Dermal fillers comprising silk fibroin hydrogels and uses thereof

Abstract

The present specification provides compositions useful as dermal fillers and methods using such compositions to treat a condition of skin.

1 . A composition comprising a gel phase, the gel phase including
 a) hydrogel particles comprising a substantially sericin-depleted silk fibroin and an amphiphilic peptide; and   b) hydrogel particles comprising a matrix polymerand,   
     
     
         2 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles comprises about 1% (w/v) to about 10% (w/v) of silk fibroin. 
     
     
         3 . The composition of  claim 1 , wherein the final concentration of the silk fibroin is from about 3 mg/g to about 30 mg/g. 
     
     
         4 . The composition of  claim 1 , wherein the amphiphilic peptide comprising a RGD motif or a non-RDG integrin. 
     
     
         5 . The composition of  claim 3 , wherein the amphiphilic peptide is 23 RGD. 
     
     
         6 . The composition of  claim 1 , wherein the amphiphilic peptide comprises of a tail region, followed by a spacer region and finally a RGD motif. 
     
     
         7 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles comprises a molar ratio of 1:10 to 10:1 moles of the amphiphilic peptide per mole of the silk fibroin. 
     
     
         8 . The composition of  claim 6 , wherein the silk fibroin hydrogel particles comprises a molar ratio of 3:1 moles of the amphiphilic peptide per mole of the silk fibroin. 
     
     
         9 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles comprises a protein structure having a β-sheet conformation of at least 80%. 
     
     
         10 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles comprises a protein structure having a β-sheet conformation of at least 50%. 
     
     
         11 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles comprises a protein structure having a β-sheet conformation of at least 20%. 
     
     
         12 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles comprises a protein structure having an α-helical and random coil conformation of at most 20%. 
     
     
         13 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles further comprise a synthetic molecule having the formula: (molecule X) n —(spacer peptide) 0-300 −(five-amino-acid peptide tail) is conjugated to the silk fibroin. 
     
     
         14 . The composition of  claim 1 , wherein the matrix polymer is a glycosaminoglycan, a lubricin, a polysaccharide, or any combination thereof. 
     
     
         15 . The composition of  claim 14 , wherein the glycosaminoglycan is a chondroitin sulfate, a dermatan sulfate, a keratan sulfate, a heperan sulfate, a hyaluronan, or any combination thereof. 
     
     
         16 . The composition of  claim 14 , wherein the polysaccharide is a dextran, a dextrin, a starch, a hetastarch, a glycogen, a polyvinyl acetate, a polyvinyl pyrrolidone, a polyethylene glycol, a polyethylene imine, a cellulose, a methyl cellulose, a carboxymethyl cellulose, a hydroxyethyl cellulose, a hydroxypropyl cellulose, a hydroxyethyl methyl cellulose, a hydroxypropyl methyl cellulose, or any combination thereof. 
     
     
         17 . The composition of  claim 1 , wherein the matrix polymer is crosslinked. 
     
     
         18 . The composition of  claim 17 , wherein the crosslinked matrix polymer has a degree of crosslinking of at least 1%. 
     
     
         19 . The composition of  claim 17 , wherein the crosslinked matrix polymer has a degree of crosslinking of at most 17%. 
     
     
         20 . The composition of  claim 17 , wherein the crosslinked matrix polymer has a degree of crosslinking of about 1% to about 17%. 
     
     
         21 . The composition of  claim 1 , wherein the uncrosslinked matrix polymer represents about 90% or more by weight of the total matrix polymer present in the composition. 
     
     
         22 . The composition of  claim 1 , wherein the final concentration of the matrix polymer is from about 12 mg/g to about 22.8 mg/g. 
     
     
         23 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles and matrix polymer hydrogel particles have a cross-sectional area from about 0.1 μm 2  to about 1000 μm 2 . 
     
     
         24 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles and matrix polymer hydrogel particles have a cross-sectional area from about 0.1 μm 2  to about 10 μm 2 . 
     
     
         25 . The composition of  claim 1 , wherein the silk fibroin hydrogel particles and matrix polymer hydrogel particles have a cross-sectional area from about 20 μm 2  to about 50 μm 2 . 
     
