Controllable self-annealing microgel particles for biomedical applications

Abstract

A microporous gel system for certain applications, including biomedical applications, includes an aqueous solution containing plurality of microgel particles including a biodegradable crosslinker. In some aspects, the microgel particles act as gel building blocks that anneal to one another to form a covalently-stabilized scaffold of microgel particles having interstitial spaces therein. In certain aspects, annealing of the microgel particles occurs after exposure to an annealing agent that is endogenously present or exogenously added. In some embodiments, annealing of the microgel particles requires the presence of an initiator such as exposure to light. In particular embodiments, the chemical and physical properties of the gel building blocks can be controlled to allow downstream control of the resulting assembled scaffold. In one or more embodiments, cells are able to quickly infiltrate the interstitial spaces of the assembled scaffold.

1 - 66 . (canceled) 
     
     
         67 . A formulation comprising a covalently-stabilized, porous scaffold of microgel particles, wherein the covalently-stabilized, porous scaffold of microgel particles comprises:
 (a) a plurality of flowable microgel particles, wherein the plurality of flowable microgel particles comprises:   (i) a hydrogel polymer, wherein the hydrogel polymer comprises a poly(ethylene glycol) (PEG), a hyaluronic acid, or a combination thereof;   (ii) one or more annealing components comprising an acrylate, an α,β-unsaturated carbonyl group, a vinyl sulfone, or a maleimide; and   (iii) diameters comprising 5 μm to 1000 μm; and   (b) an annealing agent that, when exposed to the plurality of flowable microgel particles, couples adjacent microgel particles of the plurality of flowable microgel particles together in a covalent annealing reaction at points of physical contact between the adjacent microgel particles to form the covalently-stabilized porous scaffold, wherein the covalently-stabilized porous scaffold comprises pores, wherein the pores comprise a median pore diameter sufficient to integrate cells from tissue therein.   
     
     
         68 . The formulation of  claim 67 , wherein the hyaluronic acid comprises one or more reactive groups. 
     
     
         69 . The formulation of  claim 68 , wherein the one or more reactive groups comprises a thiol-containing molecule. 
     
     
         70 . The formulation of  claim 67 , wherein the α,β-unsaturated carbonyl group is a Michael acceptor in a Michael or pseudo-Michael addition reaction. 
     
     
         71 . The formulation of  claim 67 , wherein the annealing agent comprises a nucleophilic group comprising a thiol, an amine, or an aminoxy. 
     
     
         72 . The formulation of  claim 67 , wherein the hydrogel polymer comprises the combination of the PEG and the hyaluronic acid. 
     
     
         73 . The formulation of  claim 72 , wherein the hyaluronic acid comprises one or more reactive groups. 
     
     
         74 . The formulation of  claim 73 , wherein the one or more reactive groups comprises a thiol-containing molecule. 
     
     
         75 . The formulation of  claim 72 , wherein the α,β-unsaturated carbonyl group is a Michael acceptor in a Michael or pseudo-Michael addition reaction. 
     
     
         76 . The formulation of  claim 72 , wherein the annealing agent comprises a nucleophilic group comprising a thiol, an amine, or an aminoxy. 
     
     
         77 . The formulation of  claim 67 , wherein the covalently-stabilized scaffold of microgel particles has a void volume of from 10% to 50%. 
     
     
         78 . The formulation of  claim 67 , wherein the plurality of flowable microgel particles in (a) are present at a 30-99% volume fraction in an aqueous solution. 
     
     
         79 . The formulation of  claim 67 , wherein the plurality of flowable microgel particles has a minimum storage moduli of 10 Pa. 
     
     
         80 . The formulation of  claim 67 , wherein the plurality of flowable microgel particles is capable of undergoing annealing in 30 minutes or less. 
     
     
         81 . The formulation of  claim 67 , wherein formation of the pores in the covalently-stabilized porous scaffold does not require degradation of the covalently-stabilized porous scaffold. 
     
     
         82 . The formulation of  claim 67 , wherein the median pore diameter comprises 12 μm to 37 μm. 
     
     
         83 . The formulation of  claim 67 , formulated for delivery to the tissue by injection, wherein the plurality of flowable microgel particles and the annealing agent are formulated for simultaneous or sequential delivery to the tissue. 
     
     
         84 . A method of treating a tissue, the method comprising: administering to the tissue:
 (a) a plurality of flowable microgel particles, wherein the plurality of flowable microgel particles comprises:   (i) a hydrogel polymer, wherein the hydrogel polymer comprises a poly(ethylene glycol) (PEG), a hyaluronic acid, or a combination thereof;   (ii) one or more annealing components comprising an acrylate, an α,β-unsaturated carbonyl group, a vinyl sulfone, or a maleimide; and   (iii) diameters comprising between 5 μm to 1000 μm; and   (b) an annealing agent, that when exposed to the plurality of flowable microgel particles, couples adjacent microgel particles of the plurality of flowable microgel particles together in a covalent annealing reaction at points of physical contact between the adjacent microgel particles to form a covalently-stabilized porous scaffold, wherein the covalently-stabilized porous scaffold comprises pores into which cells from the tissue become integrated.   
     
     
         85 . The method of  claim 84 , wherein the hyaluronic acid comprises one or more reactive groups. 
     
     
         86 . The method of  claim 85 , wherein the one or more reactive groups comprises a thiol-containing molecule. 
     
     
         87 . The method of  claim 84 , wherein the α,β-unsaturated carbonyl group is a Michael acceptor in a Michael or pseudo-Michael addition reaction. 
     
     
         88 . The method of  claim 84 , wherein the annealing agent comprises a nucleophilic group comprising a thiol, an amine, or an aminoxy. 
     
     
         89 . The method of  claim 84 , wherein the administering is performed by injection of the plurality of flowable microgel particles into the tissue. 
     
     
         90 . The method of  claim 84 , wherein the hydrogel polymer comprises the combination of the PEG and the hyaluronic acid. 
     
     
         91 . The method of  claim 84 , wherein the cells from the tissue become integrated in the pores within forty-eight hours after contact with the covalently-stabilized porous scaffold. 
     
     
         92 . The method of  claim 84 , wherein the treatment of the tissue comprises tissue filling. 
     
     
         93 . The method of  claim 92 , wherein the tissue filling comprises improving volume loss related to aging, lipoatrophy, lipodystrophy, dermal scarring, or superficial or deep rhytides. 
     
     
         94 . The method of  claim 92 , wherein the tissue filling comprises improving tissue contour. 
     
     
         95 . The method of  claim 92 , wherein the tissue filling comprises repairing tissue displacement. 
     
     
         96 . The method of  claim 84 , wherein the administering the plurality of flowable microgel particles and the annealing agent to the tissue is performed simultaneously or sequentially.