CN102028968B - 外科用组合物 - Google Patents
外科用组合物 Download PDFInfo
- Publication number
- CN102028968B CN102028968B CN201010501269.XA CN201010501269A CN102028968B CN 102028968 B CN102028968 B CN 102028968B CN 201010501269 A CN201010501269 A CN 201010501269A CN 102028968 B CN102028968 B CN 102028968B
- Authority
- CN
- China
- Prior art keywords
- hydrogel
- precursor
- weight
- organization bracket
- hydrogel precursor
- 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.)
- Expired - Fee Related
Links
- 239000000203 mixture Substances 0.000 title description 10
- 239000000017 hydrogel Substances 0.000 claims abstract description 134
- 125000000524 functional group Chemical group 0.000 claims abstract description 51
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 27
- 102000004190 Enzymes Human genes 0.000 claims abstract description 9
- 108090000790 Enzymes Proteins 0.000 claims abstract description 9
- 239000002243 precursor Substances 0.000 claims description 116
- 229920001223 polyethylene glycol Polymers 0.000 claims description 50
- 239000000470 constituent Substances 0.000 claims description 45
- -1 serum Polymers 0.000 claims description 28
- 230000008520 organization Effects 0.000 claims description 26
- 102000008186 Collagen Human genes 0.000 claims description 25
- 108010035532 Collagen Proteins 0.000 claims description 25
- 229920001436 collagen Polymers 0.000 claims description 25
- 230000007547 defect Effects 0.000 claims description 24
- 230000005611 electricity Effects 0.000 claims description 24
- 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 23
- 229920002674 hyaluronan Polymers 0.000 claims description 22
- 229960003160 hyaluronic acid Drugs 0.000 claims description 22
- 108010010803 Gelatin Proteins 0.000 claims description 18
- 239000008273 gelatin Substances 0.000 claims description 18
- 229920000159 gelatin Polymers 0.000 claims description 18
- 235000019322 gelatine Nutrition 0.000 claims description 18
- 235000011852 gelatine desserts Nutrition 0.000 claims description 18
- 210000002966 serum Anatomy 0.000 claims description 13
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims description 12
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- 230000008439 repair process Effects 0.000 claims description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- AASBXERNXVFUEJ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) propanoate Chemical compound CCC(=O)ON1C(=O)CCC1=O AASBXERNXVFUEJ-UHFFFAOYSA-N 0.000 claims description 7
- BTBWSRPRAGXJJV-UHFFFAOYSA-N 2h-benzotriazole;carbonic acid Chemical compound OC(O)=O.C1=CC=C2NN=NC2=C1 BTBWSRPRAGXJJV-UHFFFAOYSA-N 0.000 claims description 7
- QXZGLTYKKZKGLN-UHFFFAOYSA-N 4-(2,5-dioxopyrrolidin-1-yl)oxy-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)ON1C(=O)CCC1=O QXZGLTYKKZKGLN-UHFFFAOYSA-N 0.000 claims description 7
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 7
- 102000013275 Somatomedins Human genes 0.000 claims description 7
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 claims description 7
- 150000001718 carbodiimides Chemical class 0.000 claims description 7
- 150000003949 imides Chemical class 0.000 claims description 7
- 239000012948 isocyanate Substances 0.000 claims description 7
- 150000002513 isocyanates Chemical class 0.000 claims description 7
- 108020004414 DNA Proteins 0.000 claims description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 3
- 210000000130 stem cell Anatomy 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000000463 material Substances 0.000 description 36
- 210000001519 tissue Anatomy 0.000 description 34
- 239000000243 solution Substances 0.000 description 29
- 230000015572 biosynthetic process Effects 0.000 description 27
- 238000000034 method Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000007822 coupling agent Substances 0.000 description 18
- 229920000642 polymer Polymers 0.000 description 16
- 210000000845 cartilage Anatomy 0.000 description 14
- 239000007853 buffer solution Substances 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000000499 gel Substances 0.000 description 12
- 239000003431 cross linking reagent Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 7
- 239000000975 dye Substances 0.000 description 6
- 229940088597 hormone Drugs 0.000 description 6
- 239000005556 hormone Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 239000003114 blood coagulation factor Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229920006037 cross link polymer Polymers 0.000 description 5
- 238000004132 cross linking Methods 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 4
- 102000009123 Fibrin Human genes 0.000 description 4
- 108010073385 Fibrin Proteins 0.000 description 4
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 description 4
- 108090000190 Thrombin Proteins 0.000 description 4
- 239000001961 anticonvulsive agent Substances 0.000 description 4
- 229960003965 antiepileptics Drugs 0.000 description 4
- 239000000739 antihistaminic agent Substances 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 229950003499 fibrin Drugs 0.000 description 4
- 150000004676 glycans Chemical class 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- 229920001282 polysaccharide Polymers 0.000 description 4
- 239000005017 polysaccharide Substances 0.000 description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 3
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229920001503 Glucan Polymers 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000000150 Sympathomimetic Substances 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 229940035674 anesthetics Drugs 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 3
- 239000002327 cardiovascular agent Substances 0.000 description 3
