CN113736043A - 一种pH响应型水凝胶生物载体及应用 - Google Patents
一种pH响应型水凝胶生物载体及应用 Download PDFInfo
- Publication number
- CN113736043A CN113736043A CN202111296151.2A CN202111296151A CN113736043A CN 113736043 A CN113736043 A CN 113736043A CN 202111296151 A CN202111296151 A CN 202111296151A CN 113736043 A CN113736043 A CN 113736043A
- Authority
- CN
- China
- Prior art keywords
- hydrogel
- biovector
- pdgf
- therapeutic protein
- responsive hydrogel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000017 hydrogel Substances 0.000 title claims abstract description 119
- 230000004044 response Effects 0.000 title claims abstract description 16
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 12
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 12
- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims abstract description 7
- 229920002385 Sodium hyaluronate Polymers 0.000 claims abstract description 6
- 229940010747 sodium hyaluronate Drugs 0.000 claims abstract description 6
- 230000001678 irradiating effect Effects 0.000 claims abstract description 5
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 239000003431 cross linking reagent Substances 0.000 claims description 44
- 102000004169 proteins and genes Human genes 0.000 claims description 17
- 108090000623 proteins and genes Proteins 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 13
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 11
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 claims description 10
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 claims description 10
- GJKGAPPUXSSCFI-UHFFFAOYSA-N 2-Hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone Chemical group CC(C)(O)C(=O)C1=CC=C(OCCO)C=C1 GJKGAPPUXSSCFI-UHFFFAOYSA-N 0.000 claims description 7
- 238000004132 cross linking Methods 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 238000011068 loading method Methods 0.000 claims description 5
- 230000001737 promoting effect Effects 0.000 claims description 5
- 230000037314 wound repair Effects 0.000 claims description 5
- 238000007654 immersion Methods 0.000 claims description 4
- 230000017423 tissue regeneration Effects 0.000 claims description 4
