Controlled Shrinkage of Microfluidically Generated Microbubbles by Tuning Lipid Concentration

Abstract

Monodisperse microbubbles with diameters less than 10 μm are desirable in several ultrasound imaging and therapeutic delivery applications. However, conventional approaches to synthesize microbubbles, which are usually agitation-based, produce polydisperse bubbles that are less desirable because of their heterogeneous response when exposed to an ultrasound field. Microfluidics technology has the unique advantage of generating size-controlled monodisperse microbubbles, and it is now well established that the diameter of microfluidically made microbubbles can be tuned by varying the liquid flow rate, gas pressure, and dimensions of the microfluidic channel. It is also observed that once the microbubbles form, the bubbles shrink and eventually stabilize to a quasi-equilibrium diameter, and that the rate of stabilization is related to the lipid solution. However, how the lipid solution concentration affects the degree of bubble shrinkage, and the stable size of microbubbles, has not been thoroughly examined. Here, we investigate whether and how the lipid concentration affects the degree of microbubble shrinkage. Namely, we utilize a flow-focusing microfluidic geometry to generate monodisperse bubbles, and observe the effect of gas composition (2.5, 1.42, and 0.17 wt % octafluoropropane in nitrogen) and lipid concentration (1−16 mg/mL) on the degree of microbubble shrinkage. For the lipid system and gas utilized in these experiments, we observe a monotonic increase in the degree of microbubble shrinkage with decreasing lipid concentration, and no dependency on the gas composition. We hypothesize that the degree of shrinkage is related to lipid concentration by the self-assembly of lipids on the gas−liquid interface during bubble generation and subsequent lipid packing on the interface during shrinkage, which is arrested when a maximum packing density is achieved. We anticipate that this approach for creating and tuning the size of monodisperse microbubbles will find utility in biomedical applications, such as contrast-enhanced ultrasound imaging and ultrasound-triggered gene delivery.

Microfluidic nanobubbles: observations of a sudden contraction of microbubbles into nanobubbles

“…In a recently published paper, we found a linear relationship between the initial diameter, D i , of bubbles and their post-shrinkage final diameter, D f . 17 We also found that when the continuous lipid phase concentration is decreased, bubbles experience increased levels of shrinkage. 17 We suggest that this happens because when bubbles form in a solution of higher lipid concentration, more lipid molecules are initially adsorbed onto the gas–liquid interface in comparison with bubbles produced using a lower lipid concentration solution.…”

“…This means D f is approximately 6.7 times smaller than D i . Therefore, in this paper, we expand the previous research 17 by hypothesizing that decreasing the initial diameter D i of MBs and the concentration of the lipid solution would further increase the degree of shrinkage and lead to the formation of BNBs. We also hypothesize that the size of the resulting BNBs can be tuned by adjusting the initial diameter D i of MBs, and the lipid solution concentration.…”

“…Consequently, in solutions with higher lipid concentration, lipids at bubble interfaces jam earlier, and result in lower levels of shrinkage. 17 For example, when we utilize a lipid concentration of 1.10 mg mL −1 , and make MBs with D i ≈ 25.0 μm, the post-shrinkage final mean diameter D f ≈ 3.7 μm. This means D f is approximately 6.7 times smaller than D i .…”

“…In this paper, we utilize a microfluidic MB shrinkage method our group recently developed, 17 and extend the scope of the technology to produce BNBs. We previously showed that the degree of MB shrinkage in a microfluidic setting can be controlled by the solution's lipid concentration, and the MBs can shrink in diameter by as much as tenfold.…”

Microfluidic Methods for Generation of Submicron Droplets: A Review

“…In other works, which are destined to form micro- and nano-bubbles, similar strategy of solvent extraction can be adopted. The bubble size can further be controlled by the maximum packing density of lipids at the gas–liquid interface [ 105 ].…”