- 229940125692 cardiovascular agent Drugs 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000000812 cholinergic antagonist Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 230000007515 enzymatic degradation Effects 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 239000003193 general anesthetic agent Substances 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000565 sealant Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 230000001975 sympathomimetic effect Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- 108010076119 Caseins Proteins 0.000 description 2
- 102000011632 Caseins Human genes 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 2
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 101800004361 Lactoferricin-B Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 229920003091 Methocel™ Polymers 0.000 description 2
- 229920002201 Oxidized cellulose Polymers 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000012062 aqueous buffer Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 125000003636 chemical group Chemical group 0.000 description 2
- 229940045110 chitosan Drugs 0.000 description 2
- 230000000718 cholinopositive effect Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 2
- 229960004193 dextropropoxyphene Drugs 0.000 description 2
- 239000000032 diagnostic agent Substances 0.000 description 2
- 229940039227 diagnostic agent Drugs 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 102000005525 fibrillarin Human genes 0.000 description 2
- 108020002231 fibrillarin Proteins 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 239000004083 gastrointestinal agent Substances 0.000 description 2
- 229940127227 gastrointestinal drug Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000008348 humoral response Effects 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000003999 initiator Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000003149 muscarinic antagonist Substances 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229940107304 oxidized cellulose Drugs 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 2
- 229940099765 pipracil Drugs 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 2
- 229920001308 poly(aminoacid) Polymers 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004632 polycaprolactone Substances 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229920005604 random copolymer Polymers 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000002048 spasmolytic effect Effects 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 229920002994 synthetic fiber Polymers 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-UHFFFAOYSA-N 0.000 description 1
- OQXSRALAOPBHPM-UHFFFAOYSA-N 2-hydroxypropanoic acid;silver Chemical compound [Ag].CC(O)C(O)=O OQXSRALAOPBHPM-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- NWAGXLBTAPTCPR-UHFFFAOYSA-N 5-(2,5-dioxopyrrolidin-1-yl)oxy-5-oxopentanoic acid Chemical compound OC(=O)CCCC(=O)ON1C(=O)CCC1=O NWAGXLBTAPTCPR-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 101000798100 Bos taurus Lactotransferrin Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 1
- BRDWIEOJOWJCLU-LTGWCKQJSA-N GS-441524 Chemical compound C=1C=C2C(N)=NC=NN2C=1[C@]1(C#N)O[C@H](CO)[C@@H](O)[C@H]1O BRDWIEOJOWJCLU-LTGWCKQJSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 101000746367 Homo sapiens Granulocyte colony-stimulating factor Proteins 0.000 description 1
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- 101000844802 Lacticaseibacillus rhamnosus Teichoic acid D-alanyltransferase Proteins 0.000 description 1
- 239000002616 MRI contrast agent Substances 0.000 description 1
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
- 101710127797 Macrophage colony-stimulating factor 1 Proteins 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 101001055320 Myxine glutinosa Insulin-like growth factor Proteins 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 229910021612 Silver iodide Inorganic materials 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 229920002359 Tetronic® Polymers 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 210000002934 adrenergic neuron Anatomy 0.000 description 1
- 239000003043 adrenergic neuron blocking agent Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229920000180 alkyd Polymers 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000010539 anionic addition polymerization reaction Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 230000001022 anti-muscarinic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 230000000680 avirulence Effects 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 229920013641 bioerodible polymer Polymers 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 229940072440 bovine lactoferrin Drugs 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000013590 bulk material Substances 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 238000010538 cationic polymerization reaction Methods 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- JQXXHWHPUNPDRT-YOPQJBRCSA-N chembl1332716 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CCN(C)CC1 JQXXHWHPUNPDRT-YOPQJBRCSA-N 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960002152 chlorhexidine acetate Drugs 0.000 description 1
- 229960003333 chlorhexidine gluconate Drugs 0.000 description 1
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 description 1
- 229940097572 chloromycetin Drugs 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 238000005137 deposition process Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- KQTXIZHBFFWWFW-UHFFFAOYSA-L disilver;carbonate Chemical compound [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- SAHQDLLFHZPWGK-UHFFFAOYSA-N dodecanoic acid;silver Chemical compound [Ag].CCCCCCCCCCCC(O)=O SAHQDLLFHZPWGK-UHFFFAOYSA-N 0.000 description 1