     
         26 . The composition of  claim 1 , wherein the composition further comprises a carrier phase. 
     
     
         27 . The composition of  claim 26 , wherein the carrier phase comprises saline. 
     
     
         28 . The composition of  claim 26 , wherein the carrier phase comprises a surfactant solution. 
     
     
         29 . The composition of  claim 26 , wherein the gel phase is 50% to 99% of the total formulation volume, the remainder being a carrier solution. 
     
     
         30 . The composition of  claim 29 , wherein the gel phase is 75% of the total formulation volume, the remainder being a carrier solution. 
     
     
         31 . The composition of  claim 1 , wherein the composition further comprising lidocaine. 
     
     
         32 . The composition of  claim 1 , wherein, upon injection, the hydrogel particles remains substantially at the injection site for one month to eighteen months. 
     
     
         33 . A composition comprising a gel phase, the gel phase including hydrogel particles comprising a substantially sericin-depleted silk fibroin and a matrix polymer. 
     
     
         34 . The composition of  claim 33 , wherein the matrix polymer is a glycosaminoglycan, a lubricin, a polysaccharide, or any combination thereof. 
     
     
         35 . The composition of  claim 34 , wherein the glycosaminoglycan is a chondroitin sulfate, a dermatan sulfate, a keratan sulfate, a heperan sulfate, a hyaluronan, or any combination thereof. 
     
     
         36 . The composition of  claim 34 , wherein the polysaccharide is a dextran, a dextrin, a starch, a hetastarch, a glycogen, a polyvinyl acetate, a polyvinyl pyrrolidone, a polyethylene glycol, a polyethylene imine, a cellulose, a methyl cellulose, a carboxymethyl cellulose, a hydroxyethyl cellulose, a hydroxypropyl cellulose, a hydroxyethyl methyl cellulose, a hydroxypropyl methyl cellulose, or any combination thereof. 
     
     
         37 . The composition of  claim 33 , wherein the matrix polymer is crosslinked. 
     
     
         38 . The composition of  claim 33 , wherein the crosslinked matrix polymer has a degree of crosslinking of at least 1%. 
     
     
         39 . The composition of  claim 33 , wherein the crosslinked matrix polymer has a degree of crosslinking of at most 17%. 
     
     
         40 . The composition of  claim 33 , wherein the crosslinked matrix polymer has a degree of crosslinking of about 1% to about 17%. 
     
     
         41 . The composition of  claim 33 , wherein the uncrosslinked matrix polymer represents about 90% or more by weight of the total matrix polymer present in the composition. 
     
     
         42 . The composition of  claim 33 , wherein the final concentration of the matrix polymer is from about 12 mg/g to about 22.8 mg/g. 
     
     
         43 . The composition of  claim 33 , wherein the hydrogel particles comprises about 1% (w/v) to about 10% (w/v) of silk fibroin. 
     
     
         44 . The composition of  claim 33 , wherein the final concentration of the silk fibroin is from about 3 mg/g to about 30 mg/g. 
     
     
         45 . The composition of  claim 33 , wherein the hydrogel particles further comprise an amphiphilic peptide. 
     
     
         46 . The composition of  claim 33 , wherein the silk fibroin hydrogel particles and matrix polymer hydrogel particles have a cross-sectional area from about 0.1 μm 2  to about 1000 μm 2 . 
     
     
         47 . The composition of  claim 33 , wherein the silk fibroin hydrogel particles and matrix polymer hydrogel particles have a cross-sectional area from about 0.1 μm 2  to about 10 μm 2 . 
     
     
         48 . The composition of  claim 33 , wherein the silk fibroin hydrogel particles and matrix polymer hydrogel particles have a cross-sectional area from about 20 μm 2  to about 50 μm 2 . 
     
     
         49 . The composition of  claim 33 , wherein the composition further comprises a carrier phase. 
     
     
         50 . The composition of  claim 49 , wherein the carrier phase comprises saline. 
     
     
         51 . The composition of  claim 49 , wherein the carrier phase comprises a surfactant solution. 
     
     
         52 . The composition of  claim 49 , wherein the gel phase is 50% to 99% of the total formulation volume, the remainder being a carrier solution. 
     