- 239000000539 dimer Substances 0.000 claims description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 2
- PSYGHMBJXWRQFD-UHFFFAOYSA-N 2-(2-sulfanylacetyl)oxyethyl 2-sulfanylacetate Chemical compound SCC(=O)OCCOC(=O)CS PSYGHMBJXWRQFD-UHFFFAOYSA-N 0.000 claims 3
- 108010081589 Becaplermin Proteins 0.000 abstract description 44
- 230000004071 biological effect Effects 0.000 abstract description 4
- 238000011065 in-situ storage Methods 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 150000002734 metacrylic acid derivatives Chemical class 0.000 abstract description 2
- 238000010526 radical polymerization reaction Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 230000000379 polymerizing effect Effects 0.000 abstract 1
- 206010052428 Wound Diseases 0.000 description 20
- 208000027418 Wounds and injury Diseases 0.000 description 20
- 239000000243 solution Substances 0.000 description 16
- 239000004971 Cross linker Substances 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 230000008961 swelling Effects 0.000 description 11
- 239000002609 medium Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000015556 catabolic process Effects 0.000 description 9
- 238000006731 degradation reaction Methods 0.000 description 9
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 8
- 238000013508 migration Methods 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 229940014041 hyaluronate Drugs 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003102 growth factor Substances 0.000 description 6
- 230000005012 migration Effects 0.000 description 6
- 230000012292 cell migration Effects 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000029663 wound healing Effects 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 125000005395 methacrylic acid group Chemical group 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000011056 performance test Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 102100040681 Platelet-derived growth factor C Human genes 0.000 description 1
- 102100040682 Platelet-derived growth factor D Human genes 0.000 description 1
- 101710170209 Platelet-derived growth factor D Proteins 0.000 description 1
- 102100037596 Platelet-derived growth factor subunit A Human genes 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 108010017843 platelet-derived growth factor A Proteins 0.000 description 1