- 239000002961 echo contrast media Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 229960004675 fusidic acid Drugs 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 239000007952 growth promoter Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000003668 hormone analog Substances 0.000 description 1
- 239000002944 hormone and hormone analog Substances 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 1
- 229960004657 indocyanine green Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000003903 lactic acid esters Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 210000003041 ligament Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 229960002509 miconazole Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 229960000321 oxolinic acid Drugs 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000000734 parasympathomimetic agent Substances 0.000 description 1
- 238000002161 passivation Methods 0.000 description 1
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 description 1
- 229960004236 pefloxacin Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 238000012643 polycondensation polymerization Methods 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229940076372 protein antagonist Drugs 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- TVRGPOFMYCMNRB-UHFFFAOYSA-N quinizarine green ss Chemical compound C1=CC(C)=CC=C1NC(C=1C(=O)C2=CC=CC=C2C(=O)C=11)=CC=C1NC1=CC=C(C)C=C1 TVRGPOFMYCMNRB-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- YSVXTGDPTJIEIX-UHFFFAOYSA-M silver iodate Chemical compound [Ag+].[O-]I(=O)=O YSVXTGDPTJIEIX-UHFFFAOYSA-M 0.000 description 1
- 229940045105 silver iodide Drugs 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229960003600 silver sulfadiazine Drugs 0.000 description 1
- UEJSSZHHYBHCEL-UHFFFAOYSA-N silver(1+) sulfadiazinate Chemical compound [Ag+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1 UEJSSZHHYBHCEL-UHFFFAOYSA-N 0.000 description 1
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007155 step growth polymerization reaction Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 239000012209 synthetic fiber Substances 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000008542 thermal sensitivity Effects 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 239000005425 throughfall Substances 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 229960003500 triclosan Drugs 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/222—Gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/258—Genetic materials, DNA, RNA, genes, vectors, e.g. plasmids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/64—Animal cells
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Transplantation (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physical Education & Sports Medicine (AREA)
- Materials For Medical Uses (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Polymers & Plastics (AREA)
Abstract
本发明公开涉及多组分水凝胶。该水凝胶可以包含具有亲核官能团的天然组分和亲电组分。在实施方式中,至少一种组分可以被支化,使得药物、抗体、酶等被引入到其中,该组分可以与水凝胶的至少一种其它组分反应。
Description
相关申请的交叉引用
本申请要求受益于并享受在2009年10月2日提交的美国临时专利申请第61/247,998号的优先权,其公开的内容以整体引用的方式并入说明书中。
背景技术
本发明公开涉及水凝胶。具体而言,本公开涉及一种其中可以包含生物活性剂的多组分水凝胶。
已知具有亲电和亲核官能团的生物相容的交联聚合物在形成水凝胶中的用途。这些水凝胶可以用于多种外科应用中。例如,这些水凝胶可以用作伤口的密封剂、将外科植入物粘附到组织上的胶水、药物传输装置、涂层及其组合等。
目前仍然渴望可以用作能够为细胞提供生长发育成分的组织支架的生物相容的聚合物。
发明内容
本发明公开提供了组织支架,制备该组织支架的方法,以及使用该组织支架修复组织缺陷的方法。在实施方式中,本发明公开的组织支架可以包含:第一水凝胶前体,其包含天然组分,例如胶原、血清、明胶、透明质酸及其组合;和第二水凝胶前体,其包含亲电官能团,例如N-羟基琥珀酰亚胺、琥珀酰亚胺琥珀酸酯、琥珀酰亚胺丙酸酯、磺化琥珀酰亚胺、异氰酸酯、硫氰酸酯、碳二亚胺、苯并三唑碳酸盐(benzotrizole carbonate)及其组合,其中,所述第一水凝胶前体与第二水凝胶前体反应形成组织支架。
在实施方式中,本发明公开的方法可以包括如下步骤:确认软骨缺陷;清洗软骨缺陷;向缺陷处引入包含天然组分(例如胶原、血清、明胶、透明质酸及其组合)的第一水凝胶前体和包含N-羟基琥珀酰亚胺亲电官能团的第二水凝胶前体,其中,所述第二水凝胶前体可以为聚乙二醇、聚环氧乙烷、聚环氧乙烷-共聚-聚环氧丙烷、共聚环氧乙烷嵌段或无规共聚物、聚乙烯醇、聚(乙烯基吡咯烷酮)、聚(氨基酸)、葡聚糖、壳聚糖、藻酸盐、羧甲基纤维素、氧化纤维素、羟乙基纤维素、羟甲基纤维素、透明质酸、白蛋白、胶原、干酪素、明胶及其组合;和使所述第一水凝胶前体与第二水凝胶前体反应形成水凝胶,其中所述水凝胶在软骨缺陷处形成组织支架。
在另一方面,本发明公开提供了用于修复组织缺陷(特别是修复软骨缺陷)的包含天然组分(例如胶原、血清、明胶、透明质酸及其组合)的第一水凝胶前体和包含亲电官能团(例如,N-羟基琥珀酰亚胺、琥珀酰亚胺琥珀酸酯、琥珀酰亚胺丙酸酯、磺化琥珀酰亚胺、异氰酸酯、硫氰酸酯、碳二亚胺、苯并三唑碳酸盐及其组合)的第二水凝胶前体,其中,所述第一水凝胶前体与第二水凝胶前体反应形成如在说明书中所述的组织支架。
根据本发明公开的上述方面,在将所述第一和/或第二水凝胶前体引入前,清洗软骨缺陷是有利的。
在又一方面,本发明公开提供了在修复组织缺陷(特别是软骨缺陷)时同时、分别或依次施用包含天然组分(例如胶原、血清、明胶、透明质酸及其组合)的第一水凝胶前体和包含亲电官能团(例如N-羟基琥珀酰亚胺、琥珀酰亚胺琥珀酸酯、琥珀酰亚胺丙酸酯、磺化琥珀酰亚胺、异氰酸酯、硫氰酸酯、碳二亚胺、苯并三唑碳酸酸及其组合)的第二水凝胶前体。
在另一方面,本发明公开提供了用于修复组织缺陷(特别是软骨缺陷)的试剂盒,其包含:包含天然组分(例如胶原、血清、明胶、透明质酸及其组合)的第一水凝胶前体和包含亲电官能团(例如N-羟基琥珀酰亚胺、琥珀酰亚安琥珀酸酯、琥珀酰亚胺丙酸酯、磺化琥珀酰亚胺、异氰酸酯、硫氰酸酯、碳二亚胺、苯并三唑碳酸盐及其组合)的第二水凝胶前体。在实施方式中,根据本发明的试剂盒还包括合适的包装和/或关于组织缺陷(特别是软骨缺陷)的修复的使用说明书。
具体实施方式
本发明公开提供了包含亲电前体(有时在说明书中称作亲电交联剂)和亲核组分的水凝胶。在实施方式中,所述亲核组分为天然组分,其可以被亲电交联剂交联形成水凝胶。在实施方式中,所述水凝胶可以为可生物降解的。在说明书中使用的术语“可生物降解”定义为同时包括可生物吸收的和可生物再吸收的物质。可生物降解指的是所述物质在体内环境下分解或者失去结构完整性(例如酶降解或水解)或在体内的生理环境下分解(物理地或化学地)使得降解产物可被身体排泄出去或吸收。
所述水凝胶可以在原位形成,并可以用作药物传送装置或组织支架及其组合等。在实施方式中,所述水凝胶在植入位置可以传输和/或释放生物因子/分子和/或细胞。因而,本发明公开的水凝胶被用作组织支架,其可以通过向周围组织提供所需的营养和生物活性剂促进本身组织的再生长。在一些实施方式中(将在后面进一步描述),水凝胶本身可以包括天然的组分,例如,胶原、明胶、透明质酸及其组合等,因而,随着水凝胶的降解,天然组分可以在植入位置处被释放。在说明书中使用的术语“天然组分”包括可以在自然界中发现的或者由自然界中发现的组合物/有机物中衍生得到的聚合物、物质的组分、材料及其组合等。天然的组分也可以包括在自然界中发现的但是可以通过人工合成的组分,例如,通过使用用于产生天然/合成/生物重组体物质的方法,以及能够产生具有与在自然界中发现的蛋白具有相同序列的蛋白的方法,和/或能够产生具有与天然物质相同的结构和组分的物质的方法人工合成的组分,例如,市售可得的合成的透明质酸,如,其可以从SigmaAldrich购买。
例如,用于在组织上或者组织中形成水凝胶的组分包括原位形成材料。所述原位形成材料可以包括在“原位”形成水凝胶的单一前体或多种前体,这意味着水凝胶的形成发生在活的动物或人体内的组织中。一般而言,在实施方式中,这可以通过使在施用时能够被活化的前体形成水凝胶来实现。可以通过多种方法进行活化,这些方法包括,但不限于,如pH、电离度、温度等的环境变化。在其它实施方式中,所述用于形成水凝胶的组分可以在身体外面接触,然后作为植入体(例如,(预形成)的组织支架)引入到患者体内。
如上所述,原位形成材料可以由一种或多种前体制备。所述前体可以为,例如单体或大分子单体。一种前体可以含有亲电或亲核的官能团。亲电试剂与亲核试剂反应形成共价键。共价交联或共价键指的是通过不同聚合物上的官能团的反应形成的化学基团,该化学基团起到使不同的聚合物相互共价地结合的作用。在某一实施方式中,第一前体的第一组亲电官能团可以与第二前体的第二组亲核官能团反应。当在允许反应的环境(例如,涉及pH或溶剂)中混合所述前体时,所述官能团相互反应形成共价键。当至少一些前体可以与不止一种的其它前体反应时,所述前体就被交联。例如,具有两个第一类官能团的前体可以与具有至少3个能够与第一类官能团反应的第二类官能团的交联前体反应。
在实施方式中,所述水凝胶可以由一种或多种前体形成。例如,在所述水凝胶由多种前体形成时,例如,两种前体,所述前体可以称作第一和第二水凝胶前体。术语“第一水凝胶前体”和“第二水凝胶前体”分别指的是可以参与反应形成交联分子的网络(如,水凝胶)的聚合物、功能聚合物、大分子、小分子或交联剂。
