Fluid Viscosity Affects the Fragmentation and Inertial Cavitation Threshold of Lipid-Encapsulated Microbubbles

Helfield, Brandon; Black, John J.; Qin, Bin; Pacella, John J.; Chen, Xucai; Villanueva, Flordeliza S.

doi:10.1016/j.ultrasmedbio.2015.10.023

Cited by 53 publications

(40 citation statements)

References 64 publications

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“…The efficacy of UMGD in vivo may depend on additional factors that are not captured in the end-point cavitation study. One consideration that also affects microbubble behavior is the viscosity of the fluid as proposed by Helfield et al and others [17,36–39]. Our in vitro studies were performed in water, which is a less viscid fluid than that of blood.…”

Section: Discussionmentioning

confidence: 99%

Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals

Tran¹,

Harrang²,

Song³

et al. 2018

Journal of Controlled Release

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While ultrasound-mediated gene delivery (UMGD) has been accomplished using high peak negative pressures (PNPs) of 2 MPa or above, emerging research showed that this may not be a requirement for microbubble (MB) cavitation. Thus, we investigated lower-pressure conditions close to the MB inertial cavitation threshold and focused towards further increasing gene transfer efficiency and reducing associated cell damage. We created a matrix of 21 conditions (n = 3/cond.) to test in HEK293T cells using pulse durations spanning 18 μs–36 ms and PNPs spanning 0.5–2.5 MPa. Longer pulse duration conditions yielded significant increase in transgene expression relative to sham with local maxima between 20 J and 100 J energy curves. A similar set of 17 conditions (n = 4/cond.) was tested in mice using pulse durations spanning 18 μs–22 ms and PNPs spanning 0.5–2.5 MPa. We observed local maxima located between 1 J and 10 J energy curves in treated mice. Of these, several low pressure conditions showed a decrease in ALT and AST levels while maintaining better or comparable expression to our positive control, indicating a clear benefit to allow for effective transfection with minimized tissue damage versus the high-intensity control. Our data indicates that it is possible to eliminate the requirement of high PNPs by prolonging pulse durations for effective UMGD in vitro and in vivo, circumventing the peak power density limitations imposed by piezo-materials used in US transducers. Overall, these results demonstrate the advancement of UMGD technology for achieving efficient gene transfer and potential scalability to larger animal models and human application.

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Section: Discussionmentioning

confidence: 99%

Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals

Tran¹,

Harrang²,

Song³

et al. 2018

Journal of Controlled Release

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“…The effect of separation steps such as centrifugation or dialysis on the physical properties of the particles also needs to be studied further. In addition, the effect of blood viscosity on the threshold of stable cavitation nucleation from µtELIP should be assessed (Helfield et al 2016). …”

Section: Discussionmentioning

confidence: 99%

Microfluidic manufacture of rt-PA -loaded echogenic liposomes

Kandadai

Mukherjee

Shekhar

et al. 2016

Biomed Microdevices

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Echogenic liposomes (ELIP), loaded with recombinant tissue-type plasminogen activator (rt-PA) and microbubbles that act as cavitation nuclei, are under development for ultrasound-mediated thrombolysis. Conventional manufacturing techniques produce a polydisperse rt-PA-loaded ELIP population with only a small percentage of particles containing microbubbles. Further, a polydisperse population of rt-PA-loaded ELIP has a broadband frequency response with complex bubble dynamics when exposed to pulsed ultrasound. In this work, a microfluidic flow-focusing device was used to generate monodisperse rt-PA-loaded ELIP (µtELIP) loaded with a perfluorocarbon gas. The rt-PA associated with the µtELIP was encapsulated within the lipid shell as well as intercalated within the lipid shell. The µtELIP had a mean diameter of 5 µm, a resonance frequency of 2.2 MHz, and were found to be stable for at least 30 min in 0.5%bovine serum albumin. Additionally, 35 % of µtELIP particles were estimated to contain microbubbles, an order of magnitude higher than that reported previously for batch-produced rt-PA-loaded ELIP. These findings emphasize the advantages offered by microfluidic techniques for improving the encapsulation efficiency of both rt-PA and perflurocarbon microbubbles within echogenic liposomes.

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“…However, very little is known on how the various tissue types influence the agents as most experiments are simply performed in aqueous fluids. As mentioned before, both the presence of a boundary and the viscosity of the fluid 142 are known to have a major effect on the microbubble behavior; therefore, the viscoelastic properties of human tissues can be expected to change the response of the agents to ultrasound in terms of activation threshold, as well as its resonance frequency and amplitude response. This aspect, often forgotten, is nonetheless a crucial part of the intricate problem of bubble-cell interactions.…”

Section: Agent Behavior and Tissue Typementioning

confidence: 99%

In vitro methods to study bubble-cell interactions: Fundamentals and therapeutic applications

et al. 2016

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Besides their use as contrast agents for ultrasound imaging, microbubbles are increasingly studied for a wide range of therapeutic applications. In particular, their ability to enhance the uptake of drugs through the permeabilization of tissues and cell membranes shows great promise. In order to fully understand the numerous paths by which bubbles can interact with cells and the even larger number of possible biological responses from the cells, thorough and extensive work is necessary. In this review, we consider the range of experimental techniques implemented in in vitro studies with the aim of elucidating these microbubble-cell interactions. First of all, the variety of cell types and cell models available are discussed, emphasizing the need for more and more complex models replicating in vivo conditions together with experimental challenges associated with this increased complexity. Second, the different types of stabilized microbubbles and more recently developed droplets and particles are presented, followed by their acoustic or optical excitation methods. Finally, the techniques exploited to study the microbubble-cell interactions are reviewed. These techniques operate over a wide range of timescales, or even off-line, revealing particular aspects or subsequent effects of these interactions. Therefore, knowledge obtained from several techniques must be combined to elucidate the underlying processes. V C 2016 AIP Publishing LLC.

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Fluid Viscosity Affects the Fragmentation and Inertial Cavitation Threshold of Lipid-Encapsulated Microbubbles

Cited by 53 publications

References 64 publications

Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals

Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals

Microfluidic manufacture of rt-PA -loaded echogenic liposomes

In vitro methods to study bubble-cell interactions: Fundamentals and therapeutic applications

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