- 108010017992 platelet-derived growth factor C Proteins 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 238000012876 topography Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F299/00—Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1858—Platelet-derived growth factor [PDGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/46—Polymerisation initiated by wave energy or particle radiation
- C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Polymers & Plastics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了一种pH响应型水凝胶生物载体,所述pH响应型水凝胶生物载体由透明质酸钠与甲基丙烯酸酐在光引发剂存在的条件下,用365nm紫外激光照射,透明质酸钠侧链上的羟基通过光致交联经过酯化作用聚合而成透明质酸的甲基丙烯酸酯衍生物。本发明还公开了一种装载有治疗性蛋白PDGF‑BB的pH响应型水凝胶生物载体。本发明采用原位自由基聚合的方法合成,反应条件温和,对PDGF‑BB的生物活性不会产生影响;把PDGF‑BB包裹在水凝胶内,避免暴露在酶环境中,提高了PDGF‑BB生物活性的稳定性。
Description
技术领域
本发明公开一种水凝胶生物载体,属于制药学技术领域。
背景技术
血小板衍生生长因子(Platelet-derived growth factor, PDGF)是一种耐热、耐酸以及易被蛋白酶水解的阳离子糖蛋白,可由多种细胞分泌,如:血小板、成纤维细胞、巨噬细胞等等。PDGF有四种单体PDGF-A、PDGF-B、PDGF-C和PDGF-D,这些单体通过二硫键连接形成二聚体形式。其中,PDGF-B 的二聚体形式PDGF-BB作为一种有丝分裂促进剂,可以刺激成纤维细胞和平滑肌细胞增殖和迁移、促进巨噬细胞产生和分泌生长因子。在伤口修复、组织再生骨骼和牙齿再生以及关节修复方面的作用更为显著。尤其在伤口修复方面,是美国食品药品监督管理局(FDA)唯一批准的用于糖尿病溃疡治疗的生长因子。
伤口修复和组织再生类疾病需要生长因子在患病部位长期维持一定浓度,但PDGF-BB半衰期短(<2min),容易被蛋白酶降解,而像慢性伤口床中存在大量蛋白酶,使得PDGF-BB更容易失活。一般会采用多次大剂量给药的方式来维持药物浓度,但这样存在致瘤的风险。所以本领域需要一种载体,所述载体既能够提高PDGF-BB稳定性,又同时能够长期维持一定的药物浓度,以保证PDGF用药的安全性和有效性。
发明内容
基于本领域存在的上述技术问题,本发明的目的就是提供一种水凝胶生物载体,该载体既能够通过可控性释放PDGF-BB的生物活性,提高其在药效作用上的稳定性,还能够通过所述载体的降解保证药物使用的生物安全性。
本发明综合考虑了甲基丙烯酸酐化透明质酸水凝胶的生物相容性和能够保护生长因子缓慢释放的特点,通过将PDGF-BB引入到甲基丙烯酸酐化透明质酸水凝胶网络中,制备得到结合生长因子型pH响应型水凝胶生物载体,目的在于提高传统水凝胶的生物相容性、pH响应性、细胞片层脱附和保护并缓慢释放生长因子等特性。
基于上述目的,本发明首先提供了一种pH响应型水凝胶生物载体,所述pH响应型水凝胶生物载体由甲基丙烯酸化透明质酸在光引发剂、交联剂存在的条件下,用365nm紫外激光照射引发交联反应制备而成。
在一个优选的技术方案中,所述光引发剂为I2959,所述交联剂为第一交联剂GDMA和第二交联剂AI102。
在另一个优选的技术方案中,所述甲基丙烯酸化透明质酸是由透明质酸钠与甲基丙烯酸酐以摩尔比例为 1:30经过酯化作用合成。
在一个优选的技术方案中,所述第一交联剂GDMA与第二交联剂AI102的摩尔比为(1-4):(0-2)。
其次,本发明提供了一种上述的pH响应型水凝胶生物载体的制备方法,所述方法包括使甲基丙烯酸化透明质酸在光引发剂、第一交联剂GDMA和第二交联剂AI102存在的条件下,用365nm紫外激光照射引发交联反应。
第三,本发明提供了一种装载有治疗性蛋白的上述的pH响应型水凝胶生物载体,所述装载有治疗性蛋白的pH响应型水凝胶生物载体装载是通过将水凝胶生物载体冻干,以干态浸泡法将治疗性蛋白负载在pH响应型水凝胶生物载体内制备而成。
在一个优选的技术方案中,所述治疗性蛋白为血小板衍生生长因子。
在一个更为优选的技术方案中,所述血小板衍生生长因子为BB型二聚体形式。
