Systems, methods, and devices for production of gas-filled microbubbles

Abstract

Systems, methods, and devices are described to synthesize gas-filled microbubbles using a continuous flow chamber with a reaction volume and a sonicator positioned therein, by flowing a lipid solution at a first flow rate and gas at a first pressure into the reaction volume while ultrasonically agitating an interface between the lipid solution and the gas in the reaction volume using the sonicator member to generate a solution of gas-filled microbubbles, which solution can be concentrated to obtain a concentrated solution of microbubbles containing at least 23% of the core gas by volume.

1 . A method for generating gas-filled microbubbles, comprising:
 flowing a lipid solution at a first flow rate into a reaction volume of a continuous flow chamber, the reaction volume having an end of a sonicator member located therein;   flowing gas at a first pressure into the reaction volume at a same time as the flowing of a lipid solution;   ultrasonically agitating an interface between the lipid solution and the gas in the reaction volume using said sonicator member so as to generate a solution of gas-filled microbubbles; and   during the ultrasonically agitating, adjusting at least the first pressure based on a location of the interface in the reaction volume with respect to the end of the sonicator member,   ensuring the lipid solution ultrasonically agitated is saturated with a core gas; and   concentrating the solution of gas-filled microbubbles to obtain a concentrated solution of microbubbles containing at least 23% of the core gas by volume.   
     
     
         2 . The method of  claim 1 , wherein the concentrating step comprises sorting the generated gas-filled microbubbles responsively to size. 
     
     
         3 . The method of  claim 1 , wherein the concentrating step comprises sorting the generated gas-filled microbubbles responsively to size using differential flotation. 
     
     
         4 . The method of  claim 1 , wherein said lipid solution further comprises a calcium ion source. 
     
     
         5 . The method of  claim 1 , wherein the lipid solution is maintained at approximately 10 degrees centigrade during the step of ultrasonically agitating the interface between the lipid solution and the gas in the reaction volume using said sonicator. 
     
     
         6 . The method of  claim 1 , wherein the concentrating step comprises concentrating the generated gas-filled microbubbles to form a cake. 
     
     
         7 . The method of  claim 6 , wherein said cake loses less than 15% of the core gas by volume within a storage period of 6 days. 
     
     
         8 . The method of  claim 1 , wherein the gas is an elemental gas. 
     
     
         9 . The method of  claim 1 , wherein the gas is a composition gas. 
     
     
         10 . The method of  claim 1 , wherein said lipid solution includes one of DPPC and DSPC. 
     
     
         11 . The method of  claim 1 , wherein said lipid solution includes a phospholipid and an emulsifier. 
     
     
         12 . The method of  claim 1 , wherein said phospholipid and emulsifier are combined in a molar ratio of 9:1. 
     
     
         13 . The method of  claim 1 , wherein the gas is oxygen. 
     
     
         14 . The method of  claim 1 , further comprising storing the concentrated gas-filled microbubble solution in a container. 
     
     
         15 . The method of  claim 1 , wherein the step of concentrating the solution of gas-filled microbubbles comprises removing at least a portion of a lipid mixture from the gas-filled microbubble solution. 
     
     
         16 . The method of  claim 15 , wherein the step of concentrating the solution of gas-filled microbubbles comprises removing an infernatant from the gas-filled microbubble solution. 
     
     
         17 . The method of  claim 14 , further comprising the step of introducing a storage gas into the container. 
     
     
         18 . The method of  claim 17 , wherein the storage gas comprises oxygen. 
     
     
         19 . The method of  claim 14 , wherein the container of gas-filled microbubble solution is cooled below an ambient temperature during a storage period. 
     
     
         20 . The method of  claim 14 , wherein the container of gas-filled microbubble solution is sealed from an atmospheric gas during a storage period.