Self-Assembling Biomimetic Hydrogels Having Bioadhesive Properties

Abstract

The disclosure relates to a composition that is liquid at a temperature below the body temperature of a mammal and that solidifies at or above the body temperature of the mammal. The composition includes a thermally-desolubilizable polymer interspersed with a polymeric component of extracellular matrix and an encapsulated form of an amine compound (preferably an aminated component of extracellular matrix) that is de-encapsulated in the body of the mammal. The polymeric component is able to form covalent bonds with amine moieties in the aminated component, in one or more tissues in the body of the mammal, or both. Upon injection off liquid suspension of these components into the body of the mammal, the thermally-desolubilizable polymer condenses, entrapping the polymeric component. The polymeric component binds covalently with a tissue in the body, and the aminated component end-caps the remaining reactive moieties of the polymeric component, forming a matrix at the site of injection. The disclosure also relates to uses of such compositions for forming a matrix on or within the body of a mammal. The compositions have a variety of uses, such as bioadhesives, as sealants for ruptured tissues, as drug or imaging agent depots, or as mechanical cushions.

1 - 101 . (canceled) 
     
     
         102 . A method of forming a solidified matrix fixed within the body of a mammal, the method comprising:
 suspending in an aqueous solvent:
 a) a biocompatible thermally-desolubilizable (TD) polymer selected from the group consisting of poly(ethylene oxides) (PEOs), poly(propylene oxides) (PPOs), copolymers of PEO and poly(lactide acid) (PLA), poly (n-isopropyl acrylamides) (PNIPPAms), mixtures and copolymers thereof, wherein the polymer exists in an extended form below a critical solution temperature (CST) that is lower than the normal body temperature of the mammal and in a condensed form at or above the CST; 
 b) an aminated component of a mammalian extracellular matrix, in a releasable encapsulated form, wherein the aminated component is releasable from the encapsulated form within the body of the mammal; and 
 c) a polymeric component of a mammalian extracellular matrix, the polymeric component bearing functional moieties capable of forming covalent bonds with both the aminated component and amine moieties at a tissue in the body of the mammal, and 
   injecting the suspension to the mammal at a desired location for the matrix,   whereby, following such injection, the polymer is transformed from its extended form to its condensed form, the aminated component is released from its encapsulated form, and the polymeric component binds with both the tissue and the aminated component, thereby forming the matrix fixed at the location.   
     
     
         103 . The method of  claim 102 , wherein the TD polymer is a PNIPAAm. 
     
     
         104 . The method of  claim 102 , wherein the TD polymer is covalently linked with an ECM polymer. 
     
     
         105 . The method of  claim 102 , wherein the ECM polymer is selected from the group consisting of chondroitins, hyaluronates, keratins, alginates, celluloses, gums and dextrans. 
     
     
         106 . The method of  claim 105 , wherein the mammal is a human. 
     
     
         107 . The method of  claim 105 , further comprising the step of suspending in the aqueous solvent human cells. 
     
     
         108 . The method of  claim 107 , wherein the human cells are selected from the group consisting of pluripotent cells, fibroblasts, and cells of a tissue contacted by the polymeric component following injection of the composition into the body. 
     
     
         109 . The method of  claim 108 , wherein the cells are pluripotent cells. 
     
     
         110 . The method of  claim 109 , wherein the cells are adipose derived stem cells. 
     
     
         111 . A liquid composition for forming a solidified matrix within the body of a mammal, the composition comprising
 (a) an aqueous solvent having suspended therein mammalian cells selected from the group consisting of pluripotent cells, fibroblasts, and cells of a tissue contacted by the polymeric component following injection of the composition into the body,   (b) a biocompatible thermally-desolubilizable (TD) polymer that exists in an extended form below a critical solution temperature (CST) that is lower than the normal body temperature of the mammal and in a condensed form at or above the CST;   (c) an aminated component of a mammalian extracellular matrix (ECM), in a releasable encapsulated form, wherein the aminated component is releasable from the encapsulated form within the body of the mammal; and   (d) a polymeric component of a mammalian ECM, the polymeric component bearing functional moieties capable of forming covalent bonds with amine moieties, whereby when the composition is injected into the body of the mammal, the polymer is transformed from its extended form to its condensed form, the aminated component is released from its encapsulated form, and the polymeric component binds with the aminated component, thereby forming the matrix.   
     
     
         112 . The composition of  claim 111 , wherein the composition further comprises an imaging agent, a biomechanical agent providing a cushion between abutting bones or sealing a body cavity, a pharmaceutical agent, a radionuclide or a combination thereof. 
     
     
         113 . The composition of  claim 112 , wherein the TD polymer is selected from the group consisting of poly(ethylene oxides) (PEOs), poly(propylene oxides) (PPOs), copolymers of PEO and poly(lactic acid) (PLA), poly(n-isopropyl acrylamides) (PNIPAAms), mixtures of two or more thereof, and copolymers of two or more thereof. 
     
     
         114 . The composition of  claim 113 , wherein the TD polymer is a PNIPAAm. 
     
     
         115 . The composition of  claim 114 , wherein the TD polymer is a covalently linked with an ECM polymer. 
     
     
         116 . The composition of  claim 115 , wherein the ECM polymer is the same polymer as the polymeric component. 
     
     
         117 . The composition of  claim 116 , wherein the aminated component is encapsulated in lipid vesicles. 
     
     
         118 . The composition of  claim 117 , wherein the aminated component is thermally-releasible. 
     
     
         119 . The composition of  claim 117 , wherein the aminated component is diffusionally-releasible. 
     
     
         120 . The composition of  claim 117 , wherein the aminated component is selected from the group consisting of chondroitins, hyaluronates, keratins, alginates, celluloses, gums, and dextrans. 
     
     
         121 . The composition of  claim 111 , wherein the polymeric component is functionalized to render it capable of covalently bonding with amine moieties in the tissue. 
     
     
         122 . The composition of  claim 121 , wherein the polymeric component is selected from the group consisting of chondroitins, hyaluronates, keratins, alginates, celluloses, gums, and dextrans. 
     
     
         123 . The composition of  claim 122 , wherein the polymeric component is chondroitin sulfate (CS). 
     
     
         124 . The composition of  claim 123 , wherein the imaging agent, the biomechanical agent, or the pharmaceutically active agent are dissolved or suspended in the solvent. 
     
     
         125 . A method of regenerating tissue in vivo comprising delivering to or into a mammalian tissue, a liquid composition comprising an aqueous solvent having suspended therein:
 (a) an aqueous solvent having suspended therein mammalian cells selected from the group consisting of pluripotent cells, fibroblasts, and cells of a tissue contacted by the polymeric component following injection of the composition into the body,   (b) a biocompatible thermally-desolubilizable (TD) polymer that exists in an extended form below a critical solution temperature (CST) that is lower than the normal body temperature of the mammal and in a condensed form at or above the CST;   (c) an aminated component of a mammalian extracellular matrix (ECM), in a releasable encapsulated form, wherein the aminated component is releasable from the encapsulated form within the body of the mammal; and   (d) a polymeric component of a mammalian ECM, the polymeric component bearing functional moieties capable of forming covalent bonds with amine moieties,   whereby when the composition is injected into the body of the mammal, the polymer is transformed from its extended form to its condensed form, the aminated component is released from its encapsulated form, and the polymeric component binds with the aminated component, thereby replacing the tissue.