Mechanism of Membrane Poration by Shock Wave Induced Nanobubble Collapse: A Molecular Dynamics Study

Adhikari, Upendra; Goliaei, Ardeshir; Berkowitz, Max L.

doi:10.1021/acs.jpcb.5b02218

Cited by 71 publications

(83 citation statements)

References 50 publications

(83 reference statements)

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“…4 A, B, and F). The critical pressure impulse above which sonoporation occurred, for example at 1 MHz, can be estimated as J ≈ τ thresh · t = 1.45 · 10 −2 Pa · s. This is consistent with recent studies investigating cell membrane perforation induced by ultrasound shock waves (approximately megapascal range) applied over nanosecond timescales, which determined critical pressure impulses on the order of 10 −3 -10 −1 Pa · s when bubbles are present (17,18). In addition to the short timescales, the shear stress is limited to a small area of contact with the adjacent cell.…”

Section: Resultssupporting

confidence: 88%

Biophysical insight into mechanisms of sonoporation

Helfield

Chen

Watkins

et al. 2016

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

201

177

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This study presents a unique approach to understanding the biophysical mechanisms of ultrasound-triggered cell membrane disruption (i.e., sonoporation). We report direct correlations between ultrasound-stimulated encapsulated microbubble oscillation physics and the resulting cellular membrane permeability by simultaneous microscopy of these two processes over their intrinsic physical timescales (microseconds for microbubble dynamics and seconds to minutes for local macromolecule uptake and cell membrane reorganization). We show that there exists a microbubble oscillation-induced shear-stress threshold, on the order of kilopascals, beyond which endothelial cellular membrane permeability increases. The shear-stress threshold exhibits an inverse squareroot relation to the number of oscillation cycles and an approximately linear dependence on ultrasound frequency from 0.5 to 2 MHz. Further, via real-time 3D confocal microscopy measurements, our data provide evidence that a sonoporation event directly results in the immediate generation of membrane pores through both apical and basal cell membrane layers that reseal along their lateral area (resealing time of ∼<2 min). Finally, we demonstrate the potential for sonoporation to indirectly initiate prolonged, intercellular gaps between adjacent, confluent cells (∼>30-60 min). This real-time microscopic approach has provided insight into both the physical, cavitation-based mechanisms of sonoporation and the biophysical, cell-membrane-based mechanisms by which microbubble acoustic behaviors cause acute and sustained enhancement of cellular and vascular permeability.ultrasound therapy | microbubble contrast agent | endothelial membrane | gene delivery | sonoporation D elivery vehicles for therapeutic nucleic acids (e.g., siRNA, mRNA, plasmids, oligonucleotides), including nanoparticles or viruses, are intended to increase the local effectiveness of the therapeutic within a target tissue while reducing off-target effects. A major barrier to the successful delivery of molecular therapeutics in this manner is the endothelial cell membrane. Viral vectors, although able to efficiently deliver genetic material to target cells via their intracellular trafficking machinery, may elicit specific inflammatory and nonspecific antiviral immune responses (1, 2). As an alternative, nonviral vectors--for example, localized needle injection of naked therapeutic nucleic acids or lipofection--use physical forces or compounds, respectively, to deliver a genetic payload into a cell and are generally less toxic and immunogenic than viral vectors (3). However, direct needle injection into the target poses challenges in achieving homogeneous tissue distribution of the payload (4), and clinical implementation is limited by the impractical requirements of repetitive needle injections into sites which may be difficult to access. Systemically injected liposomes face the endothelial barrier, are vulnerable to intravascular destruction and/or renal excretion (depending on size), and, when endocytosed b...