在说明书中使用的术语“官能团”指的是能够彼此反应形成键的亲电或亲核基团,例如,亲电官能团包括N-羟基琥珀酰亚胺(″NHS″);磺化琥珀酰亚胺;碳酰二咪唑;磺酰氯;芳基卤化物;磺化琥珀酰亚胺酯;N-羟基琥珀酰亚胺酯;琥珀酰亚胺酯,例如琥珀酰亚胺琥珀酸酯和/或琥珀酰亚胺丙酸酯;异氰酸酯;硫氰酸酯;碳二亚胺;苯并三唑碳酸盐;环氧化物;醛;马来酰亚胺;亚氨酸酯及其组合等。在实施方式中,所述亲电官能团为琥珀酰亚胺酯。
所述亲电水凝胶前体可以具有生物惰性的和水溶性核,以及非水溶性的核。当所述核为水溶性的聚合物区域时,可以使用的合适的聚合物包括:聚醚,例如聚环氧烷烃,如聚乙二醇(“PEG”)、聚环氧乙烷(“PEO”)、聚环氧乙烷-聚环氧丙烷共聚物(“PPO”)、环氧乙烷的嵌段或无规共聚物和聚乙烯醇(“PVA”);聚(乙烯基吡咯烷酮)(“PVP”);聚(氨基酸);聚(糖),例如,葡聚糖、壳聚糖、藻酸盐、羧甲基纤维素、氧化纤维素、羟乙基纤维素、羟甲基纤维素;透明质酸;以及蛋白,例如白蛋白、胶原、干酪素和明胶。在实施方式中,可以使用前述聚合物的组合。
在一些实施方式中可以使用聚醚,特别是聚(氧化烯)或聚(乙二醇)或聚乙二醇。当就分子性能而言核较小时,任意种类的亲水官能团可以用于使第一和第二水凝胶前体可水溶。例如,如羟基、胺基、磺酸根(sulfonate)和羧酸根的官能团为可水溶性的,可以用于使前体可水溶。例如,琥珀酸的N-羟基琥珀酰亚胺(″NHS″)酯在水中为不溶的,但是通过将磺酸根加入到琥珀酰亚胺环上可以使琥珀酸的NHS酯水溶,而不影响胺基的反应性。
第一和第二水凝胶前体各自可以为多官能度,意味着其可以包含两个以上的亲电或亲核官能团,例如,使得第一水凝胶前体上的亲核官能团可以与第二水凝胶前体上的亲电官能团反应形成共价键。第一或第二水凝胶前体中的至少一种包含超过两个的官能团,因此,作为亲电-亲核反应的结果,所述前体结合形成交联的聚合产物。
具有亲电官能团的大分子可以为多臂。例如,所述大分子可以为具有从核中延伸出的具有4、6、8或更多臂的多臂PEG。所述核可以与形成臂的大分子相同或不同。例如,所述核可以为PEG,以及所述多臂也可以为PEG。在实施方式中,所述核可以为天然聚合物。
亲电交联剂的分子量(Mw)为大约2,000道尔顿(Da)至大约100,000Da;在实施方式中,为大约10,000Da至大约40,000Da。多臂前体的分子量可以根据臂的数目的不同而不同。例如,具有1000Mw的PEG的臂具有足够的CH2CH2O基团来达到总数至少1000Mw。单个臂的相加分子量可以为大约250Da至大约5,000Da;在实施方式中,为大约1,000Da至大约3,000Da,在实施方式中为大约1,250Da至大约2,500Da。在实施方式中,所述亲电交联剂可以为被多个NHS基团官能化的多臂PEG,例如,该多臂PEG具有4、6或8臂,分子量为大约5,000Da至大约25,000Da。在美国专利第6,152,943号;第6,165,201号;第6,179,862号;第6,514,534号;第6,566,406号;第6,605,294号;第6,673,093号;第6,703,047号;第6,818,018号;第7,009,034号和第7,347,850号中描述了合适的前体的其它实例,其各自公开的内容以引用方式整体并入本文。
所述亲电前体可以为交联剂,该交联剂提供能够与另一组分上的亲核官能团结合的亲电官能团,在实施方式中,所述另一组分为天然组分。所述天然组分对施用亲电交联剂的患者来说可以是内源性的,或者可以外源性地施用。
在实施方式中,所述前体之一可以为具有亲核基团的天然组分。可以存在的亲核基团包括,例如,-NH2、-SH、-OH、-PH2和-CO-NH-NH2。
例如,所述天然组分可以为胶原、明胶、血液(包括血清,其可以是全血清或其提取物)、透明质酸、蛋白、白蛋白、其它血清蛋白、血清浓缩物、富含血小板的血浆(prp)及其组合等。可以使用的或者可以加入到另一种天然组分中的另外的合适的天然组分(有时在本说明书中称作生物活性剂)包括,例如,干细胞、DNA、RNA、酶、生长因子、肽、多肽、抗体、其它含氮的天然分子及其组合等。其它天然组分可以包括上述化合物的衍生物,例如,改性的透明质酸、葡聚糖、其它多糖、聚合物和/或多肽,包括:可以为天然得到的、合成的或生物学上得到的胺化的多糖。例如,在实施方式中,可以改性透明质酸以使其亲核。
在实施方式中,任意上述天然组分可以通过合成制备,例如使用本领域的技术人员已知的方法合成透明质酸。同样地,在实施方式中,所述天然组分可以为天然或合成的长链胺化的聚合物。也可以改性天然组分,即,胺化以形成亲核聚合物。
所述天然组分可以在原位向与其接触的组织提供细胞构成团块或细胞营养。例如,血清包含用于组织的形成或再生的蛋白、葡萄糖、凝固因子、矿物离子和激素。
在实施方式中,所述天然组分包括全血清。在实施方式中,所述天然组分为自体同源的,即,来自形成(或即将形成)水凝胶的体内的胶原、血清、血液等。照这样,即将使用水凝胶的人或动物可以提供用于形成水凝胶的天然组分。在这个实施方式中,所得的水凝胶为半自体同源的,包括合成的亲电前体和自体同源/内源的亲核前体。
在实施方式中,多官能的亲核聚合物(例如具有多个胺基的天然组分)可以用作第一水凝胶前体,以及多官能亲电聚合物(例如被多个NHS官能团官能化的多臂PEG)可以用作第二水凝胶前体。在实施方式中,所述前体可以为溶液形式,其可以结合形成水凝胶。作为原位形成材料体系的部分的任何溶液不能包含有害的或有毒的溶剂。在实施方式中,所述前体基本上可以溶于溶剂(例如水)中而使得与生理相容的溶液的形式施用,例如缓冲的等渗生理盐水(buffered isotonic saline)。
在实施方式中,水凝胶可以由作为天然组分的胶原和明胶与用作交联剂的多官能化的PEG化合反应形成。在实施方式中,使用合适的溶剂可以将所述胶原或明胶置于溶液中。这种缓冲溶液可以具有大约8至大约12的pH值,在实施方式中,具有大约8.2至大约9的pH值。这种缓冲溶液的实例包括,但不限于,硼酸盐缓冲溶液等。
在第二溶液中,亲电交联剂(在实施方式中,被亲电基团(例如,N-羟基琥珀酰亚胺)官能化的多臂PEG)可以在缓冲溶液中制备,例如,Hanks平衡盐溶液(Hanks Balanced Salt solution)、达尔伯克改良伊格尔培养基(Dulbecco′s Modified Eagle′s Medium)、磷酸盐缓冲生理盐水、水、磷酸盐缓冲液及其组合等。亲电交联剂(在实施方式中为被N-羟基琥珀酰亚胺基团官能化的多臂PEG)可以以大约0.02g/mL至大约0.5g/mL(在实施方式中以大约0.05g/mL至大约0.3g/mL)的浓度存在于包含上述缓冲溶液的溶液中。
可以原位引入所述两种组分,其中,所述多臂PEG的亲电基团交联胶原和/或明胶的胺亲核组分。天然组分与亲电组分的比率(即,胶原∶PEG)可以为大约0.1∶1至大约100∶1,在实施方式中,为大约1∶1至大约10∶1。
所述天然组分,例如,胶原、明胶和/或透明质酸可以至少以水凝胶的大约1.5重量%的浓度一起存在,在实施方式中,以水凝胶的大约1.5重量%至大约20重量%存在,在其它实施方式中,以水凝胶的大约2重量%至大约10重量%存在。在某些实施方式中,胶原可以以水凝胶的大约0.5重量%至大约7重量%存在,在另一实施方式中,以水凝胶的大约1重量%至大约4重量%存在。在又一实施方式中,明胶可以以水凝胶的大约1重量%至大约20重量%存在,在另一实施方式中,以水凝胶的大约2重量%至大约10重量%存在。在再一实施方式中,混合(combine)作为天然组分的透明质酸和胶原可以以水凝胶的大约0.5重量%至大约8重量%存在,在另一实施方式中,以水凝胶的大约1重量%至大约5重量%存在。还可以预见所述透明质酸可以不作为“结构性”组分存在,而是作为生物活性剂存在。例如,透明质酸可以以低达溶液/凝胶的0.001重量%的浓度存在于溶液/凝胶中,并具有生物活性。
所述亲电交联剂可以以水凝胶的大约0.5重量%至大约20重量%存在,在实施方式中,以水凝胶的大约1.5重量%至大约15重量%存在。
原位形成材料可以通过共价键、离子键或疏水键形成。络合作用、氢键、去溶剂化、范德华相互作用、离子键合及其组合等可以导致物理(非共价)交联,并且可以通过混合两种前体(直至原位混合前它们是物理上分开的)而被引发,或者作为生理环境的通常条件的结果而被引发,这些条件包括:温度、pH、离子强度及其组合等。化学(共价)交联可通过许多机理中的任意一种机理实现,这些机理包括:自由基聚合、缩聚、阴离子或阳离子聚合、逐步增长聚合、亲电-亲核反应及其组合等。
在一些实施方式中,原位形成材料体系可以包括生物相容的多前体体系,当将前体混合时,所述多前体体系自动交联,但是其中两种以上的前体在沉积期间(deposition process)各自稳定。在其它实施方式中,原位形成材料可以包括与内源材料和/或组织交联的单一的前体。
通过交联剂和天然组分的总分子量和每个分子能够提供的的官能团的数目可以控制所得的生物相容的交联聚合物的交联密度。与更高的分子量(例如10,000Da)相比,交联体之间的低分子量(例如600Da)将得到更高的交联密度。用具有大于3000Da的分子量的更高分子量的天然组分可以得到弹性凝胶。
通过交联剂和天然组分溶液的总体固体百分比也可以控制交联密度。增加固体百分比将会在水解钝化之前增加亲电基团与亲核基团化合反应的几率。控制交联密度的又一方法是调节亲核基团与亲电基团的化学计量。1∶1可以导致最高的交联密度,然而,可以预见其它反应活性官能团的比率(例如,亲电∶亲核)适合于所需的配方(to suit a desired formulation)。
包含亲核官能团的天然组分与亲电官能化的前体反应形成水凝胶。所述反应可以在原位发生或在身体外面发生反应以将来移植到其中或其上。在实施方式中,本发明公开的水凝胶可以通过前体化合反应制备,所述前体在被施用到表面上(例如,在患者的组织上)之后迅速交联形成原位形成材料。
如此制备的水凝胶可以为可生物吸收的,因而无需从体内回收。可吸收的材料被生物组织吸收并在一定的期间内在体内消失,例如,根据所述材料的化学性质,所述期间是可以变化的,例如,其可以为一天至数月。可吸收的材料同时包括天然的和合成的可生物降解的聚合物和可生物蚀解的聚合物。
在实施方式中,可以包含具有存在于官能团之间的可生物降解的连接的一种或多种前体以制备生物可降解或可吸收的水凝胶。在一些实施方式中,例如,这些连接可以为在生理溶液中可以通过水解降解的酯。使用这种连接可与可以被蛋白水解作用降解的蛋白连接相媲美(be in contrast to)。可生物降解的连接也可以非必需地形成一种或多种前体的的水溶性核部分。或者,或此外,可以选择前体的官能团使得它们之间的反应的产物生成可生物降解的连接。对于各种方法,可以选择可生物降解的连接使得所得的可生物降解的生物相容的交联聚合物在所需的时期内降解或者被吸收。一般而言,可以选择在生理条件下将所述水凝胶降解成无毒的或低毒产物的可生物降解的连接。
不管是天然组分部分或者引入到合成的亲电交联剂的部分,由于可生物降解区域的水解或酶促降解使得本发明公开的凝胶可以降解。包含合成肽序列的凝胶的降解将取决于特异酶及其浓度。在一些情形下,在交联反应过程中可加入特异酶以加速降解过程。在没有任何可降解酶的情况下,所述交联聚合物可以单独地通过可生物降解部分的水解而降解。在其中聚甘醇酸酯(polyglycolate)被用作可生物降解部分的实施方式中,根据网络的交联密度所述交联的聚合物可以在大约1天至大约30天内降解。类似地,在其中使用聚己酸内酯基的交联网络的实施方式中,在大约1个月至大约8个月的时期内可以发生降解。降解的时间通常根据所使用的可降解的部分的类型而变化,降解时间的次序如下:聚甘醇酸酯<聚乳酸酯<聚碳酸亚丙基酯<聚己酸内酯。因此,使用合适的降解部分,可以制备具有所需的降解性能的水凝胶,从数天至数月。
在使用时,由可生物降解链段(例如,用于形成亲电交联剂的PLURONICTM或TETRONIC TM聚合物中的低聚醇酸链段或疏水性的PPO链段)产生的疏水性可以有助于溶解小有机药物分子。由于加入可生物降解的或疏水链段而受到影响的其它性能包括:吸水率、机械性能和热敏性。
可以根据所需的用途选择原位形成材料体系的性能。例如,如果原位形成材料打算用于暂时堵塞生殖器官,例如输卵管,较理想地,原位形成材料体系经历显著的溶胀并为可生物降解的。或者,原位形成材料具有血栓形成性,或者其前体可以与血液或其它体液反应形成凝块。在实施方式中,所述前体(其可以内源性的或外源性地施用)与血液或体液反应,从而形成组织支架。
其它用途可能需要所述原位形成材料体系的不同特性。一般而言,应该基于显示的生物相容性和无毒性来选择材料。
可以应用原位形成材料的某些性能,这些性能包括:对各种组织的粘附性、能够使外科医生精确和方便地放置原位形成材料的合意的凝固时间、用于生物相容性的高含水量(其与水凝胶紧密相关)、用于密封剂的机械强度和/或在植入后对抗破坏的韧性。可以使用容易消毒并可避免由于使用天然材料引起的疾病的传播的合成材料。实际上,使用合成的前体制备的某些原位可聚合的水凝胶是本领域的技术人员所熟知的,例如,所使用的市售可得的产物,如(Genzyme,Inc.)、(Angiotech Pharmaceuticals)和(Confluent Surgical,Inc)。其它已知的水凝胶包括,例如,在美国专利申请第6,656,200号;第5,874,500号;第5,543,441号;第5,514,379号;第5,410,016号;第5,162,430号;第5,324,775号;第5,752,974号;和第5,550,187号描述的那些水凝胶。