第四,本发明提供了上述的载有治疗性蛋白的pH响应型水凝胶生物载体的制备方法,所述方法包括将水凝胶生物载体冻干,以干态浸泡法将治疗性蛋白负载在pH响应型水凝胶生物载体内制备的步骤。
最后,本发明提供了上述的载有治疗性蛋白的pH响应型水凝胶生物载体在制备促进伤口修复和组织再生类药物中的应用。
本发明采用原位自由基聚合的方法合成pH响应型水凝胶生物载体,并使用干态浸泡法将治疗性蛋白负载在pH响应型水凝胶生物载体内,反应条件温和,对PDGF-BB的生物活性不会产生影响;把PDGF-BB包裹在水凝胶内,避免暴露在酶环境中,提高稳定性。PDGF-BB的释放是通过水凝胶的降解实现的,本发明选用了响应碱性pH值降解的两种交联剂:第一交联剂GDMA和第二交联剂AI102,两种交联剂的降解基于自身酯键基团,但这两种交联剂在碱性条件下降解速率不同。本发明提供的pH响应型水凝胶生物载体可根据伤口类型的不同,即,伤口部位的pH值的不同,通过控制配伍比例,从而控制了凝胶降解速度,以适应应用要求。鉴于人体伤口部位的pH值是在8.0左右,所述的两种交联剂在8.0时,降解的速度是不同的,第二交联剂比第一交联剂水溶性好,且含有的酯键数量相对较多,所以在降解速率上比第一交联剂快。通过调整两者的比例,例如GDMA:AI102比例为1:2时,释放速率最慢,这样就提供控制两个交联剂之间的比例实现水凝胶不同速率的降解。可以针对不同疾病以及伤口类型的治疗选择合适的交联剂比例(见图1)。
附图说明
图1:可控释放PDGF-BB pH响应性水凝胶制备的示意图;
图2:m-HA 1H-NMR谱图;
图3:可控释放PDGF-BB pH响应性水凝胶实物图;
图4:不同交联剂比例pH响应性水凝胶压缩性能测试;
图5:不同交联剂比例pH响应性水凝胶扫描电子显微镜图;
图6:不同交联剂比例pH响应性水凝胶溶胀率图;
图7:不同交联剂比例pH响应性水凝胶累计PDGF-BB释放速率图;
图8:pH响应性水凝胶细胞毒性实验;
图9:pH响应性水凝胶对于3T3细胞的迁移作用统计图;
图10. pH响应性水凝胶对于3T3细胞的迁移作用观察图;
图11.不同处理方式小鼠全层皮肤伤口愈合情况观察图;
图12.不同处理方式小鼠全层皮肤伤口面积随时间变化曲线。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的,并不对本发明的权利要求所限定的保护范围构成任何限制。
实施例1. pH响应型水凝胶生物载体的制备
图1给出了PDGF-BB pH响应性水凝胶制备的示意图,其中A为甲基丙烯酸酐,B为透明质酸钠,1为第一交联剂GDMA,2为第二交联剂AI102。以下具体介绍制备步骤。
1. 甲基丙烯酸化透明质酸(m-HA)的制备
使透明质酸钠(HA)与甲基丙烯酸酐(MA)经过酯化作用合成透明质酸的甲基丙烯酸酯衍生物, 具体步骤包括如下:
(1)称取2g透明质酸钠(HA)粉末,溶解于100mL去离子水中,在4℃冰箱中搅拌过夜,将粉末充分溶解。
(2)通过加入5mol/L氢氧化钠调节HA溶液的pH,使反应的pH保持在8到9之间,随后在HA溶液中缓慢滴加1.6mL的甲基丙烯酸酐并在4℃连续搅拌反应24小时。
(3)随后,将m-HA沉淀在过量丙酮中,再用乙醇洗涤,然后溶解在50ml去离子水中。
(4)采用截留分子量为14000Da的透析袋用去离子水透析48小时,以去除未反应的甲基丙烯酸酐和其他副产物,获得纯化的m-HA,将其冻干备用。
以氘代水为溶剂溶解m-HA,浓度为6mg/ml,进行核磁表征,m-HA核磁图见图2。从1H-NMR谱图可以看出,在δ4.79ppm处为D2O的特征峰;δ3-4ppm为HA环结构中质子氢的特征峰;δ1.86ppm为HA中甲基上H的特征峰;δ2.03ppm为侧链N-乙酰葡糖胺上甲基H的特征峰。与HA核磁谱图相比,m--HA在δ5.68ppm和δ6.13ppm出现的两个新的峰为甲基丙烯酸酐中烯烃质子的特征峰,可以表明甲基丙烯酸酐成功接枝到了HA分子结构中。
2. pH响应型水凝胶生物载体的制备
装载有血小板衍生生长因子的m-HA水凝胶的制备
以m-HA为单体,GDMA(二甲基丙烯酸甘油酯,第一交联剂)和AI102(聚乳酸-聚乙二醇-聚乳酸丙烯酸酯,第二交联剂)为交联剂,然后加入引发剂I2959(2-羟基-4’-(2-羟乙氧基)-2-甲基苯丙酮),在紫外光365nm处引发反应,制备成pH响应型水凝胶生物载体,随后将其冷冻干燥。
具体步骤如下:
取甲基丙烯酸化透明质酸、第二交联剂AI102制备成水溶液;第一交联剂GDMA和引发剂I2959分别加入DMSO制备成溶液;
将m-HA、AI102水溶液、I2959溶液、GDMA溶液在反应管中混合均匀,在365nm紫外光下反应2min,形成pH响应型水凝胶生物载体。将其冻干后,将PDGF-BB负载到水凝胶上。
其中第一交联剂GDMA:第二交联剂AI102的摩尔比为(1-4):(0-2);
(1) 溶液配制:
取冻干m-HA 20mg,加入去离子水1ml,制成20mg/ml的溶液;
取AI102 50mg,加入去离子水500μl,制成100mg/ml的溶液;
取GDMA 250mg,加入DMSO 500μl,制成500mg/ml的溶液;
取I2959 100mg,加入DMSO1ml,制成100mg/ml的溶液。
