NZ623909B2 - Threads of cross-linked hyaluronic acid and methods of use thereof - Google Patents
Threads of cross-linked hyaluronic acid and methods of use thereof Download PDFInfo
- Publication number
- NZ623909B2 NZ623909B2 NZ623909A NZ62390912A NZ623909B2 NZ 623909 B2 NZ623909 B2 NZ 623909B2 NZ 623909 A NZ623909 A NZ 623909A NZ 62390912 A NZ62390912 A NZ 62390912A NZ 623909 B2 NZ623909 B2 NZ 623909B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- thread
- hyaluronic acid
- weight
- linked
- cross
- Prior art date
Links
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 426
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 424
- MAKUBRYLFHZREJ-JWBQXVCJSA-M sodium;(2S,3S,4R,5R,6R)-3-[(2S,3R,5S,6R)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylate Chemical compound [Na+].CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@H](O)[C@H]1O MAKUBRYLFHZREJ-JWBQXVCJSA-M 0.000 title claims abstract description 422
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 claims abstract description 142
- 230000037303 wrinkles Effects 0.000 claims abstract description 63
- 239000003814 drug Substances 0.000 claims abstract description 35
- 210000003491 Skin Anatomy 0.000 claims abstract description 32
- 230000001815 facial Effects 0.000 claims abstract description 21
- 238000011068 load Methods 0.000 claims abstract description 17
- 238000007920 subcutaneous administration Methods 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 191
- 238000001035 drying Methods 0.000 claims description 49
- 239000002253 acid Substances 0.000 claims description 46
- 239000007787 solid Substances 0.000 claims description 40
- 239000011230 binding agent Substances 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002537 cosmetic Substances 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 4
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 claims description 2
- 230000002708 enhancing Effects 0.000 claims description 2
- 230000000887 hydrating Effects 0.000 claims description 2
- 125000000600 disaccharide group Chemical group 0.000 claims 6
- 230000003416 augmentation Effects 0.000 abstract description 25
- 210000004872 soft tissue Anatomy 0.000 abstract description 15
- 210000001519 tissues Anatomy 0.000 abstract description 14
- 229940079593 drugs Drugs 0.000 abstract description 12
- 238000001356 surgical procedure Methods 0.000 abstract description 8
- 238000009581 negative-pressure wound therapy Methods 0.000 abstract description 3
- 239000000499 gel Substances 0.000 description 97
- 238000004132 cross linking Methods 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- 200000000019 wound Diseases 0.000 description 34
- 239000007943 implant Substances 0.000 description 28
- 239000003431 cross linking reagent Substances 0.000 description 24
- 238000000034 method Methods 0.000 description 24
- 150000002016 disaccharides Chemical group 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 210000000088 Lip Anatomy 0.000 description 22
- 238000004513 sizing Methods 0.000 description 19
- 230000036499 Half live Effects 0.000 description 17
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 17
- 230000036571 hydration Effects 0.000 description 17
- 238000006703 hydration reaction Methods 0.000 description 17
- 239000001110 calcium chloride Substances 0.000 description 13
- 229910001628 calcium chloride Inorganic materials 0.000 description 13
- 235000011148 calcium chloride Nutrition 0.000 description 13
- 230000001965 increased Effects 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- 239000007983 Tris buffer Substances 0.000 description 12
- 238000001125 extrusion Methods 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 102000001974 Hyaluronidase Human genes 0.000 description 11
- 108010074224 Hyaluronoglucosaminidase Proteins 0.000 description 11
- 230000015556 catabolic process Effects 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- -1 crosslinked forms Chemical compound 0.000 description 11
- 230000004059 degradation Effects 0.000 description 11
- 238000006731 degradation reaction Methods 0.000 description 11
- 229960002773 hyaluronidase Drugs 0.000 description 11
- 210000004207 Dermis Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000001954 sterilising Effects 0.000 description 10
- 206010028980 Neoplasm Diseases 0.000 description 9
- 210000001138 Tears Anatomy 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 230000002522 swelling Effects 0.000 description 9
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- 235000010323 ascorbic acid Nutrition 0.000 description 8
- 239000011668 ascorbic acid Substances 0.000 description 8
- 229960005070 ascorbic acid Drugs 0.000 description 8
- 239000012530 fluid Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000003125 aqueous solvent Substances 0.000 description 7
- 230000002500 effect on skin Effects 0.000 description 7
- 150000002118 epoxides Chemical class 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 239000011148 porous material Substances 0.000 description 7
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 6
- NNJVILVZKWQKPM-UHFFFAOYSA-N Xylocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 6
- 239000003570 air Substances 0.000 description 6
- 230000002255 enzymatic Effects 0.000 description 6
- 239000000945 filler Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 238000002513 implantation Methods 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 238000002559 palpation Methods 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 5
- 229940053128 Nerve Growth Factor Drugs 0.000 description 5
- 102000015336 Nerve Growth Factor Human genes 0.000 description 5
- 108010025020 Nerve Growth Factor Proteins 0.000 description 5
- 230000003444 anaesthetic Effects 0.000 description 5
- 239000000032 diagnostic agent Substances 0.000 description 5
- 239000000017 hydrogel Substances 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000006011 modification reaction Methods 0.000 description 5
- 201000002528 pancreatic cancer Diseases 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 4
- 206010046996 Varicose vein Diseases 0.000 description 4
- 229940046009 Vitamin E Drugs 0.000 description 4
- 229930003427 Vitamin E Natural products 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive Effects 0.000 description 4
- 238000006065 biodegradation reaction Methods 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 238000002224 dissection Methods 0.000 description 4
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 4
- 229960004194 lidocaine Drugs 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 4
- 239000004810 polytetrafluoroethylene Substances 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 4
- 235000019165 vitamin E Nutrition 0.000 description 4
- 239000011709 vitamin E Substances 0.000 description 4
- 150000003712 vitamin E derivatives Chemical class 0.000 description 4
- 238000009941 weaving Methods 0.000 description 4
- 229940035674 ANESTHETICS Drugs 0.000 description 3
- 229940077737 Brain-Derived Neurotrophic Factor Drugs 0.000 description 3
- 102000004219 Brain-Derived Neurotrophic Factor Human genes 0.000 description 3
- 108090000715 Brain-Derived Neurotrophic Factor Proteins 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 210000004262 Dental Pulp Cavity Anatomy 0.000 description 3
- 210000001508 Eye Anatomy 0.000 description 3
- 210000001061 Forehead Anatomy 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 239000000560 biocompatible material Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 229960005188 collagen Drugs 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000010894 electron beam technology Methods 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 239000003193 general anesthetic agent Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 230000002829 reduced Effects 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 235000011008 sodium phosphates Nutrition 0.000 description 3
- 230000003068 static Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 239000010409 thin film Substances 0.000 description 3
- WERYXYBDKMZEQL-UHFFFAOYSA-N 1,4-Butanediol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 206010059837 Adhesion Diseases 0.000 description 2
- 102100015886 BMP4 Human genes 0.000 description 2
- 108010049955 Bone Morphogenetic Protein 4 Proteins 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 239000004971 Cross linker Substances 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N Ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 210000002615 Epidermis Anatomy 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229960002897 Heparin Drugs 0.000 description 2
- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 241000270923 Hesperostipa comata Species 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 241000282619 Hylobates lar Species 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 229940090044 Injection Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- 229940025300 Lidocaine Injection Drugs 0.000 description 2
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 description 2
- 210000002445 Nipples Anatomy 0.000 description 2
- 210000001331 Nose Anatomy 0.000 description 2
- 229940037201 Oris Drugs 0.000 description 2
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 229920005830 Polyurethane Foam Polymers 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 210000002435 Tendons Anatomy 0.000 description 2
- 229960000278 Theophylline Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 210000003462 Veins Anatomy 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- 201000004384 alopecia Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000003078 antioxidant Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000003247 decreasing Effects 0.000 description 2
- 230000001419 dependent Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 235000019525 fullness Nutrition 0.000 description 2
- 150000004676 glycans Polymers 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000003676 hair loss Effects 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000002209 hydrophobic Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- 230000036961 partial Effects 0.000 description 2
- 230000002085 persistent Effects 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Polymers 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 239000011496 polyurethane foam Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000001172 regenerating Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 238000009495 sugar coating Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 230000002459 sustained Effects 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 230000000699 topical Effects 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- PUSNGFYSTWMJSK-GSZQVNRLSA-N (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan- Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](OC)O[C@@H]1COC.CC(O)CO[C@@H]1[C@@H](OCC(C)O)[C@H](OCC(C)O)[C@@H](COCC(O)C)O[C@H]1O[C@H]1[C@H](OCC(C)O)[C@@H](OCC(C)O)[C@H](OCC(C)O)O[C@@H]1COCC(C)O PUSNGFYSTWMJSK-GSZQVNRLSA-N 0.000 description 1
- OJHZNMVJJKMFGX-BWCYBWMMSA-N (4R,4aR,7aR,12bS)-9-methoxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;(2R,3R)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC OJHZNMVJJKMFGX-BWCYBWMMSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- IDUWIXCWGYJVKL-UHFFFAOYSA-N 2-(aminomethyl)propane-1,3-diol Chemical compound NCC(CO)CO IDUWIXCWGYJVKL-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- AOHMFUYIHARAGR-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;magnesium Chemical compound [Mg].[Mg].[Mg].OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O AOHMFUYIHARAGR-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FVXBTPGZQMNAEZ-UHFFFAOYSA-N 3-amino-2-methylpropan-1-ol Chemical compound NCC(C)CO FVXBTPGZQMNAEZ-UHFFFAOYSA-N 0.000 description 1
- 239000007991 ACES buffer Substances 0.000 description 1
- 239000007988 ADA buffer Substances 0.000 description 1
- 101710034857 ATIC Proteins 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- KDXHLJMVLXJXCW-UHFFFAOYSA-J Alcian blue stain Chemical compound [Cl-].[Cl-].[Cl-].[Cl-].[Cu+2].[N-]1C(N=C2C3=CC(CSC(N(C)C)=[N+](C)C)=CC=C3C(N=C3C4=CC=C(CSC(N(C)C)=[N+](C)C)C=C4C(=N4)[N-]3)=N2)=C(C=C(CSC(N(C)C)=[N+](C)C)C=C2)C2=C1N=C1C2=CC(CSC(N(C)C)=[N+](C)C)=CC=C2C4=N1 KDXHLJMVLXJXCW-UHFFFAOYSA-J 0.000 description 1
- 229960003556 Aminophylline Drugs 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N Ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- VBIXEXWLHSRNKB-UHFFFAOYSA-N Ammonium oxalate Chemical compound [NH4+].[NH4+].[O-]C(=O)C([O-])=O VBIXEXWLHSRNKB-UHFFFAOYSA-N 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N Ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 206010068168 Androgenetic alopecia Diseases 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 229940088710 Antibiotic Drugs 0.000 description 1
- 108010082858 ArteFill Proteins 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 229960002756 Azacitidine Drugs 0.000 description 1
- 102100013894 BCL2 Human genes 0.000 description 1
- 108060000885 BCL2 Proteins 0.000 description 1
- 210000001142 Back Anatomy 0.000 description 1
- 229960005274 Benzocaine Drugs 0.000 description 1
- BLFLLBZGZJTVJG-UHFFFAOYSA-N Benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N Bis-tris methane Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 210000001218 Blood-Brain Barrier Anatomy 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 229940089093 Botox Drugs 0.000 description 1
- 208000003508 Botulism Diseases 0.000 description 1
- 239000008001 CAPS buffer Substances 0.000 description 1
- 239000008000 CHES buffer Substances 0.000 description 1
- 102100006435 CSF3 Human genes 0.000 description 1
- XOYXELNNPALJIE-UHFFFAOYSA-N C[NH+](C)C.C[NH+](C)C.C[NH+](C)C.[O-]P([O-])([O-])=O Chemical compound C[NH+](C)C.C[NH+](C)C.C[NH+](C)C.[O-]P([O-])([O-])=O XOYXELNNPALJIE-UHFFFAOYSA-N 0.000 description 1
- 229960004015 Calcitonin Drugs 0.000 description 1
- 102400000113 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 229960005069 Calcium Drugs 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L Calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229940105329 Carboxymethylcellulose Drugs 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 229940045110 Chitosan Drugs 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- KXKPYJOVDUMHGS-OSRGNVMNSA-N Chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 description 1
- 229920002676 Complementary DNA Polymers 0.000 description 1
- 206010011401 Crohn's disease Diseases 0.000 description 1
- 229920001651 Cyanoacrylate Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229960000958 Deferoxamine Drugs 0.000 description 1
- 229920000045 Dermatan sulfate Polymers 0.000 description 1
- AVJBPWGFOQAPRH-FWMKGIEWSA-L Dermatan sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS([O-])(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C([O-])=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-L 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 Dexamethasone Drugs 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 210000000624 Ear Auricle Anatomy 0.000 description 1
- 229940088598 Enzyme Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N Epinephrine Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229940117927 Ethylene Oxide Drugs 0.000 description 1
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- 206010072064 Exposure to body fluid Diseases 0.000 description 1
- 210000002744 Extracellular Matrix Anatomy 0.000 description 1
- 210000000416 Exudates and Transudates Anatomy 0.000 description 1
- 210000000744 Eyelids Anatomy 0.000 description 1
- 102100006624 F9 Human genes 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 229960000301 Factor VIII Drugs 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 229960004177 Filgrastim Drugs 0.000 description 1
- 108010029961 Filgrastim Proteins 0.000 description 1
- 229940028334 Follicle Stimulating Hormone Drugs 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 229960002442 Glucosamine Drugs 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 229920000544 Gore-Tex Polymers 0.000 description 1
- 210000001126 Granulation Tissue Anatomy 0.000 description 1
- ACGDKVXYNVEAGU-UHFFFAOYSA-N Guanethidine Chemical compound NC(N)=NCCN1CCCCCCC1 ACGDKVXYNVEAGU-UHFFFAOYSA-N 0.000 description 1
- 229960003602 Guanethidine Drugs 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- VZJFGSRCJCXDSG-UHFFFAOYSA-N Hexamethonium Chemical compound C[N+](C)(C)CCCCCC[N+](C)(C)C VZJFGSRCJCXDSG-UHFFFAOYSA-N 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 241000229754 Iva xanthiifolia Species 0.000 description 1
- 208000009883 Joint Disease Diseases 0.000 description 1
- 239000001358 L(+)-tartaric acid Substances 0.000 description 1
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- XIXADJRWDQXREU-UHFFFAOYSA-M Lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
- 229940071257 Lithium acetate Drugs 0.000 description 1
- WJSIUCDMWSDDCE-UHFFFAOYSA-K Lithium citrate Chemical compound [Li+].[Li+].[Li+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WJSIUCDMWSDDCE-UHFFFAOYSA-K 0.000 description 1
- 229940040129 Luteinizing Hormone Drugs 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 239000007987 MES buffer Substances 0.000 description 1
- DVLFYONBTKHTER-UHFFFAOYSA-N MOPS Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 229940041033 Macrolides Drugs 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L Magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H Magnesium phosphate tribasic Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 229940091250 Magnesium supplements Drugs 0.000 description 1
- 229960002160 Maltose Drugs 0.000 description 1
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl 2-cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 description 1
- CUXQLKLUPGTTKL-UHFFFAOYSA-M Microcosmic salt Chemical compound [NH4+].[Na+].OP([O-])([O-])=O CUXQLKLUPGTTKL-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 210000003205 Muscles Anatomy 0.000 description 1
- DBXNUXBLKRLWFA-UHFFFAOYSA-N N-(2-acetamido)-2-aminoethanesulfonic acid Chemical compound NC(=O)CNCCS(O)(=O)=O DBXNUXBLKRLWFA-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-Acetylglucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MKWKNSIESPFAQN-UHFFFAOYSA-N N-Cyclohexyltaurine Chemical compound OS(=O)(=O)CCNC1CCCCC1 MKWKNSIESPFAQN-UHFFFAOYSA-N 0.000 description 1
- IBONACLSSOLHFU-KEWYIRBNSA-N N-[(3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]acetamide Chemical compound CC(=O)NC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O IBONACLSSOLHFU-KEWYIRBNSA-N 0.000 description 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 1
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 1
- 208000008721 Needlestick Injury Diseases 0.000 description 1
- PGSADBUBUOPOJS-UHFFFAOYSA-N Neutral red Chemical compound Cl.C1=C(C)C(N)=CC2=NC3=CC(N(C)C)=CC=C3N=C21 PGSADBUBUOPOJS-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- DIVDFFZHCJEHGG-UHFFFAOYSA-N Oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycontin Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- 229940074439 POTASSIUM SODIUM TARTRATE Drugs 0.000 description 1
- 210000000496 Pancreas Anatomy 0.000 description 1
- 229960001999 Phentolamine Drugs 0.000 description 1
- 229960003073 Pirfenidone Drugs 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- WFIZEGIEIOHZCP-UHFFFAOYSA-M Potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 1
- LJCNRYVRMXRIQR-UHFFFAOYSA-L Potassium sodium tartrate Chemical compound [Na+].[K+].[O-]C(=O)C(O)C(O)C([O-])=O LJCNRYVRMXRIQR-UHFFFAOYSA-L 0.000 description 1
- 241000048284 Potato virus P Species 0.000 description 1
- 206010036596 Premature ejaculation Diseases 0.000 description 1
- MVFGUOIZUNYYSO-UHFFFAOYSA-N Prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 description 1
- 206010051482 Prostatomegaly Diseases 0.000 description 1
- FYBHCRQFSFYWPY-UHFFFAOYSA-N Purmorphamine Chemical compound C1CCCCC1N1C2=NC(OC=3C4=CC=CC=C4C=CC=3)=NC(NC=3C=CC(=CC=3)N3CCOCC3)=C2N=C1 FYBHCRQFSFYWPY-UHFFFAOYSA-N 0.000 description 1
- 230000025458 RNA interference Effects 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- BJOIZNZVOZKDIG-MDEJGZGSSA-N Reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 1
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 1
- 229920001954 Restylane Polymers 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N Retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229940039790 Sodium Oxalate Drugs 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M Sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L Sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 description 1
- HELHAJAZNSDZJO-UHFFFAOYSA-L Sodium tartrate Chemical compound [Na+].[Na+].[O-]C(=O)C(O)C(O)C([O-])=O HELHAJAZNSDZJO-UHFFFAOYSA-L 0.000 description 1
- 229960002167 Sodium tartrate Drugs 0.000 description 1
- 210000000278 Spinal Cord Anatomy 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 210000004304 Subcutaneous Tissue Anatomy 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- 229960004793 Sucrose Drugs 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J Tetrasodium pyrophosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- CFMYXEVWODSLAX-QOZOJKKESA-N Tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 1
- 229950010357 Tetrodotoxin Drugs 0.000 description 1
- 229940035295 Ting Drugs 0.000 description 1
- 231100000765 Toxin Toxicity 0.000 description 1
- 239000007997 Tricine buffer Substances 0.000 description 1
- AVBGNFCMKJOFIN-UHFFFAOYSA-N Triethylammonium acetate Chemical compound CC(O)=O.CCN(CC)CC AVBGNFCMKJOFIN-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N U-18,496 Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- 229940072358 Xylocaine Drugs 0.000 description 1
- 210000000216 Zygoma Anatomy 0.000 description 1
- JUIUXBHZFNHITF-IEOSBIPESA-N [(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] dihydrogen phosphate Chemical compound OP(=O)(O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C JUIUXBHZFNHITF-IEOSBIPESA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 230000003187 abdominal Effects 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000012080 ambient air Substances 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial Effects 0.000 description 1
- 230000003510 anti-fibrotic Effects 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 230000001746 atrial Effects 0.000 description 1
- 230000002238 attenuated Effects 0.000 description 1
- 230000003190 augmentative Effects 0.000 description 1
- NGPGDYLVALNKEG-UHFFFAOYSA-N azanium;azane;2,3,4-trihydroxy-4-oxobutanoate Chemical compound [NH4+].[NH4+].[O-]C(=O)C(O)C(O)C([O-])=O NGPGDYLVALNKEG-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 201000004569 blindness Diseases 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000001010 compromised Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 108010034748 copper-binding protein Proteins 0.000 description 1
- NZWIFMYRRCMYMN-ACMTZBLWSA-M copper;(2S)-6-amino-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoate Chemical compound [Cu+2].NCCCC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 NZWIFMYRRCMYMN-ACMTZBLWSA-M 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 229940051593 dermatan sulfate Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- UNXNGGMLCSMSLH-UHFFFAOYSA-N dihydrogen phosphate;triethylazanium Chemical compound OP(O)(O)=O.CCN(CC)CC UNXNGGMLCSMSLH-UHFFFAOYSA-N 0.000 description 1
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 description 1
- GOMCKELMLXHYHH-UHFFFAOYSA-L dipotassium;phthalate Chemical compound [K+].[K+].[O-]C(=O)C1=CC=CC=C1C([O-])=O GOMCKELMLXHYHH-UHFFFAOYSA-L 0.000 description 1
- LVSJLTMNAQBTPE-UHFFFAOYSA-N disodium tetraborate Chemical compound [Na+].[Na+].O1B(O)O[B-]2(O)OB(O)O[B-]1(O)O2 LVSJLTMNAQBTPE-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 201000008220 erythropoietic protoporphyria Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229960004222 factor IX Drugs 0.000 description 1
- 230000037320 fibronectin Effects 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000000834 fixative Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940044627 gamma-interferon Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N glucosamine group Chemical group OC1[C@H](N)[C@@H](O)[C@H](O)[C@H](O1)CO MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine zwitterion Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229950002932 hexamethonium Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 229940071264 lithium citrate Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 239000004337 magnesium citrate Substances 0.000 description 1
- 235000002538 magnesium citrate Nutrition 0.000 description 1
- 229960005336 magnesium citrate Drugs 0.000 description 1
- 239000004137 magnesium phosphate Substances 0.000 description 1
- 229960002261 magnesium phosphate Drugs 0.000 description 1
- 229910000157 magnesium phosphate Inorganic materials 0.000 description 1
- 235000010994 magnesium phosphates Nutrition 0.000 description 1
- GMDNUWQNDQDBNQ-UHFFFAOYSA-L magnesium;diformate Chemical compound [Mg+2].[O-]C=O.[O-]C=O GMDNUWQNDQDBNQ-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 102000005614 monoclonal antibodies Human genes 0.000 description 1
- 108010045030 monoclonal antibodies Proteins 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229930014694 morphine Natural products 0.000 description 1
- 230000001002 morphogenetic Effects 0.000 description 1
- 230000001452 natriuretic Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 229940005931 ophthalmologic Fluoroquinolone antiinfectives Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000399 orthopedic Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- XMNPUFGPSRCSQJ-UHFFFAOYSA-N piperazine;potassium Chemical compound [K].C1CNCCN1 XMNPUFGPSRCSQJ-UHFFFAOYSA-N 0.000 description 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- GANDVAJEIJXBQJ-UHFFFAOYSA-M potassium;hydron;2-hydroxy-2-oxoacetate Chemical compound [K+].OC(=O)C(O)=O.OC(=O)C([O-])=O GANDVAJEIJXBQJ-UHFFFAOYSA-M 0.000 description 1
- 230000001376 precipitating Effects 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 229960001807 prilocaine Drugs 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229960003147 reserpine Drugs 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N silicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 230000001340 slower Effects 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 229960003339 sodium phosphate Drugs 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 229940048086 sodium pyrophosphate Drugs 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- LLVQEXSQFBTIRD-UHFFFAOYSA-M sodium;2,3,4-trihydroxy-4-oxobutanoate;hydrate Chemical compound O.[Na+].OC(=O)C(O)C(O)C([O-])=O LLVQEXSQFBTIRD-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 229940041075 systemic Fluoroquinolone antibacterials Drugs 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000011099 tissue engineering Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- KYWVDGFGRYJLPE-UHFFFAOYSA-N trimethylazanium;acetate Chemical compound CN(C)C.CC(O)=O KYWVDGFGRYJLPE-UHFFFAOYSA-N 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- PIEPQKCYPFFYMG-UHFFFAOYSA-N tris acetate Chemical compound CC(O)=O.OCC(N)(CO)CO PIEPQKCYPFFYMG-UHFFFAOYSA-N 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000011240 wet gel Substances 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/04—Surgical instruments, devices or methods, e.g. tourniquets for suturing wounds; Holders or packages for needles or suture materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/0204—Specific forms not provided for by any of groups A61K8/0208 - A61K8/14
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/0216—Solid or semisolid forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/28—Polysaccharides or their derivatives
-
- 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
- A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
- A61L17/06—At least partially resorbable materials
- A61L17/10—At least partially resorbable materials containing macromolecular materials
-
- 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
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Abstract
Disclosed a hyaluronic acid threads cross-linked with butanediol diglycidyl ether (BDDE) with ultimate tensile strength of 2-20 kpsi and a failure load of 0.3-1.3 pounds. Also disclosed are methods of making the thread and the use of the thread in aesthetic applications (e.g., facial contouring, soft tissue augmentation products), surgery (e.g., sutures), drug delivery, negative pressure wound therapy, and moist wound dressing. In a particular embodiment, an aesthetic application relates to the treatment of wrinkles by threading into skin or subcutaneous space adjacent or under the wrinkle. t tissue augmentation products), surgery (e.g., sutures), drug delivery, negative pressure wound therapy, and moist wound dressing. In a particular embodiment, an aesthetic application relates to the treatment of wrinkles by threading into skin or subcutaneous space adjacent or under the wrinkle.