     
         53 . The composition of  claim 52 , wherein the gel phase is 75% of the total formulation volume, the remainder being a carrier solution. 
     
     
         54 . The composition of  claim 33 , wherein the composition further comprising lidocaine. 
     
     
         55 . The composition of  claim 33 , wherein, upon injection, the hydrogel particles remains substantially at the injection site for one month to eighteen months. 
     
     
         56 . A method of treating a soft tissue condition in an individual in need thereof, the method comprising the step of administering a composition of  claim 1  into a skin region of the individual, wherein the administration improves the condition. 
     
     
         57 . The method of  claim 56 , wherein the soft tissue condition is a breast tissue condition, a facial tissue condition, a neck condition, a skin condition, an upper arm condition, a lower arm condition, a hand condition, a shoulder condition, a back condition, a torso including abdominal condition, a buttock condition, an upper leg condition, a lower leg condition including calf condition, a foot condition including plantar fat pad condition, an eye condition, a genital condition, or a condition effecting another body part, region or area. 
     
     
         58 . The method of  claim 57 , wherein the breast tissue condition is a breast imperfection, a breast defect, a breast augmentation, or a breast reconstruction. 
     
     
         59 . The method of  claim 57 , wherein the facial tissue condition is a facial imperfection, a facial defect, a facial augmentation, or a facial reconstruction. 
     
     
         60 . The method of  claim 57 , wherein the facial tissue condition is a dermal divot, a sunken check, a thin lip, a nasal imperfection or defect, a retro-orbital imperfection or defect, a facial fold, a facial line, a facial wrinkle, or other size, shape or contour imperfection or defect of the face. 
     
     
         61 . The method of  claim 60 , wherein the wrinkle is a glabellar line, a nasolabial line, a perioral line, or a marionette line. 
     
     
         62 . The method of  claim 57 , wherein the facial tissue condition is skin dehydration, a lack of skin elasticity, skin roughness, a lack of skin tautness, a skin stretch line or mark, or skin paleness. 
     
     
         63 . The method of  claim 56 , wherein the soft tissue condition is Parry-Romberg syndrome or lupus erythematosus profundus. 
     
     
         64 . The method of  claim 56 , wherein the soft tissue condition is urinary incontinence, fecal incontinence, or gastroesophageal reflux disease (GERD). 
     
     
         65 . A method of treating a soft tissue condition in an individual in need thereof, the method comprising the step of administering a composition of  claim 33  into a skin region of the individual, wherein the administration improves the condition. 
     
     
         66 . The method of  claim 65 , wherein the soft tissue condition is a breast tissue condition, a facial tissue condition, a neck condition, a skin condition, an upper arm condition, a lower arm condition, a hand condition, a shoulder condition, a back condition, a torso including abdominal condition, a buttock condition, an upper leg condition, a lower leg condition including calf condition, a foot condition including plantar fat pad condition, an eye condition, a genital condition, or a condition effecting another body part, region or area. 
     
     
         67 . The method of  claim 66 , wherein the breast tissue condition is a breast imperfection, a breast defect, a breast augmentation, or a breast reconstruction. 
     
     
         68 . The method of  claim 66 , wherein the facial tissue condition is a facial imperfection, a facial defect, a facial augmentation, or a facial reconstruction. 
     
     
         69 . The method of  claim 66 , wherein the facial tissue condition is a dermal divot, a sunken check, a thin lip, a nasal imperfection or defect, a retro-orbital imperfection or defect, a facial fold, a facial line, a facial wrinkle, or other size, shape or contour imperfection or defect of the face. 
     
     
         70 . The method of  claim 69 , wherein the wrinkle is a glabellar line, a nasolabial line, a perioral line, or a marionette line. 
     
     
         71 . The method of  claim 66 , wherein the facial tissue condition is skin dehydration, a lack of skin elasticity, skin roughness, a lack of skin tautness, a skin stretch line or mark, or skin paleness. 
     
     
         72 . The method of  claim 65 , wherein the soft tissue condition is Parry-Romberg syndrome or lupus erythematosus profundus. 
     
     
         73 . The method of  claim 65 , wherein the soft tissue condition is urinary incontinence, fecal incontinence, or gastroesophageal reflux disease (GERD).