Biodegradable, Porous, Thermally Responsive Injectable Hydrogel as Soft Tissue Defect Filler

Abstract

Provided herein is an injectable hydrogel composition that forms a porous gel rapidly after injection. Methods of making and using the composition are provided. A kit also is provided comprising the ingredients for making the hydrogel.

1 - 22 . (canceled) 
     
     
         23 . A composition comprising:
 a biodegradable, biocompatible, gelling polymer composition, that is reverse-gelling;   an ECM material; and   a biocompatible porogen that dissolves in vivo within 48 hours, and   wherein the composition forms a gel at 37° C. within one hour.   
     
     
         24 . The composition of  claim 23 , wherein the composition forms a gel in vivo within ten minutes. 
     
     
         25 . The composition of  claim 23 , comprising:
 from 10% to 94.9% of the biodegradable, biocompatible, gelling polymer composition;   from 0.1% to 50% of the solubilized ECM material; and   from 5% to 65% of the biocompatible porogen.   
     
     
         26 . The composition of  claim 23 , wherein the biodegradable, biocompatible, gelling polymer composition comprises:
 N-isopropylacrylamide (NIPAAm) residues, hydroxyethyl methacrylate (HEMA) residues, methacrylate-polylactide (MAPLA) macromer residues, and methacrylic acid (MAA) residues; or   NIPAAm residues, acrylic acid residues, hydroxyethyl methacrylate-poly(trimethylene carbonate) (HEMAPTMC) macromer residues, and MAA residues; or   NIPAAm residues, N-vinylpyrrolidone residues, and MAPLA residues.   
     
     
         27 . The composition of  claim 23 , wherein the ECM material is solubilized by digestion with an acid protease at pH 1 to 4. 
     
     
         28 . The composition of  claim 23 , wherein the porogen particles have a size or average size of between 30 μm and 300 μm. 
     
     
         29 . The composition of  claim 23 , wherein the porogen is a salt, sugar, polysaccharide, protein, or polypeptide. 
     
     
         30 . A method of making a composition for use in tissue repair, comprising: mixing a biodegradable, biocompatible, gelling polymer composition, that is reverse gelling, with a comminuted or solubilized ECM material, and a biocompatible porogen that dissolves in vivo within 48 hours, wherein the composition forms a gel at 37° C. within one hour, and the porogen particles have a size or average size of between 30 μm and 300 μm. 
     
     
         31 . The method of  claim 30 , comprising:
 from 10% to 94.9% of the biodegradable, biocompatible, gelling polymer composition;   from 0.1% to 50% of the solubilized ECM material; and   from 5% to 65% of the biocompatible porogen.   
     
     
         32 . The method of  claim 30 , wherein the biodegradable, biocompatible, polymer composition comprises:
 N-isopropylacrylamide (NIPAAm) residues, hydroxyethyl methacrylate (HEMA) residues, methacrylate-polylactide (MAPLA) macromer residues, and methacrylic acid (MAA) residues; or   NIPAAm residues, acrylic acid residues, hydroxyethyl methacrylate-poly(trimethylene carbonate) (HEMAPTMC) macromer residues, and MAA residues; or   NIPAAm residues, N-vinylpyrrolidone residues, and MAPLA residues.   
     
     
         33 . The method of  claim 30 , wherein the ECM material is solubilized by digestion with an acid protease at pH 1 to 4. 
     
     
         34 . The method of  claim 30 , wherein the porogen is a salt, sugar, polysaccharide, protein, or polypeptide. 
     
     
         35 . The method of  claim 30 , wherein the porogen is added to a mixture of the polymer composition and the comminuted or solubilized ECM material at a time after the time when the polymer composition and the comminuted or solubilized ECM material are mixed; wherein one or more of the polymer composition and the comminuted or solubilized ECM material is lyophilized and re-hydrated, or frozen and thawed prior to mixing; and/or further comprising lyophilizing or freezing the composition after mixing. 
     
     
         36 . A method of treating a defect or wound in a patient, comprising administering to the patient at or adjacent to the site of the wound or defect in the patient, an amount of the composition of  claim 23  effective to treat or repair the wound or defect in a patient, wherein the defect or wound is a soft tissue defect or wound. 
     
     
         37 . A kit comprising one or more vessels containing:
 a biodegradable, biocompatible, gelling polymer composition that is reverse-gelling;   comminuted or solubilized ECM material; and   a biocompatible porogen that dissolves in vivo within 48 hours,   wherein the polymer composition, the comminuted or solubilized ECM material, and the porogen are contained together or in separate vessels in a liquid, frozen, dried, or lyophilized state.   
     
     
         38 . The kit of  claim 37 , wherein the polymer composition and the comminuted or solubilized ECM material are provided in a single vessel in liquid, frozen, or lyophilized state, and the porogen particles are provided in a separate vessel. 
     
     
         39 . The kit of  claim 37 , wherein the polymer composition, the comminuted or solubilized ECM material, and the porogen, when mixed in an aqueous solution, form a gel at 37° C. within one hour. 
     
     
         40 . The kit of  claim 37 , comprising:
 from 10% to 94.9% of the biodegradable, biocompatible, gelling polymer composition;   from 0.1% to 50% of the solubilized ECM material; and   from 5% to 65% of the biocompatible porogen, wherein the porogen particles have a size or average size of between 30 μm and 300 μm.   
     
     
         41 . The kit of  claim 37 , wherein the biodegradable, biocompatible, gelling polymer composition comprises:
 N-isopropylacrylamide (NIPAAm) residues, hydroxyethyl methacrylate (HEMA) residues, methacrylate-polylactide (MAPLA) macromer residues, and methacrylic acid (MAA) residues; or   NIPAAm residues, acrylic acid residues, hydroxyethyl methacrylate-poly(trimethylene carbonate) (HEMAPTMC) macromer residues, and MAA residues; or   NIPAAm residues, N-vinylpyrrolidone residues, and MAPLA residues.   
     
     
         42 . The kit of  claim 37 , wherein the ECM material is solubilized by digestion with an acid protease at pH 1 to 4, and wherein the acid-protease digested ECM material is reverse-gelling.