Description
THREADS OF CROSS-LINKED HYALURONIC ACID AND METHODS OF USE
THEREOF
Cross-Reference to Related Applications
This application claims the benefit under 35 U.S.C. 119(e) to Provisional Application
Numbers 61/545,962, filed October 11, 2011, 61/568,077, filed December 7, 2011, and
61/644,945, filed May 9, 2012, each of which is incorporated herein in its entirety.
Field
This disclosure relates generally to threads of hyaluronic acid, methods of making such
threads and uses thereof, for example, in aesthetic applications (e.g., facial contouring, dermal
filling), surgery (e.g., sutures), drug delivery, negative pressure wound therapy, moist wound
dressing, and the like.
ound
Hyaluronic acid (HA) is a linear polysaccharide (i.e., lfated glycosaminoglycan)
consisting of a repeated disaccharide unit of alternately bonded β-D-N-acetylglucosamine and β-
D-glucuronic acid which can be depicted by the formula:
where n is the number of repeating units. Hyaluronic acid is sometimes ed to by the
nomenclature (-4GlcUAβ1-3GlcNAcβ1-)n) and is a chief component of the extracellular matrix
found, for e, in connective, epithelial and neural tissue. Natural hyaluronic acid is highly
biocompatible e of its lack of species and organ specificity and is often used as a
biomaterial in tissue engineering and as a common ingredient in soft tissue augmentation
products.
Natural hyaluronic acid has poor in vivo stability due to rapid enzymatic degradation and
hydrolysis and, accordingly, various chemically modified forms of hyaluronic acid (e.g., crosslinked
forms, ionically modified forms, esterified forms, etc.) have been synthesized to s
this problem. Currently, hyaluronic acid or linked ns thereof are used in various gel
forms, for example as soft tissue augmentation ts, on barriers, and the like.
However, issues exist with the use of gels of hyaluronic acid or its cross-linked versions
as soft tissue augmentation products. First, the force required to dispense gels of hyaluronic acid
or its linked versions is non-linear which can cause an initial ejection of a “glob” of gel that
many physicians report when using injectable hyaluronic acid gels. Second, precisely dispensing
hyaluronic gels to specific locations can be difficult because such gels have little ical
strength. Further, the gel will occupy the space of least resistance which makes its use in many
applications (e.g., treatment of fine wrinkles) problematic as the gel will often migrate into
unintended spatial areas ing the cosmetic procedure difficult and possibly even dangerous.
Third, many common soft tissue augmentation ts which are injected into the treatment site
as a liquid or a gel, such as Restylane® (hyaluronic acid), Juvederm® ronic acid)
Radiesse® (calcium hydroxyl apatite), Sculptra® (poly-L-lactic acid) and Perlane® (hyaluronic
acid), are e of migration and/or causing unsightly “lumps” which are painful to treat.
Fourth, these soft tissue augmentation ts are not recommended for use around the eyes as
migration from the injection site can cause blindness, tissue necrosis, and in rare cases even
stroke. Finally, clinicians also find performing lip augmentations using these fillers time
consuming and patients find treatments in this area so painful that nerve blocks are routinely
performed.
Accordingly, threaded forms of hyaluronic acid and its cross-linked versions have been
developed that can be dispensed uniformly to specific ons regardless of tissue resistance, and
without the risk of migration at implantation. These threaded forms are cial because they
have ed tensile strength and greater ease of delivery.
Due to the significant therapeutic potential of threaded forms of hyaluronic acid, there
remains a need to develop reaction conditions and manufacturing protocols that will yield
improved threads and soft tissue augmentation products having superior physical ties. It is
an object of the present invention to go someway s meeting this need and/or to provide the
public with a useful choice.
Summary
s have been developed comprising cross-linked hyaluronic acid. It has been
surprisingly found that tions, as described hout, in the relative amounts of the
components, reaction conditions, covalent modification of the onic acid, and manufacturing
protocols can have significant effects upon certain properties of threads comprising cross-linked
hyaluronic acid.
In a first aspect, there is provided a composition sing at least 5% onic acid
by weight, wherein the hyaluronic acid is substantially linked with from about 17 to about
mole % of a butanediol diglycidyl ether (BDDE) derivative relative to the repeating
disaccharide unit of the hyaluronic acid.
[0009a]In a second aspect, there is provided a thread comprising the ition of the
invention.
[0009b]In a third aspect, there is provided a thread prepared by the process of drying the thread of
the invention.
[0009c] In a fourth aspect, there is ed a thread comprising substantially cross-linked
hyaluronic acid, wherein the onic acid is substantially cross-linked with from about 17 to
about 20 mole % of a butanediol diglycidyl ether (BDDE) tive relative to the repeating
disaccharide unit of the hyaluronic acid, and at least about 5% ss-linked hyaluronic acid
relative to the weight of total hyaluronic acid solids.
]In a fifth aspect, there is provided a dry thread comprising substantially cross-linked
hyaluronic acid prepared by the steps of:
a) forming a ntially cross-linked hyaluronic acid composition by contacting a
composition comprising having at least 5% hyaluronic acid with butanediol diglycidyl ether
(BDDE), such that the hyaluronic acid is cross-linked with from about 17 to about 20 mole
% of a butanediol diglycidyl ether (BDDE) derivative relative to the repeating disaccharide
unit of the hyaluronic acid;
b) adding noncross-linked hyaluronic acid to the composition;
c) extruding the substantially cross-linked composition to form a wet thread; and
d) drying the wet thread to form a dry thread.
[0009e] In a sixth aspect, there is provided a dried thread comprising cross-linked hyaluronic acid,
wherein the onic acid is cross-linked with from about 17 to 20 mole % of a butanediol
diglycidyl ether (BDDE) derivative relative to the repeating disaccharide unit of the hyaluronic
acid, and at least 5 weight % noncross-linked hyaluronic acid relative to the weight of the total
hyaluronic acid , wherein the cross-linked hyaluronic acid is present in an amount of from
60 weight % to 90 weight % based on the total weight of the thread excluding moisture.
[0009f] In a seventh aspect, there is provided a kit of part comprising thread of the ion and a
needle.
[0009g]In an eighth aspect, there is provided a cosmetic use of the thread of the invention for
filling a wrinkle in a patient, for facial contouring or for wound dressing.
[0009h]Also described is a ition comprising cross-linked hyaluronic acid, from which the
threads as described herein are made. For example, in one embodiment, is provided a gel
composition composition sing at least 5% hyaluronic acid, wherein the hyaluronic acid is
substantially cross-linked with at least about 15 mole % of a butanediol diglycidyl ether (BDDE)
derivative relative to the repeating disaccharide unit of the hyaluronic acid. Also encompassed are
compositions comprising cross-linked hyaluronic acid, further comprising a binder, such as
ss-linked hyaluronic acid.
The threads described herein can be ed using a composition comprising
ntially cross-linked hyaluronic acid, wherein onic acid is cross-linked with at least
about 15 mole % of a butanediol diglycidyl ether (BDDE) derivative relative to the ing
disaccharide unit of the hyaluronic acid. It has been discovered that the concentration of crosslinking
agent, i.e. BDDE, used to prepare the substantially cross-linked hyaluronic acid, is used to
tune and/or improve certain physical properties of the thread. In addition, in certain embodiments,
the composition comprises at least 5% hyaluronic acid before cross-linking, such as 8%, 10% or
12% hyaluronic acid.
Further, threads as described herein comprise both cross-linked and ss-linked
hyaluronic acid. Surprisingly, the relative concentrations of these two components was
discovered to impact certain physical properties of the threads, which ultimately led to an
sed in vivo effectiveness as soft tissue augmentation products.
In addition, as is detailed herein, various aspects of the thread manufacturing process
(e.g., rinsing, tion, extrusion, and drying of precursor gels, as well as the terminal
sterilization of the dry threads) can be altered to produce threads having improved physical
characteristics. ically, s comprising cross-linked hyaluronic acid have been prepared
with significant linking (e.g., at least about 15% BDDE derivative) relative to the ing
haride unit of the hyaluronic acid. This increased cross-linking within the cross-linked
hyaluronic acid composition is contemplated to result in threads with a longer ife in vivo.
The hyaluronic acid threads described herein possess an increased in vivo half-life when
compared to the hyaluronic acid threads described previously in the art. When implanted in the
dorsum of rabbits, sterilized threads described in the art were fully resorbed within 30 days
whereas the threads described herein were still present at 3 months or longer in some cases.
In another aspect, there is described a thread having physical characteristics which can
be attenuated by altering the s of preparation as described herein. For example, in one
embodiment, there is provided a dry thread comprising substantially cross-linked onic acid
prepared by the steps of: a) forming a substantially cross-linked hyaluronic acid composition by
contacting hyaluronic acid with BDDE; b) adding noncross-linked hyaluronic acid to the
composition; c) extruding the substantially cross-linked composition to form a wet ; and d)
drying the wet thread to form a dry thread.
In one of its method ments, there is bed a method of treating a wrinkle in a
subject in need thereof. In such an aspect, the thread is inserted into the skin of a patient adjacent
to or under the wrinkle. The thread is then applied under the wrinkle, thereby treating the wrinkle.
In one embodiment, upon exposure to body fluids or by manually hydrating, the thread expands
upon hydration and such expansion is typically ient to fill-in the wrinkle. It is advantageous
to have a thread expand upon hydration because the invasiveness of the insertion profile is
minimized, however, threads designed to not expand can also be used to treat the wrinkle.
In r embodiment, there is described a method of providing facial ring in a
subject in need thereof. In this ment, the thread is inserted into the skin at or nt to
the desired treatment on, e.g., the lips, the nasolabial fold, the tear trough, etc. The thread is
then applied thereby providing facial contouring. In one embodiment, a thread is applied to
various planes of the dermal tissue. In one embodiment, several threads can be placed generally
parallel to each other and additional threads can be placed in a generally perpendicular direction
with respect to the first set of parallel threads y forming a mesh structure whose aggregate
effect is to contour a larger defect or more widespread defect such as the tear trough or the
infraorbital region of the eye.
Also encompassed is a kit of parts comprising the thread. In some embodiments, the kit
further comprises a means for delivering the . The means for delivery can either be a
syringe or a needle.
In still other aspects, methods of using threads of onic acid as soft tissue
augmentation products, facial contouring, adhesion barriers, wound dressings including ve
pressure wound dressings, sutures, and the like is provided. Further described are methods of
using threads of hyaluronic acid, for example, in surgery, ophthalmology, wound closure, drug
delivery, and the like. These embodiments, as well as others, are discussed in more detail below.
Brief Description of the Drawings
Certain aspects are best understood from the following detailed ption when read in
conjunction with the accompanying gs. It is emphasized that, according to common
practice, the various features of the drawings are not to-scale. On the contrary, the dimensions of
the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are
the following s:
Fig. 1 shows a schematic of hyaluronic acid cross-linked with butanediol diglycidyl ether
(BDDE).
Fig. 2 illustrates a thread attached to the proximal end of a needle, in its entirety (N =
needle; T = thread).
Figs. 3A and 3B show a needle attached to the thread (N = needle; T = thread). Fig. 3A
illustrates a close-up view of a thread inserted into the inner-diameter of a needle; and Fig. 3B
illustrates a close-up view of the proximal end of a solid needle with the thread overlapping the
needle.
Figs. 4A-4F show treatment of a wrinkle. Fig. 4A illustrates a fine, facial wrinkle in the
peri-orbital region of a human; Fig. 4B illustrates a needle and thread being inserted into the skin
of the wrinkle at the medial margin; Fig. 4C illustrates the needle being adjusted to traverse
beneath the wrinkle; Fig. 4D illustrates the needle exiting at the lateral margin of the e; Fig.
4E illustrates the needle having pulled the thread into the on it previously occupied beneath
the wrinkle; and Fig. 4F illustrates the thread implanted h the wrinkle, with excess thread
having been cut off.
Figs. 5A-5C show treatment of a wrinkle. Fig. 5A illustrates a cross-sectional view of a
fold or a wrinkle; Fig. 5B illustrates a thread implanted beneath a wrinkle that is not yet hydrated;
and Fig. 5C illustrates a thread implanted beneath a wrinkle that is fully hydrated and has
flattened the surface appearance of the wrinkle.
Fig. 6 illustrates how a needle and thread could be used to place a thread in a specific,
linear location to promote nerve or vessel th in a specific line.
Fig. 7A shows ent of threads in a relatively parallel orientation for facial
contouring in the tear trough (Thread 1, 2, 3, 4, 5, and 6). This figure also shows ent of the
thread for facial contouring of the nasolabial fold (Thread 7 and 8). Fig. 7B shows an alternative
placement of the threads for facial contouring in the tear trough (Thread 1, 2, 3, 4, 5, 6, 7, and 8).
Figs. 8A and 8B show a schematic of the contemplated microanatomy of a thread
implanted into a patient both in cross-section of the skin and dimensional cross-section.
Figs. 9A, 9B, 9C, 9D and 9E show (at 14x magnification) a ogical cross section of
a rabbit, one month (9A), two months (9B), three months (9C), six months (9D) and nine months
(9E) after being treated with s prepared from 8/40@15/20 thread composition (phosphate
buffer wash; 15% HA solids, 20% of HA is noncross-linked binder in water). Details of the
histological s illustrated in Figs. 9A, 9B, 9C, 9D and 9E can be found in Example 9.
Fig. 10 shows a gross dissection of a rabbit one month after being treated with threads
prepared from 8/40@15/20 thread composition (phosphate buffer wash; 15% HA solids, 20% of
HA is ss-linked HA ). Details of the dissection illustrated in Fig. 10 can be found in
Example 10.
Fig 11 shows a gross dissection of a rabbit two months after being treated with threads
prepared from 8/40@15/20 thread composition (phosphate buffer wash; 15% HA solids, 20% of
HA is noncross-linked HA binder). Details of this dissection illustrated in Fig. 11 can be found in
e 10.
The following thread lature is used in Figs. 12 and 13 to describe the gel
compositions: AA/BB@XX/YY, n (AA) is the weight % of hyaluronic acid relative to the
weight of the cross-linking solution; (BB) is the weight % of BDDE relative to the weight of the
hyaluronic acid; (XX) is the weight % of cross-linked and ss-linked onic acid
“solids” relative to the weight of the composition (pre-extrusion); and (YY) is the weight % of
noncross-linked hyaluronic acid relative to the weight of total cross-linked and noncross-linked
hyaluronic acid “solids”.
Fig. 12 shows the s of a thread degradation study with hyaluronidase (1 mg/mL).
Details of these enzymatic degradations represented in Fig. 12 can be found in e 7. For
threads A-F: A = 10/40@15/20 CaCl2; B = 10/40@15/40; C = 10/40@15/20; D = 10/40@10/50;
E = 8/40@15/20 H2O wash; F = 8/40@15/20; G = Control for 10/40@15/20 CaCl2; H = Control
for 10/40@15/40; I = Control for 10/40@15/20; J = Control for 8/40@15/20. Vertical arrows
correspond to the addition of fresh 1 mg/mL of hyaluronidase.