(2)制备不同交联剂比例的水凝胶:
表1水凝胶合成参数(交联剂比例为GDMA:AI102)
将m-HA、AI102水溶液、I2959溶液、GDMA溶液在反应管中混合均匀,在365nm紫外光下反应2min,得到不同比例的水凝胶。
图3为可控释放PDGF-BB pH响应性水凝胶实物图。不同交联剂比例pH响应性水凝胶压缩性能测试结果如图4。随着交联剂量的增加,杨氏模量显著增加。杨氏模量越大,材料越不容易发生形变。相同的压缩应变下交联剂的量越多,水凝胶需要的应力就高,压缩模量就大。由结果可知,当GDMA:AI102=4:1时杨氏模量最大,说明受力时形变最小。
3. pH响应型水凝胶生物载体的PDGF-BB装载
使用干态浸泡法将PDGF-BB(购自军事医学科学院)装载于pH响应型水凝胶生物载体之中,即,待水凝胶完全冻干,将其浸泡在PDGF-BB溶液中,使PDGF-BB充分负载到水凝胶上。反应完成形成包含PDGF-BB的水凝胶。
具体步骤如下:
将水凝胶用打孔器打孔取样,制成直径为15mm,高度为8mm的圆柱体,随后将水凝胶冻干3天,之后将冻干的水凝胶浸泡于5ml浓度为50ng/ml的含有PDGF-BB溶液中48h,以确保水凝胶充分吸收,之后用PBS冲洗3次,将未结合到水凝胶中的PDGF-BB冲洗掉,制得结合生长因子的水凝胶生物载体。
实施例2. 装载有血小板衍生生长因子的m-HA水凝胶的表征
1、水凝胶形貌表征
将达到平衡溶胀的水凝胶样品置于-50℃的冻干机中冷冻干燥48h,所得样品在液氮中冷冻脆断后喷金制样,其截面形貌使用扫描电子显微镜(SEM)观察。图5为不同交联剂比例pH响应性水凝胶扫描电子显微镜图像。由此可见,交联剂比例越大,孔径越小,说明交联程度越高。当GDMA与AI102的摩尔比例为1:2时,交联程度最大。
2、水凝胶的溶胀率表征
利用冷冻干燥后的水凝胶支架进行溶胀性能测试。将水凝胶样品用打孔器打孔,制成直径为1.5cm,高度为12mm的圆柱体,随后将样品冻干。利用分析天平称量并记录各组水凝胶的原始重量 W0,然后将水凝胶置于10mL的 PBS 缓冲溶液中浸泡,观察水凝胶的溶胀变化,分别在 2 h,6 h,12 h,24 h,48 h 和 72 h 取样。用滤纸小心吸去水凝胶表面的水分,称量并记录水凝胶样品的重量 Wi,每种样品至少设置 3 个重复样,最后结果取平均值。水凝胶的溶胀率(W)可用以下公式计算:
溶胀率(W)=(Wi–W0 )/W0×100%
如图6所示,当GDMA:AI102比例为1:0时,溶胀率最大。当两者比例为4:1时,溶胀率最小。水凝胶支架在刚开始 14 h 内,溶胀程度急剧上升,尤其是两种加入交联剂量少的水凝胶,主要是由于加入的交联剂少,交联度较低,形成的聚合物网络比较疏散,可以吸收大量的水。在浸泡 24 h 左右水凝胶支架达到了溶胀平衡。
3、不同交联剂比例pH响应性水凝胶释放动力学表征
将负载PDGF-BB的不同交联剂比例的干燥HA-MA水凝胶放置于pH=8的PBS缓冲液中,37℃水浴锅中温育,进行药物控释研究。在特定时间(1、2、3、4、5、7、10天)取出200μL的释放液,同时补充200μL纯净的PBS缓冲液。将收集的释放液通过酶联免疫反应(ELISA)测定释放的PDGF-BB的含量。
不同交联剂比例pH响应性水凝胶累计PDGF-BB释放速率图见图7。当GDMA:AI102比例为1:0时,释放速率最快。当两者比例为1:2时,释放速率最慢。
4. pH响应性水凝胶生物相容性表征
细胞毒性测试:
取制备好的不含PDGF-BB的水凝胶和含PDGF-BB的水凝胶适量加入24孔板中,加入适量只含P/S的培养基(pH=8),在培养箱中继续孵育24 h后,取出培养基,过0.22 μm滤膜。每孔中接种1×104个细胞,37 ℃,5% CO2条件下孵育过夜。把上述浸提液加入后继续孵育24h,然后使用CCK-8试剂盒来验证水凝胶是否具有细胞毒性。所用到的水凝胶的第一交联剂:第二交联剂的比例为1:2。
pH响应性水凝胶细胞毒性实验结果见图8。包裹不同浓度PDGF-BB的水凝胶的生物活性都大于75%,所以认为制备的水凝胶生物相容性良好。
5. pH响应性水凝胶对于3T3细胞的迁移作用
(1)无血清 DMEM 培养基(pH=8)配制:取 0.5 ml 双抗,然后加入 49.5 ml DMEM高糖培养基。
(2)把直尺和记号笔放在超净台紫外杀菌 30 min,然后把 DMEM 完全培养基, 1×PBS 放到 37 ℃水浴锅温育 20 min,胰酶放在室温条件下温育。
(3)铺板:取 6 孔板,在板背部,用记号笔画 5 条过孔的横线。将细胞稀释成5×104个/ml,每孔接种 2 ml。37 ℃,5% CO2条件下孵育,使孔板底部被单层铺满。
(4)为了消除完全培养基促进细胞增殖迁移对于结果的影响,加样前12 h,换成只含 P/S 的培养基。用10μL 枪头垂直于标记线方向划直线。移除旧培养基,用 1×PBS 冲洗3 次以除去划落的细胞。
(5)用无血清 DMEM 培养基分别浸泡不含PDGF的水凝胶和包含PDGF-BB的水凝胶。取上述提取液 2 ml 分别加入到各个孔中。设置空白组(只含 P/S 的培养基)。加样后放入5% CO2,37 ℃培养箱孵育。在同一个视野下分别拍摄 0、12、24、36、48 h的照片,使用Image J 软件计算面积,进而计算出细胞迁移率。
