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 flowable microporous gel system comprising:
 a. a collection of flowable microgel particles comprising a backbone polymer and an annealing component; and   b. an annealing agent that links the flowable microgel particles together via the annealing component to form a covalently-stabilized scaffold of microgel particles having interstitial spaces therein.   
     
     
         68 . The microporous gel system of  claim 67 , wherein at least a portion of the flowable microgel particles further comprises a degradable crosslinker. 
     
     
         69 . The microporous gel system of  claim 68 , wherein the degradable crosslinker comprises a matrix metalloprotease (MMP)-degradable crosslinker. 
     
     
         70 . The microporous gel system of  claim 67 , wherein the annealing agent comprises a photoinitiator, a free radical transfer agent, or a vinyl group. 
     
     
         71 . The microporous gel system of  claim 70 , wherein the photoinitiator is Eosin Y. 
     
     
         72 . The microporous gel system of  claim 67 , wherein the annealing agent is a transglutaminase enzyme. 
     
     
         73 . The microporous gel system of  claim 67 , wherein the annealing component is a transglutaminase peptide substrate. 
     
     
         74 . The microporous gel system of  claim 67 , wherein the annealing component is a peptide substrate of enzyme Factor XIII. 
     
     
         75 . The microporous gel system of  claim 67 , wherein the flowable microgel particles comprise a cell adhesive peptide exposed on surfaces thereof. 
     
     
         76 . The microporous gel system of  claim 75 , wherein the cell adhesive peptide is an RGD peptide. 
     
     
         77 . The microporous gel system of  claim 67 , wherein the interstitial spaces within the covalently-stabilized scaffold of microgel particles occupy a volume of from about 10% to about 50%. 
     
     
         78 . The microporous gel system of  claim 67 , wherein the backbone polymer comprises a polymer that comprises poly(ethylene glycol), hyaluronic acid, polyacrylamide, or polymethacrylate. 
     
     
         79 . The microporous gel system of  claim 67 , wherein the flowable microgel particles comprise spheres having a diameter within the range of from about 15 micrometers to about 150 micrometers. 
     
     
         80 . A method of treating a tissue comprising:
 delivering to the tissue a plurality of flowable microgel particles that comprise an annealing component; and exposing the flowable microgel particles to an annealing agent that anneals the flowable microgel particles to form a covalently-stabilized scaffold of microgel particles having interstitial spaces therein.   
     
     
         81 . The method of  claim 80 , further comprising exposing the flowable microgel particles in the tissue to a light source. 
     
     
         82 . The method of  claim 80 , wherein exposing the flowable microgel particles to an annealing agent comprises applying an enzyme to the flowable microgel particles. 
     
     
         83 . The method of  claim 80 , wherein the tissue is selected from epithelial tissue, skin tissue, dermal tissue, cardiac tissue, and gastrointestinal tissue. 
     
     
         84 . The method of  claim 80 , wherein the flowable microgel particles are delivered to a site in the tissue selected from a surgical incision, a surgical resection, a diabetic ulcer, a venous ulcer, and a pressure ulcer. 
     
     
         85 . A method of making microgel particles comprising:
 providing a water-in-oil droplet generating microfluidic device having a plurality of input channels leading to a common channel and a pair of oil-pinching channels intersecting with the common channel at a downstream location;   flowing a first pre-polymer solution containing a polymer backbone modified with oligopeptides into a first input channel;   flowing a second solution containing a biodegradable crosslinker into a second input channel;   flowing an oil and a surfactant into the pair of oil pinching channels to form droplets containing the first pre-polymer solution and the second solution; and   collecting microgel particles formed by cross-linking of the droplets.   
     
     
         86 . The method of  claim 85 , having a third input channel interposed between the first input channel and the second input channel, wherein an inert solution is flowed into the third input channel, with the purpose of preventing device fouling and to extend the lifetime of operation of the method of  claim 85 .