Fig. 13 shows average palpation scores for exemplary threads as bed hereins.
Details of these palpation studies represented in Fig. 13 can be found in Example 8. For threads
A-F: A = 8/40@15/20; B = 8/40@15/20; C = 10/50; D = 10/40@15/20; E =
/40@15/20; F = 15/40; Needle = pre-sized (20G); terminally sterilized (20kGy); thread
size ~0.01 inches.
Fig. 14 shows the particle size distribution of particles up to 0.3 square mm in diameter
of the gel with one sizing and multiple sizing steps.
Detailed Description
Described herein are threads of substantially cross-linked hyaluronic acid, the
compositions from which they are made, methods for their preparation and uses thereof and to
ic shapes formed there from. However, the following terms will first be d.
It is to be understood that this sure is not limited to particular embodiments
described, as such may, of course, vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular embodiments only, and is not intended to be
limiting, since the scope of the present disclosure will be limited only by the appended claims.
It must be noted that as used herein and in the appended claims, the singular forms “a”,
“an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for
example, reference to “a ” includes a plurality of threads.
1. Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same
meaning as commonly tood by one of ordinary skill in the art to which this disclosure
belongs. As used herein the following terms have the following meanings.
As used herein, the term “comprising” or ises” is intended to mean that the
compositions and methods include the recited elements, but not excluding others. sting
essentially of” when used to define compositions and methods, shall mean excluding other
elements of any essential significance to the combination for the stated purpose. Thus, a
composition consisting essentially of the elements as defined herein would not exclude other
materials or steps that do not materially affect the basic and novel characteristic(s) claimed.
“Consisting of” shall mean excluding more than trace elements of other ingredients and
substantial method steps. Embodiments defined by each of these transition terms are within the
scope of this disclosure.
The term “about” when used before a numerical designation, e.g., temperature, time,
, and concentration, including range, indicates approximations which may vary by ( + ) or
( - ) 10 %, 5 % or 1 %.
The term “hyaluronic acid” or “HA” refers to the polymer having the formula:
where n is the number of repeating units. All sources of onic acid are useful, including
bacterial and avian s. Hyaluronic acids useful have a molecular weight of from about 0.5
MDa (mega Dalton) to about 3.0 MDa. In some embodiments, the lar weight is from
about 0.6 MDa to about 2.6 MDa and in yet another embodiment, the molecular weight is from
about 1.4 MDa to about 1.7 MDa. In some embodiments, the lar weight is about 0.7 MDa
and in yet r embodiment, the molecular weight is about 1.7 MDa. In some embodiments,
the molecular weight is about 2.7 MDa.
At least a portion of the thread as described herein is cross-linked. The term “crosslinked”
is ed to refer to two or more r chains of hyaluronic acid which have been
covalently bonded via a cross-linking agent. Such cross-linking is differentiated from
intermolecular or olecular ation which results in lactone, anhydride, or ester
formation within a single polymer chain or between two or more chains. Although, it is
contemplated that intramolecular cross-linking may also occur in the threads as described herein.
The term “cross-linked” is also intended to refer to hyaluronic acid covalently linked to a BDDE
derivative. In some embodiments, the term “cross-linked” also refers to covalently modified
hyaluronic acid.
“Cross-linking ” contain at least two reactive functional groups that create
covalent bonds between two or more molecules. The cross-linking agents can be
functional (i.e. have two reactive ends that are cal) or heterobifunctional (i.e. have
two ent reactive ends). The cross-linking agents to be used in the t disclosure should
comprise complimentary functional groups to that of hyaluronic acid such that the linking
reaction can proceed. In one ment, the cross-linking does not form esterified hyaluronic
acid. Suitable cross-linking agents include, by way of example only, butanediol diglycidyl ether
(BDDE), divinyl sulfone (DVS), or 1-ethyl(3-dimethylaminopropyl) carbodimide
hydrochloride (EDC), or a combination thereof. In one embodiment, the cross-linking agent is
BDDE. In one embodiment, the cross-linking agent is not a photocurable cross-linking agent.
As used herein, the term “BDDE derivative” refers to a form of BDDE wherein one or
both epoxides of BDDE have reacted with hyaluronic acid. BDDE has the following chemical
structure:
BDDE
One example of a BDDE derivative of hyaluronic acid is shown below.
a BDDE derivative
The BDDE derivative of hyaluronic acid, as shown above, can be covalently bound to
hyaluronic acid at both ends with both epoxides having been reacted. Additional BDDE
derivatives of hyaluronic acid are contemplated herein. For example, certain BDDE derivatives of
hyaluronic acid can be covalently bound at both ends between two te hyaluronic acid
polymers (i.e., cross-linked), while other BDDE derivatives can be covalently bound at both ends
within a single onic acid polymer. Also contemplated are BDDE derivatives that are
covalently bound at one or both ends to a hydroxyl group from one or more additional BDDE
derivatives that are lves covalently bound to hyaluronic acid.
Also contemplated are BDDE derivatives that that are covalently bound to onic
acid at just one end. For example, one of the epoxide rings can be opened by covalent attachment
to a single stretch of a hyaluronic acid polymer while the other epoxide ring can remain closed
(i.e., unreacted). It is further contemplated that, within the cross-linked onic acid
compositions, the concentration of such BDDE derivatives with an ted epoxide is
sufficiently low so as not to affect the biocompatibility of threads prepared from such
compositions. Further contemplated is a BDDE derivative in which one of the epoxide rings has
been opened by covalent ment to a single stretch of hyaluronic acid polymer while the other
epoxide ring has been opened by hydrolysis. However, it is contemplated that the cross-linked
hyaluronic acid compositions comprise at least about 2 mole % BDDE (with respect to the
disaccharide monomer) which is covalently bound at both ends between two separate hyaluronic
acid polymers.
As used herein, the term “binder” refers to a naturally occurring or synthetic substance
which provides uniform consistency and/or cohesion in the composition comprising the crosslinked
hyaluronic acid, which when ed, forms a thread. In one embodiment, the binder is
noncross-linked hyaluronic acid. In another ment, the binder is selected from a group
consisting of sugars and polysaccharides such as sucrose, maltose, chondroitin sulfate, dermatan
sulfate, heparin, chitosan, cellulose, gelatin, collagen, acacia, , PVP inyl pyrrolidone),
HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methylcellulose), PEG, PLGA
(poly(lactic-co-glycolic acid), carboxy methyl cellulose, ethylcellulose, gelatin polyethylene
oxide, dextrin, magnesium um silicate, thacrylates, and the like.
As used herein, the term “skin” refers to the three layers: the epidermis, the dermis, and
the hypodermis or the deeper subcutaneous tissue.
As used herein, the terms “smoother,” “smooth,” and “smoothness” refer to the property
of a thread that provides decreased drag when pulled through tissue. The more smooth the thread,
the less drag when pulled through the skin.
As used herein, the term “thread” refers to a long, thin, le form of a material. The
thread as described herein can have a variety of shapes in the cross-section which are discussed
below.
The term “ultimate tensile strength” is intended to refer to the tensile th of the
thread which has been normalized with respect to cross-sectional area. The term “tensile
strength” is ed to refer to the maximum stress a thread can withstand without failing when
ted to tension. In one embodiment, it is contemplated that the ultimate tensile strength is
sufficient to pull the thread through the skin and manipulate it once in the skin such that the
integrity of the thread is not substantially compromised by, for example, breaking or segmenting.
It is plated that threads as described herein preferably have an ultimate tensile strength of
about 3 kpsi pounds per square inch”) or r, or 5 kpsi or greater, or 10 kpsi or greater,
or 15 kpsi or greater or 20 kpsi or greater or 50 kpsi or greater or 75 kpsi or greater. In some
embodiments, the threads have a tensile strength of about 0.4 lbf (pound force) or greater, or 0.6
lbf or greater, or 0.8 lbf or greater, or 1.0 lbf or greater, or 1.1 lbf or greater. In some
embodiments, the threads have a tensile strength of about 0.7 lbf.
In some embodiments, tensile strength may be measured by using a force gauge and
measuring the peak force required to break the thread. Of imately 9 thread lots tested, the
average tensile th was about 0.71 pounds force using a 20 gauge extrusion nozzle.
The term “percent moisture” is intended to refer to the total percent of water by weight.
In one embodiment, the percent moisture of the thread is about 30% or less, or alternatively, about
% or less, or alternatively, about 10% or less. This can typically be measured by Karl Fisher
titration.
The threads as described herein can be made into a y of shapes. The term
“substantially cylindrical” refers to a thread wherein the cross-section of the thread is round. The
term “substantially” as used to refer to shapes of the threads means that at least 50% of the thread
has the approximate shape described. The term substantially is also used to encompass threads
which have a variety shapes along the length of the thread. For example, a thread could be
substantially cylindrical but the ends of the thread may be d. The substantially cylindrical
threads can be ed when the contact angle of the gel composition and the substrate on which
it is extruded have an equilibrium contact angle of greater than about 90 degrees.
The term “substantially D-shaped” refers to a thread wherein the cross-section is D-
shaped or substantially semi-circular. The substantially D-shaped s have one flat side and
one substantially round side. The substantially ed threads can be provided when the
contact angle of the gel composition and the substrate on which it is extruded have an equilibrium
contact angle of about 90 degrees.
The term “substantially -shaped” refers to a thread wherein the thickness of the
thread is less than about 50% of the width of the thread. In some embodiments, the cross-section
is substantially rectangular. The ribbon-shaped threads can be provided when the contact angle of
the gel composition and the substrate on which it is ed have an equilibrium contact angle of
less than about 90 degrees. atively, the ribbon-shaped threads can be formed by cutting a
wet gel to achieve the desired cross-sectional shape. “Ribbon-shaped” may also include shapes
that are substantially ellipsoidal. The term antially ellipsoidal” refers to a thread wherein
the section is substantially oblong or elliptical.
The term “therapeutic agent” can include one or more therapeutic agents. In still other of
the above embodiments, the therapeutic agent is an anesthetic, including but not limited to,
lidocaine, xylocaine, ine, benzocaine, prilocaine, ripivacaine, ol, or combinations
thereof. In still other of the above embodiments, the therapeutic agent includes, but is not limited
to, epinephrine, ephedrine, aminophylline, theophylline or combinations f. In still other of
the above embodiments, the therapeutic agent is botulism toxin. In still other of the above
embodiments, the therapeutic agent is n-511. In still other of the above embodiments, the
therapeutic agent is glucosamine, which can be used, for example, in the treatment of regenerative
joint disease. In still other of the above embodiments, the therapeutic agent is an antioxidant,
including but not limited to, vitamin E or all-trans retinoic acid such as retinol. In still other of the
above embodiments, the therapeutic agent includes stem cells. In still other of the above
embodiments, the therapeutic agent is n, a growth factor such as, for e, NGF (nerve
growth factor),BDNF (brain-derived neurotrophic factor), PDGF (platelet-derived growth factor)
or Purmorphamine Deferoxamine NGF (nerve growth factor), dexamethasone, ascorbic acid, 5-
azacytidine, 4,6-disubstituted pyrrolopyrimidine, cardiogenols, cDNA, DNA, RNAi, BMP-4
(bone morphogenetic protein-4), BMP-2 (bone morphogenetic n-2), an antibiotic agent such
as, for example, ß lactams, quinolones including fluoroquinolones, aminoglycosides or
macrolides, an anti-fibrotic agent, including but not limited to, cyte growth factor or
Pirfenidone, an anti-scarring agent, such as, for example, anti-TGF-b2 monoclonal antibody
(rhAnti-TGF-b2 mAb), a peptide such as, for example, GHK copper binding peptide, a tissue
regeneration agent, a steroid, fibronectin, a cytokine, an analgesic such as, for example,
adol HCl, opiates, (e.g., morphine, codone, oxycodone, etc.) an ptic, alpha- beta or
gamma-interferon, EPO, ons, calcitonin, heparin, interleukin-1, interleukin-2, filgrastim, a
protein, HGH, luteinizing hormone, atrial natriuretic , Factor VIII, Factor IX, or a folliclestimulating
hormone.
The term “diagnostic agent” refers to an agent which is used as part of a diagnostic test
(e.g., a fluorescent dye to be used for viewing the thread in vivo). In one embodiment, the
diagnostic agent is e TB (tuberculosis) protein.
The term “lubricity-enhancing agent” is intended to refer to a substance or solution
which when contacted with the dry thread, acts to ate the dry thread. A lubricity-enhancing
agent can comprise, for example, water and/or an alcohol, an aqueous buffer, and may further
comprise additional agents such as polyethylene glycol, hyaluronic acid, and/or collagen.
The term “biodegradation impeding agent” is intended to refer to a biocompatible
substance that slows or ts the in vivo degradation of the thread. For example, a
biodegradation impeding agent can include hydrophobic agents (e.g., lipids) or sacrificial
biodegradation agents (e.g., sugars).
The term “failure load” is ed to refer to the maximum force which, when applied
to the thread, causes the thread to fail. By “failing,” it meant that the thread can break or segment
or otherwise lose structural integrity. In some embodiments, the failure load is about 0.1 pounds
or 0.22 kilograms or greater.
The term “firm” is intended to refer to a cohesive material that maintains its form in an
unconstrained environment (ie as opposed to a flowable/amorphous material) and demonstrates
some degree of structural integrity under compression. A gelatin cube is an example of a firm gel.
The term “aqueous gel composition” or “gel composition” or “gel mixture” is intended to
refer to an aqueous composition comprising water, hyaluronic acid, and a cross-linking agent
and/or cross-linked hyaluronic acid. In some embodiments, the composition may further
comprise a buffer such that that the pH of the solution changes very little with the on of
components of the composition. In these ments, the composition is referred to as an
aqueous buffered gel composition. The pH of the buffered gel composition is lly from
about 7 to about 13. In certain embodiments the pH is about 7. In certain embodiments, the pH is
higher at about 9 or about 10. In some embodiments, the pH can be adjusted by adding an
appropriate amount of a le base, such as Na2CO3 or NaOH. In some embodiments, the
aqueous gel buffered composition comprises phosphate buffered saline. In some embodiments,
the aqueous gel buffered composition comprises ydroxymethyl)aminomethane (Tris), which
has the formula (HOCH2)3CNH2. In some embodiments, additional solutes are added to adjust the
osmolarity and ion trations, such as sodium chloride, calcium chloride, and/or potassium
chloride.
The term r” is ed to refer to a solution that stabilizes pH, wherein the
solution comprises a mixture of a weak acid and its conjugate base or a weak base and its
conjugate acid. Buffer solutions include, but are not limited to, 2-aminomethyl-1,3-
propanediol, 2-aminomethylpropanol, L-(+)-tartaric acid, D-(-)-tartaric acid, ACES, ADA,
acetic acid, um acetate, ammonium onate, um e, ammonium formate,
ammonium oxalate, ammonium ate, ammonium sodium phosphate, ammonium sulfate,
ammonium tartrate, BES, , BIS-TRIS, bicarbonate, boric acid, CAPS, CHES, calcium
acetate, calcium carbonate, calcium e, citrate, citric acid, diethanolamine, EPP,
ethylenediaminetetraacetic acid disodium salt, formic acid solution, Gly-Gly-Gly, Gly-Gly,
glycine, HEPES, imidazole, lithium acetate, lithium citrate, MES, MOPS, magnesium acetate,
magnesium citrate, magnesium formate, magnesium phosphate, oxalic acid, PIPES, phosphate
buffered , piperazine potassium D-tartrate, potassium acetate, potassium onate,
potassium carbonate, potassium chloride, potassium e, potassium formate, potassium oxalate,
potassium phosphate, potassium phthalate, potassium sodium tartrate, potassium orate,
potassium tetraoxalate dehydrate, nic acid solution, STE buffer solution, sodium 5,5-
lbarbiturate, sodium acetate, sodium bicarbonate, sodium bitartrate monohydrate, sodium
carbonate, sodium citrate, sodium chloride, sodium formate, sodium oxalate, sodium phosphate,
sodium pyrophosphate, sodium tartrate, sodium tetraborate, TAPS, TES, TNT, TRIS-glycine,
cetate, TRIS buffered saline, TRIS-HCl, TRIS phosphate–EDTA, tricine, triethanolamine,
triethylamine, triethylammonium acetate, triethylammonium phosphate, trimethylammonium
acetate, trimethylammonium phosphate, Trizma® acetate, Trizma® base, Trizma® carbonate,
Trizma® hydrochloride or Trizma® maleate.
The term “aqueous solvent” is intended to refer to a non-toxic, non-immunogenic
aqueous composition. The aqueous solvent can be water and/or an l, and may r
comprise s, salts (e.g., CaCl2) and other such non-reactive solutes.
The term ct angle” or “equilibrium contact angle” refers to a measure of a liquid’s
affinity for a solid and quantifies the degree of a liquid drop’s spread when placed on the solid. In
the case as bed herein, the liquid is the aqueous gel composition and the rigid or solid
surface is the substrate on which the composition is extruded. The contact angle is a measure of
the angle that the edge of an ideal drop makes with a flat surface. The lower that the contact angle
is, the greater attraction between the surface and the liquid. For example, water spreads almost
completely on glass and has a very low contact angle of nearly 0 degrees. Mercury, in contrast,
beads up and spreads very little; its contact angle is very large.
2. Threads and Methods of Preparing Threads
As mentioned above, it has been surprisingly found that alterations of the relative
amounts of the components, reaction conditions, nt modification of the hyaluronic acid,
and/or manufacturing protocols can have notable s upon certain properties of threads
comprising cross-linked hyaluronic acid. Accordingly, such threads with improved characteristics
have been developed and s of their preparation are described herein. Such threads are
contemplated to be smoother. Some of the threads that are described below are stronger. They
have greater tensile strengths and improved ties to absorb water. It is thus contemplated
that the threads described herein are easier for the clinician to handle and implant into to a patient.
Preparation of Cross-Linked Hyaluronic Acid
Threads comprising cross-linked hyaluronic acid have been prepared according to
methods described herein having increased ratios of linking agent (e.g., BDDE derivatives)
relative to the repeating disaccharide unit of the onic acid.
Generally, hyaluronic acid (HA) used herein has a molecular weight of from about 0.5
MDa (mega Dalton) to about 3.0 MDa. In some ments, the molecular weight is from
about 0.6 MDa to about 2.6 MDa, and in yet r embodiment the molecular weight is from
about 1.4 MDa to about 1.7 MDa. In some embodiments, the molecular weight is about 0.7 MDa,
and in yet another embodiment the molecular weight is about 1.7 MDa. In some embodiments,
the molecular weight is about 2.7 MDa.
In one aspect, there is ed a composition comprising at least 5% hyaluronic acid by
weight, wherein the hyaluronic acid is substantially cross-linked with from about 17 to about 20
mole % of a butanediol idyl ether (BDDE) derivative relative to the repeating disaccharide
unit of the hyaluronic acid.
[0071a]Also described are itions comprising cross-linked hyaluronic acid formed under
aqueous conditions. In certain embodiments, such aqueous compositions form gels. In certain
embodiments, the hyaluronic acid is hydrated for between about one minute and about 60 minutes
prior to cross-linking. In other embodiments, the hyaluronic acid is hydrated for between about
one hour and about 12 hours prior to cross-linking. In certain embodiments, the hyaluronic acid is
hydrated for about one hour and in yet r embodiment the onic acid is allowed to
hydrate for about two hours prior to cross-linking. In n embodiments, the hyaluronic acid is
hydrated for about three hours and in yet another embodiment the hyaluronic acid is allowed to
hydrate for four hours prior to cross-linking.
Prior to addition of the HA, the aqueous solution is adjusted to the desired pH. In one
embodiment, the aqueous solution has a pH > about 7. In n embodiments, the solution has a
pH of about 9, or about 10, or about 11, or about 12 or about 13, or greater than 13. Typically, the
solution comprises water and can optionally comprise phosphate buffered saline (PBS) or
tris(hydroxymethyl)aminomethane (Tris) buffer. The buffer can be selected based on the desired
pH of the composition. For example, PBS can be used for compositions at a pH of about 7,
whereas Tris can be used for compositions having a higher pH of about 9 or about 10. In some
embodiments, the pH is from between about 9 and about 13. In some embodiments, the pH is at
least about 13. In some embodiments, the pH is adjusted with the appropriate amount of a
suitable base, such as Na2CO3 or NaOH to reach the desired pH. In some embodiments, the
tration of base is from about 0.00001 M to about 0.5 M. In some embodiments, the
concentration of base is from about 0.1 M to about 0.25 M. In some embodiments, the
concentration of base is about 0.2 M.
