Systems, Methods, and Devices for Production of Gas-Filled Microbubbles

Abstract

Gas-filled microbubbles can be synthesized using a continuous flow chamber and a sonicator. The resulting microbubble solution can be size-sorted for a particular application, such as injection into a patient for gas delivery thereto. The microbubble solution may be concentrated to have greater than 50% volume gas while maintaining microbubble sizes below 10 μm. Control of the microbubble generation process can yield highly stable microbubbles. The microbubbles may retain over half of their original gas payload for over three weeks while exhibiting minimal change in microbubble size. The systems, methods, and devices described herein thus allow for continuous or batch-wise continuous production of gas-filled microbubbles that readily release their gas payload when introduced into an under-saturated or de-saturated solution.

1 . A method for generating 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 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 to a level between 50% and 90%, inclusive, during the ultrasonically agitating.   
     
     
         2 . The method of  claim 1 , further comprising, after the ultrasonically agitating, sorting the generated microbubbles responsively to size. 
     
     
         3 . The method of  claim 1 , further comprising, after the ultrasonically agitating, sorting the generated microbubbles responsively to size using differential flotation. 
     
     
         4 . The method of  claim 3 , wherein the sorting includes:
 filling a container with the generated microbubbles; and   after the filling, creating isolated compartments in the container, each compartment containing a different size population of the generated microbubbles.   
     
     
         5 . The method of  claim 4 , wherein the creating isolated compartments occurs a predetermined time after the filling. 
     
     
         6 . The method of  claim 4 , wherein the container is a flexible bag and the creating includes clamping different portions of the flexible bag. 
     
     
         7 . The method of  claim 1 , further comprising, after the ultrasonically agitating, concentrating the generated microbubbles to form a cake. 
     
     
         8 . The method of  claim 7 , wherein said cake has a concentration of at least 50% volume gas. 
     
     
         9 . The method of  claim 7 , wherein said concentrating includes passing the microbubble solution through a dialyzer so as to remove water therefrom. 
     
     
         10 . The method of  claim 7 , wherein said concentrating includes passing the microbubble solution through a dessicant so as to remove water therefrom. 
     
     
         11 . The method of  claim 7 , wherein said concentrating includes passing the microbubble solution through an absorbent so as to remove excess lipids therefrom. 
     
     
         12 . The method of  claim 1 , wherein said lipid solution includes one of DPPC and DSPC. 
     
     
         13 . The method of  claim 1 , wherein said lipid solution includes a phospholipid and an emulsifier. 
     
     
         14 . The method of claim  31 , wherein said phospholipid and emulsifier are combined in a molar ration of 9:1. 
     
     
         15 . The method of  claim 1 , wherein the gas is oxygen. 
     
     
         16 . The method of  claim 1 , further comprising storing the generated microbubble solution in a container. 
     
     
         17 . A method of generating microbubbles, comprising: ultrasonically agitating a shell precursor in the presence of gas, collapsing microbubbles a sufficient degree to strengthen the shells of the microbubbles, the collapsing including regulating a saturation of the precursor to remain in a predefined range during the agitating. 
     
     
         18 . The method of  claim 17 , wherein the ultrasonically agitating includes flowing the shell precursor into a reaction vessel, the method further comprising flowing microbubbles of a selected size range from the reaction vessel to a container, extracting microbubbles of a further selected size range from the container after a settling time interval, compacting the microbubbles extracted in the extracting by one of removing water or shell precursor that remains unformed into microbubbles from between the microbubbles. 
     
     
         19 . The method of  claim 18 , wherein the removing includes centrifuging the extracted microbubbles. 
     
     
         20 . The method of  claim 18 , wherein the removing includes dialyzing the extracted microbubbles.