Microvesicle Size Control via Gas Solubility Mixture
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Solution Overview
Problem
Conventional methods for preparing size-controlled gas-filled microvesicles result in high polydispersity index (PDI) and foaming phenomena, which are undesirable for ultrasound imaging and therapeutic applications, especially when using gases with low aqueous solubility.
Innovation Solution
A method involving a mixture of gases with low and high water solubility, where the volume percentage of the low solubility gas is 15% or lower, and the highly soluble gas is 60% or higher in the final stabilized microvesicles, is used in a microfluidic flow-focusing process to stabilize microvesicles rapidly and reduce PDI and foaming.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional methods are used to prepare gas-filled microvesicles, then the preparation process is simple, but the polydispersity index (PDI) is high and foaming phenomena occur
Solution Approach 1:
The patent applies parameter changes by controlling the gas composition (using mixtures of perfluorocarbon gas with other gases), temperature (maintaining 20-40°C during preparation and storage), and flow rates in the microfluidic device to achieve monodisperse microvesicles with PDI < 10%, resolving the contradiction between manufacturing precision and process complexity
Solution Approach 2:
The patent uses an intermediary approach by introducing a stabilizing envelope comprising phospholipids and proteins that form a protective layer around the gas-filled microvesicles, preventing coalescence and foaming while maintaining size control, thus improving manufacturing precision without excessive complexity
2Duration of action of stationary object
If gases with low aqueous solubility are used to improve persistence, then the persistence of microvesicles is enhanced, but foaming phenomena and PDI increase occur
Solution Approach 1:
The patent applies local quality by creating a stabilizing envelope with specific composition (phospholipids and proteins) that localizes at the gas-liquid interface of each microvesicle, providing localized stabilization that prevents foaming while allowing the use of low-solubility gases for enhanced persistence
Solution Approach 2:
The patent uses composite materials by combining perfluorocarbon gas (for persistence) with other gases, and combining phospholipids with proteins in the stabilizing envelope, creating a composite system that achieves both long persistence and prevents foaming phenomena
3Stability of the object's composition
If temperature is increased to limit coalescence, then coalescence is reduced, but microvesicle stability decreases over time
Solution Approach 1:
The patent applies preliminary action by forming a complete stabilizing envelope comprising both phospholipids and proteins around the microvesicles during the preparation process itself, rather than relying on post-formation stabilization. This preliminary protective layer prevents both coalescence during formation and maintains stability over time
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach significantly reduces PDI and foaming, stabilizing microvesicles quickly, ensuring consistent size distribution and preventing the formation of large microvesicles, thus enhancing their suitability for imaging and therapeutic applications.
Implementation Method 1
a flow of a gas component is focused by a flow of a liquid component through a narrow orifice
Implementation Method 2
the liquid component comprises an envelope forming material (typically surfactants such as lipids, including phospholipids and/or fatty acids), which entraps the gaseous component to form the desired gas-filled microvesicles, which are stabilized against coalescence and dissolution by said envelope forming material
Implementation Method 3
aqueous suspensions of gas-filled microvesicles where the bubbles of gas are bounded, at the gas/liquid interface, by a very thin envelope (film) involving a stabilizing amphiphilic material (typically a phospholipid) disposed at the gas to liquid interface
Implementation Method 4
A method involving a mixture of gases with low and high water solubility, where the volume percentage of the low solubility gas is 15% or lower, and the highly soluble gas is 60% or higher in the final stabilized microvesicles
Data Source
Figure 1
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AI summary
A method for preparing a suspension of "size-controlled" gas-filled microvesicles by microfluidic manufacturing techniques, which comprises using a gaseous flow comprising a first gas having high solubility in water and a second gas having low 5 solubility in water.