It has been surprisingly found that the concentration of hyaluronic acid used during the
cross-linking butes to the quality of the compositions comprising cross-linked hyaluronic
acid, and ultimately improves certain properties of threads that are prepared from such
compositions. For example, the gels become increasingly firm when the concentration of
hyaluronic acid used during cross-linking is at least about 5%. Further, it has been found that the
gel ng ratio in water can be increased by decreasing the concentration of hyaluronic acid
used during the cross-linking. In one embodiment, the composition during the cross-linking
comprises from about 1 weight % to about 25 weight % hyaluronic acid, before cross-linking. In
another embodiment, the composition during the cross-linking comprises about 14 weight %
hyaluronic acid, before cross-linking. In another embodiment, the composition during the crosslinking
ses about 12 weight % hyaluronic acid, before cross-linking. In another
embodiment, the composition during the cross-linking comprises about 8 weight % onic
acid, before cross-linking. In another embodiment, the composition during the cross-linking
comprises about 5 weight % hyaluronic acid, before cross-linking.
In an alternative embodiment, the cross-linking is med neat, i.e., t a solvent.
Therefore, in certain embodiments, neat BDDE is ted with dry hyaluronic acid to provide
the cross-linked hyaluronic acid. The composition can then be hydrated with the desired amount
of aqueous medium to provide the gel ition.
Compositions comprising cross-linked hyaluronic acid are formed when hyaluronic acid
is contacted with a cross-linking agent. The cross-linking agent to be used in the present
disclosure should comprise complimentary functional groups to that of hyaluronic acid such that
the cross-linking reaction can proceed. The cross-linking agent can be functional or
heterobifunctional. It is contemplated that the percent hydration of the thread may be at least
partially controlled by the type of cross-linking agent employed. For example, if the cross-linking
leaves the yl groups of the hyaluronic acid unfunctionalized, the percent hydration of the
thread may be higher than esterified hyaluronic acid. Suitable cross-linking agents e, but
are not limited to, butanediol diglycidyl ether , divinyl sulfone (DVS), and 1-ethyl(3-
dimethylaminopropyl) carbodiimide hydrochloride (EDC), or a combination f. In some
aspects, there is provided a composition comprising substantially cross-linked onic acid,
wherein hyaluronic acid is cross-linked or covalently modified with a BDDE derivative.
It has also been discovered that the concentration of cross-linking agent, e.g., BDDE,
used during cross-linking contributes to the quality of the compositions sing cross-linked
hyaluronic acid and, ultimately, to improve certain properties of the threads that are prepared from
such compositions. The amount of BDDE used is sufficient to produce a ition comprising
at least 15 mole % of a BDDE derivative relative to the repeating disaccharide unit of the
hyaluronic acid. In one embodiment, the composition comprises from about 15 mole % to about
% mole percent, or about 17 mole % to about 20 mole % of the BDDE derivative, or about 18
mole % to about 19 mole %. In one embodiment, the composition comprises 18.75% of the
BDDE derivative.
The amount of BDDE selected will be sufficient enough to provide a firm composition.
For example, the gels become increasingly firm when the concentration of BDDE used during
cross-linking is at least about 10 weight % relative to the weight of the hyaluronic acid. The
amount of BDDE used during cross-linking, upon formation of the ition comprising crosslinked
hyaluronic acid, may also be expressed as a weight % relative to the weight of the
hyaluronic acid used during cross-linking. In one embodiment, between 25 weight % and 100
weight % BDDE is used relative to the weight of hyaluronic acid. In another embodiment, at least
% BDDE is used relative to the weight of onic acid. In another embodiment, about 30%
BDDE is used relative to the weight of onic acid. In another embodiment, at least 40%
BDDE is used relative to the weight of hyaluronic acid. In another embodiment, about 40%
BDDE is used relative to the weight of hyaluronic acid. In r embodiment, at least 50%
BDDE is used relative to the weight of hyaluronic acid. In another embodiment, about 50%
BDDE is used relative to the weight of hyaluronic acid. In another embodiment, between about
50% BDDE and about 75% BDDE is used ve to the weight of onic acid. In another
ment, between about 75% BDDE and about 100% BDDE is used ve to the weight of
hyaluronic acid.
In certain aspects, hyaluronic acid is cross-linked or covalently modified to form
compositions comprising substantially linked hyaluronic acid. In certain embodiments, the
amount of cross-linking agent incorporated therein, or cross-link density, should be sufficiently
high such that the thread formed thereby is elastomeric, however it should not be so high that the
resulting thread becomes too rigid such that it cannot be moved within the skin during delivery
when used as a soft tissue augmentation product. The appropriate stiffness or elastic modulus is
ined by the intended use of the thread.
Washing, Drying, and Formulating Cross-Linked Hyaluronic Acid
After the cross-linked hyaluronic acid has been prepared, any excess cross-linking agent
can be washed away. Water rinsing alone is typically insufficient to remove all excess crosslinking
agent. Water rinsing can also be followed with or replaced by rinsing with a buffer and/or
alcohol solvent, such as ethanol to remove the unreacted BDDE. It is contemplated that multiple
washings may be necessary to remove all or substantially all of the excess cross-linking agent. It
is further contemplated that the gels may be cut into smaller pieces or ed from a syringe to
improve the efficiency of the washing steps.
In some ments, the hydrated or washed gel pieces have been sized. The sizing be
accomplished by loading the gel into a e and extruding through a needle (typically a 20
gauge (G) blunt needle) or through a screen (e.g., 355 μm screen). More than one or even a series
of sizing steps can be performed using the same or a different, typically a r, gauge needle or
screen than the previous sizing step. For example, the gel can be first ed through a 20G
needle once or twice, and then optionally extruded through a 23G or a 25G needle one or more
times. The more sizing steps implemented, the smoother the resultant thread. Such results would
be beneficial as a smoother thread would ease delivery through the skin as the smoother thread
would exhibit less drag. In addition, it is contemplated that additional sizing steps also may
increase the tensile strength of the thread. For example, certain threads which have been sized
once using a 20G needle have a e strength of from about 0.381 pounds to about 0.476
pounds, or of about 0.436 pounds. n threads which have been sized twice using a 20G
needle have a tensile th of from about 0.416 pounds to about 0.579 pounds, or of about
0.479 . Certain threads which have been sized twice using a 20G needle and then once
using a 25G needle have a tensile strength of from about 0.462 pounds to about 0.605 pounds, or
of about 0.529 pounds.
Although the smoothness of the thread is enhanced by implementing more than one
sizing step, the particle size of the gel is not substantially changed (Fig. 14). Thread swell ratio
does not change substantially with increased sizing (between 1.66 and 1.70 for one, two and three
sizing steps), although the dry diameter of the thread decreases slightly with increased sizing.
In one embodiment, the itions comprising cross-linked hyaluronic acid, as
described above, are ntially dried (e.g., dehydrated) before being further combined with
binder. In one embodiment, the aqueous gel compositions sing cross-linked hyaluronic
acid, as described above, are substantially dried (e.g., dehydrated) before being further combined
with noncross-linked hyaluronic acid. In some embodiments, drying is lished by airdrying
or first decanting the solvent before air drying at ambient or elevated temperatures. In one
embodiment, drying is accomplished by lyophilization. In one embodiment, drying is partial.
In one ment, the compositions comprising cross-linked hyaluronic acid, as
described above, are ed via precipitation from a suitable solvent, such as ethanol, before
being further combined with binder. The precipitation can be ented multiple, i.e., more
than one, time. In some embodiments, the particle size of the gel isolated via precipitation are
ntially the same size as, or smaller than, the particles of the lized gel. In certain
embodiments, the s made from the gel isolated via precipitation have a small dried thread
diameter (e.g., about -0.015”), yet exhibit a faster rate of swelling, enhanced softness and
larger swell diameter.
In one embodiment, the aqueous gel composition comprising cross-linked hyaluronic
acid is dehydrated to remove about 25% of the water content by weight. In one embodiment, the
aqueous gel ition comprising cross-linked hyaluronic acid is dehydrated to remove about
50% of the water content by weight. In one embodiment, the aqueous gel ition comprising
cross-linked hyaluronic acid is dehydrated to remove about 75% of the water content by weight.
In one embodiment, the aqueous gel composition comprising cross-linked hyaluronic acid is
dehydrated to remove about 90% of the water content by weight.
It has been surprisingly found that the concentration of total HA solids, including crosslinked
hyaluronic acid and noncross-linked binder, within the aqueous gel compositions prior to
extrusion, improves certain properties of the threads as described herein such as smoothness and
ease of handling either before or after extrusion.
The dried cross-linked hyaluronic acid composition, as described above, can be
combined with water to form a substantially cross-linked hyaluronic acid gel, which can then
optionally be formulated with a binder (e.g., noncross-linked hyaluronic acid) and/or additive
(e.g., a salt, excipient, lidocaine, or the like). The resulting ated gel composition
comprising cross-linked hyaluronic acid, and optional binder such as noncross-linked onic
acid, can then be extruded into a wet thread which can then be dried.
In one embodiment, the cross-linked hyaluronic acid is present in the composition,
before thread drying and ally with a binder such as noncross-linked hyaluronic acid, in an
amount of from about 5 weight % to about 20 weight % based on the total weight of the
composition. In still another embodiment, the cross-linked onic acid is present in the
composition, before thread drying and optionally with a binder such as noncross-linked onic
acid, in an amount of from about 5 weight % to about 12 weight % or about 8 weight % to about
weight % based on the total weight of the composition, excluding moisture.
In one embodiment, there is described a composition comprising the ntially crosslinked
hyaluronic acid of any of the above embodiments, that has been dried and rehydrated, and
further comprises a binder. In one embodiment, the binder is noncross-linked hyaluronic acid. In
one embodiment, the binder, such as noncross-linked hyaluronic acid, is provided as an aqueous
solution. In one embodiment, the binder, such as noncross-linked hyaluronic acid, is provided as
an aqueous solution further comprising a salt, such as CaCl2. In one embodiment, the binder, such
as noncross-linked hyaluronic acid, is provided as an aqueous solution further comprising 1 mM
CaCl2, 2.5 mM CaCl2, 10 mM CaCl2, or greater than 10 mM CaCl2.
Yet another surprising finding has been that the y of the dry threads as described
herein is dependent, at least partially, upon the quantity of the total hyaluronic acid solids used to
make the wet thread compositions, as described above. The “hyaluronic acid solids” include any
combination of substantially cross-linked hyaluronic acid and/or ss-linked hyaluronic acid
(i.e., binder). In some embodiments, a minimum quantity of hyaluronic acid solids contributes to
the quality of the dry threads, for example, by supporting the cross-sectional shape (e.g., relatively
round er) of the wet threads used to make the dry threads. A minimum quantity of
hyaluronic acid solids may further contribute to the quality of the dry threads, for example, by
increasing the tensile th of the dry threads and/or the swelling ratio by which the dry threads
absorb water. A minimum quantity of hyaluronic acid solids may contribute still further to the
quality of the dry s by increasing the smoothness of the dry threads. Exemplary minimum
quantities of hyaluronic acid solids are described below.
In one ment, the wet thread comprises from about 2% to about 50% hyaluronic
acid solids. In one embodiment, the wet thread comprises from about 2% to about 40%
hyaluronic acid solids. In one embodiment, the wet thread comprises from about 2% to about
% hyaluronic acid solids. In one embodiment, the wet thread comprises at least 7% hyaluronic
acid solids. In one embodiment, the wet thread comprises at least 10% hyaluronic acid solids. In
one ment, the wet thread ses at least 12% hyaluronic acid solids. In one
embodiment, the wet thread comprises at least 15% hyaluronic acid solids. In one embodiment,
the wet thread comprises at least 18% hyaluronic acid solids. In one embodiment, the wet thread
comprises at least 20% onic acid solids. In one embodiment, the wet thread comprises at
least 25% hyaluronic acid solids.
As described above, the hyaluronic acid solids that are used to make the wet and dry
s as described herein can e any combination of cross-linked hyaluronic acid and/or
noncross-linked hyaluronic acid (i.e., binder). Adjustments in the quantity and/or ratio of crosslinked
onic acid and/or ss-linked hyaluronic acids can improve certain properties of
the s (e.g., the cross-sectional shape of the wet threads, the tensile strength of the dry
threads, the swelling ratio by which the dry s absorb water, the smoothness of the dry
threads, the resistance of the dry threads to in vitro enzymatic digestion by hyaluronidase, and/or
an sed in vivo half-life).
In one embodiment, the linked hyaluronic acid is present in itions used to
make threads in an amount of from about 1 weight % to about 25 weight % based on the total
weight of the composition. In another embodiment, the cross-linked onic acid is t in
an amount of from about 2 weight % to about 15 weight % based on the total weight of the
composition. In another embodiment, the cross-linked hyaluronic acid is t in an about 14
weight %. In another embodiment, the cross-linked hyaluronic acid is present in an about 12
weight %. In another embodiment, the cross-linked hyaluronic acid is present in an about 8
weight %. In another embodiment, the cross-linked hyaluronic acid is present in an about 5
weight %.
In one embodiment, the ss-linked hyaluronic acid is present in compositions used
to make threads in an amount of from about 1 weight % to about 20 weight % based on the total
weight of the composition. In another embodiment, the noncross-linked hyaluronic acid is present
in an amount of from about 1 weight % to about 8 weight % based on the total weight of the
composition. In another embodiment, the noncross-linked onic acid is present in an about 5
weight %. In another embodiment, the noncross-linked hyaluronic acid is t in an about 3
weight %. In another embodiment, the noncross-linked hyaluronic acid is present in an about 2
weight %.
In one embodiment, the itions used to make threads comprise from about 5
weight % to about 15 weight % cross-linked hyaluronic acid and from about 2 weight % to about
8 weight % noncross-linked hyaluronic acid. In one embodiment, the composition comprises
about 12 weight % cross-linked hyaluronic acid and about 3 weight % noncross-linked hyaluronic
acid. In one ment, the composition comprises about 8 weight % cross-linked hyaluronic
acid and about 2 weight % ss-linked hyaluronic acid. In one embodiment, the composition
comprises about 5 weight % cross-linked hyaluronic acid and about 5 weight % noncross-linked
hyaluronic acid. Compositions used to make threads can be made with higher or lower
concentrations of HA and cross-linked HA; the above three compositions are given as examples
only.
Deaerating, Extruding, and Drying Gels Into Threads
In some embodiments, the aqueous gel composition comprising cross-linked and
noncross-linked hyaluronic acid is deaerated (i.e., degassed), prior to extrusion to minimize air
bubbles after extrusion. The degassing can also be done by using a syringe. It has been
discovered that the tensile strength of threads generally improves upon deaeration of the
compositions used to make the threads.
In some embodiments, the compositions used to make the threads are deaerated at least
once. In some embodiments, the compositions used to make the threads are deaerated more than
once. In some embodiments, the compositions used to make the threads are deaerated between
two and ten times. In some embodiments, the compositions used to make the threads are
deaerated twice. In some embodiments, the compositions used to make the threads are ted
three times, four, five, six, seven, eight, nine, or ten times. In some embodiments, the
compositions used to make the threads are deaerated at least ten times.
To form the thread, the aqueous gel composition comprising cross-linked and noncrosslinked
hyaluronic acid is typically extruded onto a substrate, as described below, to form a wet
thread. The composition is extruded using a rized syringe d to a nozzle. The nozzle
can have various geometries, such as various lengths, internal ers and shapes.
Generally, it has been discovered that many of the properties of the dry thread
compositions can be improved by increased nozzle size (e.g., width) during ion of the wet
thread. Such improved properties in the threads can include, for example, the cross-sectional
shape of the threads, the tensile th of the threads, the swelling ratio by which the threads
absorb water, the smoothness of the s, the resistance of the dry threads to in vitro enzymatic
digestion by hyaluronidase, and/or an increased in vivo half-life of the dry threads.
The nozzle may be circular or non-circular in shape, for example, a flattened shape or a
“D” shape. The syringe nozzle may be anywhere from about a 15 gauge to a 25 gauge syringe
nozzle. In some embodiments, the syringe nozzle is a 15 gauge nozzle, whereas in other
embodiments the syringe nozzle is a 16 gauge nozzle. In some embodiments, the e nozzle is
a 17 gauge nozzle, s in other embodiments the syringe nozzle is a 18 gauge nozzle. In
some ments, the syringe nozzle is a 19 gauge nozzle, whereas in other embodiments the
syringe nozzle is a 20 gauge nozzle. In some embodiments, the syringe nozzle is a 21 gauge
nozzle, s in other embodiments the e nozzle is a 22 gauge nozzle. Typically, the
pressure employed is from about 10 to about 2000 psi or from about 20 to about 240 psi. The
pressure requirements are dictated by the nozzle geometry and other attributes such as consistency
of the ition and desired flow rate. The pressure can be applied tically, for example
using ambient air or nitrogen, hydraulically, or mechanically. The speed at which the gel is
extruded takes into consideration minimization of air bubbles in the length of the thread and
maximization of a consistent uniform shape. Air bubbles can reduce the structural integrity of the
thread by causing weak spots.
Pneumatic pressure and plate speed are not fixed but are instead adjusted and monitored
in-process so that the gel is extruded in a uous, linear manner. For a given lot of s,
the pneumatic pressure is first increased to the point of consistent but controllable gel flow. The
plate speed is then continuously fine-tuned so that threads are extruded in a uniform linear
manner. If the plate speed is too slow zig-zagged threads may result; too fast and threads may
stretch leading to g and/or breakage.
Various substrates are contemplated for use by methods as described herein. Substrates
include by hydrophilic and hydrophobic substrates and may be ed from, but are not limited
to, polytetrafluoroethylene , expanded PTFE, nylon, hylene terephthalate (PET),
polystyrene, silicon, polyurethane, and activated cellulose.
The substrate employed, along with the viscosity of the gel ition, dictates the
general shape of the thread. For example, if the gel and the substrate have an equilibrium contact
angle of less than 90 degrees, it is contemplated that the thread formed could be substantially
ribbon-shaped. Further, if the gel and the substrate have an equilibrium contact angle of about 90
degrees, the thread formed could be substantially D-shaped. Still further, if the gel and the
substrate have an brium contact angle of greater than 90 degrees, then the thread formed
could be substantially round. For example, a 10% 1.5 MDa gel will have a substantially circular
section (e.g., about 80% of a circle) when extruded on PTFE, while a 5% 1.5 MDa gel will
form a flat ribbon when extruded on PTFE.
Alternative to pressurized extrusion, the gel composition can be rolled out into an
elongated cylinder and/or cut into ted strips before drying.
The wet thread is then dried to form a dry thread. Drying may be conducted under static
conditions or, alternatively, with the assistance of a c air flow (i.e., within a laminar flow
hood). In some embodiments, yields of the threads e with static drying. The drying step is
required to form threads with a sufficient tensile strength, as discussed below. As the thread may
lose some of its properties when exposed to heat in excess of water boiling temperature, it is
preferred that the drying step be performed under ambient conditions. This drying procedure
provides a thread with a higher tensile strength, such as, for example, an ultimate tensile strength
of about 5 kpsi to 100 kpsi or 20 kpsi to 80 kpsi. In other words, the threads as described herein
have a failure load of at least about 0.1 pounds or 0.22 kilograms.
The thread is allowed to dry for anywhere from about 30 minutes to about 72 hours to
form threads having a diameter of from 0.05 mm to about 1.0 mm and having 10%-30% by
weight hydration. In some embodiments, the thread can be dried for about 12 hours or about 24
hours. It is contemplated that the larger the molecular weight of HA ed or the more
concentrated the HA in the composition, the longer the drying times that are required. Further,
during the drying process, a non-thermal stimulus, such UV light, radiation, or a chemical initiator
or a catalyst, may be employed to assist in the cross-linking reaction.