如上所述,在实施方式中,可以包含支化的多臂PEG(在本说明书中有时称作星形PEG)以形成本发明公开的水凝胶。可以使星形PEG官能化使得其臂包含生物官能团(例如氨基酸、肽、抗体、酶、药物及其组合),或使在其核、臂或在臂的末端的其它部分(例如生物活性剂)官能化。也可以将生物官能团引入到PEG的主链上,或者附着到包含在PEG主链上的反应基团上。所述结合可以为共价或非共价结合,包括静电、硫醇介导的、肽介导的或使用已知的反应化学试剂,例如具有卵白素的生物素。
引入到星形PEG上的氨基酸可以为天然的或合成的,并可以单独使用或作为肽部分使用。可以使用序列进行细胞粘附、细胞分化及其组合等,并可以有利于结合其它生物分子,例如生长因子、药物、细胞活素类、DNA、抗体、酶及其组合等。这些氨基酸可以通过星形PEG的酶促降解而释放。
这些星形PEG还可以包含上述官能团来其引入到水凝胶中。所述星形PEG可以用作亲电交联剂或者,在实施方式中,除了上述的亲电交联剂外,还可以用作单独的组分。在实施方式中,所述星形PEG可以包含结合到亲核基团上的亲电基团。如上所述,所述亲核基团可以为用于形成本发明公开的水凝胶的天然组分部分。
在一些实施方式中,生物官能团可以通过可降解连接包括在星形PEG中,所述连接包括通过PEG羧酸或活化的PEG羧酸与生物官能团上的醇基反应形成的酯连接。在这种情况下,所述酯基团可以在生理条件下水解以释放生物官能团。
在实施方式中,原位形成材料还可以包含引发剂。引发剂可以为能够引发形成所述原位形成材料的聚合反应的任何前体或基团。
原位聚合
在使用前可以溶解所述前体以形成溶液,将该溶液施用给患者。如在本说明书中所使用,溶液可以为均相的,异相的、相分离的等。在其它实施方式中,所述前体可以在乳液中。适合于本发明公开的用途的溶液包括可以在腔中或空隙中形成植入体的那些溶液。当采用两种溶液时,各溶液可以包含一种通过接触形成原位形成材料的前体。所述溶液可以分别存储并在传输给组织时混合。
如上所述的亲电交联剂可以与天然组分反应以产生交联的聚合网络。一般而言,可以将交联剂的水溶液与天然组分混合以产生交联的水凝胶。形成交联的聚合水凝胶的反应条件取决于官能团的性能。在实施方式中,在pH为大约5至大约12的缓冲水溶液进行反应。缓冲水溶液包括,例如,磷酸盐缓冲生理盐水(PBS)、Hanks平衡盐溶液、达尔伯克改良伊格尔培养基、水、磷酸盐缓冲溶液、硼酸钠缓冲溶液、三乙醇胺缓冲溶液及其组合等。在一些实施方式中,可以加入有机溶剂(例如乙醇或异丙醇)以提高反应速率或调节给定制剂的粘度。
当亲电交联剂是合成的(例如,基于聚环氧烷烃),合意的是使用摩尔当量的反应物。在一些情况下,可以加入摩尔过量的亲电交联剂以补偿副反应,例如由于官能团的水解引起的反应。
如果需要所得的生物相容的交联的聚合物为生物可降解的,当选择亲电交联剂和天然组分时,至少一种前体可以具有超过两个官能团/分子和至少一个可降解的区域。
可以制备适合于使前体交联反应原位发生的制剂。一般而言,这可以通过使前体形成水凝胶来实现,所述前体在施用到组织上时能够被活化。假定使前体在交联前与组织的形状一致且相关的凝胶化作用不是太提前,可以在将前体施用到组织之前、之中或之后进行活化。活化包括,例如,使含有相互反应的官能团的前体混合。因此,原位聚合包括使化学部分活化形成共价键以在患者体内、体表或者同时在体内和体表上植入材料的地方形成不溶的材料,例如,水凝胶。原位可聚合的聚合物可以由能够反应的前体制备,以使所述前体在患者体内形成聚合物。因此可以使含有亲电官能团的前体与亲核官能团的前体混合,要不然,在含有亲核官能团的前体的存在下使含有亲电官能团的前体活化。
至于涂布组织,本公开不受限于具体的操作理论,相信在与组织表面接触后迅速交联的活性反应前体形态可以形成与涂布的组织机械互锁的三维结构。这种互锁促成组织的涂布区域的粘附、密切接触和持续覆盖。在其它实施方式中,在使用亲电前体时,这种前体可与组织中的自由胺反应,从而用作将所述水凝胶粘附到组织上的方法。
在一些实施方式中,在大约1秒至大约5分钟,在实施方式中,在大约3秒至大约1分钟的时间内可以发生导致胶凝的交联反应;本领域的技术人员将会立即理解这些明确声明范围内的所有范围和数值都是经慎重考虑的。例如,在实施方式中,根据本发明公开的水凝胶的原位胶凝时间少于大约20秒,以及在一些实施方式中,少于大约10秒,以及在再一实施方式中,少于大约5秒。
施用
如上所述,亲电交联剂可以通过自身引入,由此其可以交联内源性天然组分。或者,可以从患者身上得到的或者从其它来源上得到天然组分,然后,与亲电交联剂一起引入以形成本发明公开的水凝胶,例如,如血浆。在使用前,可以将前体置入到溶液中,将该溶液施用给患者。可以使用注射器来传输单一的前体,即,亲电交联剂,或使用双注射器或类似的装置来传输超过一一种的前体溶液,例如,在美国专利第4,874,368号、第4,631,055号、第4,735,616号、第4,359,049号、第4,978,336号、第5,116,315号、第4,902,281号、第4,932,942号、第6,179,862号、第6,673,093号和第6,152,943号中所述的那些。
在其它实施方式中,可以将所述前体结合来生成膜或泡沫,然后可以将这些膜和泡沫植入到患者体内。生成膜和泡沫的方法为本领域的技术人员所知,其包括但不限于喷雾法、膜铸塑法、冻干技术等。
用途
如上所述,本发明公开的水凝胶可以用作组织粘合剂或密封剂。所述水凝胶也可以用于修复组织缺陷。如在本说明书中所用的“组织缺陷”可以包括任何偏离正常、健康状态的损坏(breakdown)。这种损坏可能归因于内因(退行性疾病)或者外因(例如受伤)。组织的正常结构的任何变异可以为“组织缺陷”。在一些实施方式中,当用于修复组织缺陷时,本发明公开的水凝胶可以称作组织支架。
所述水凝胶组合物可以用于软骨修复、腱修复、韧带修复、骨关节炎的治疗、骨填充剂、修复软组织缺陷、作为软/硬组织界面的填料、和/或一般器官或组织修复。一般器官或组织修复可以包括,例如,肠胃、胸腔、心脏、神经或其它器官的修复。
在实施方式中,当用于软骨修复时,使用本发明公开的水凝胶的方法可以包括确认软骨缺陷,然后清洗软骨缺陷。一旦软骨被清洗,可以将本发明公开的水凝胶组合物引入到缺陷中。如上所述,在实施方式中,可以将至少一种水凝胶前体引入到其中。在实施方式中,前体中的一种,有时称作第一水凝胶前体,可以为具有亲核基团的天然组分。如上所述,所述天然组分可以为内源性的或外源性施用的。含有亲电官能团的第二前体也可以使用上述的或者在本领域的技术人员已知的范围内的方法或装置施用到缺陷上。然后,使第一水凝胶前体和第二水凝胶前体反应形成水凝胶,其可在软骨缺陷处用作组织支架。
所述水凝胶可以为多孔或光滑的。在某些实施方式中,所述水凝胶可以为多孔。在本说明书中使用的术语“多孔”指的是所述水凝胶可以具有作为表面特征或疏松材料性能存在的部分或完全穿透水凝胶的限定开口和/或空间。可以使用本领域的技术人员已知的办法生成孔,这些方法包括,但不限于,例如,烧结方法、盐浸取法、糖或淀粉结晶法。多孔材料可以具有开孔(opencell)结构,其中,所述孔相互连接,形成互联的网络。相反,水凝胶可以为闭孔结构,其中,所述孔没有互联。
所述水凝胶可以涂布或包含额外的生物活性剂。如在说明书中所使用的术语“生物活性剂”是以最广泛的意义使用,并且包括具有临床用途的任何物质或物质的混合物。因此,生物活性剂本身可具有或不具有药理学上的活性,例如染料。
或者,生物活性剂可以为提供治疗或预防效果的任何试剂;影响或参与组织的生长、细胞生长、细胞分化的化合物;抗粘附化合物;能够激起生物响应(例如免疫响应)或者在一个或多个生物过程中起到任何其它作用的化合物。可以预想到,所述生物活性剂可以以任何合适的物质形式(例如,膜、粉、液体、凝胶等)施用到水凝胶上。
如上所述,在包括多臂PEG或PEG星的实施方式中,可以将所述生物活性剂引入到PEG的核、PEG的臂或其组合中。在实施方式中,可以将生物活性剂附着到PEG链的反应性基团上。生物活性剂可以通过硫醇介导或肽介导,或者使用生物素-卵白素化学品等共价地、非共价地(例如静电)结合。
根据本发明公开可以使用的生物活性剂类的实例包括,例如,抗粘附剂(anti-adhesives)、抗菌剂(antimicrobials)、镇疼剂(analgesics)、退热药(antipyretics)、麻醉剂(anesthetics)、抗癫痫剂(antiepileptics)、抗组胺类(antihistamines)、消炎药(anti-inflammatories)、心血管药物(cardiovasculardrugs)、诊断用药(diagnostic agents)、拟交感神经药(sympathomimetics)、拟胆碱能药(cholinomimetics)、抗毒蕈碱药(antimuscarinics)、镇痉剂(antispasmodics)、激素(hormones)、生长因子(growth factors)、肌松药(musclerelaxants)、肾上腺素能神经元阻滞剂(adrenergic neuron blockers)、抗肿瘤药(antineoplastics)、免疫原性试剂(immunogenic agent)、免疫抑制剂(immunosuppressants)、胃肠药(gastrointestinal drugs)、利尿剂(diuretics)、类固醇(steroids)、类脂(lipids)、脂多糖类(lipopolysaccharides)、多糖(polysaccharides)、血小板活化剂(platelet activating drug)、凝固因子(clottingfactors)和酶。还包括可以使用的生物活性剂的组合。
抗粘附剂可以用于防止在水凝胶和与目标组织相对的周围组织之间形成粘附。此外,抗粘附剂可以用于防止涂布的可植入的医疗器件与包装材料之间形成粘附。这些试剂的一些实例包括,但不限于,亲水聚合物,例如聚(乙烯基吡咯烷酮)、羧甲基纤维素、透明质酸、聚环氧乙烷、聚乙烯醇及其组合。
合适的抗菌剂(可以包含其作为生物活性剂)包括,例如,三氯生(又称2,4,4′-三氯-2′-羟基二苯基醚);洗必泰及其盐,包括醋酸洗必泰、葡萄糖酸洗必泰、洗必泰盐酸盐和洗必泰硫酸盐;银及其盐,包括醋酸银、苯甲酸银、碳酸银、柠檬酸银、碘酸银、碘化银、乳酸银、月桂酸银、硝酸银、氧化银、棕榈酸银、蛋白银、磺胺嘧啶银;多粘菌素;四环素;氨基糖甙类,例如,妥布拉霉素和庆大霉素;利福平;枯草杆菌肽;新霉素;氯霉素;咪康唑;喹诺酮类,例如奥索利酸、诺氟沙星、萘啶酮酸、培氟沙星、依诺沙星和环丙沙星;青霉素类,例如苯唑西林和哌拉西林钠输注液(pipracil);壬苯醇醚9;夫西地酸;先锋霉素类及其组合。此外,可以包含抗菌蛋白和肽,例如牛乳铁蛋白和乳铁蛋白肽B(lactoferricin B)作为生物活性剂。
可以作为生物活性剂包含的其它生物活性剂包括:局部麻醉药;非类固醇类的抗生育剂;拟副交感神经药;精神治疗药物;安定药;解充血药;镇静催眠药;类固醇;磺胺类药;拟交感神经药;疫苗;维生素;抗疟药;抗偏头痛药;抗震颤麻痹药,例如左旋多巴;镇痉剂;抗胆碱能药物(例如奥昔布宁);镇咳药;支气管扩张剂;心血管药,例如冠脉扩张药和硝化甘油;生物碱(alkaloids);镇痛药;麻醉药,例如可待因、二氢可待因酮、哌替啶、吗啡等;非-麻醉药,例如水杨酸盐、阿斯匹林、扑热息痛、右丙氧芬(d-propoxyphene)等;阿片受体拮抗剂,例如纳屈酮和纳洛酮;抗癌药;抗惊厥剂;止吐药;抗组胺类;抗炎药,例如激素药、氢化可的松、泼尼松龙、泼尼松、非激素药、别嘌呤醇、吲哚美辛、保泰松等;前列腺素和细胞毒类药物;化学治疗药物;雌激素;抗菌药物;抗生素;抗真菌药;抗病毒药物;抗凝血剂;抗惊厥剂;抗抑郁药;抗组胺类;和免疫药。
可以包含在水凝胶中的合适的生物活性剂的其它实例包括,例如,病毒和细胞,包括干细胞;肽、多肽和蛋白及其类似物、突变蛋白和它们的活性片段;免疫球蛋白类;抗体;细胞活素类(例如,淋巴因子、单核因子、化学增活素);血液凝血因子;造血因子;白细胞介素(IL-2、IL-3、IL-4、IL-6);干扰素类(β-IFN、α-IFN和γ-IFN);红细胞生成素;核酸酶;肿瘤坏死因子;集落刺激因子(例如,GCSF、GMCSF、MCSF);胰岛素;抗肿瘤剂和肿瘤抑制基因;血液蛋白,例如纤维蛋白、凝血酶、纤维蛋白素原、合成凝血酶、合成纤维蛋白、合成维蛋白素原;维蛋白素原(例如,FSH、LH、CG等);激素类和激素类似物(例如,生长激素);疫苗(例如肿瘤、细菌和病毒抗原);促生长素抑制素;抗原类;凝血因子;生长因子(例如,神经生长因子、胰岛素样生长因子);成骨蛋白;TGF-B;蛋白抑制剂;蛋白拮抗剂;核酸,例如反义分子、DNA、RNA、RNAi;低聚核苷酸;聚核苷酸p;和核酶。
所述前体和/或由所述前体形成的水凝胶可以包含显色剂(visualizationagent)以提高在手术过程中它们的可见性。显色剂可以选自一系列无毒有色物质,例如适合用于可植入的医疗器件的染料。合适的染料在本领域的技术人员所知的范围内,并可以包括,例如当原位形成时用于显现水凝胶厚度的染料,例如,在美国专利第7,009,034号中所述的那些染料。在一些实施方式中,合适的染料可以包括,例如,FD&C Blue#1、FD&C Blue#2、FD&C Blue#3、FD&C Blue#6、D&C Green#6、亚甲蓝、吲哚花青绿、其它有色染料及其组合。可以预见的是可以使用额外的显色剂,例如荧光化合物(例如荧光素(flurescein)或曙红)、X射线造影剂(例如碘化的化合物)、超声波造影剂和MRI造影剂(例如含钆的化合物)。
