Precision Manufacture of Phase-Change Perfluorocarbon Droplets Using Microfluidics

Martz, Thomas D.; Sheeran, Paul S.; Bardin, David; Lee, Abraham P.; Dayton, Paul A.

doi:10.1016/j.ultrasmedbio.2011.08.012

Cited by 51 publications

(51 citation statements)

References 29 publications

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“…Couture and colleagues demonstrated the use of microfluidics to create complex monodisperse PCCAs carrying fluorescent payloads [108]. Recent studies by Martz and colleagues [120] and Bardin and colleagues [121] have used microfluidics to generate monodisperse, microscale DDFP droplets that remain monodisperse for several weeks in storage. When vaporized by acoustic pressure, the droplets exhibit a highly uniform response – confirming the primary benefit of the production method.…”

Section: Discussionmentioning

confidence: 99%

Phase-Change Contrast Agents for Imaging and Therapy

Sheeran¹,

Dayton²

2012

CPD

221

192

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Phase-change contrast agents (PCCAs) for ultrasound-based applications have resulted in novel ways of approaching diagnostic and therapeutic techniques beyond what is possible with microbubble contrast agents and liquid emulsions. When subjected to sufficient pressures delivered by an ultrasound transducer, stabilized droplets undergo a phase-transition to the gaseous state and a volumetric expansion occurs. This phenomenon, termed acoustic droplet vaporization, has been proposed as a means to address a number of in vivo applications at the microscale and nanoscale. In this review, the history of PCCAs, physical mechanisms involved, and proposed applications are discussed with a summary of studies demonstrated in vivo. Factors that influence the design of PCCAs are discussed, as well as the need for future studies to characterize potential bioeffects for administration in humans and optimization of ultrasound parameters.

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Section: Discussionmentioning

confidence: 99%

Phase-Change Contrast Agents for Imaging and Therapy

Sheeran¹,

Dayton²

2012

CPD

221

192

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“…The required threshold has been found to decrease with increasing frequency, whereas the cavitation threshold in liquids is expected to increase with increasing frequency (16). There is also an unexplained decrease of the threshold pressure with increasing size of the droplets (20,21). Finally, ultrahigh-speed imaging has allowed for the construction of spatial and temporal nucleation maps (22).…”

mentioning

confidence: 99%

Acoustic droplet vaporization is initiated by superharmonic focusing

Shpak

Verweij

Vos

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

173

148

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Acoustically sensitive emulsion droplets composed of a liquid perfluorocarbon have the potential to be a highly efficient system for local drug delivery, embolotherapy, or for tumor imaging. The physical mechanisms underlying the acoustic activation of these phase-change emulsions into a bubbly dispersion, termed acoustic droplet vaporization, have not been well understood. The droplets have a very high activation threshold; its frequency dependence does not comply with homogeneous nucleation theory and localized nucleation spots have been observed. Here we show that acoustic droplet vaporization is initiated by a combination of two phenomena: highly nonlinear distortion of the acoustic wave before it hits the droplet and focusing of the distorted wave by the droplet itself. At high excitation pressures, nonlinear distortion causes significant superharmonics with wavelengths of the order of the droplet size. These superharmonics strongly contribute to the focusing effect; therefore, the proposed mechanism also explains the observed pressure thresholding effect. Our interpretation is validated with experimental data captured with an ultrahigh-speed camera on the positions of the nucleation spots, where we find excellent agreement with the theoretical prediction. Moreover, the presented mechanism explains the hitherto counterintuitive dependence of the nucleation threshold on the ultrasound frequency. The physical insight allows for the optimization of acoustic droplet vaporization for therapeutic applications, in particular with respect to the acoustic pressures required for activation, thereby minimizing the negative bioeffects associated with the use of high-intensity ultrasound.

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“…The droplets formed using microfluidics have a narrower size distribution. The vaporization threshold and vaporization efficiency are a function of droplet diameter [5], [7], [10], [11], and narrower size distributions may provide more control over droplet vaporization.…”

Section: Discussionmentioning

confidence: 99%

“…There is a potential to optimize the droplet size. Both Martz et al [11] and Fabiilli et al [13] have demonstrated that a higher flow rate through a microfluidic chip results in smaller droplet diameters. Exploration of alternate flow parameters in the microfluidic chip, or modification of the channel sizes in the chips, may enable the production of smaller droplets that would not embolize the capillaries.…”

Section: Discussionmentioning

confidence: 99%

Dissolved oxygen scavenging by acoustic droplet vaporization using intravascular ultrasound

Haworth¹,

Goldstein²,

Mercado-Shekhar³

et al. 2017

2017 IEEE International Ultrasonics Symposium (IUS)

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Modification of dissolved gas content by acoustic droplet vaporization (ADV) has been proposed for several therapeutic applications. Reducing dissolved oxygen (DO) during reperfusion of ischemic tissue during coronary interventions could inhibit reactive oxygen species production and rescue myocardium. The objective of this study was to determine whether intravascular ultrasound (IVUS) can trigger ADV and reduce DO. Perfluoropentane emulsions were created using high-speed shaking and microfluidic manufacturing. High-speed shaking resulted in a polydisperse droplet distribution ranging from less than 1 micron to greater than 16 microns in diameter. Microfluidic manufacturing produced a narrower size range of droplets with diameters between 8.0 microns and 9.6 microns. The DO content of the fluids was measured before and after ADV triggered by IVUS exposure. Duplex B-mode and passive cavitation imaging was performed to assess nucleation of ADV. An increase in echogenicity indicative of ADV was observed after exposure with a clinical IVUS system. In a flow phantom, a 20% decrease in DO was measured distal to the IVUS transducer when droplets, formed via high-speed shaking, were infused. In a static fluid system, the DO content was reduced by 11% when droplets manufactured with a microfluidic chip were exposed to IVUS. These results demonstrate that a reduction of DO by ADV is feasible using a clinical IVUS system. Future studies will assess the potential therapeutic efficacy of IVUS-nucleated ADV and methods to increase the magnitude of DO scavenging.

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Precision Manufacture of Phase-Change Perfluorocarbon Droplets Using Microfluidics

Cited by 51 publications

References 29 publications

Phase-Change Contrast Agents for Imaging and Therapy

Phase-Change Contrast Agents for Imaging and Therapy

Acoustic droplet vaporization is initiated by superharmonic focusing

Dissolved oxygen scavenging by acoustic droplet vaporization using intravascular ultrasound

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