In some embodiments, after drying, the thread is washed with an aqueous or nonaqueous
solvent, a gas or a supercritical fluid. In some instances, this washing removes excess
cross-linking agent. The washing can be accomplished by a variety of methods, such as
submersion in an aqueous solvent or by using a concurrent flow system by placing the thread in a
trough at an incline and allowing an aqueous solvent to flow over the thread. Threads can also be
suspended, for example vertically, and washed by dripping or flowing water down the length of
the thread.
In one ment, water is used to wash the threads. In this embodiment, the water not
only washes the threads to remove excess cross-linking agent, it also rehydrates the thread into a
hydrated elastomeric state. In one embodiment, an antioxidant solution is used to wash the
s. For example, in one embodiment, a buffer on comprising ascorbic acid, vitamin E
and/or sodium phosphate is used to wash the threads. In one embodiment, a buffer solution
sing about 1 mM, or about 10 mM or about 100 mM, or about 1 M ic acid is used to
wash the s.
The percent hydration of hyaluronic acid can range from about 1% to greater than about
1000% based on the total weight. The t hydration of the thread of the present disclosure
can be controlled by adjusting the percent hyaluronic acid in the gel and/or lling the amount
and type of cross-linking agent added. It is contemplated that a lower percent hydration thread
would result in a thread with a higher tensile strength. In some embodiments, the thread has no
more than about 30% percent, or no more than 15%, or no more than 10% by weight hydration
based on the total weight. The percent hydration will be determined by the environment to which
the thread is subjected to during or after the drying process.
It should be noted that the half-life of the hyaluronic acid thread in vivo can be controlled
by controlling the thickness of the thread, the density, the degree of cross-linking, the molecular
weight of the hyaluronic acid and the degree of ion, which can then be further controlled by
adjusting the amounts of hyaluronic acid and cross-linking agent both dually and relatively.
It is contemplated that the s disclosed herein can have an enhanced half-life in vivo of from
about 1 month to up to about 12 months as compared to less than 1 day for natural hyaluronic
acid. In certain embodiments, it is contemplated that the threads described herein have an in vivo
half-life of at least 1 month. In certain embodiments, it is contemplated that the threads described
herein have an in vivo half-life of at least 2 months. In certain embodiments, it is plated
that the threads described herein have an in vivo half-life of at least 3 months. In certain
ments, it is contemplated that the threads described herein have an in vivo half-life of at
least 4 months. In n embodiments, it is contemplated that the threads described herein have
an in vivo half-life of at least 6 months. In certain embodiments, it is contemplated that the
s described herein have an in vivo half-life of at least 8 months. In certain embodiments, it
is contemplated that the threads described herein have an in vivo half-life of at least 10 months. In
n embodiments, it is contemplated that the threads described herein have an in vivo half-life
of at least 12 months. In certain embodiments, it is contemplated that the threads described herein
have an in vivo half-life of at least 14 months. In certain embodiments, it is contemplated that the
threads bed herein have an in vivo half-life of at least 16 months. In certain embodiments, it
is contemplated that the s described herein have an in vivo half-life of at least 18 months.
It is contemplated that the threads described herein can be sterilized using typical
sterilization methods known in the art, such as autoclave, ethyleneoxide, electron beam (e-beam),
supercritical CO2 (with peroxide), etc. For example, the threads as described herein can be
sterilized using electron beam (e-beam) sterilization methods. In some embodiments, the threads
are first washed in a buffer solution at high pH (i.e., pH 9 or pH 10). In some embodiments, the
wash solutions further comprise ethanol, ascorbic acid, vitamin E and/or sodium ate.
Optionally and as necessary, the thread is mechanically stretched while hydrated, either
soon after being hydrated or gradually before the first drying or after the rehydrating. The
stretching or e of stretching can provide a thread of the desired length and/or rehydration
swelling . In some ments, the length of the thread can be from about 0.5 cm to
about 15 cm. In another embodiment, the length of the thread can be from about 2 cm to about
12 cm. In another embodiment, the length of the thread can be from about 5 cm to about 10 cm.
After the thread is rehydrated it is allowed to dry again under t conditions for
from anywhere from 30 minutes to about 72 hours. Upon drying, the thread, in some
embodiments, cures to e a more uniform surface of the thread.
This washing hydration/dehydration step can be performed multiple times to allow
excess unreacted reagent to be washed from the thread or to continue to improve the degree of
cross-linking or covalent modification. This is an improvement over methods such as the use of
organic solvents to remove excess BDDE.
3. Thread Nomenclature
Threads as bed herein are prepared from compositions comprising substantially
cross-linked hyaluronic acid. In certain embodiments, threads are prepared from compositions
sing substantially cross-linked hyaluronic acid, and r comprising a binder such as
noncross-linked hyaluronic acid. Threads can be described according to the following
nomenclature AA/BB@XX/YY, wherein AA/BB describes the initially formed composition
sing substantially cross-linked hyaluronic acid and XX/YY bes the composition with
a binder, such as noncross-linked hyaluronic acid.
For example, a thread referred to as “10/40@15/20” refers to a composition of
substantially cross-linked hyaluronic acid, wherein the cross-linking reaction is performed with 10
weight % hyaluronic acid relative to the weight of the on (e.g., an aqueous solution), using
40 weight % cross-linker (e.g., BDDE) relative to the weight of the hyaluronic acid.
As referred to herein, AA of AA/BB@XX/YY is at least 2%. In some embodiments,
AA is at least 5%. In some embodiments, AA is about 8%. In some embodiments, AA is about
%. In some embodiments, AA is at least 10%. In some embodiments, AA is about 12%. In
some embodiments, AA is at least 15%.
In some embodiments, BB of AA/BB@XX/YY is at least 10%. In some embodiments,
BB is at least 20%. In some embodiments, BB is at least 30%. In some ments, BB is
about 30%. In some ments, is at least 40%. In some embodiments, BB is about 40%. In
some embodiments, BB is at least 50%. In some embodiments, BB is about 50%.
In some embodiments, AA/BB of AA/BB@XX/YY is about 8/10. In some
embodiments, AA/BB is at least or about or exactly 8/20. In some ments, AA/BB is about
8/30. In some embodiments, AA/BB is about 8/40. In some embodiments, AA/BB is about 8/50.
In some embodiments, AA/BB is about 10/10. In some embodiments, AA/BB is about 10/20. In
some embodiments, AA/BB is about 10/30. In some embodiments, AA/BB is about 10/40. In
some embodiments, AA/BB is about 10/50.
In some ments, one or more binding agents, such as noncross-linked hyaluronic
acid, are added to the compositions comprising cross-linked hyaluronic acid, and the resulting
compositions are converted by additional methods described herein to e novel threads. In
some embodiments, the compositions comprising linked onic acid further comprise
noncross-linked hyaluronic acid. The added noncross-linked hyaluronic acid is optionally
referred to herein as a “binder.” The combination of linked hyaluronic acid and sslinked
hyaluronic acid, within the ition, is optionally referred to herein as “hyaluronic acid
.” As referred to herein, the XX of AA/BB@XX/YY refers to the weight % of total
hyaluronic acid solids relative to the weight of the composition, wherein the hyaluronic acid solids
includes both the substantially cross-linked hyaluronic acid and any noncross-linked hyaluronic
acid. As referred to herein, the YY of AA/BB@XX/YY refers to the weight % of noncross-linked
hyaluronic acid relative to the weight of total hyaluronic acid solids.
In some embodiments, XX of AA/BB@XX/YY is at least 2%. In some embodiments,
XX is at least 5%. In some embodiments, XX is at least 10%. In some embodiments, XX is
about 10%. In some embodiments, XX is at least 15%. In some embodiments, XX is about 15%.
In some embodiments, XX is at least 20%. In some embodiments, XX is about 20%. In some
embodiments, XX is at least 25%. In some embodiments, XX is about 25%.
In some embodiments, YY of AA/BB@XX/YY is at least 5%. In some embodiments,
YY is at least 10%. In some embodiments, YY is at least 20%. In some embodiments, YY is
about 20%. In some embodiments, YY is at least 30%. In some embodiments, YY is about 30%.
In some embodiments, YY is at least 40%. In some embodiments, YY is about 40%. In some
embodiments, YY is at least 50%. In some embodiments, YY is about 50%.
In some ments, AA/BB@XX/YY is 8/10@2/5, 8/20@5/10, 8/30@10/20,
8/40@15/20, 8/50@20/30, 10/10@20/40, 10/20@25/50, 10/30@20/40, 10/40@10/50,
/50@20/40, and the like.
It has been shown that the threads provided using the AA/BB@XX/YY compositions
disclosed herein t an enhanced in vivo persistence, as well as other beneficial qualities.
In certain embodiments, sed herein are threads comprising substantially crosslinked
hyaluronic acid, wherein the onic acid is substantially cross-linked with at least
about 15 mole % of a butanediol diglycidyl ether (BDDE) derivative relative to the repeating
disaccharide unit of the hyaluronic acid, and at least about 5% noncross-linked hyaluronic acid
relative to the weight of total hyaluronic acid solids, wherein the cross-linked onic acid is
t in an amount of from about 60 weight % to about 90 weight % based on the total weight
of the thread excluding moisture and the ss-linked hyaluronic acid is present in an amount
of from about 10 weight % to about 40 weight % based on the total weight of the thread excluding
moisture.
4. Modification of the Threads
In addition to washing the thread, it can also be further functionalized by adsorbing a
sufficient amount of a member selected from the group consisting of a therapeutic agent, a
diagnostic agent, a fibrogenesis-enhancing agent, a biodegradation impeding agent, a lubricityenhancing
agent and combinations thereof, optionally followed by re-drying the thread. Such
therapeutic agents include antibacterials, anesthetics, dyes for viewing placement in vivo, and the
like. In some embodiments, a dry or ed thread is coated to alter the ties with a
bioabsorbable biopolymer, such as collagen, PEG, PLGA or a phase transfer PluronicTM which
can be introduced as a liquid and which solidifies in vivo.
In one ment, the thread can be coated to modulate the rate at which the thread is
rehydrated. For example, the thread can be coated with a hobic layer, such as a lipid. The
ess of the lipid layer can then be adjusted to achieve the desired rate of rehydration. In
another embodiment, the thread can be coated with an aqueous composition of noncross-linked
hyaluronic acid. This can be performed just prior to implantation of the thread to act as a
lubricant. It is also contemplated that this coating with noncross-linked hyaluronic acid may slow
the rate of hydration of the thread. In some embodiments, the thread is , either totally or in
part, with the gel composition to form a d material. Woven constructs, whether single layer
or 3D, can be coated in their entirety to create weaves or meshes with altered physical properties
from that of a free-woven mesh.
The threads as bed herein can be braided, coiled, layered or woven. In some
embodiments, braids may be formed from the threads described above. A braid can be formed by
intertwining three or more s wherein each thread is functionally equivalent in zigzagging
forward through the overlapping mass of the others. The braids can be a flat, strand
structure, or more complex braids can be constructed from an arbitrary (but usually odd) number
of threads to create a wider range of structures, such as wider ribbon-like bands, hollow or solid
cylindrical cords, or broad mats which resemble a rudimentary perpendicular weave.
In one embodiment, a plasticizer is added to adjust the stiffness of the .
Alternatively, or in addition to, threads of varying ess may be weaved together to produce a
braided thread or al having the desired stiffness.
In some ments, a three-dimensional structure may be constructed by weaving or
wrapping or coiling or layering the threads described above. In other embodiments, a threedimensional
structure may be constructed by weaving or wrapping or coiling or layering the
braids described above. In still other embodiments, a three-dimensional structure may be
constructed by weaving or wrapping or coiling or layering the cords described above. In still
other embodiments, a dimensional structure may be constructed by weaving or wrapping or
coiling or layering the meshes described above.
In some embodiments, a three-dimensional, cylindrical implant is made of any of the
threads is described. An exemplary use for such an t is for nipple reconstruction. In some
embodiments, the threads used to make the cylindrical implant are cross-linked and include
chrondrocyte adhesion compounds. In other embodiments, the cylindrical shape is provided by
multiple, concentric coils of threads.
Thread Embodiments
In one aspect, there is provided a dry thread comprising hyaluronic acid, wherein at least
a portion of the hyaluronic acid is substantially cross-linked with at least about 15 mole % of a
BDDE derivative relative to the repeating disaccharide unit of the hyaluronic acid. In another
embodiment, the substantially linked hyaluronic acid is cross-linked with from about 15
mole % to about 20 mole % of the BDDE derivative. In one embodiment, the ntially crosslinked
hyaluronic acid is linked with from about 16 mole % to about 19 mole % of the
BDDE derivative.
In one embodiment, the cross-linked hyaluronic acid is present in an amount of from
about 50 weight % to about 90 weight % based on the total weight of the dry . In r
embodiment, the cross-linked hyaluronic acid is present in an amount of from about 60 weight %
to about 80 weight % based on the total weight of the dry thread.
In one embodiment, the dry thread further comprises a binder, such as for example,
ss-linked onic acid. The ss-linked hyaluronic acid may be present in an
amount of from about 1 weight % to about 50 weight % based on the total weight of the dry
thread. In one embodiment, the noncross-linked hyaluronic acid is present in an amount of from
about 15 weight % to about 20 weight % based on the total weight of the dry thread.
In another embodiment, the dry thread has an ultimate tensile strength of from about 2
kpsi to about 20 kpsi. In one embodiment, the thread has an ultimate e strength of from
about 4 kpsi to about 10 kpsi.
In another embodiment, the dry thread has a er of at least about 0.004 inches. In
one embodiment, the dry thread has a diameter of from about 0.008 to about 0.018 inches.
In another embodiment, the dry thread has a weight/length ratio from about 1.5 to about
3.5 mg/inch.
In one embodiment, the dry thread has a failure load of about 0.3 pounds or greater. In
another embodiment, the dry thread has a failure load of from about 0.3 to about 1.3 pounds.
In one embodiment, the dry thread further comprises a needle.
In yet another aspect, there is described a dry thread comprising substantially crosslinked
hyaluronic acid prepared by the steps of: a) forming a substantially cross-linked hyaluronic
acid ition by contacting hyaluronic acid with BDDE; b) adding noncross-linked hyaluronic
acid to the substantially cross-linked hyaluronic acid composition; c) extruding the substantially
cross-linked hyaluronic acid ition to form a wet thread; and d) drying the wet thread to
form a dry thread.
In one embodiment, from about 5 to about 15 weight % hyaluronic acid is contacted with
from about 2 to about 8 weight % BDDE relative to the weight of the hyaluronic acid. In r
embodiment, the hyaluronic acid is contacted with about 40 weight % BDDE relative to the
weight of the hyaluronic acid. In one embodiment, the cross-linked hyaluronic acid is crosslinked
with at least about 15 mole % of a BDDE derivative relative to the repeating disaccharide
unit of the hyaluronic acid. In another ment, the cross-linked hyaluronic acid is crosslinked
with from about 15 to about 25 mole % of the BDDE derivative relative to the repeating
disaccharide unit of the hyaluronic acid. In one embodiment, the cross-linked hyaluronic acid is
cross-linked with from about 17 to about 20 mole % of the BDDE derivative relative to the
repeating disaccharide unit of the hyaluronic acid. In another embodiment, the cross-linked
onic acid is cross-linked with at least about 12 weight % of the BDDE derivative relative to
the weight of the hyaluronic acid.
In one embodiment, at least 5% hyaluronic acid is contacted with from about 2 to about 8
weight % BDDE relative to the weight of the hyaluronic acid composition. In another
embodiment, about 8% hyaluronic acid is contacted with from about 2 to about 8 weight % BDDE
relative to the weight of the hyaluronic acid composition. In one embodiment, about 10%
hyaluronic acid is contacted with from about 2 to about 8 weight % BDDE relative to the weight
of the hyaluronic acid ition.
In one embodiment, the composition formed by contacting hyaluronic acid with BDDE
comprises linked hyaluronic acid in an amount of from about 1 weight % to about 50 weight
% hyaluronic acid based on the total weight of the ition. In one embodiment, the
composition formed by contacting hyaluronic acid with BDDE comprises cross-linked onic
acid in an amount of from about 5 weight % to about 20 weight % hyaluronic acid based on the
total weight of the composition. In another embodiment, the dry thread further comprises drying
the composition formed by contacting hyaluronic acid with BDDE.
In one embodiment, from about 1 weight % to about 50 weight % noncross-linked
hyaluronic acid is added, based on the total weight of the composition. In another embodiment,
from about 2 weight % to about 15 weight % noncross-linked hyaluronic acid is added, based on
the total weight of the composition. In another embodiment, about 3 weight % noncross-linked
hyaluronic acid is added, based on the total weight of the composition.
In one embodiment, the dry thread has an ultimate tensile th of from about 2 kpsi
to about 20 kpsi. In one embodiment, the dry thread has an ultimate tensile strength of about 20
kpsi or greater.
In one embodiment, the dry thread has a failure load of about 0.3 pounds or greater. In
one ment, the thread has a failure load of from about 0.3 to about 1.3 pounds.
In one embodiment, there is described a thread ing to any of the above
embodiments, wherein the thread is terminally sterilized.
. Methods of Using the Cross-Linked Hyaluronic Acid Threads
The threads, braids, cords, woven meshes or three-dimensional structures described
herein can be used, for example, to fill wrinkles, to fill aneurysms, occlude blood flow to ,
(i.e., tumor occlusion), in eye-lid surgery, in penile augmentation (e.g., for enlargement or for
ivity reduction, i.e., pre-mature ejaculation treatment), inter-nasal (blood-brain barrier)
delivery devices for diagnostic and/or therapeutic agents, corneal implants for drug delivery, nose
augmentation or reconstruction, lip augmentation or reconstruction, facial augmentation or
reconstruction, ear lobe augmentation or reconstruction, spinal implants (e.g., to support a bulging
disc), root canal filler (medicated with therapeutic agent), glottal insufficiency, laser photorefractive
therapy (e.g., hyaluronic acid thread/weave used as a cushion), scaffolding for organ
regrowth, spinal cord ent (BDNF and NGF), in Parkinson’s e (stereotactic delivery),
precise delivery of eutic or diagnostic molecules, in pulp implantation, ement pulp
root canal treatment, shaped root canal system, negative pressure wound y, adhesion
barriers (e.g., nal, pelvic, cardiac, spinal, and tendon adhesions), wound dressings,
acellular dermal matrix, non-hydraulic drug delivery (e.g., pain (orthopedic), ophthalmic, etc.),
luminal drug delivery (e.g., enlarged prostate, crohn’s diease, vascular is, etc.), and
sustained, local drug delivery.
Methods of Treating a Wrinkle
Tissue repair could prolong the “filler” effects of the thread when used to treat or fill a
wrinkle in vivo far beyond the half-life of the hyaluronic acid-based thread as described herein.
This is described in Example 11.
In some embodiments, there is described a method of treating a wrinkle in a patient in
need thereof by 1) inserting the thread as described herein into the dermis or subcutaneous space
of the patient adjacent to or under the wrinkle; and 2) ng the thread adjacent to or under the
e y treating the wrinkle. These steps can be performed at least once and up to 6 times
to treat each wrinkle. In some embodiments, the thread is attached to the proximal end of a needle
as shown in Figs. 2, 3A and 3B. The thread is inserted by a needle which needle is then removed.
Optionally and as necessary, the thread is hydrated with water or saline, or by the fluids normally
perfusing the surrounding tissue. Further, the remainder of the wrinkle can be filled with a
biocompatible material such as a phase transfer PluronicTM which can be introduced as a liquid
and which solidifies in vivo. Alternatively, conventional hyaluronic acid gel can be uced to
fill the wrinkle. In either case, the formed web acts to maintain the biocompatible filler at the site
of the wrinkle.
In some embodiments, a method of treating a wrinkle in a subject is bed. In some
ments, the attending clinician may numb the treatment area according to ures
known in the art using a variety of anesthetics, including, but not limited to, topical lidocaine, ice
or a block with lidocaine injection. For example, the wrinkle may be in the peri-orbital region as
illustrated in Fig. 4A. The thread may be attached to a needle as illustrated, for example, in Figs.