所述显色剂可以存在于交联剂或者天然组分溶液中。所述有色物质可以或没有被并入到所得水凝胶中。然而,在实施方式中,所述显色剂没有能够与交联剂或天然组分反应的官能团。
所述显色剂的用量很小,在实施方式中,少于1%重量/体积,以及在其他实施方式中,少于0.01%重量/体积,在又一实施方式中,少于0.001%重量/体积浓度。
在实施方式中,所述生物活性剂可以被所述水凝胶所包裹。例如,所述水凝胶可以在生物活性剂周围形成聚合物微球。
当所述水凝胶被用作组织支架时,合意的是包含促进伤口愈合和/或组织生长的生物活性剂,包括菌落刺激因子、血液蛋白、血纤蛋白、凝血酶、纤维蛋白素原、激素或激素类似物、血液凝血因子、生长因子、成骨蛋白、TGF-β、IGF及其组合等。
由于所述水凝胶在原位水解,生物活性组分和加入的任何生物活性剂被释放。这可以从天然组分和生物活性剂向周围组织提供营养,从而促进组织的生长和/或再生。
提出的下面的实施例用于阐明本发明公开的实施方式。这些实施例意欲仅用于阐明,而非限制本发明公开的范围。此外,除非另外指出,份或者百分数均为重量份或重量百分数。
实施例1
按照如下方法制备水凝胶。使用超声发生器在大约37℃下将胶原溶解在硼酸盐缓冲溶液(pH 8.75)中大约5分钟得到最终浓度为大约3重量%至大约6重量%。然后离心所述胶原溶液以除去气体/气泡。另外,将多臂PEG溶解在Hanks缓冲溶液(中性pH)中以得到最终浓度为大约4重量%至大约40重量%。然后将两种溶液以1∶1的比率原位同时喷雾得到最终的凝胶浓度:大约1.5重量%至大约3重量%的胶原,以及大约2.5重量%至大约20重量%的PEG。
实施例2
除了胶原∶PEG为10∶1之外,按照实施例1中的方法制备水凝胶以得到最终凝胶浓度:大约0.5重量%至大约4重量%的多臂PEG,以及大约3重量%至大约6重量%的胶原。
实施例3
按照如下方法制备水凝胶。将明胶以大约5重量%至大约15重量%溶解在pH为大约8.25的硼酸盐缓冲溶液中。另外,将多臂PEG以大约5重量%至大约20重量%溶解在Hanks缓冲溶液中。将溶液以1∶1的比率原位同时喷雾得到最终的凝胶浓度:2.5重量%至大约7.5重量%的明胶,以及大约2.5重量%至大约10重量%的多臂PEG。
实施例4
按照如下方法制备水凝胶。将透明质酸以最高大约2重量%溶解在pH为中性的Hanks缓冲溶液中。接着,将多臂PEG以大约5重量%至大约20重量%的浓度加入到透明质酸溶液中。在另一容器中,将胶原以最终浓度为大约3重量%至大约6重量%溶解在硼酸盐缓冲溶液(pH 8.75)中。然后将两种溶液以1∶1的比率原位喷雾。最终的凝胶浓度:大约1重量%的透明质酸,大约1.5重量%至大约3重量%的胶原,以及大约2.5重量%至大约10重量%的多臂PEG。
实施例1、3和4的凝胶的组分归结在下面的表1中。
表1原位形成水凝胶配方和条件
4a10kSS:4臂PEG;分子量(Mw)10kDa;SS(琥珀酰亚胺琥珀酸酯)连接体
4a20kSG:4臂PEG;Mw 20kDa;SG(琥珀酰亚胺戊二酸酯)连接体
8a15kSG:8臂PEG;Mw 15kDa;SG连接体
*注意:浓度为各组分在按1∶1混合前的浓度。
应该指出当在原位形成上述列出的实施例时,所述材料可以在体外形成,然后用作原位植入物。
虽然上面的描述包含许多细节,但是这些细节不应该解释成限制本发明公开的范围,而是仅仅作为其优选的实施方式的例证。本领域的技术人员将会预见在本发明公开实质和范围内的许多其它可能的变化。
Claims (9)
1.一种组织支架,其包含:
第一水凝胶前体,其包含选自胶原、血清、明胶、透明质酸及其组合中的天然组分;和
第二水凝胶前体,其包含选自N-羟基琥珀酰亚胺、琥珀酰亚胺琥珀酸酯、琥珀酰亚胺丙酸酯、磺化琥珀酰亚胺、异氰酸酯、硫氰酸酯、碳二亚胺、苯并三唑碳酸盐及其组合中的亲电官能团,
其中,所述第一水凝胶前体与第二水凝胶前体反应形成所述组织支架,
其中,所述组织支架进一步包含用组分功能化的至少一种多臂聚乙二醇,所述组分选自生物活性剂。
2.根据权利要求1所述的组织支架,其中,所述天然组分包含亲核官能团。
3.根据权利要求1所述的组织支架,其中,所述第一水凝胶前体为外源性施用的。
4.根据权利要求1所述的组织支架,其中,所述第一水凝胶前体为内源性的,并且所述组织支架为半自体同源的。
5.根据权利要求1所述的组织支架,其中,所述第二水凝胶前体包含含有N-羟基琥珀酰亚胺基团的聚乙二醇。
6.根据权利要求1所述的组织支架,其中,所述至少一种多臂聚乙二醇具有4个臂。
7.根据权利要求1所述的组织支架,其中,所述第一水凝胶前体以组织支架的1.5重量%至20重量%存在,以及所述第二水凝胶前体以组织支架的0.5重量%至20重量%存在。
8.根据权利要求1所述的组织支架,其中,所述生物活性剂选自干细胞、DNA、RNA、酶、生长因子、肽、抗体及其组合。
9.一种用于修复组织缺陷的试剂盒,其包含:
第一水凝胶前体,其包含选自胶原、血清、明胶、透明质酸及其组合中的天然组分;和
第二水凝胶前体,其包含选自N-羟基琥珀酰亚胺、琥珀酰亚胺琥珀酸酯、琥珀酰亚胺丙酸酯、磺化琥珀酰亚胺、异氰酸酯、硫氰酸酯、碳二亚胺、苯并三唑碳酸盐及其组合中的亲电官能团,
其中,所述试剂盒进一步包含用组分功能化的至少一种多臂聚乙二醇,所述组分选自生物活性剂。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24799809P | 2009-10-02 | 2009-10-02 | |
US61/247,998 | 2009-10-02 | ||
US12/888,456 US8968785B2 (en) | 2009-10-02 | 2010-09-23 | Surgical compositions |
US12/888,456 | 2010-09-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102028968A CN102028968A (zh) | 2011-04-27 |
CN102028968B true CN102028968B (zh) | 2015-03-25 |
Family
ID=43733336
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201010501269.XA Expired - Fee Related CN102028968B (zh) | 2009-10-02 | 2010-10-08 | 外科用组合物 |
Country Status (6)
Country | Link |
---|---|
US (1) | US8968785B2 (zh) |
EP (1) | EP2314326A3 (zh) |
JP (1) | JP5721386B2 (zh) |
CN (1) | CN102028968B (zh) |
AU (1) | AU2010226931A1 (zh) |
CA (1) | CA2715959A1 (zh) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2435646A (en) * | 2006-03-01 | 2007-09-05 | Spin Tec Engineering Gmbh | Apparatus and method of extraction of an arthropod gland |
US8105633B2 (en) * | 2006-03-01 | 2012-01-31 | Spintec Engineering Gmbh | Method and apparatus for extraction of arthropod gland |
KR101279812B1 (ko) * | 2012-05-16 | 2013-06-28 | 세원셀론텍(주) | 연골조직 수복용 조성물의 제조방법 |
US9402710B2 (en) | 2012-07-16 | 2016-08-02 | The Board Of Trustees For The Leland Stanford Junior University | Macroporous 3-D scaffolds for tissue engineering |
CN102911493A (zh) * | 2012-09-28 | 2013-02-06 | 山东赛克赛斯药业科技有限公司 | 可生物降解的医用水凝胶及其制备方法与应用 |
KR101453219B1 (ko) * | 2013-12-09 | 2014-10-22 | 주식회사 엘지생활건강 | 생체 접합용 조성물 |
WO2015088126A1 (ko) * | 2013-12-09 | 2015-06-18 | 주식회사 엘지생활건강 | 카르보디이미드계 화합물을 포함하는 조성물 |
CN104399118B (zh) * | 2014-12-10 | 2017-11-17 | 武汉理工大学 | 一种神经生长因子可注射原位水凝胶、制备及其应用 |
KR20180103818A (ko) * | 2015-08-31 | 2018-09-19 | 코르메딕스, 인코포레이티드 | 관절 치료용 조성물 |
NL2016524B1 (en) | 2016-03-31 | 2017-10-17 | Polyganics Ip B V | Tissue-adhesive material |
DE102016216182A1 (de) * | 2016-08-29 | 2018-03-01 | Tetec Tissue Engineering Technologies Ag | Kombination, insbesondere zum Behandeln eines Knorpeldefekts |
CN106750249B (zh) * | 2016-12-26 | 2019-09-13 | 深圳迈普再生医学科技有限公司 | 医用水凝胶前体及其制备方法和医用水凝胶以及应用 |
CA3106231A1 (en) * | 2018-07-09 | 2020-01-16 | Regeneron Pharmaceuticals, Inc. | Tuning of release kinetics in hydrogels |
CN109142759B (zh) * | 2018-08-31 | 2021-08-06 | 江苏力博医药生物技术股份有限公司 | 一种高质量血型检测卡用微柱凝胶的制备方法 |
EP3848063A4 (en) * | 2018-09-03 | 2021-10-27 | FUJIFILM Corporation | GEL, GEL FORMATION KIT AND GEL PRODUCTION PROCESS |
EP3897456A4 (en) * | 2018-12-20 | 2022-09-21 | The Steadman Clinic and Steadman Philippon Research Institute | METHODS BASED ON DECELLULARIZED TENDON MATRIX AND THEIR USES |
CN109568641B (zh) * | 2018-12-27 | 2021-02-12 | 山东百多安医疗器械股份有限公司 | 一种可促进伤口愈合的医用封闭胶及其制备方法 |
CN111939324B (zh) * | 2020-08-14 | 2022-06-17 | 深圳市人民医院 | 一种天然多糖基可注射原位成型水凝胶及其制备方法和应用 |
CN112920425B (zh) * | 2021-01-22 | 2023-05-23 | 华东数字医学工程研究院 | 医用水凝胶组合物,医用水凝胶及其制备方法 |
CN113827766B (zh) * | 2021-10-11 | 2022-05-24 | 赛克赛斯生物科技股份有限公司 | 一种载药型外科密封剂及其制备方法和应用 |
CN115177779B (zh) * | 2022-06-14 | 2023-12-05 | 深圳凡旻生物科技有限公司 | 一种生物胶及其制备方法与应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5376375A (en) * | 1988-11-21 | 1994-12-27 | Collagen Corporation | Method of augmenting tissue using collagen-polymer conjugates |
WO2006116137A3 (en) * | 2005-04-21 | 2007-11-22 | Univ Leland Stanford Junior | Artificial cornea |
Family Cites Families (68)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT366916B (de) | 1980-04-02 | 1982-05-25 | Immuno Ag | Vorrichtung zur applikation eines gewebeklebstoffes auf basis von menschlichen oder tierischenproteinen |
