Active self-healing biomaterial system

Abstract

Methods and compositions are provided that load and encapsulate an agent, such as a protein, in a porous self-healing polymer. A delivery system includes a porous self-healing polymer, an ionic affinity trap within the pores of the self-healing polymer, and an agent associated with the ionic affinity trap. Methods of encapsulating an agent in a polymer include providing a porous self-healing polymer comprising an ionic affinity trap within the pores. The polymer is incubated with an agent having an affinity for the ionic affmity trap. At least a portion of the pores in the polymer are then healed. Active encapsulation of macromolecules at low concentrations may be achieved due to affinity of the agent for the ionic affinity trap within the pores.

1 . A method of making a solid delivery system comprising:
 providing a biodegradable polymer matrix having no peptide disposed within the matrix structure; and   admixing the biodegradable polymer matrix with an aqueous solution of an peptide under conditions sufficient to sorb the peptide to the biodegradable polymer matrix, thereby forming a suspension of particles or microspheres of a biodegradable polymer matrix having the peptide disposed within the matrix structure, wherein the temperature of the aqueous solution and formed suspension is at or above the hydrated Tg of the polymer;   wherein the biodegradable polymer matrix comprises a copolymer of lactic acid and glycolic acid having ionized carboxylate end groups, and the polymer matrix partially or fully encapsulates the peptide thereby forming the solid delivery system.   
     
     
         2 . The method of  claim 1 , wherein the peptide comprises a positively charged biomolecule, drug, or antigen. 
     
     
         3 . The method of  claim 2 , wherein the peptide comprises a moderate molecular weight peptide. 
     
     
         4 . The method of  claim 3 , wherein the peptide absorbs to the biodegradable polymer matrix. 
     
     
         5 . The method of  claim 1 , wherein the biodegradable lactic acid and glycolic acid polymer matrix comprises a microparticle or a porous microsphere. 
     
     
         6 . The method of  claim 1 , wherein the admixing comprises incubating the aqueous solution of the peptide with the biodegradable polymer within 24 hours. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the solid delivery system provides sustained release of the peptide over at least two weeks. 
     
     
         9 . The method of  claim 1 , wherein the peptide is encapsulated at greater than 30% encapsulation efficiency. 
     
     
         10 . The method of  claim 1 , wherein the particles of the biodegradable polymer matrix comprises a microparticle or a porous microsphere. 
     
     
         11 . The method of  claim 10 , wherein the microspheres have a diameter in a range of about 20 to about 63 micron. 
     
     
         12 . The method of  claim 1 , further comprising sterilizing the biodegradable polymer matrix prior to admixing with the aqueous solution of the peptide. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the admixing step is free of organic solvents. 
     
     
         15 . The method of  claim 1 , wherein the biodegradable polymer matrix comprises poly(D,L-lactic-co-glycolic acid) 50:50. 
     
     
         16 . The method of  claim 1 , further comprising isolating the solid delivery system from the aqueous solution. 
     
     
         17 . A method of making a solid delivery system comprising:
 providing solid, dried, particles of a biodegradable polymer matrix having an interconnected porous structure and an ionic affinity trap operable to sorb an agent from an aqueous solution disposed within the pores of the porous structure, and no agent disposed within the porous structure; and   admixing the biodegradable polymer matrix with an aqueous solution of an agent under conditions sufficient to bind the agent to the ionic affinity trap, thereby forming a suspension of particles or microspheres of a biodegradable polymer matrix having the agent disposed within the porous structure, wherein the temperature of the aqueous solution and formed suspension is at or below the hydrated Tg of the polymer;   wherein the polymer matrix partially or fully encapsulates the agent, thereby forming the solid delivery system, and wherein the aqueous solution comprises less than 100 mg/mL of the agent and the agent is encapsulated at greater than 50% encapsulation efficiency.   
     
     
         18 .- 50 . (canceled) 
     
     
         51 . A solid delivery system comprising:
 particles of a biodegradable polymer matrix having an interconnected porous structure, an ionic affinity trap disposed within the pores of the porous structure, and an agent disposed within the porous structure; the ionic affinity trap and interconnected pores being present in an amount sufficient to allow loading of at least 1% w/w agent into the pores, wherein the polymer matrix partially or fully encapsulates the agent; wherein the ionic affinity trap comprises aluminum hydroxide, aluminum phosphate, calcium phosphate, potassium phosphate, or combinations thereof.   
     
     
         52 . A solid delivery system comprising:
 particles of a biodegradable polymer matrix having an peptide disposed within the matrix structure; wherein the biodegradable polymer matrix comprises a copolymer of lactic acid and glycolic acid having ionized carboxylate end groups, the peptide is bound to the ionized carboxylate end groups of the copolymer and occupies about 68% or greater of the total acids of the copolymer, and the polymer matrix partially or fully encapsulates the peptide.   
     
     
         53 . The solid delivery system of  claim 1 , wherein the peptide is selected from the group consisting of leuprolide acetate, octreotide acetate, and goserelin acetate. 
     
     
         54 . The solid delivery system of  claim 1 , wherein the peptide is leuprolide acetate.