2, 3A and 3B. The distal end of the needle may be inserted through the skin surface of the subject
into the dermis adjacent to or within the wrinkle as illustrated, for example, in Fig. 4B. In some
embodiments, the thread is inserted into the subcutaneous space d of the dermis. The needle
then may traverse the dermis or subcutaneous space of the subject beneath the wrinkle as
rated, for example, in Fig. 4C. The needle then may exit the skin of the subject at the
opposite margin of the wrinkle, as illustrated, for example, in Fig. 4D. The needle may then be
pulled distally until it is removed from the subject such that the thread is pulled into the location
previously occupied by the needle beneath the wrinkle, as illustrated, for example, in Fig. 4E.
Finally, excess thread is cut from the needle at the skin surface of the subject which leaves the
thread implanted as illustrated, for example, in Fig. 4F.
The method above may successfully treat wrinkles as shown in Figs. 5A, 5B and 5C. A
typical wrinkle is rated in Fig. 5A. Fig. 5B rates a thread implanted beneath a wrinkle
that is not yet hydrated. As the thread implanted beneath the wrinkle becomes fully hydrated the
surface appearance of the wrinkle is concurrently flattened as illustrated in Fig. 5C.
In some embodiments, the thread is manipulated in such a fashion such that one end of
the thread is sufficiently hard such that the thread is used to penetrate the skin. This may be
accomplished by coating the thread with a hardening material, such as a sugar coating, In another
embodiment, the thread is coated in its entirety, for example with a sugar coating, to provide the
thread with increased columnar strength.
Facial Contouring
The threads as described herein are useful in facial contouring. What is meant by facial
contouring is that the threads can be d to any area of the face, neck, or chest that the patient
desires to have augmented, including, by way of example only, the lips, the nasolabial fold, and
tear trough.
Lip tation is a commonly desired aesthetic procedure. Typically, the aesthetic
goal is fuller, plumper lips. Available treatment options for lip augmentation include temporary
fillers such as ane® and rm®, permanent fillers such as ArteFill®, Radiesse® and
Goretex® implants, as well as surgical procedures. Areas of enhancement can include the
vermillion border (or white roll) for lip effacement and contouring and the wet-dry mucosal
junction for sing fullness. Other ques include more diffuse infiltration of the
orbicularis oris .
Lip contouring and augmentation by temporary soft tissue tation products is a
popular, low risk option due to the minimal invasiveness and temporary nature of the procedure.
The major shortcomings of soft tissue augmentation products tly used in lip procedures are
that it is (a) painful, (b) difficult to tently and homogenously inject the gel into the desired
location, and (c) the gel can migrate over the lifetime of the implant causing the aesthetic results
to change.
The present disclosure addresses the shortcomings described above. Beyond addressing
the listed shortcomings for existing temporary soft tissue augmentation products described
above, it has been found that the HA -based method of enhancing lip appearance is very
quick. A typical patient may have 3 threads in their lip(s) in only 3 minutes. Current soft tissue
augmentation product lip procedures can take 15 to 20 minutes.
In embodiments directed to facial ring, the attending clinician may numb the
treatment area according to procedures known in the art using a variety of anesthetics, including,
but not d to, l lidocaine, ice, or a block with lidocaine injection. Threads made of HA
(hyaluronic acid) can be attached to the proximal end of a needle and pulled into the lip. The
needle can serve as a precise guide, and also be used to t and correct the implant on
prior to pulling the thread into the desired location. This precise delivery mechanism can be used
to deliver threads along the vermillion border for contouring, superficially if desired, as well as at
the wet-dry junction for plumping, deeper into the lip if desired.
It is contemplated that when the thread is used for facial contouring, any number of
threads may be used ing on the d effect and the size of the thread. For example,
ption of the procedure done for the lip augmentation and contouring is discussed below in
Example 11.
It is has been surprisingly and unexpectedly found that that threads may be implanted in
various tissue planes of the t to provide a more natural look when performing facial
contouring. For example, the threads may be implanted in a manner that forms a hammock in the
desired location. Given the unique properties of the threads as described herein, the attending
clinician may deposit or implant the threads in the epidermis, the dermis, and/or the subcutaneous
layer.
This technique is enabled by the precision with which the threads can be placed, and
their size relative to the dermis and underlying structures. Threads can impart ent effects on
facial features such as wrinkles, contours, folds and troughs depending on where they are
implanted.
For example, recent clinical experience indicates that placing a thread (in this case, one
that was imately 008” in diameter) deeply, for example in the subcutaneous space, along
the axis of a forehead wrinkle can help soften then appearance of the e that forms when the
t animates, by flexing their forehead – which would typically exacerbate the appearance of
the wrinkle. These types of dynamic wrinkles are currently only well treated with Botox®, which
has the undesirable effect of preventing the patient from expressing all facial expressions.
Further, recent clinical experience shows that static wrinkles, ones that are visible in repose, can
be effectively treated by placement of a thread (from .004 to .008” in diameter) superficially, for
example within the dermis.
The technique of stratifying the thread implant tissue planes is also successfully used in
ing the appearance of bial folds (up to 4x .008” threads), glabellar lines, marionette
lines, and lips.
This is another technique that is enabled by the HA threads and their implantation
method. To smooth the appearance of hollows or troughs such as the tear trough, or otherwise
contour the face in areas such as the cheek bones, chin, for example, threads can be implanted in
hatch (see, Fig. 7A) and/or hatched patterns (see, Fig. 7B) to effect areas greater than the
width of a single thread. As seen in Figs. 7A and 7B, two patients have their tear troughs
ively smoothed out by placing threads el in one case (Fig. 7A) and cross-hatched in
another case (Fig. 7B). The cross-hatching could be done obliquely to the initial direction, as was
the case in Fig. 7B, or dicularly. Further, the hatches can be in different tissue planes as
well.
In another embodiment of this technique, the hatching can be done obliquely to the
directionality of the area being treated. For example, in Fig. 7A the threads are placed aligned to
the axis of the tear trough. Instead, the threads could be placed obliquely to the axis of the tear
trough to support the tissue in the area differently.
It is contemplated that implanting the threads in various planes may also be done in the
treatment of wrinkles as described above.
Wound Therapy
In some embodiments, the threads, braids, cords, woven meshes or three-dimensional
structures described herein are used in wound dressings including negative pressure wound
dressings.
In some embodiments, wound dressing remains in contact with the wound for at least 72
hours. In other embodiments, the ve pressure wound dressing remains in contact with the
wound for at least 1 week. In still other embodiments, the wound ng remains in contact
with the wound for at least 2 weeks. In still other embodiments, the wound dressing remains in
contact with the wound for at least 3 weeks. In still other embodiments, the wound dressing
remains in t with the wound for at least 4 weeks. In the above ments, it should be
understood that granulation tissue is not retaining the threads, braids, cords, woven meshes or
three-dimensional ures described herein as these components are fully absorbable. In some
of these embodiments, the wound ng is between about 1 cm and about 5 cm thick.
Accordingly, in some of these embodiments, wound bed closure may be achieved without
changing the dressing.
In some ments, the woven meshes described herein are used in wound dressings
including negative pressure wound dressings. In other embodiments, the dressing include
between 2 and about 10 layers of woven meshes.
In still other embodiments, the woven meshes se identical threads. In still other
ments, the woven meshes se different threads.
In some embodiments, the woven meshes are between about 1 mm and about 2 mm thick
when dry. In other embodiments, the woven meshes are n about 2 mm and about 4 mm
thick when dry.
In some embodiments, the pore size of the woven mesh is between about 1 mm and
about 10 mm in width. In other embodiments, the pore size of the woven mesh is between about
0.3 mm and about 0.6 mm in width. In still other embodiments, the pores of the woven mesh are
aligned. In still other embodiments, the pores of the woven mesh are red. In still other
embodiments, the woven meshes are collimated to create pores of desired size.
In some embodiments, the woven mesh is mechanically stable at a minimum vacuum
level of about 75 mm Hg. In other embodiments, the woven mesh is mechanically stable at a
vacuum up to about 150 mm Hg.
In some embodiments, the woven mesh includes en. In other embodiments, the
dressing is attached to a polyurethane foam. In still other embodiments, the polyurethane foam is
open celled. In still other embodiments, the dressing is attached to a thin film. In still other
embodiments, the thin film is silicone or polyurethane. In still other embodiments, the dressing is
attached to the thin film with a water soluble adhesive.
In some embodiments, the thread used in the dressing includes a therapeutic agent or a
diagnostic agent.
In some embodiments, a negative pressure wound dressing (Johnson et al., U.S. Patent
No. 7,070,584, Kemp et al., U.S. Patent No. 5,256,418, Chatelier et al., U.S. Patent No. 5,449383,
Bennet et al., U.S. Patent No. 5,578,662, Yasukawa et al., U.S. Patent Nos. 5,629,186 5,780,281
and 7,611,500) is provided for use in vacuum induced healing of wounds, particularly open
surface wounds rski U.S. Patent Nos. 4,969,880, 5,100,396, 5,261,893, 5,527,293 and
6,071,267 and a et al., U.S. Patent Nos. 643 and 5,645,081). The dressing includes a
pad which ms to the wound location, an air-tight seal which is removably adhered to the
pad, a negative pressure source in fluid communication with the pad and the threads, braids, cords,
woven meshes or three-dimensional structures described herein attached to the wound contacting
surface of the pad. The pad, seal, and vacuum source are implemented as described in the prior
art.
In other embodiments, the threads, braids, cords, woven meshes or three-dimensional
structures described herein are mechanically stable at a minimum vacuum level of about 75 mm
Hg. In still other embodiments, the threads, braids, cords, woven meshes or three-dimensional
structures bed herein are ically stable at a vacuum up to about 150 mm Hg. In still
other embodiments, the dressing includes at least one layer of woven mesh. In still other
embodiments, the dressing include between 2 and about 10 layers of woven mesh.
In some embodiments a tube connects the pad to the negative pressure source. In still
other embodiments, a removable canister is inserted between the pad and the negative pressure
source and is in fluid communication with both the pad and the ve pressure source.
In some embodiments, the threads, , cords, woven meshes or three-dimensional
structures described herein are not hydrated. Accordingly, in these embodiments, the dressing
could absorb wound exudates when placed in contact with the wound. In other embodiments, the
threads, , cords, woven meshes or three-dimensional structures described herein are
ed. Accordingly, in these embodiments, the dressing could keep the wound moist when
placed in contact with the wound.
In some embodiments, an input port attached to a fluid is connected with the pad.
Accordingly, in these embodiments, fluid could be dispensed in the wound. In some
embodiments, the fluid is saline. In other embodiments, the fluid ns stic or
therapeutic agents.
In some embodiments, the threads, , cords, woven meshes or three-dimensional
structures described herein are used as adhesion barriers. In some embodiments, the woven
meshes described herein are used in adhesion barriers. In some embodiments, the adhesion
barriers can be implemented in conjunction with other types of adhesion barriers, such as liquids,
gels, sprays, other films or solids, ceuticals and/or ar therapies.
Hair Loss Treatment
In some embodiments, a method of treating hair loss in a subject is provided. A subject
such as, for example, a male with l male-pattern baldness may be treated with a thread,
optionally attached to a needle, as illustrated, for example, in Figs. 2, 3A, and 3B. The distal end
of the needle may be inserted into one of the hair lines. The needle then may traverse the area
beneath the hairline of the subject and then may exit the skin of the subject. The needle may then
be pulled ly until it is removed from the subject such that the thread is pulled into the
location previously occupied by the needle. Finally, excess thread is cut from the needle at the
skin surface of the subject which leaves the thread implanted. In some embodiments, the thread
further comprises one or more compounds which e hair growth.
Additional Medical and Surgical ents
In some embodiments, the threads, braids, cords, woven meshes or three-dimensional
structures described herein are used as soft tissue augmentation products in various aesthetic
applications as described above. In other embodiments, the threads, braids, cords, woven meshes
or three-dimensional structures described herein are used as sutures in various medical and/or
surgical applications. In still other embodiments, the threads, braids, cords, woven meshes or
three-dimensional structures described herein are used in ophthalmologic surgery, drug delivery,
and intra-articular injection. In other embodiments, the threads, braids, cords, woven meshes or
three-dimensional structures described herein are used as adhesion barriers, for e to treat
abdominal, pelvic, cardiac, spinal, and/or tendon adhesions. In other embodiments, the threads,
braids, cords, woven meshes or three-dimensional structures described herein are incorporated
into an acellular dermal matrix. It is contemplated that an acellular dermal matrix integrated with
the threads, braids, cords, woven meshes or three-dimensional structures described herein provide
improved revascularization and/or biological ation. The threads, braids, cords, woven
meshes or dimensional structures bed herein can r comprise other regenerative
biomaterials, ics, and/or pharmacologics. In other embodiments, the threads, braids, cords,
woven meshes or three-dimensional structures described herein are used as sustained, local drug
delivery devices. In some embodiments, the drugs include reserpine, guanethidine,
ybenzamine and phentolamine, hexamethonium, 6-hydroxydopamine, tetrodotoxin,
glutamate, etc. In other embodiments, the threads, braids, cords, woven meshes or threedimensional
structures described herein are used as passive drug eluting stents.
In some ments, a method for ng tumors in a subject in need thereof is
described. The thread may be attached to a needle as illustrated, for example, in Figs. 2, 3A and
3B. The distal end of the needle may be inserted into the tumor of the subject. The needle then
may traverse the tumor and then may exit the tumor. The needle may then be pulled distally until
it is removed from the tumor of the t such that the thread is pulled into the location
previously ed by the needle. Finally, excess thread is cut from the needle which leaves the
thread implanted in the tumor of the subject. In some of the above embodiments, the thread
includes an anti-cancer agent. In some embodiments, the thread is linked and includes Bcl-
2 inhibitors.
In an exemplary embodiment, methods of the current disclosure may be used to treat
pancreatic tumors. The pancreas may be accessed by surgery or lly invasively methods
such as by laparoscopy. The distal end of the needle may be ed into the pancreatic tumor.
The needle then may traverse the pancreatic tumor and then may exit the tumor. The needle may
then be pulled distally until it is removed from the atic tumor such that the thread is pulled
into the location previously occupied by the needle. Finally, excess thread is cut from the needle
which leaves the thread implanted in the pancreatic tumor. The process may be repeated any
number of times to e a pancreatic tumor which has been implanted with a number of
threads. In some embodiments, the thread includes an anti-cancer agent.
In some embodiments, a method for treating a se vein in subject in need thereof is
described. The thread may be attached to a needle as illustrated, for e, in Figs. 2, 3A and
3B. The distal end of the needle may be inserted into the varicose vein of the subject. The needle
then may se the varicose vein and then may exit the vein. The needle may then be pulled
ly until it is removed from the varicose vein of the subject such that the thread is pulled into
the location previously occupied by the needle. Finally, excess thread is cut from the needle
which leaves the thread implanted in the varicose vein of the subject. In some embodiments, the
needle is a flexible. In other embodiments, the thread coils when ed, more readily
occluding the vessel.
In some embodiments, a method for nipple reconstruction is described where a threedimensional
, cylindrical implant comprised of cross-linked threads is implanted underneath the
skin. The implant may include therapeutic agents, for example chrondrocyte adhesion
compounds.
In some embodiments, methods for nerve or vessel regrowth are described. As
rated in Fig. 6, a needle can be used to place a thread in a specific line which could promote
nerve or vessel ration.
6. Kits
Also described herein is a kit of parts comprising a thread as described herein. In some
embodiments, the kit comprises a thread and a means for delivering or implanting the thread to a
patient. In one embodiment, the means for delivery to a patient is a syringe or a needle. In
another embodiment, the means for delivery to a patient is an air gun. The size (or diameter) of
the needle may depend on the use of the thread, and therefore also be based on the cross-sectional
area of the thread used. The outer diameter of the needle or syringe may be greater than or equal
to the cross-sectional area of the thread used to lessen the tensile requirement of the thread as it is
being applied to the dermis. It is r contemplated that the outer diameter of the thread may
be larger than the outer diameter of the needle. Skin is quite pliable so by having a smaller
diameter needle can allow the re size to be small even with the use of a larger diameter
thread. r, the thickness of the thread would be different in the case where the thread is a
suture in comparison to the treatment of fine lines and wrinkles where it may be that a thinner
thread is used. More than one thread may also be attached to a single needle.
Further, the size of the delivery , a needle, will be dependent on its ed use
and the size of the thread. It is contemplated that for use in facial contouring and or e
filling an about (inch) to about 0.008” diameter thread or even an about 0.003” to about
0.004” diameter thread will be sufficient. However, in some embodiments, the thread is from
about 0.003” to about , or from about 0.005” to about 0.030”, or from about 0.005” to about
0.025”. In some ments, the size of the thread is from about 0.010” to about 0.020” in
diameter, or from about 0.011” to about 0.016”.
The thread attachment to the needle can be either a mechanical attachment and/or with
the use of an adhesive, such as cyanoacrylate. In one embodiment, the needle is stainless steel. In
one embodiment, the thread woven or looped through holes in the proximal end of the needle, or
alternatively, the thread wrapped around the proximal end of the needle, or alternatively, the
thread ed thru an eyelet of the needle and either tied or bonded with an adhesive to form a
loop, or alternatively, the thread secured (either mechanically or bonded with an adhesive) within
a hole in the proximal end of the needle. In another embodiment, the thread can be made to form
a physical attachment to the needle during the drying process as the thread forms from the gel.
For example, if a needle is used which has pores in the proximal end, the pores can fill with the
gel during the extrusion process and the thread would be thus be secured upon drying. The needle
can be rigid or flexible to enable the user to track the needle under the wrinkle within the skin.
Further, the needle may be ed with a ramp to guide the needle at a desired depth within the
skin, and after needle insertion, the guide may be unclasped as the needle is t through the
skin surface. In some embodiments, the thread is attached to a needle.
It is further contemplated that the kit comprises a needle and the thread attached thereto,
is packaged sterile, and intended for single use. atively, a kit can comprise several needles,
each with an attached thread. In an additional embodiment, a kit includes threads of different sizes
to enable treatment options for the physician while minimizing the number of required needle
sticks. In yet another embodiment, the kit includes threads and needles of different length and
curved shapes to simplify implantation in areas that are ult to access or treat with a straight
needle, for example near the nose, around the eyes and the middle portion of the upper lip.
Examples
The present disclosure is further defined by reference to the following examples. It will
be apparent to those d in the art that many modifications, both to threads and methods, may
be practiced without departing from the scope of the current sure. The hyaluronic acid and
cross-linking agents are available from commercial sources.
e 1: Synthesis of a Cross-Linked Thread
Cross-linked hyaluronic acid s can be made according to the following procedures.
Cross-linking: preparation of cross-linked hyaluronic acid gel
Hyaluronic acid (HA) powder is hydrated in about 75% of a desired total volume of
NaOH for about 30 minutes at about 50 °C in an appropriate container. The hydrated HA is then
added to a syringe and mixed thoroughly (e.g., syringe-to-syringe about 20 times). g is
ued for approximately 30 s.
Cross-linker (e.g., BDDE) is then dissolved in the remaining portion of the desired total
volume of NaOH (i.e., about 25% of the desired total volume), added to the hydrated hyaluronic
acid solution (dropwise or in one portion), mixed thoroughly (e.g., syringe-to-syringe about 20
times), heated for about 30 minutes, re-mixed (e.g., syringe-to-syringe about 20 times), and
transferred to an appropriate ner. Heating is then continued at about 50 °C for an additional
3 to 5 hours.
Various cross-linked gels were prepared with differing concentrations of components
using the ure described hereinabove.
• HA molecular weight (MDa): e.g., 0.7, 1.7, 2.7.
• HA hydration time: e.g., 0 minutes, 30 minutes, 1 hour, 2 hours, overnight.
• Reaction pH: 9-13.4 using, e.g., 0.00001-0.25 M NaOH.
• Cross-linking reaction time: e.g., 3-4.5 hours.
• HA concentration (% w/w HA:aqueous NaOH): e.g., 5, 6, 7, 8, 9, 10, 11, 12.
• BDDE concentration (% w/w BDDE:HA): e.g., 0.5, 2, 2.5, 5, 7.5, 8, 10, 20, 30,
40, 100.
