Silk-hyaluronic acid based tissue filers and methods of using the same

Abstract

Hyaluronic acid and silk protein fragments based tissue fillers and methods of the same are provided herein.

1 - 33 . (canceled) 
     
     
         34 . A biocompatible tissue filler, comprising hyaluronic acid (HA), an anesthetic agent, and silk fibroin protein or silk fibroin-based protein fragments (SPF), wherein a portion of the HA or silk fibroin protein or SPF is modified or crosslinked by one or more linker moieties comprising one or more of an alkane or alkyl chain, an ether group, and a secondary alcohol, wherein the linker moieties are covalently attached to the modified or crosslinked HA or SPF. 
     
     
         35 - 36 . (canceled) 
     
     
         37 . The tissue filler of  claim 34 , wherein the SPF have an average weight average molecular weight ranging from about 1 kDa to about 250 kDa. 
     
     
         38 . The tissue filler of  claim 34 , wherein the SPF have an average weight average molecular weight ranging from about 5 kDa to about 150 kDa. 
     
     
         39 . The tissue filler of  claim 34 , wherein the SPF have an average weight average molecular weight selected from the group consisting of from about 6 kDa to about 17 kDa, from about 17 kDa to about 39 kDa, and from about 39 kDa to about 80 kDa. 
     
     
         40 - 44 . (canceled) 
     
     
         45 . The tissue filler of  claim 34 , wherein the silk fibroin-based protein fragments (SPF) have a polydispersity of between about 1.5 and about 3.0. 
     
     
         46 . (canceled) 
     
     
         47 . The tissue filler of  claim 34 , wherein a portion of the SPF are modified or cross-linked. 
     
     
         48 . The tissue filler of  claim 47 , wherein the % w/w amount of modified or cross-linked SPF relative to the total amount of SPF is about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%. 
     
     
         49 . The tissue filler of  claim 47 , wherein the degree of modification or cross-linking of the modified or cross-linked SPF is between about 1% and about 100%. 
     
     
         50 . (canceled) 
     
     
         51 . The tissue filler of  claim 47 , wherein the degree of modification or cross-linking of the modified or cross-linked SPF is between about 1% and about 15%. 
     
     
         52 - 53 . (canceled) 
     
     
         54 . The tissue filler of  claim 47 , wherein the modified or cross-linked SPF comprises a linker or cross-linking moiety comprising a polyethylene glycol (PEG) chain. 
     
     
         55 . The tissue filler of  claim 47 , wherein the modified or cross-linked SPF comprises a linker or cross-linking moiety comprising a secondary alcohol. 
     
     
         56 - 63 . (canceled) 
     
     
         64 . The tissue filler of  claim 34 , wherein a portion of SPF is cross linked to HA. 
     
     
         65 . The tissue filler of  claim 34 , wherein a portion of the SPF are cross-linked to SPF 
     
     
         66 . (canceled) 
     
     
         67 . The tissue filler of  claim 34 , wherein the tissue filler is a hydrogel. 
     
     
         68 . (canceled) 
     
     
         69 . The tissue filler of  claim 34 , wherein the total concentration of SPF in the tissue filler is from about 0.1 mg/mL to about 15 mg/mL. 
     
     
         70 . (canceled) 
     
     
         71 . The tissue filler of  claim 47 , wherein the concentration of modified or cross linked SPF in the tissue filler is from about 0.1 mg/mL to about 15 mg/mL. 
     
     
         72 - 74 . (canceled) 
     
     
         75 . The tissue filler of  claim 34 , wherein the tissue filler is injectable. 
     
     
         76 . The tissue filler of  claim 34 , wherein the tissue filler has a storage modulus (G′) of from about 25 Pa to about 1500 Pa. 
     
     
         77 . The tissue filler of  claim 34 , wherein the tissue filler has a storage modulus (G′) of from about 50 Pa to about 100 Pa. 
     
     
         78 . The tissue filler of  claim 34 , wherein the tissue filler has a storage modulus (G′) of from about 100 Pa to about 200 Pa. 
     
     
         79 . The tissue filler of  claim 34 , wherein the tissue filler has a storage modulus (G′) of from about 200 Pa to about 300 Pa. 
     
     
         80 - 81 . (canceled) 
     
     
         82 . The tissue filler of  claim 34 , wherein the tissue filler has a complex viscosity from about 1 Pa·s to about 10 Pa·s. 
     
     
         83 - 86 . (canceled) 
     
     
         87 . A method of treating a condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the tissue filler of  claim 34 . 
     
     
         88 . (canceled) 
     
     
         89 . The method of  claim 87 , wherein the condition is a skin condition selected from the group consisting of skin dehydration, lack of skin elasticity, skin roughness, lack of skin tautness, a skin stretch line, a skin stretch mark, skin paleness, a dermal divot, a sunken cheek, a thin lip, a retro-orbital defect, a facial fold, and a wrinkle, wherein the tissue filler is administered into a dermal region of the subject. 
     
     
         90 - 92 . (canceled) 
     
     
         93 . The method of  claim 89 , wherein the method is a facial augmentation, a facial reconstruction, treating a facial disease, treating a facial disorder, treating a facial defect, or treating a facial imperfection. 
     
     
         94 . The method of  claim 87 , wherein the tissue filler resists biodegradation, bioerosion, bioabsorption, and/or bioresorption, for at least about 3 days, about 7 days, about 14 days, about 21 days, about 28 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months. 
     
     
         95 . The method of  claim 87 , wherein administration of the tissue filler to the subject results in a reduced inflammatory response compared to the inflammatory response induced by a control tissue filler comprising a polysaccharide and lidocaine, wherein the control tissue filler does not include silk protein fragments (SPF). 
     
     
         96 . (canceled)