Acoustic Droplet Vaporization

 

BACKGROUND/OBJECTIVE


Acoustic droplet vaporization (ADV) is a process first proposed by the late Dr. Apfel to use ultrasound to phase-transition superheated liquid droplets into gas bubbles.  This was first demonstrated by Kripfgans et al. in 2000 and can be seen schematically and via ultrasound imaging in figure 1. 




Figure 1: (Top) Schematic showing the conversion of a superheated droplet (ADV droplet) into a gass bubble.  (Bottom)  An ultrasound image shows the conversion of superheated droplets (which have low echogenicity and thus are not seen) into highly echogenic gas bubbles.



These gas bubbles can be used for many applications such as occlusion therapy, drug delivery, and aberration correction, among other uses.  The formulation and properties of this droplets have been extensively investigated by our group in both in vitro and in vivo work.



DROPLET FORMULATION

There are three primary components to superheated droplet production: the dispersed medium, the continuous medium, and the surfactant.  The dispersed medium forms the core of the droplets, while the surfactant forms a shell to stabilize the droplet.  Perfluorocarbons and halocarbons are typically used for the dispersed medium while albumin or lipids are used for the surfactant.  The continuous medium, which is immiscible with the dispersed medium, is used to contain the droplets after production.  The droplets are formed via mechanical agitation.  The process yields droplets with less than 1% larger than 10 microns.  As a result the droplets are able to pass through capillary beds.  The large droplets can be eliminated using centrifugation (figure 2).



Figure 2: Droplet diameter distribution after being formed (blue) and after filtering via centrifugation (pink)



Additional components may be added to the droplets for a variety of applications.  A chemotherapy agent or other drug may be included to form a two-phase core.  This drug can be released locally by vaporizing the droplets at a target site.  Cell-specific ligands can also be embedded in the shell of the droplet so that they preferentially attach to certain sites within the body.



VAPORIZATION

Many studies have been performed on the threshold and efficiency of vaporization using different acoustic parameters.  It is currently hypothesized that there are two main methods for vaporizing droplets.  The first mechanism is vaporization within the core of the droplet resulting from the transmitted ultrasonic field interacting with the dispersed medium.  Vaporization via this mechanism seems to be supported from high-speed photography images taken by Kripfgans et al. (2004).  The second mechanism is vaporization due to inertial cavitation in or near the droplet.  During inertial cavitation a secondary shock-wave is emitted which causes vaporization of the droplet.  Support for multiple mechanisms is further supported when comparing the acoustic pressure thresholds that induce vaporization (figure 3).  Using short pulses Kripfgans et al. (2000) found the vaporization threshold to decrease with increasing frequency.  Giesecke and Hynynen (2003) on the other-hand found the vaporization threshold to increase with increasing frequency, similar to an inertial cavitation threshold curve.



Figure 3: Vaporization thresholds as measured by Kripfgans et al. (2000) and Giesecke et al. (2003).



DISCUSSION

Our group is currently investigating different droplet formulations for additional in vitro work.  A current focus is to transition from albumin coated droplets to lipid coated droplets.  This transition is meant to take advantage of the large amount of research that has already been done on targeting lipid particles with cell-specific receptors.  We are also investigating the mechanism question using a variety of approaches, including acoustic emissions, high-speed photography, and different core materials.  These studies are being performed to supplement previously mentioned in vivo work.



Acknowldgements

This work is supported in part by NIH Grant 5R01EB000281.



REFERENCES

Lo AH, Kripfgans OD, Carson PL, Rothman ED, Fowlkes JB.  Acoustic droplet vaporization threshold: effects of pulse duration and contrast agent.  IEEE Trans Ultrason Ferroelectr Freq Control. 2007 May;54(5):933-46.


Lo AH, Kripfgans OD, Carson PL, Fowlkes JB.  Spatial control of gas bubbles and their effects on acoustic fields.  Ultrasound Med Biol. 2006 Jan;32(1):95-106.


Kripfgans OD, Orifici CM, Carson PL, Ives KA, Eldevik OP, Fowlkes JB.  Acoustic droplet vaporization for temporal and spatial control of tissue occlusion: a kidney study.  IEEE Trans Ultrason Ferroelectr Freq Control. 2005 Jul;52(7):1101-10.


Kripfgans OD, Fabiilli ML, Carson PL, Fowlkes JB.  On the acoustic vaporization of micrometer-sized droplets.  J Acoust Soc Am. 2004 Jul;116(1):272-81.


Kripfgans OD, Fowlkes JB, Woydt M, Eldevik OP, Carson PL.  In vivo droplet vaporization for occlusion therapy and phase aberration correction.  IEEE Trans Ultrason Ferroelectr Freq Control. 2002 Jun;49(6):726-38.


Kripfgans OD, Fowlkes JB, Miller DL, Eldevik OP, Carson PL.  Acoustic droplet vaporization for therapeutic and diagnostic applications.  Ultrasound Med Biol. 2000 Sep;26(7):1177-89.


Apfel RE. Activatable Infusable Dispersions Containing Drops of a Superheated Liquid for Methods of Therapy and Diagnosis. US Patent 5,840,276. 1998


Giesecke T, Hynynen K.  Ultrasound-mediated cavitation thresholds of liquid perfluorocarbon droplets in vitro. Ultrasound Med Biol. 2003 Sep;29(9):1359-65.

 

General Concepts


Paul L. Carson, J. Brian Fowlkes, Oliver D. Kripfgans, Man (Maggie) Zhang, Kevin J. Haworth, Mario L. Fabiilli, Kimberly Ives, Andrea H. Lo, Catherine M. Orifici, M. Woydt, O. P. Eldevik

Department of Radiology, University of Michigan, Ann Arbor, MI 48109-0553 USA