Rinsing/Optional Sizing
The cross-linked hyaluronic acid gel is rinsed to remove the sodium hydroxide and any
unreacted BDDE. Water can also be removed, and the gels may be fragmented to facilitate the
extrusion step and/or for rinsing efficiency. In such an instance, sizing is accomplished by cutting
the gel into approximately 0.5 cm cubes. Rinsing is then achieved by rinsing with about 40
volumes of 10 mM sodium phosphate, at pH 6.0, three times for about 30 minutes each, g
with 100% ethanol six times for about 30 minutes, and then rinsing with water four times for
about 30 minutes.
The swollen gel pieces can then be further sized into approximately 0.25 cm cubes,
loaded into a syringe, and ed through a 20 gauge (G) blunt . More than one sizing
step can be performed using the same or a different, typically smaller, gauge needle (e.g., 20G,
then two 25G sizing steps).
Drying
The cross-linked hyaluronic acid gel is then diluted approximately 2:1 with water, loaded
into a pan dried. The drying is accomplished by air drying under ambient conditions or
lyophilization. Alternatively, the gel is ed via precipitation from ethanol. The gel is either
partially dried to a desired final concentration or dried tely.
Formulating
The completely dried cross-linked hyaluronic acid gel is formulated as an aqueous
composition to the desired final HA concentration (e.g., 2.5%, 5%, 7.5%, 10%, 12.5%, 15%,
%). The partially dried cross-linked hyaluronic acid gel can be used as an s composition
in the formulation without further treatment.
The s ition of cross-linked hyaluronic acid gel can then be further
formulated with a binder such as noncross-linked hyaluronic acid. In such a case, noncross-linked
hyaluronic acid is hydrated (e.g., overnight at 4 °C) at the desired final HA concentration (e.g.,
2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 20%). The binder is mixed with the cross-linked onic
acid gel. Typical binders include noncross-linked hyaluronic acid, salts (e.g., CaCl2), ents,
Lidocane, and the like.
The aqueous composition can comprise any aqueous medium, such as an acid, a base, a
buffer or a salt. Buffers such as phosphate buffered saline can be used (e.g., 10 mM PBS at pH
7.4). Calcium chloride solutions can also be used (e.g., 1 mM, 2.5 mM, or 5 mM). Sodium
hydroxide (NaOH) solutions may be used, (e.g., 0.1M, 0.2M, 0.3M, or 0.5M).
Compositions can be made with higher or lower concentrations of hyaluronic acid and
cross-linked HA; the following three compositions are given as examples only.
In one composition, for example, the final extruded composition contained 12% (w/w)
cross-linked hyaluronic acid and 3% (w/w) noncross-linked HA, wherein the cross-linked
hyaluronic acid was derived from a cross-linking reaction with either 10% onic acid and 4%
BDDE, or 8% onic acid and 3.2% BDDE.
In another composition, the final extruded composition contained 8% (w/w) cross-linked
hyaluronic acid and 2% (w/w) ss-linked HA, the cross-linked hyaluronic acid being derived
from a cross-linking reaction with either 10% hyaluronic acid and 4% BDDE, or 8% onic
acid and 3.2% BDDE.
In yet another composition, the final extruded ition contained 5% (w/w) inked
hyaluronic acid and 5% (w/w) noncross-linked HA, the cross-linked hyaluronic acid being
derived from a cross-linking reaction with 10% hyaluronic acid and 4% BDDE.
Extruding
The final gel formulations are then extruded onto a suitable surface to yield wet threads.
Various nozzle sizes are used depending on the final desired thread thickness (e.g., 20G, 19G,
18G, 17G, 16G).
The final gel formulations are transferred to a pressurized extruder (e.g., EFD Model
XL1500 pneumatic dispense machine). The nozzle of the extruder can have a tip ranging from a
gauge to about 25 gauge. The syringe pressure may be n about 10 psi and about 2000
psi, depending on the viscosity of the final gel formulation. For very viscous gel formulations, a
re multiplier can be used.
The wet thread was then formed by extruding the final gel formulation onto a substrate
by an extruder to achieve the desired wet thread ess. For example, to achieve a similar
dried diameter, one can use a 20 gauge needle for 15% hyaluronic acid compositions, or a 19
gauge needle for 10% hyaluronic acid compositions.
Thread Drying
The wet thread can then be dried under ambient conditions to a percent hydration of less
than about 30%, or less than about 15%, or less than about 10%, thus providing a dry thread.
Optionally, the thread can be allowed to dry under a relative humidity of from about 20% to about
80% at a ature of from about 20 °C to about 37 °C. For e, threads can be air-dried
for two days at ambient conditions.
Optionally, prior to thread drying, the wet thread can be stretched to a desired length and
reduced diameter prior to dying. The stretching can be by either hanging the thread by one end
and ng weight to the ng end, or by horizontally stretching the wet thread on a surface
(either the same or different from the ion surface) and adhering the ends to the surface.
ing to a Needle
The dry threads can be attached to a needle using known techniques (see, e.g., Figs. 2,
3A and 3B).
Sterilizing
The threads as described herein can be sterilized using electron beam (e-beam)
sterilization methods. Threads as prepared in Example 1 cross-linked with BDDE were washed in
a phosphate buffer or Tris buffer on at pH 10. Some of the solutions further contained 1
mM ascorbic acid, 10 mM ascorbic acid, 100 mM ascorbic acid, 1 M ascorbic acid, 10 mM
vitamin E, and 50 mM Na3PO4. The threads were then sterilized using standard e-beam
techniques at 4 kGy or 20 kGy. In some embodiments, the temperature of the thread can be
altered prior to sterilizing. In some embodiments, the temperature is reduced of the thread to
about -20 C. In some embodiments, the thread is just below 5 C after izing.
Using the steps disclosed above, threads can be prepared using any one of the ses
disclosed below.
Example 1A: Process 1
Threads can be prepared using the following steps:
1. Cross-linking;
2. Rinsing;
3. Sizing;
4. Drying;
. Formulating the cross-linked HA with binder;
6. ting;
7. Extruding;
8. Thread Drying;
9. Attaching to a needle; and
. Sterilizing.
Example 1B: Process 2
Threads can also be prepared using the following steps:
1. Cross-linking;
2. Rinsing;
3. Sizing;
4. Drying;
. Formulating the cross-linked HA with binder;
6. Deaerating and autoclaving;
7. Extruding;
8. Thread Drying;
9. ing to a needle; and
. Sterilizing (optional).
Example 1C: Process 3
Threads can also be prepared using the following steps:
1. Cross-linking;
2. Extruding;
3. Thread Drying;
4. Rinsing;
. Thread Drying;
6. Attaching to a needle; and
7. Auto-claving.
Example 1D: Process 4
Threads can also be prepared using the ing steps:
1. Cross-linking;
2. Rinsing;
3. Sizing and Formulating the cross-linked HA with ;
4. Drying;
. Deaerating;
6. ing;
7. Thread Drying;
8. Attaching to a needle; and
9. Sterilizing.
Example 1E: Process 5
Threads can also be prepared using the following steps:
1. Cross-linking;
2. Rinsing;
3. Sizing;
4. Precipitating from ethanol and drying;
. Formulating the cross-linked HA with binder;
6. Deaerating;
7. Extruding;
8. Thread Drying;
9. ing to a needle; and
. Sterilizing (optional).
Example 2: Washing (Re-Hydrating) and Re-Drying the Thread
The dry threads can be washed with an aqueous solvent to remove any contaminants,
such as unreacted linking agent. The g can be performed by various methods, such
as submersion in an aqueous solvent or by using a concurrent flow system by placing the thread in
a trough at an incline and allowing an aqueous solvent to flow over the thread. In addition, the
thread, once it is rehydrated, can be stretched prior to re-drying. The stretching can be performed
by the means described above in Example 1. The rehydrated and washed thread is then re-dried to
e the dry thread. The re-drying is typically performed under ambient conditions (i.e.
ambient ature and/or pressure) for from about 8 hours to about 24 hours or until the dry
thread has a t hydration of less than about 30%. The thread can be washed l times
(e.g. 10 or more times) without losing its structural integrity. Over the course of multiple washing
cycles the overall length of the thread can be increased by between about 25% to about 100%.
Example 3: Sample Threads
Sample threads prepared from the methods of e 1 are provided in Table 1 below.
Table 1
Sample Gel Pre-size % HA % NXL Deaeration Extrusion
Thread Solids HA Nozzle
113 8/40 20G-taper 15 20 4X 20G
114 8/40 20G-taper 15 20 2X 20G
115 8/40 20G-taper 15 20 6X 20G
116 8/40 20G-taper 15 20 6X, Overnight 20G
117 10/40 16G/20G-taper 15 20 6X 20G, 19G
118 10/40 16G/20G-taper 15 40 6X 20G, 19G
119 10/40 16G/20G-taper 15 40 10X 20G, 19G
120 10/40 16G/20G-taper 15 20 10X 20G, 19G
121 10/40 16G/20G-taper 10 50 3X 19G, 18G
122 10/40 16G/20G-taper 10 50 6X 19G, 18G
123 10/40 16/18/20-taper 10 50 6X 19G, 18G
124 10/40 16/18/20-taper 15 20 6X 20G, 19G
125 10/40 16/18/20-taper 15 40 6X 20G, 19G
126 10/40 16/18/20-taper (2X) 15 40 6X 20G, 19G
127 8/40 20G-taper 15 20 6X 20G, 19G
128 8/40 15 20 8X 19G
129 8/40 15 20 8X 19G
% HA Solids = cross-linked and noncross-linked HA; NXL = noncross-linked HA
Example 4: Physical Characteristics of the Threads
s s prepared as described above were evaluated for thread density, dry
thread arity and diameter. Thread density was determined by measuring the weight of a
thread of a measured length and calculating the ratio of weight to length. Dry thread circularity
(W:T) and diameter (D) were determined by sectioning threads axially and measuring the shortest
(W) and longest diameter (T) for a given section. Circularity or aspect ratio is the ratio of
W:T. Thread diameter (D) is an average of short (W) and long (T) ers. The average thread
density for threads made with 20G, 19G and 18G needles were 1.78 mg/in (n=7), 2.61 mg/in
(n=8), and 2.07 mg/in (n=3), tively.
Example 5: Comparison of Ultimate Tensile Strength of Different Threads
Various threads prepared as described above were tested for tensile strength using a force
gauge (e.g. Digital Force Gauge by Precision Instruments or Chatillon). Failure was determined
by weight at which the thread broke. The ultimate tensile th was calculated by dividing the
e force/failure load by the cross-sectional area of the thread. The average failure load (in
pounds) for unsterilized s made with 20G and 19G needles were from about 0.420 lb to
about 1.172 lb. The average e load (in pounds) for e-beam sterilized threads made with 20G,
19G and 18G needles were from about 0.330 lb to about 0.997 lb. The average elongation (in
inches) for unsterilized threads made with 20G and 19G needles were from about 0.028 inches to
about 0.192 inches. The average elongation (in inches) for e-beam sterilized threads made with
20G, 19G and 18G needles were from about 0.021 inches to about 0.078 inches. The average
tensile th (in psi) for unsterilized s made with 20G and 19G needles were from about
3236 psi to about 19922 psi. The e tensile th (in psi) for e-beam sterilized threads
made with 20G and 19G needles were from about 1943 psi to about 12859 psi.
Example 6: Swelling Data
The mass swelling ratio, as represented by V2/V0, is the ratio of the swollen gel weight
relative to the fully dried gel weight (Tables 2 and 3).
The diameter swelling ratio (ratio of hydrated thread to dry thread) of threads extruded
from a 20G extrusion nozzle having an average dry thread diameter of 0.0132 inches was
calculated. Each thread tested had a diameter ng ratio of 1.5 or more, with the e
diameter swelling ratio being 1.55.
Table 2
Threads Swollen in Water (V2/V0)
HA/BDDE 5/40 6/40 7/40 8/40 9/40 10/40 10/10 10/100
Avg 682.7 396.7 306.2 494.7 85.3 183.3 967.5 56.1
Std 322.8 188.4 11.9
Min 122.3 50.1 54.5
Max 696.2 696.2 76.4
Table 3
Threads Swollen in PBS (V2/V0)
HA/BDDE 10/10 10/20 10/30 10/40 10/100
Avg 71.6 45.2 38.4 37.3 23.7
Std 5.2 0.9 1.0 4.8 1.4
Min 62.8 44.6 37.7 32.0 22.4
Max 78.3 45.8 39.1 54.4 25.3
Example 7: Enzymatic Degradation of the Threads with Hyaluronidase
Threads were incubated with hyaluronidase at 1 mg/mL in 1 mL of buffer (100 mM
sodium acetate, pH 4.5, 150 mM NaCl) at 37 °C; control threads were are not in the presence of
hyaluronidase. At various times, 40 µL aliquots of supernate were withdrawn and assayed by the
Carbazole Assay (Cesaretti, M, et al., Carbohydrate Polymers 54: 59-61 (2003) for hyaluronic
acid. Vertical arrows pond to the addition of fresh 1 mg/mL of hyaluronidase. The
supernates were replaced with fresh 1 mg/mL enzyme in buffer. For threads A-F: A =
/40@15/20 CaCl2; B = 10/40@15/40; C = 10/40@15/20; D = 10/40@10/50; E = 8/40@15/20
H2O wash; F = 8/40@15/20; G = Control for 10/40@15/20 CaCl2; H = Control for 10/40@15/40;
I = Control for 10/40@15/20; J = Control for 8/40@15/20. Details of these enzymatic
degradations represented are in Fig. 12 and Table 4. This shows that the control threads, which
are not in the presence of hyaluronidase, do not e over the time monitored, whereas the
threads which are in the presence of hyaluronidase do e.
Table 4: Degradation Rate (Slope of linear fit of first five data points)
A B C D E F G H I J
Degradation 0.014 0.011 0.010 0.007 0.041 0.023 0.00 0.00 0.00 0.00
Rate*
*mg HA/day
Example 8: Palpation Data
A blinded evaluator palpates and scores all sample sites per animal and records the value
on pre-printed data sheets. The data was ed and averaged based on the sample site. The
evaluators’ scores are 0=no tactile signs of implant, 1= slight tactile sign of implant, and 2= high
tactile sign of implant. Implant tactile scoring (qualitative palpation) was performed per protocol
on test subjects at pre-specified intervals spanning the duration of the study, measuring the surface
dermal response post implantation. The se measured was the length continuity of the
implant. For example, if palpating from two points, and the implant feels continuous, with no
breaks, then that would rate a “2”, if the t feels udinally intermittent then that would
rate a “1”, and if no t is detected, then the score would rate “0”. A plot of number of days
vs. average palpation score is shown in Fig. 13.
Example 9: Histological Studies
Tissue samples containing thread implants were fixed in an acid-formalin ethanol
fixative before embedding in methyl rylate. Histological sections were stained with
xylin and eosin (H&E) as well as Alcian blue with neutral red to visualize cellular
responses and implant presence, respectively. The h, 2-month, 3-month, 6-month and 9-
month histology images of 8/40 @ 15/20 ation are shown in Fig. 9A, 9B, 9C, 9D, 9E and
9E. The samples were similar in appearance indicating that the threads were persisting in vivo.
Example 10: Studies of Hyaluronic Acid Threads in Rabbits
The in vivo performance, including persistence and ical response, of thread
formulations was evaluated in a chronic rabbit study. Thread ations described herein were
implanted in the dorsal dermis of New Zealand White rabbits and evaluated at , 1-month,
2-month, 3-month, 6-month, and 9-month time points. During the in-life phase, t sites
were evaluated for implant presence via palpation and a tactile scoring system (See Example 8).
At the scheduled time intervals, s were euthanized and implant sites harvested for gross and
histological evaluation. A subset of implant sites were cross-sectioned axially with a scalpel and
evaluated under microscope for the visual presence of implant material in the dermal tissue.
Pressure was applied to the implant site to assess if implants were well-integrated within the tissue
or could be extruded from the implant site. The remaining subset of implant sites were fixed and
processed for histological evaluation (see e 9). The 1-month and 2-month histology
images of 8/40 @ 15/20 formulation are shown in Figs. 10 and 11, respectively, g that the
thread is still present.
Example 11: Treatment of Wrinkles with Hyaluronic Acid Threads
Hypodermic needles (22 to 25 Ga) are affixed with single or double s of
hyaluronic acid threads (cross-linked with BDDE), ranging from thicknesses of 0.004 in to 0.008
in. The samples are e-beam sterilized by NuTek Corp. at 29 kGy. The needle pulls the attached
thread or threads into the skin. Wrinkles which are treated are es in the naso-labial fold,
peri-orals, peri-orbitals, frontalis (forehead), and glabellar. The needle would then pull the thread
through the skin such that the thread is located where the needle was previously inserted. More
than one thread can be used to treat the wrinkles in order to achieve the desired fill effect (two to
four or more threads). The wrinkle is visibly lessened upon thread hydration.
e 12: Lip Augmentation
A patient may be implanted with HA threads for lip enhancement, either contouring
and/or plumping. The patient may receive topical anesthetic on the face, but it is not applied
specifically to the lips according to the ing ure:
• Peal open the pouch and remove the sterile tray holding the HA (hyaluronic acid) threads.
• Using sterile gloves or a sterile ent such as forceps, remove the desired HA thread
from the tray.
• Insert the sharp end of the needle into one margin of the intended treatment area.
• Translate the needle within the skin under or near the ed ent area. If the
needle is not in a d location at any point, gently retract the needle and reinsert to
correct the location.
• Exit the skin at the opposing margin of the intended treatment area using the sharp end of
the . If the needle is not in the desired location, gently retract the needle and
reinsert to correct the on.
• Upon confirming the desirable on of the needle, swiftly pull the needle distally,
pulling the thread into place within the skin.
• Using sterile surgical scissors or scalpel, cut the excess thread protruding from the skin on
both margins of the treatment area. This effectively separates the needle, which should be
discarded appropriately.
Areas of enhancement include the vermillion border (or white roll) for lip effacement
and contouring, the wet-dry mucosal junction for sing fullness. Other techniques include
more diffuse infiltration of the orbicularis oris muscle. The attending clinician is able to select the
location of the thread placement, the number of s and the size of the threads depending on
desired effect. It is contemplated that each area is treated with 1 to 2 threads wherein each thread
has a diameter of anywhere from 200 microns to about 500 s when the thread is dry. After
hydration, it is contemplated that the thread has a diameter of from 0.5 millimeters to about 5
millimeters.
Example 13: NMR study to determine the ratio of BDDE tive to HA in cross-linked
hydrogels
An NMR study was undertaken to determine the ratio of 1,4-butanediol diglycidyl ether
derivative (BDDE) to the disaccharide subunit of hyaluronic acid (HA) in cross-linked HA
hydrogels. Hydrogels were made at HA concentrations of 8 and 10 percent, cross-linked with 3.2
and 4 percent BDDE, respectively. The gels were rinsed ively to remove residual BDDE,
digested with hyaluronidase, and dried. The resulting powders were dissolved in D2O and
analyzed by proton NMR. The ratio of BDDE to the disaccharide subunit of HA was determined
by comparing the peak from the inner methylene hydrogens of 1,4-butanediol at 1.6 ppm to the
acetyl methyl group of N-acetylglucosylamine at 2.0 ppm. At equal molar amounts of BDDE and
disaccharide subunit these peak areas should ate to 4 and 3, respectively. The results with
the 8% HA hydrogel gave peak areas integrating to 0.75 and 3, respectively, which ponds to
about 0.19 mole of BDDE per mole disaccharide subunit. The results with the 10% HA hydrogel
gave peak areas integrating to 0.72 and 3, respectively, which corresponds to about 0.18 mole of
BDDE per mole disaccharide subunit.
The experiment with the 8/40 formulation was repeated with second batch of gel and
gave results of 0.217 mole of BDDE per mole disaccharide subunit. The average percent BDDE in
the 8/40 gel is therefore 20% ± 2% S.D. Table 5, below, shows additional formulations.