AT379311B (de) | 1984-03-29 | 1985-12-27 | Immuno Ag | Vorrichtung zur applikation eines gewebeklebstoffes |
AT382783B (de) | 1985-06-20 | 1987-04-10 | Immuno Ag | Vorrichtung zur applikation eines gewebeklebstoffes |
DE3722904A1 (de) | 1987-01-09 | 1988-07-21 | Harald Maslanka | Injektionseinrichtung mit doppelkanuele fuer ein endoskop |
US4978336A (en) | 1987-09-29 | 1990-12-18 | Hemaedics, Inc. | Biological syringe system |
US4874368A (en) | 1988-07-25 | 1989-10-17 | Micromedics, Inc. | Fibrin glue delivery system |
US4902281A (en) | 1988-08-16 | 1990-02-20 | Corus Medical Corporation | Fibrinogen dispensing kit |
US5800541A (en) | 1988-11-21 | 1998-09-01 | Collagen Corporation | Collagen-synthetic polymer matrices prepared using a multiple step reaction |
US5550187A (en) | 1988-11-21 | 1996-08-27 | Collagen Corporation | Method of preparing crosslinked biomaterial compositions for use in tissue augmentation |
US5614587A (en) | 1988-11-21 | 1997-03-25 | Collagen Corporation | Collagen-based bioadhesive compositions |
US5936035A (en) | 1988-11-21 | 1999-08-10 | Cohesion Technologies, Inc. | Biocompatible adhesive compositions |
US5162430A (en) | 1988-11-21 | 1992-11-10 | Collagen Corporation | Collagen-polymer conjugates |
US5116315A (en) | 1989-10-03 | 1992-05-26 | Hemaedics, Inc. | Biological syringe system |
US5410016A (en) | 1990-10-15 | 1995-04-25 | Board Of Regents, The University Of Texas System | Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers |
US20040195710A1 (en) | 1990-10-15 | 2004-10-07 | Hubbell Jeffrey A. | Gels for encapsulation of biological materials |
US5514379A (en) | 1992-08-07 | 1996-05-07 | The General Hospital Corporation | Hydrogel compositions and methods of use |
US5919455A (en) | 1993-10-27 | 1999-07-06 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
EP0713707A1 (en) | 1994-11-23 | 1996-05-29 | Collagen Corporation | In situ crosslinkable, injectable collagen composition for tissue augmention |
US5752974A (en) | 1995-12-18 | 1998-05-19 | Collagen Corporation | Injectable or implantable biomaterials for filling or blocking lumens and voids of the body |
US6833408B2 (en) * | 1995-12-18 | 2004-12-21 | Cohesion Technologies, Inc. | Methods for tissue repair using adhesive materials |
PT1704878E (pt) * | 1995-12-18 | 2013-07-17 | Angiodevice Internat Gmbh | Composições de polímeros reticulados e métodos para a sua utilização |
US7435425B2 (en) | 2001-07-17 | 2008-10-14 | Baxter International, Inc. | Dry hemostatic compositions and methods for their preparation |
US20090324721A1 (en) | 1996-09-23 | 2009-12-31 | Jack Kennedy | Hydrogels Suitable For Use In Polyp Removal |
US7009034B2 (en) | 1996-09-23 | 2006-03-07 | Incept, Llc | Biocompatible crosslinked polymers |
US6362276B1 (en) | 1998-01-07 | 2002-03-26 | Debio Recherche Pharmaceutique S.A. | Degradable heterobifunctional poly(ethylene glycol) acrylates and gels and conjugates derived therefrom |
ATE399809T1 (de) | 1998-03-12 | 2008-07-15 | Nektar Therapeutics Al Corp | Verfahren zur herstellung von polymerkonjugaten |
US6818018B1 (en) | 1998-08-14 | 2004-11-16 | Incept Llc | In situ polymerizable hydrogels |
DE69943297D1 (de) | 1998-08-14 | 2011-05-05 | Incept Llc | Apparat für die in-situ-bildung von hydrogelen |
US6152943A (en) | 1998-08-14 | 2000-11-28 | Incept Llc | Methods and apparatus for intraluminal deposition of hydrogels |
US7347850B2 (en) | 1998-08-14 | 2008-03-25 | Incept Llc | Adhesion barriers applicable by minimally invasive surgery and methods of use thereof |
US6605294B2 (en) | 1998-08-14 | 2003-08-12 | Incept Llc | Methods of using in situ hydration of hydrogel articles for sealing or augmentation of tissue or vessels |
US6703047B2 (en) | 2001-02-02 | 2004-03-09 | Incept Llc | Dehydrated hydrogel precursor-based, tissue adherent compositions and methods of use |
US6514534B1 (en) | 1998-08-14 | 2003-02-04 | Incept Llc | Methods for forming regional tissue adherent barriers and drug delivery systems |
US6179862B1 (en) | 1998-08-14 | 2001-01-30 | Incept Llc | Methods and apparatus for in situ formation of hydrogels |
US8802146B2 (en) | 1998-11-06 | 2014-08-12 | Neomend, Inc. | Systems, methods, and compositions for prevention of tissue adhesion |
US6830756B2 (en) | 1998-11-06 | 2004-12-14 | Neomend, Inc. | Systems, methods, and compositions for achieving closure of vascular puncture sites |
US7279001B2 (en) | 1998-11-06 | 2007-10-09 | Neomend, Inc. | Systems, methods, and compositions for achieving closure of vascular puncture sites |
WO2000033764A1 (en) | 1998-12-04 | 2000-06-15 | Pathak Chandrashekhar P | Biocompatible crosslinked polymers |
US20080114092A1 (en) | 1998-12-04 | 2008-05-15 | Incept Llc | Adhesion barriers applicable by minimally invasive surgery and methods of use thereof |
GB9902412D0 (en) | 1999-02-03 | 1999-03-24 | Fermentech Med Ltd | Process |
ES2391763T3 (es) | 2000-04-07 | 2012-11-29 | Collagen Matrix, Inc. | Dispositivo de embolización |
US6315987B1 (en) | 2000-05-10 | 2001-11-13 | Isp Investments Inc. | Polymeric delivery and release systems for oral care actives |
US7265186B2 (en) | 2001-01-19 | 2007-09-04 | Nektar Therapeutics Al, Corporation | Multi-arm block copolymers as drug delivery vehicles |
WO2003040211A2 (en) | 2001-11-07 | 2003-05-15 | Nektar Therapeutics Al, Corporation | Branched polymers and their conjugates |
FR2839451B1 (fr) | 2002-05-07 | 2006-05-05 | Oreal | Compose comprenant un polymere, un espaceur et un principe actif, composition contenant ce compose et utilisations |
JP5614913B2 (ja) | 2002-07-16 | 2014-10-29 | ピラマル ヘルスケア (カナダ) リミテッド | 生細胞又は生物学的活性因子を封入し送達するための、細胞適合性、注射可能、かつ自己ゲル化性のキトサン溶液の組成物 |