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Section: Resultssupporting

confidence: 88%

Biophysical insight into mechanisms of sonoporation

Helfield

Chen

Watkins

et al. 2016

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

201

177

View full text Add to dashboard Cite

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“…2. The mechanism of bubble collapse agrees well with many existing simulation studies 23–25, 30, 31, 55, 56, 60 . It can be inferred from Fig.…”

Section: Resultssupporting

confidence: 89%

“…To investigate these issues, we used reactive molecular dynamics simulation (reaxFF potential) 49, 50 to model the events occurring at the nanometer scale and sub-nanosecond time frame. While conventional molecular dynamics simulation can capture events like bubble ripening 51–53 and collapse 23, 24, 30, 31, 54–58 in homogenous fluids, the use of reactive molecular dynamics is essential to the assessment of PNN damage because of PNN’s heterogeneous morphology. The simulation results demonstrate the possible shock-induced damage mechanisms of HA due to bubble collapse.…”

Section: Introductionmentioning

confidence: 99%

Effect of Shock-Induced Cavitation Bubble Collapse on the damage in the Simulated Perineuronal Net of the Brain

Adnan

2017

Sci Rep

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The purpose of this study is to conduct modeling and simulation to understand the effect of shock-induced mechanical loading, in the form of cavitation bubble collapse, on damage to the brain’s perineuronal nets (PNNs). It is known that high-energy implosion due to cavitation collapse is responsible for corrosion or surface damage in many mechanical devices. In this case, cavitation refers to the bubble created by pressure drop. The presence of a similar damage mechanism in biophysical systems has long being suspected but not well-explored. In this paper, we use reactive molecular dynamics (MD) to simulate the scenario of a shock wave induced cavitation collapse within the perineuronal net (PNN), which is the near-neuron domain of a brain’s extracellular matrix (ECM). Our model is focused on the damage in hyaluronan (HA), which is the main structural component of PNN. We have investigated the roles of cavitation bubble location, shockwave intensity and the size of a cavitation bubble on the structural evolution of PNN. Simulation results show that the localized supersonic water hammer created by an asymmetrical bubble collapse may break the hyaluronan. As such, the current study advances current knowledge and understanding of the connection between PNN damage and neurodegenerative disorders.

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“…The final large-sized unit cell (in some cases containing a bubble, in some without a bubble, to be able to study the effect of a bubble collapse on the integrity of the TJ by comparing results from simulations with and without the bubble collapse) was again equilibrated for another 10 ns and after this equilibration period our production runs with shock waves impinging on the system were performed. Shock waves were generated by using the momentum mirror approach which was successfully applied in previous simulation work where shock waves were created [26][27][28][34][35][36] .…”

Section: Resultsmentioning

confidence: 99%

Opening of the Blood-Brain Barrier Tight Junction Due to Shock Wave Induced Bubble Collapse: A Molecular Dynamics Simulation Study

Goliaei

Adhikari

Berkowitz

2015

ACS Chem. Neurosci.

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Passage of a shock wave across living organisms may produce bubbles in the blood vessels and capillaries. It was suggested that collapse of these bubbles imposed by an impinging shock wave can be responsible for the damage or even destruction of the blood-brain barrier. To check this possibility, we performed molecular dynamics computer simulations on systems that contained a model of tight junction from the blood-brain barrier. In our model, we represent the tight junction by two pairs of interacting proteins, claudin-15. Some of the simulations were done in the absence of a nanobubble, some in its presence. Our simulations show that when no bubble is present in the system, no damage to tight junction is observed when the shock wave propagates across it. In the presence of a nanobubble, even when the impulse of the shock wave is relatively low, the implosion of the bubble causes serious damage to our model tight junction.

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Mechanism of Membrane Poration by Shock Wave Induced Nanobubble Collapse: A Molecular Dynamics Study

Cited by 71 publications

References 50 publications

Biophysical insight into mechanisms of sonoporation

Biophysical insight into mechanisms of sonoporation

Effect of Shock-Induced Cavitation Bubble Collapse on the damage in the Simulated Perineuronal Net of the Brain

Opening of the Blood-Brain Barrier Tight Junction Due to Shock Wave Induced Bubble Collapse: A Molecular Dynamics Simulation Study

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