Table 5
Gel % BDDE input % substituted % cross-linked % pendant
Formulation (by wt) BDDE* BDDE* BDDE*
12/40 40% 35.2 8.5 26.7
12/20 20% 19.1 4.9 14.2
12/15 15% 17.2 3.5 13.7
* mol%
Example 14: Effect of cross-linking on in vivo persistency of the thread - Animal Data
Comparison
Sterilized hyaluronic acid threads produced via the following s were placed in an
animal and evaluated for in vivo persistency.
Part 14A
HA threads were prepared from a 10% w/w onic acid (MW = 1.47 MDa) gel
formulated in 10 mM sodium bicarbonate buffer (pH 10) and linked with 10% ive to
HA mass) 1,4-butanediol diglycidyl ether . Threads in Test Articles 1 and 2 were rinsed
in Tris buffer (50 mM Tris, 150 mM NaCl) containing 100 mM ascorbic acid, threads in Test
Articles 3 and 4 were rinsed in Tris buffer (50 mM Tris, 150 mM NaCl) containing 100 mM
Vitamin E, threads inTest Articles 5 and 6 were rinsed in water prior to final drying (air dried).
Threads in Test Articles 7 and 8 were prepared in 10 mM Tris buffer (pH 7) rather than 10 mM
sodium bicarbonate buffer (pH 10) and were rinsed in water prior to final . Dried threads
were cylindrical in shape, 0.006-0.008" in diameter and 1.0-1.5" in length. Hypodermic, ess
steel, 27-gauge, thin wall Keith needles were used in all test articles. Needles were 2 ½” in length
and had single bevel tips. Cross-linked HA threads were attached to the needle via mechanical
crimp. Test Articles were terminally sterilized via e-beam irradiation. Test Articles 1 and 3
received an irradiation dose of 4 kGy. Test Articles 2 and 4 received an irradiation dose of 20
kGy. Test Articles 6 and 8 received an irradiation dose of 20 kGy frozen. Test Articles 5 and 7
were sed in an c-like environment and were not terminally sterilized.
The results of the in vivo persistence study (utilizing 10 Sprague Dawley rats) indicated
that all of the threads in Test Article 2 were undetectable by one week. The implanted threads of
Test es 1, 3, 4 and 6 were largely gone by one week with only small numbers of intracellular
particles found within small cellular infiltrates at the ek timepoint. More residual material
was seen in the Test Articles 3 and 4 treated sites than Test Article 1 treated sites at one week,
which suggests that the tion rate was slower for those threads. None of the implanted
material of Test Articles 1, 2, 3, or 4 was seen at 3 weeks. In addition, all threads from Test
Articles 5, 6, 7, and 8 were undetectable by Day 30.
Part 14B
A 0.75% w/w hyaluronic acid (1.7 MDa) solution was prepared by dissolving the HA in
mM TRIS buffer (pH 7). Butanediol diglycidyl ether (BDDE) was added to the HA solution
and the solution was stirred overnight. The ratio of BDDE to HA was 2:1. The substantially
cross-linked HA solution was then dialyzed against excess deionized water using a dialysis
membrane with a molecular weight cut-off of about 12 to about 14 KDa. The dialyzed on
was then lyophilized to obtain dry substantially cross-linked hyaluronic acid. The dry cross-linked
hyaluronic acid (2.0 g) was exposed to 25 KGy e-beam (Irradiation ature 1 – 3 °C),
formulated to 16% solids (w/w) in 10 mM TRIS buffer (pH 7.00), extruded and dried for about 48
hrs at ambient temperature.
Test Article 9 was irradiated after cross-linking at 25kGy, 0.020" diameter, processed in
an aseptic-like environment and rminally sterilized. Test Article 10 was irradiated after
cross-linking at 25kGy, 0.010" diameter, sed in an c-like nment and nonterminally
sterilized. Test Article 11 was 0.020" in diameter, processed in an aseptic-like
environment and non-terminally sterilized. Test Article 12 was irradiated after cross-linking at
25kGy, 0.020" diameter, processed in an aseptic-like nment and non-terminally sterilized.
Test Article 13 was irradiated after cross-linking at 25kGy, 0.010" diameter, processed in an
aseptic-like nment and non-terminally ized. Test Article 14 was 0.020" in diameter,
processed in an aseptic-like environment and non-terminally sterilized.
The threads of Test Articles 9-14 were implanted in rabbits. Skin segments containing a
total of 20 d sites were removed from each animal. Select specimens (4/group/timepoint
taken from each thread(s) of Test Article 9-14 treated sites) were processed and analyzed.
Complete resorption of the threads of Test Articles 9, 10, and 13 occurred by 7 days. te
resorption of the threads of Test Article 12 occurred between 7 and 30 days. Nearly complete or
complete resorption of the threads of Test Article 14 had occurred and partial resorption of the
threads of Test Article 11 had occurred by 30 days.
Part 14C
Six linked threads were prepared according to Example 1. The threads of Test
Articles 15-20 were prepared as follows. Cross linked s of diameter between 0.008 inches
and 0.010 inches was made by forming a gel with a concentration of 10% hyaluronic acid and 4%
BDDE by weight relative to total ition with the remainder comprised of 0.1 N sodium
hydroxide. The ratio of BDDE to HA in the cross-linked gel was 0.18 mole of BDDE per mole
disaccharide subunit. After rinsing, presizing, lyophilizing, and combining with noncross-linked
binder, the gel was then extruded into a thread form by using a 20G nozzle. The wet thread is
then dried for about 48 hrs to provide a dry thread.
Table 6. Test Article Composition/Processing
Test Startin [BDDE Rinse Presize Ha % Formulatio Sterilizatio
Articl g ] mediu d solid Binde n medium n
e [HA] m s in r
10% 40% PB 20G 10% 50% H2O E-beam
16 10% 40% PB 20G 15% 20% H2O E-beam
17 10% 40% PB 20G 15% 20% 5 mM CaCl E-beam
18 10% 40% PB 20G 15% 40% H2O E-beam
19 8% 40% PB 20G 15% 20% H2O E-beam
8% 40% H2O 20G 15% 20% H2O E-beam
PB = 10 mM sodium phosphate buffer, pH 6
Test Articles were successfully ed for degradation by copic observation and
by histology analysis. All Test Articles were identifiable by macroscopic observation through 90
days, but with the ion of Test e 20, identification was inconsistent at 135 and 180
days. Histologically, all Test Articles were identifiable qualitiatively at early time points.
Qualitiatively, Test Articles 15, 16, 17, and 18 demonstrated more evidence of degradation than
Test Articles 19 and 20. Degradation of Test Article 20 was quantitatively analyzed and by crosssectional
area persisted t significant change at 270 days.
Thus, the more cross-linked thread of this disclosure is more persistent in vivo than the
less linked thread as can be seen from the above data.
In this specification where reference has been made to patent specifications, other al
documents, or other sources of information, this is generally for the purpose of providing a
context for discussing the features of the invention. Unless specifically stated otherwise,
reference to such external documents is not to be construed as an admission that such documents,
or such sources of information, in any iction, are prior art, or form part of the common
general knowledge in the art.
In the ption in this specification reference may be made to subject matter that is not
within the scope of the claims of the t application. That subject matter should be readily
identifiable by a person skilled in the art and may assist in putting into practice the invention as
defined in the claims of this application.
Claims (74)
1. A composition comprising at least 5% hyaluronic acid by , wherein the hyaluronic acid is substantially linked with from about 17 to about 20 mole % of a butanediol diglycidyl ether (BDDE) derivative relative to the repeating disaccharide unit of the hyaluronic acid.
2. The composition of claim 1, wherein the composition comprises about 8% hyaluronic acid.
3. The composition of claim 1, wherein the composition comprises about 10% hyaluronic acid.
4. The composition of claim 1, wherein the ition comprises about 12% hyaluronic acid.
5. The composition of any one of claims 1-4, wherein the molecular weight of the hyaluronic acid is from about 0.5 to about 3.0 MDa.
6. The composition of any one of claims 1-5, wherein the cross-linked onic acid is present in an amount of from at least 5 weight % to about 50 weight % based on the total weight of the composition.
7. The composition of claim 9, wherein the cross-linked hyaluronic acid is present in an amount of from at least 5 weight % to about 20 weight % based on the total weight of the composition.
8. The composition of any one of claims 1-7, further comprising a binder.
9. The composition of any one of claims 1-8, wherein the binder is noncross-linked hyaluronic acid.
10. The composition of claim 9, n the noncross-linked onic acid is present in an amount of from about 1 weight % to about 15 weight % based on the total weight of the composition.
11. The composition of claim 10, wherein the noncross-linked hyaluronic acid is present in an amount of from about 2 weight % to about 8 weight % based on the total weight of the composition.
12. The composition of claim 9, wherein the composition comprises from about 5 weight % to about 15 weight % cross-linked hyaluronic acid and from about 2 weight % to about 8 weight % noncross-linked hyaluronic acid.
13. A thread comprising the ition of any one of claims 1-12.
14. A thread prepared by the s of drying the thread of claim 13.
15. A thread comprising substantially cross-linked hyaluronic acid, wherein the hyaluronic acid is substantially cross-linked with from about 17 to about 20 mole % of a butanediol idyl ether (BDDE) derivative ve to the repeating disaccharide unit of the hyaluronic acid, and at least about 5% noncross-linked hyaluronic acid relative to the weight of total hyaluronic acid .
16. The thread of claim 15, wherein the substantially cross-linked hyaluronic acid is inked with at least about 18 weight % of the BDDE derivative relative to the weight of the cross-linked hyaluronic acid.
17. The thread of of claim 15 or 16, wherein the cross-linked hyaluronic acid is present in an amount of from about 60 weight % to about 90 weight % based on the total weight of the thread excluding moisture.
18. The thread of claim 17, wherein the cross-linked hyaluronic acid is present in an amount of from about 70 weight % to about 80 weight % based on the total weight of the thread excluding moisture.
19. The thread of claim 15, wherein the noncross-linked hyaluronic acid is present in an amount of from about 10 weight % to about 40 weight % based on the total weight of the thread excluding moisture.
20. The thread of claim 19, wherein the noncross-linked hyaluronic acid is present in an amount of from about 15 weight % to about 25 weight % based on the total weight of the thread excluding moisture.
21. The thread of any one of claims 13-20, n the thread has an ultimate tensile strength of from about 2 kpsi to about 20 kpsi.
22. The thread of claim 21, wherein the thread has an ultimate tensile strength of from about 4 kpsi to about 10 kpsi.
23. The thread of any one of claims 13-22, wherein the thread has a diameter of at least about 0.004 inches.
24. The thread of claim 23, wherein the thread has a diameter of from about 0.011 to about 0.016 inches.
25. The thread of any one of claims 13-24, n the thread has a /length ratio from about 1.5 to about 3.5 mg/inch.
26. The thread of any one of claims 13-25, wherein the thread has a failure load of about 0.3 pounds or r.
27. The thread of claim 26, n the thread has a failure load of from about 0.3 to about 1.3 .
28. The thread of any one of claims 13-27, further comprising a needle attached to the thread.
29. A dry thread comprising ntially cross-linked hyaluronic acid prepared by the steps a) forming a substantially cross-linked hyaluronic acid ition by contacting a composition comprising having at least 5% hyaluronic acid with butanediol diglycidyl ether (BDDE), such that the hyaluronic acid is cross-linked with from about 17 to about 20 mole % of a butanediol diglycidyl ether (BDDE) derivative relative to the repeating disaccharide unit of the hyaluronic acid; b) adding noncross-linked hyaluronic acid to the composition; c) extruding the substantially cross-linked composition to form a wet thread; and d) drying the wet thread to form a dry thread.
30. The dry thread of claim 29, wherein from about 5 to about 15 weight % hyaluronic acid is contacted with from about 2 to about 8 weight % BDDE relative to the weight of the composition.
31. The dry thread of any one of claims 29 or 30, wherein the hyaluronic acid is contacted with about 40 weight % BDDE relative to the weight of the hyaluronic acid.
32. The dry thread of claim 29, wherein the cross-linked hyaluronic acid is cross-linked with at least about 12 weight % of the BDDE derivative relative to the weight of the crosslinked hyaluronic acid.
33. The dry thread of any one of claims 29-32, wherein at least 8% hyaluronic acid is contacted with BDDE relative to the weight of the composition.
34. The dry thread of claim 33, n about 10% hyaluronic acid is contacted with BDDE relative to the weight of the composition.
35. The dry thread of claim 33, wherein about 12% hyaluronic acid is contacted with BDDE relative to the weight of the composition.
36. The dry thread of any one of claims 29-35, wherein the hyaluronic acid is an aqueous solution.
37. The dry thread of claim 36, wherein the solution has a pH > 7.0.
38. The dry thread of claim 37, wherein the solution comprises sodium hydroxide.
39. The dry thread of claim 29, wherein the cross-linked hyaluronic acid ition of step a) is washed.
40. The dry thread of claim 29, wherein the composition of step a) comprises cross-linked hyaluronic acid in an amount of from about 1 weight % to about 50 weight % based on the total weight of the composition.
41. The dry thread of claim 40, wherein the composition of step a) ses cross-linked hyaluronic acid in an amount of from about 5 weight % to about 20 weight % based on the total weight of the composition.
42. The dry thread of any one of claims 36-41, further comprising drying the composition of step a).
43. The dry thread of any one of claims 29-42, wherein from about 1 weight % to about 15 weight % ss-linked hyaluronic acid is added, based on the total weight of the composition.
44. The dry thread of claim 43, wherein from about 2 weight % to about 8 weight % noncross-linked hyaluronic acid is added, based on the total weight of the composition.
45. The dry thread of any one of claims 29-44, wherein the dry thread has an ultimate tensile strength of from about 2 kpsi to about 20 kpsi.
46. The dry thread of claim 45, wherein the dry thread has an ultimate tensile strength of about 20 kpsi or greater.
47. The dry thread of any one of claims 29-46, wherein the dry thread has a failure load of about 0.3 pounds or greater.
48. The dry thread of claim 47, wherein the thread has a failure load of from about 0.3 to about 1.3 pounds.
49. The thread of any one of claims 13-48, wherein the thread is terminally sterilized.
50. A use of 5% onic acid in the manufacture of a medicament for treating a wrinkle in a patient in need thereof, wherein the medicament is in the form of a thread, and the medicament is for use in a method comprising; a) inserting the thread into skin or aneous space of the t adjacent to or under the wrinkle; and b) applying the thread adjacent to or under the wrinkle thereby treating the wrinkle, wherein the hyaluronic acid is substantially cross-linked with from about 17 to about 20 mole % of a BDDE derivative relative to the repeating disaccharide unit of the hyaluronic acid.
51. A use of substantially linked hyaluronic acid and at least about 5% noncross-linked hyaluronic acid relative to the weight of total hyaluronic acid solids, in the manufacture of a medicament for treating a wrinkle in a t in need thereof, wherein the medicament is in the form of a , and the medicament is for use in a method comprising a) inserting the thread into skin or subcutaneous space of the patient adjacent to or under the wrinkle; and b) applying the thread adjacent to or under the e thereby treating the e, wherein the hyaluronic acid is substantially cross-linked with from about 17 to about 20 mole % of BDDE derivative relative to the repeating disaccharide unit of the hyaluronic acid.
52. A use as claimed in claim 51 wherein the thread is dry and is prepared according to the method as defined in claim 29.
53. The use of claim 50 or 51, wherein steps a) and b) are performed 2 to 6 times.
54. The use of claim 50 or 51, wherein the thread is inserted by a needle.
55. The use of claim 54, r comprising removing the needle from the skin.
56. The use of any one of claims 50-52, further comprising hydrating the thread.
57. The use of claim 50 or 51, wherein prior to step a), a lubricity enhancing agent is applied to the thread.
58. A dried thread comprising cross-linked hyaluronic acid, wherein the onic acid is cross-linked with from about 17 to 20 mole % of a butanediol diglycidyl ether (BDDE) derivative relative to the repeating disaccharide unit of the hyaluronic acid, and at least 5 weight % noncross-linked hyaluronic acid relative to the weight of the total hyaluronic acid solids, wherein the cross-linked hyaluronic acid is present in an amount of from 60 weight % to 90 weight % based on the total weight of the thread excluding moisture.
59. The dried thread of claim 58, wherein the noncross-linked hyaluronic acid is present in an amount of from 10 weight % to 40 weight % based on the total weight of the thread ing re.
60. The dried thread of claim 58 or 59, wherein the thread has an ultimate tensile strength of 3 kpsi (20.7 MPa) or greater.
61. The dried thread of any one of claims 58-60, wherein the thread has an ultimate e strength of 2 kpsi (13.8 MPa) to 20 kpsi (138 MPa).
62. The dried thread of any one of claims 58-61, wherein the thread has a diameter of from 0.008 inches (0.20 mm) to 0.018 inches (0.46 mm).
63. The dried thread of any one of claims 58-62, wherein the thread has a diameter of from 0.011 inches (0.28 mm) to 0.016 inches (0.41 mm).
64. The dried thread of any one of claims 58-63, wherein the thread has a weight/length ratio from 1.5 mg/inch (0.059 mg/mm) to 3.5 mg/inch (0.14 mg/mm).
65. The dried thread of any one of claims 58-64, n the thread has a length of from 5 cm to 10 cm.
66. The dried thread of any one of claims 58-65, wherein the thread has a e load of from 0.3 pounds (0.14 kg) to 1.3 pounds (0.59 kg).
67. The dried thread of any one of claims 58-66, further comprising a needle attached to the thread.
68. A kit of part comprising thread of any one of claims 13-49 and 58-67 and a needle.
69. A cosmetic use of the thread of any one of claims 13-49 and 58-67 for filling a wrinkle in a patient, for facial contouring or for wound dressing.
70. A composition as claimed in claim 1, ntially as herein described or exemplified and with or without reference to the accompanying drawings.
71. A thread as claimed in any one of claims 13-15, 29 and 58, substantially as herein described or exemplified and with or without nce to the accompanying drawings.
72. A use as claimed in claim 50 or 51, substantially as herein described or exemplified and with or without reference to the accompanying drawings.
73. A kit as claimed in claim 68, substantially as herein described or exemplified and with or without reference to the accompanying drawings.
74. A cosmetic use as claimed in claim 69, substantially as herein described or exemplified and with or without reference to the accompanying drawings.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161545962P | 2011-10-11 | 2011-10-11 | |
US61/545,962 | 2011-10-11 | ||
US201161568077P | 2011-12-07 | 2011-12-07 | |
US61/568,077 | 2011-12-07 | ||
US201261644945P | 2012-05-09 | 2012-05-09 | |
US61/644,945 | 2012-05-09 | ||
PCT/US2012/059618 WO2013055832A1 (en) | 2011-10-11 | 2012-10-10 | Threads of cross-linked hyaluronic acid and methods of use thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ623909A NZ623909A (en) | 2016-09-30 |
NZ623909B2 true NZ623909B2 (en) | 2017-01-05 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2012318283B2 (en) | Threads of cross-linked hyaluronic acid and methods of use thereof | |
US20160213813A1 (en) | Threads of cross-linked hyaluronic acid and methods of uses thereof | |
US20150327972A1 (en) | Soft tissue augmentation threads and methods of use thereof | |
EP2629809B1 (en) | Threads of cross-linked hyaluronic acid and methods of preparation and use thereof | |
CA2672495C (en) | Novel injectable chitosan mixtures forming hydrogels | |
AU2009288118B2 (en) | Threads of hyaluronic acid and/or derivatives thereof, methods of making thereof and uses thereof | |
EP2674147B1 (en) | Method of preparing a hyaluronic acid-based gel including lidocaine HCl. | |
US20150209265A1 (en) | Spherical forms of cross-linked hyaluronic acid and methods of use thereof | |
WO2011109130A1 (en) | Threads of hyaluronic acid and methods of use thereof | |
WO2014165113A1 (en) | Cross-linked hyaluronic acid threads for treatment of striae | |
KR20190096946A (en) | New Compositions Active on Adipose Cells | |
WO2014169300A1 (en) | Non-toxic cross-linker for halyuronic acid | |
NZ623909B2 (en) | Threads of cross-linked hyaluronic acid and methods of use thereof | |
AU2015201245B2 (en) | Threads of hyaluronic acid and/or derivatives thereof, methods of making thereof and uses thereof |