BR0317752A (pt) | 2002-12-26 | 2005-11-22 | Mountain View Pharmaceuticals | Conjugados poliméricos de citocinas, quimiocinas, fatores do crescimento, hormÈnios polipeptìdicos e seus antagonistas com atividade de ligação a receptores conservada |
CA2508015C (en) | 2002-12-30 | 2012-04-03 | Nektar Therapeutics Al, Corporation | Multi-arm polypeptide-poly(ethylene glycol) block copolymers as drug delivery vehicles |
US20040185250A1 (en) | 2003-02-07 | 2004-09-23 | John Amy T. | Triclosan containing absorbable sutures with extended antimicrobial properties |
AU2004221824B2 (en) | 2003-03-14 | 2009-08-27 | Ratiopharm Gmbh | Branched water-soluble polymers and their conjugates |
US20050020506A1 (en) * | 2003-07-25 | 2005-01-27 | Drapeau Susan J. | Crosslinked compositions comprising collagen and demineralized bone matrix, methods of making and methods of use |
US7217294B2 (en) * | 2003-08-20 | 2007-05-15 | Histogenics Corp. | Acellular matrix implants for treatment of articular cartilage, bone or osteochondral defects and injuries and method for use thereof |
EP1662973A4 (en) | 2003-08-20 | 2011-07-20 | Histogenics Corp | ACELLULAR MATRIX IMPLANTED IN JOINT CARTILAGE DAMAGE OR OSTEOCHONDRAL LESION PROTECTED BY A MODIFIED BIODEGRADABLE POLYMER IN ORDER TO HAVE A PROLONGED POLYMERIZATION TIME AND METHODS OF PREPARING AND USING SAME |
US7351787B2 (en) | 2004-03-05 | 2008-04-01 | Bioartificial Gel Technologies, Inc. | Process for the preparation of activated polyethylene glycols |
WO2006026325A2 (en) | 2004-08-26 | 2006-03-09 | Pathak Chandrashekhar P | Implantable tissue compositions and method |
US20060062768A1 (en) * | 2004-09-23 | 2006-03-23 | Olexander Hnojewyj | Biocompatible hydrogel compositions |
US20110097402A1 (en) * | 2004-09-30 | 2011-04-28 | Covalon Technologies Inc. | Non-adhesive elastic gelatin matrices |
US7365127B2 (en) | 2005-02-04 | 2008-04-29 | Enzon Pharmaceuticals, Inc. | Process for the preparation of polymer conjugates |
US20070292404A1 (en) | 2006-03-27 | 2007-12-20 | Biosynexus Incorporated | Antimicrobial polymer conjugates |
US7960498B2 (en) | 2006-06-30 | 2011-06-14 | Actamax Surgical Materials, Llc | Tissue adhesives with modified elasticity |
US8192760B2 (en) * | 2006-12-04 | 2012-06-05 | Abbott Cardiovascular Systems Inc. | Methods and compositions for treating tissue using silk proteins |
US20090227981A1 (en) | 2007-03-05 | 2009-09-10 | Bennett Steven L | Low-Swelling Biocompatible Hydrogels |
US20090227689A1 (en) | 2007-03-05 | 2009-09-10 | Bennett Steven L | Low-Swelling Biocompatible Hydrogels |
US8207264B2 (en) | 2008-07-11 | 2012-06-26 | Tyco Healthcare Group Lp | Functionalized inclusion complexes as crosslinkers |
US9271706B2 (en) | 2008-08-12 | 2016-03-01 | Covidien Lp | Medical device for wound closure and method of use |
US20110251281A1 (en) * | 2008-09-08 | 2011-10-13 | National Institute For Materials Science | Composite Material Comprising High-Molecular-Weight Matrix and Low-Molecular-Weight Organic Compound and Process For Producing Same |
JP5346763B2 (ja) * | 2009-10-15 | 2013-11-20 | ヤクモ株式会社 | シールド、推進工事における防音ハウス内の掘削土改質作業領域の換気装置及び換気方法 |
US8968783B2 (en) * | 2010-05-27 | 2015-03-03 | Covidien Lp | Hydrogel implants with varying degrees of crosslinking |
-
2010
- 2010-09-23 US US12/888,456 patent/US8968785B2/en active Active
- 2010-10-01 AU AU2010226931A patent/AU2010226931A1/en not_active Abandoned
- 2010-10-01 CA CA2715959A patent/CA2715959A1/en not_active Abandoned
- 2010-10-01 JP JP2010224398A patent/JP5721386B2/ja not_active Expired - Fee Related
- 2010-10-01 EP EP10251719.0A patent/EP2314326A3/en not_active Ceased
- 2010-10-08 CN CN201010501269.XA patent/CN102028968B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5376375A (en) * | 1988-11-21 | 1994-12-27 | Collagen Corporation | Method of augmenting tissue using collagen-polymer conjugates |
WO2006116137A3 (en) * | 2005-04-21 | 2007-11-22 | Univ Leland Stanford Junior | Artificial cornea |
Also Published As
Publication number | Publication date |
---|---|
EP2314326A2 (en) | 2011-04-27 |
JP5721386B2 (ja) | 2015-05-20 |
US20110081417A1 (en) | 2011-04-07 |
CN102028968A (zh) | 2011-04-27 |
AU2010226931A1 (en) | 2011-04-21 |
CA2715959A1 (en) | 2011-04-02 |
EP2314326A3 (en) | 2013-06-26 |
US8968785B2 (en) | 2015-03-03 |
JP2011078764A (ja) | 2011-04-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102028968B (zh) | 外科用组合物 | |
US9265828B2 (en) | Hydrogel implants with varying degrees of crosslinking | |
US9468684B2 (en) | Hydrogel implants with varying degrees of crosslinking | |
EP2389896A2 (en) | Hydrogel implants with varying degrees of crosslinking | |
AU2011202184B2 (en) | Tissue adhesives and sealants and method for their use | |
US20110081701A1 (en) | Surgical compositions | |
AU2007221051B2 (en) | Tissue adhesives and sealants and methods for their use | |
US8697111B2 (en) | Osteochondral implant comprising osseous phase and chondral phase | |
US20110081398A1 (en) | Multi-mechanism surgical compositions | |
AU2012313983B2 (en) | Multilayer implants for delivery of therapeutic agents | |
AU2009213004A1 (en) | Branched polyamines and formulations thereof for use in medical devices | |
AU2012244256B2 (en) | Novel drug delivery devices | |
US8835513B2 (en) | Drug delivery devices | |
US20140271613A1 (en) | Surgical Compositions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C53 | Correction of patent of invention or patent application | ||
CB02 | Change of applicant information |
Address after: American Connecticut Applicant after: Covidien LP Address before: American Connecticut Applicant before: TYCO Healthcare |
|
COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: TYCO HEALTHCARE TO: COVIDIEN LP COMPANY |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150325 Termination date: 20191008 |
|
CF01 | Termination of patent right due to non-payment of annual fee |