图9为pH响应性水凝胶对于3T3细胞的迁移作用统计图;图10为 pH响应性水凝胶对于3T3细胞的迁移作用观察图。所用到的水凝胶的第一交联剂:第二交联剂的比例为1:2。与只含有水凝胶的对照组相比,使用未包裹的 PDGF-BB和水凝胶包裹的PDGF-BB作用的细胞,3T3细胞不断向中间部位迁移,划痕面积显著减小。通过 ImageJ 定量伤口面积,发现未包裹PDGF-BB 的水凝胶的细胞迁移率在36h 内能达到37%,包裹PDGF-BB的水凝胶细胞迁移率在36 h 时间内能达到42%,而对照组细胞迁移率仅为10%左右。这证明了包裹PDGF-BB的水凝胶能够促进 3T3 细胞迁移,可能对于伤口愈合具有促进作用。
6.小鼠全层皮肤伤口愈合实验:
将小鼠分为不含PDGF-BB的水凝胶和含PDGF-BB的水凝胶三组。所用到的水凝胶的第一交联剂:第二交联剂的比例为1:2。负载药物的水凝胶原位注射至伤口部位(pH=8),随后覆盖非粘性无菌敷贴,并用3M敷贴固定。分别在不同时间点(0、3、7、10、14天)对小鼠伤口进行拍照,使用直尺作为参照。伤口面积使用Image J软件计算。
创面闭合率%=(S0-SN)/S0×100
其中,S0为初始创面面积,SN为N天时创面面积
图11是不同处理方式小鼠全层皮肤伤口愈合情况图示。从图11中可以看到糖尿病小鼠的伤口都在逐渐缩小,但水凝胶包裹的PDGF-BB组与其他两组相比,伤口愈合更显著。图12的小鼠伤口面积随时间变化曲线显示,7 d时,3组的平均伤口面积分别为83.4%,72.8%和65.0%;14 d时,3组的平均伤口面积变为54.9,25.1%和7.8%,与其他两组相比,水凝胶包裹的PDGF-BB组伤口面积减小的最多,由此可以看出水凝胶包裹的PDGF-BB组有利于伤口愈合。
Claims (10)
1.一种pH响应型水凝胶生物载体,其特征在于,所述pH响应型水凝胶生物载体由甲基丙烯酸化透明质酸在光引发剂、交联剂存在的条件下,用365nm紫外激光照射引发交联反应制备而成。
2.根据权利要求1所述的pH响应型水凝胶生物载体,其特征在于,所述光引发剂为I2959,所述交联剂为第一交联剂GDMA和第二交联剂AI102。
3.根据权利要求1所述的pH响应型水凝胶生物载体,其特征在于,所述甲基丙烯酸化透明质酸是由透明质酸钠与甲基丙烯酸酐以摩尔比例为 1:30经过酯化作用合成。
4.根据权利要求2所述的pH响应型水凝胶生物载体,其特征在于,所述第一交联剂GDMA与第二交联剂AI102的摩尔比为(1-4):(0-2)。
5.权利要求1-3任一所述的pH响应型水凝胶生物载体的制备方法,其特征在于,所述方法包括使甲基丙烯酸化透明质酸在光引发剂、第一交联剂GDMA和第二交联剂AI102存在的条件下,用365nm紫外激光照射引发交联反应。
6.一种装载有治疗性蛋白的权利要求1-3任一所述的pH响应型水凝胶生物载体,其特征在于,所述装载有治疗性蛋白的pH响应型水凝胶生物载体装载是通过将水凝胶生物载体冻干,以干态浸泡法将治疗性蛋白负载在pH响应型水凝胶生物载体内制备而成。
7.根据权利要求6所述的装载有治疗性蛋白的pH响应型水凝胶生物载体,其特征在于,所述治疗性蛋白为血小板衍生生长因子。
8.根据权利要求7所述的装载有治疗性蛋白的pH响应型水凝胶生物载体,其特征在于,所述血小板衍生生长因子为BB型二聚体形式。
9.权利要求6-8任一所述的载有治疗性蛋白的pH响应型水凝胶生物载体的制备方法,其特征在于,所述方法包括将水凝胶生物载体冻干,以干态浸泡法将治疗性蛋白负载在pH响应型水凝胶生物载体内制备的步骤。
10.权利要求6-8任一所述的载有治疗性蛋白的pH响应型水凝胶生物载体在制备促进伤口修复和组织再生类药物中的应用。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111296151.2A CN113736043B (zh) | 2021-11-03 | 2021-11-03 | 一种pH响应型水凝胶生物载体及应用 |
PCT/CN2022/079518 WO2023077699A1 (zh) | 2021-11-03 | 2022-03-07 | 一种pH响应型水凝胶生物载体及应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111296151.2A CN113736043B (zh) | 2021-11-03 | 2021-11-03 | 一种pH响应型水凝胶生物载体及应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113736043A true CN113736043A (zh) | 2021-12-03 |
CN113736043B CN113736043B (zh) | 2022-05-20 |
Family
ID=78727203
