Matrix bound nanovesicles and their use

Abstract

A composition is disclosed herein that includes isolated ECM-derived nanovesicles and a pharmaceutically acceptable carrier. Methods are producing the ECM-derived nanovesicles are also disclosed. These ECM-derived nanovesicles can be included in pharmaceutical compositions, bioscaffolds, and devices. Methods for using these ECM-derived nanovesicles are provided.

1 . A composition comprising isolated nanovesicles derived from an extracellular matrix and a pharmaceutically acceptable carrier. 
     
     
         2 . The composition of  claim 1 , wherein the nanovesicles do not express CD63 or CD81, or are CD63 lo CD81 lo . 
     
     
         3 . The composition of  claim 1 , wherein the extracellular matrix is a mammalian extracellular matrix. 
     
     
         4 . The composition of  claim 2 , wherein the mammalian extracellular matrix is a human extracellular matrix. 
     
     
         5 . The composition of  claim 3 , wherein the extracellular matrix is from esophageal tissue, urinary bladder, small intestinal submucosa, dermis, umbilical cord, pericardium, cardiac tissue, tumor tissue, or skeletal muscle. 
     
     
         6 . The composition of  claim 3 , wherein the nanovesicles comprise miR-145 and/or miR-181. 
     
     
         7 . The composition of  claim 3 , wherein the extracellular matrix is digested with an enzyme. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The composition of  claim 3 , further comprising an exogenous therapeutic agent. 
     
     
         11 - 12 . (canceled) 
     
     
         13 . A method of isolating nanovesicles from an extracellular matrix, comprising:
 digesting the extracellular matrix with an enzyme to produce digested extracellular matrix;   centrifuging the digested extracellular matrix to remove collagen fibril remnants and thus to produce a fibril-free supernatant;   centrifuging the fibril-free supernatant to isolate the solid materials; and   suspending the solid materials in a carrier,   thereby isolating nanovesicles from the extracellular matrix.   
     
     
         14 - 22 . (canceled) 
     
     
         23 . A method of altering cell proliferation, migration and/or differentiation on an extracellular matrix of interest, comprising
 introducing isolated nanovesicles derived from a second extracellular matrix into the extracellular matrix of interest;   thereby altering cell proliferation, migration and/or differentiation on the matrix.   
     
     
         24 - 34 . (canceled) 
     
     
         35 . A bioscaffold comprising nanovesicles derived from an extracellular matrix and a heterologous extracellular matrix. 
     
     
         36 . The bioscaffold of  claim 35 , wherein the nanovesicles are derived from a mammalian extracellular matrix. 
     
     
         37 . The bioscaffold of  claim 36 , wherein the mammalian extracellular matrix is a human or a porcine extracellular matrix. 
     
     
         38 . The bioscaffold of  claim 36 , wherein the extracellular matrix is from esophageal cells, urinary bladder cells, a small intestinal submucosa, or a dermis 
     
     
         39 . The bioscaffold of  claim 36 , wherein the heterologous extracellular matrix is derived from a different tissue than the nanovesicles. 
     
     
         40 . The bioscaffold of  claim 36 , wherein the heterologous extracellular matrix is from a different species than the nanovesicles. 
     
     
         41 . A medical device comprising the composition of  claim 1 . 
     
     
         42 . The medical device of  claim 41 , wherein the device is a surgical mesh, a stent, a pacemaker, a catheter, heart valve, biosensor, a drug delivery device, or an orthopedic implant. 
     
     
         43 . A method of isolating nanovesicles from an extracellular matrix, comprising
 a) incubating an extracellular matrix at a salt concentration of greater than about 0.1 M;   b) centrifuging the digested extracellular matrix to remove collagen fibril remnants, and isolating the supernatant;   c) centrifuging the supernatant to isolate the solid materials; and   d) suspending the solid materials in a carrier, thereby isolating nanovesicles from the extracellular matrix.   
     
     
         44 . (canceled) 
     
     
         45 . A method of isolating nanovesicles from an extracellular matrix, comprising:
 a) suspending the extracellular matrix in isotonic buffered saline solution to form a suspension; and   b) performing ultrafiltration to isolate particles from the suspension of between about 10 nm and about 10,000 nm in diameter;   thereby isolating nanovesicles from the extracellular matrix.   
     
     
         46 - 49 . (canceled) 
     
     
         50 . A method for reducing the proliferation of a tumor cell, increasing apoptosis of a tumor cell, and/or decreasing migration of a tumor cell, comprising
 contacting the tumor cell with an effective amount of the composition of  claim 3 , thereby reducing the proliferation of the tumor cell, increasing apoptosis of the tumor cell, and/or decreasing migration of the tumor cell.   
     
     
         51 - 54 . (canceled) 
     
     
         55 . A method of treating a subject with a tumor, comprising administering to the subject a therapeutically effective amount of the composition of  claim 3 , thereby treating the tumor in the subject. 
     
     
         56 - 57 . (canceled) 
     
     
         58 . A method of increasing M2 macrophages in a subject, comprising
 administering to a subject a therapeutically effect amount of the composition of  claim 1 , thereby increasing M2 macrophages in the subject.   
     
     
         59 - 60 . (canceled)