polyethylene glycol/gelatin particles and preparation method and application thereof |
| CN115887622A (en) * | 2023-01-30 | 2023-04-04 | 东莞市人民医院 | Puerarin composite hydrogel material, and preparation method and application thereof |
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