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111296151.2A Active CN113736043B (zh) | 2021-11-03 | 2021-11-03 | 一种pH响应型水凝胶生物载体及应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN113736043B (zh) |
WO (1) | WO2023077699A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114917412A (zh) * | 2022-05-06 | 2022-08-19 | 湖南师范大学 | 一种光敏性水凝胶材料在制备促进皮肤伤口愈合和/或毛囊再生产品中的应用及产品 |
WO2023077699A1 (zh) * | 2021-11-03 | 2023-05-11 | 北京华芢生物技术有限公司 | 一种pH响应型水凝胶生物载体及应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104231288A (zh) * | 2014-08-07 | 2014-12-24 | 厦门凝赋生物科技有限公司 | 一种高强度胶原凝胶及其制备方法 |
US20150250891A1 (en) * | 2012-09-06 | 2015-09-10 | Nanyang Technological University | Hyaluronic acid-based drug delivery systems |
CN111592618A (zh) * | 2020-05-09 | 2020-08-28 | 广东省医疗器械研究所 | 一种透明质酸水凝胶及其制备方法和应用 |
CN113244377A (zh) * | 2021-04-19 | 2021-08-13 | 北京化工大学 | 可控释放血小板衍生生长因子纳米胶囊的制备 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3235514A1 (en) * | 2016-04-19 | 2017-10-25 | Université de Genève | Hyaluronic acid conjugates and uses thereof |
CN113736043B (zh) * | 2021-11-03 | 2022-05-20 | 北京华芢生物技术有限公司 | 一种pH响应型水凝胶生物载体及应用 |
-
2021
- 2021-11-03 CN CN202111296151.2A patent/CN113736043B/zh active Active
-
2022
- 2022-03-07 WO PCT/CN2022/079518 patent/WO2023077699A1/zh unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150250891A1 (en) * | 2012-09-06 | 2015-09-10 | Nanyang Technological University | Hyaluronic acid-based drug delivery systems |
CN104231288A (zh) * | 2014-08-07 | 2014-12-24 | 厦门凝赋生物科技有限公司 | 一种高强度胶原凝胶及其制备方法 |
CN111592618A (zh) * | 2020-05-09 | 2020-08-28 | 广东省医疗器械研究所 | 一种透明质酸水凝胶及其制备方法和应用 |
CN113244377A (zh) * | 2021-04-19 | 2021-08-13 | 北京化工大学 | 可控释放血小板衍生生长因子纳米胶囊的制备 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023077699A1 (zh) * | 2021-11-03 | 2023-05-11 | 北京华芢生物技术有限公司 | 一种pH响应型水凝胶生物载体及应用 |
CN114917412A (zh) * | 2022-05-06 | 2022-08-19 | 湖南师范大学 | 一种光敏性水凝胶材料在制备促进皮肤伤口愈合和/或毛囊再生产品中的应用及产品 |
Also Published As
Publication number | Publication date |
---|---|
WO2023077699A1 (zh) | 2023-05-11 |
CN113736043B (zh) | 2022-05-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP3094074B2 (ja) | 多糖ゲル組成物 | |
CN113736043B (zh) | 一种pH响应型水凝胶生物载体及应用 | |
US6458386B1 (en) | Medicaments based on polymers composed of methacrylamide-modified gelatin | |
