Nanofiber-hydrogel composites for enhanced soft tissue replacement and regeneration

Abstract

A composite material can include a gel and at least one nanostructure disposed within the gel. A method for healing a soft tissue defect can include applying a composite material to a soft tissue defect, wherein the composite material includes a gel and a nanostructure disposed within the gel. A method for manufacturing a composite material for use in healing soft tissue defects can include providing a gel and disposing nanofibers within the gel.

1 . A population of substantially non-spherical microbeads comprising:
 a functionalized hyaluronic acid network covalently linked to a plurality of polycaprolactone fibers having a mean length of less than about 200 micrometers, and a crosslinking agent present at a concentration from about 1 mg/mL to about 25 mg/mL,   wherein the mean size of the microbeads is within the range of about 50 micrometers to about 300 micrometers along the longest dimension.   
     
     
         2 . The microbeads of  claim 1  wherein the microbeads are pre-reacted. 
     
     
         3 . The microbeads of  claim 1  wherein the microbeads are substantially stable at room temperature for at least about 6 months. 
     
     
         4 . A lyophilized formulation comprising a population of substantially non-spherical microbeads comprising:
 a functionalized hyaluronic acid network covalently linked to a plurality of polycaprolactone fibers having a mean length of less than about 200 micrometers, and a crosslinking agent present at a concentration from about 1 mg/mL to about 25 mg/mL.   
     
     
         5 . The formulation of  claim 4  wherein the microbeads are pre-reacted. 
     
     
         6 . The formulation of  claim 4  wherein the microbeads comprise a moisture content of less than about 15%. 
     
     
         7 . The formulation of  claim 4  wherein the microbeads are substantially stable at room temperature for at least about 12 months. 
     
     
         8 . The population of microbeads of  claim 1  wherein the microbeads are substantially non-inflammatory. 
     
     
         9 . The population of microbeads of  claim 1  wherein the functionalized hyaluronic acid comprises acrylated hyaluronic acid, and the crosslinking agent comprises thiolated poly(ethylene glycol), or a derivative thereof. 
     
     
         10 . The population of microbeads of  claim 1  wherein the functionalized hyaluronic acid comprises thiolated hyaluronic acid, and the crosslinking agent comprises poly(ethylene glycol) diacrylate (PEGDA), or a derivative thereof. 
     
     
         11 . The population of microbeads of  claim 1 , wherein the plurality of polycaprolactone fibers comprises an electrospun fiber. 
     
     
         12 . The population of microbeads of  claim 1 , wherein the diameter of the polycaprolactone fibers, is within the range of about 100 nanometers to about 5 micrometers. 
     
     
         13 . The population of microbeads of  claim 1 , wherein the microbeads has a mean storage modulus of between about 50 Pa and about 2500 Pa. 
     
     
         14 . The population of microbeads of  claim 1 , comprising a plurality of pores. 
     
     
         15 . (canceled) 
     
     
         16 . The population of microbeads of  claim 14 , wherein the plurality of pores comprises an area density of no less than about 50 pores per cm 2 , with at least about 80% of pores having a mean size of no less than about 5 micrometers. 
     
     
         17 . An implantable or injectable biomaterial comprising the population of microbeads of  claim 1 , wherein the biomaterial is formulated for dermal or subdermal administration into a target tissue of a subject. 
     
     
         18 - 22 . (canceled) 
     
     
         23 . A kit for preparation of the population of microbeads of  claim 1 , for immediate administration into a target tissue of a subject, the kit comprising: a vial containing the microbeads, said microbeads having been lyophilized and formed into powder cakes, wherein the lyophilized powder cakes are able to be reconstituted by water, saline solution or suitable reconstitution fluid. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . The population of microbeads of  claim 1  further comprising a compound that have therapeutic effects, vascularization effects, anti-vascularization effects, anti-inflammatory effects, anti-bacterial effects, antihistamine effects, and combinations thereof. 
     
     
         28 . The population of microbeads of  claim 1  further comprising a processed tissue extracellular matrix, wherein the processed tissue extracellular matrix is derivable from an adipose tissue. 
     
     
         29 . (canceled) 
     
     
         30 . A population of substantially non-spherical microbeads comprising a functionalized hydrogel network covalently linked to a plurality of polymeric fibers having a mean length of less than about 200 micrometers, and a crosslinking agent present at a concentration from about 1 mg/mL to about 25 mg/mL,
 wherein the mean size of the microbeads is within the range of about 50 micrometers to about 300 micrometers along the longest dimension,   wherein the microbeads are pre-reacted,   wherein the microbeads are substantially stable at room temperature for at least about 6 months.   
     
     
         31 - 32 . (canceled)