Ye et al. | Advances in hydrogels based on dynamic covalent bonding and prospects for its biomedical application | |
RU2395276C2 (ru) | Способ получения сохраняющих форму агрегатов частиц геля и их применение | |
Tan et al. | Development of alginate-based hydrogels: Crosslinking strategies and biomedical applications | |
Bhattarai et al. | Chitosan-based hydrogels for controlled, localized drug delivery | |
US8821933B2 (en) | Polymers and hydrogels | |
JPH07503943A (ja) | 封入及び薬剤放出に有用な架橋性の多糖類、ポリカチオン及び脂質 | |
JP2002155137A (ja) | 酸化窒素生成ヒドロゲル物質 | |
Kishida et al. | Hydrogels for biomedical and pharmaceutical applications | |
Zhou et al. | Advances and impact of arginine-based materials in wound healing | |
CN114404649B (zh) | 一种具有pH/葡萄糖双响应性释放二甲双胍的水凝胶及制备方法和应用 | |
CN112933288B (zh) | 兼具止血和术后抗肿瘤功能的交联止血海绵及其制备方法 | |
CN113230449B (zh) | 糖尿病慢性创面治疗用葡萄糖和酶双响应敷料及制备方法 | |
Luo et al. | Tailoring hyaluronic acid hydrogels for biomedical applications | |
Hu et al. | Recent advances in smart‐responsive hydrogels for tissue repairing | |
Neamtu et al. | Nanogels containing polysaccharides for bioapplications | |
EP3790603A1 (en) | Therapeutic hydrogel material and methods of using the same | |
JPH09286741A (ja) | 創傷治癒 | |
Mukherjee et al. | Alginate based semi-IPN and IPN hydrogel for drug delivery and regenerative medicine | |
Gong et al. | A review of recent advances of cellulose-based intelligent-responsive hydrogels as vehicles for controllable drug delivery system | |
CN114557958B (zh) | 一种刺激响应型聚两性离子纳米凝胶的制备方法与应用 | |
Geng et al. | Puerarin Hydrogel: Design and Applications in Biomedical Engineering | |
Yang et al. | Polysaccharides as a promising platform for the treatment of spinal cord injury: A review |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CP03 | Change of name, title or address |
Address after: Room 1901, Building 1, Xiexin Center, No. 19 Qinling Road, Laoshan District, Qingdao City, Shandong Province, 266100 Patentee after: Huaxi Biotechnology (Qingdao) Co.,Ltd. Country or region after: China Address before: 101407 Building 2, No. 36, Paradise Street, Yanqi Economic Development Zone, Huairou District, Beijing Patentee before: Beijing Huapeng Biotechnology Co.,Ltd. Country or region before: China |
|
CP03 | Change of name, title or address |