Vascular endothelial growth factor (VEGF) is a potent agonist of angiogenesis that induces proliferation and differentiation of endothelial progenitor cells (EPCs) after vascular injury. Previous studies have suggested that stromal cell-derived factor 1-alpha (SDF-1α) and VEGF have a synergistic effect on vascular stenosis. The aim of the present study was to investigate whether VEGF and SDF-1α act synergistically in EPCs and vascular smooth muscle cells (VSMCs). In this study, EPCs were isolated from rat bone marrow and their morphology and function were studied. Subsequently, VEGF was delivered into EPCs using an adenoviral vector. Tube formation, migration, proliferation, and apoptosis of VEGF-overexpressing EPCs was analyzed. Then, EPCs were co-cultured with VSMCs in the presence or absence of SDF-1α, the migration, proliferation, apoptosis, and differentiation capacity of EPCs and VSMCs were analyzed respectively. The isolated EPCs showed typical morphological features, phagocytic capacity, and expressed surface proteins. While stable expression of VEGF remarkably enhanced tube formation, migration, and proliferation capacity of EPCs, apoptosis was decreased. Moreover, the proliferation, migration, and differentiation capacity of EPCs in the co-cultured model was enhanced in the presence of SDF-1α, and apoptosis was decreased. However, these effects were reversed in VSMCs. Therefore, our results showed that VEGF and SDF-1α synergistically increased the migration, differentiation, and proliferation capabilities of EPCs, but not VSMCs. This study suggests a promising strategy to prevent vascular stenosis.

Paclitaxel (PTX) has been recognized as a promising drug for intervention of vascular reconstructions. However, it is still difficult to achieve local drug delivery in a spatio-temporally controllable manner under real-time image guidance. Here, we introduce an ultrasound (US) triggered image-guided drug delivery approach to inhibit vascular reconstruction via paclitaxel (PTX)-loaded microbubbles (PLM) in a rabbit iliac balloon injury model. PLM was prepared through encapsulating PTX in the shell of lipid microbubbles via film hydration and mechanical vibration technique. Our results showed PLM could effectively deliver PTX when exposed to US irradiation and result in significantly lower viability of vascular smooth muscle cells. Ultrasonographic examinations revealed the US signals from PLM in the iliac artery were greatly increased after intravenous administration of PLM, making it possible to identify the restenosis regions of iliac artery. The in vivo anti-restenosis experiments with PLM and US greatly inhibited neointimal hyperplasia at the injured site, showing an increased lumen area and reduced the ratio of intima area and the media area (I/M ratio). No obvious functional damages to liver and kidney were observed for those animals. Our study provided a promising approach to realize US triggered image-guided PTX delivery for therapeutic applications against iliac restenosis.

Ultrasound technology has been extensively used as one of the efficient and economic methodology to achieve the desired outcomes in many applications by harnessing the physico-chemical effects of acoustic cavitation. However, the cavitation-associated effects, primarily determined by the oscillatory dynamics of cavitation bubbles, are considerably complex and still remain poorly understood. The main objective of this study was to perform a numerical analysis of the acoustic cavitation (i.e., the cavitation dynamics, the resultant temperature, pressure and chemical yields within collapsing bubbles), particularly focusing on the influence of the interactions between bubbles. A comprehensive model was developed to simulate the acoustic cavitation dynamics via combining the influences of mass transfer, heat conduction and chemical reactions as well as the interaction effects between bubbles. The results demonstrated that only the large bubble exerts a greater impact on the small one in a two-bubble system. Specifically, within parameter ranges covered this study, there are noticeable decreases in the expansion ratio of the small bubble, the resultant temperature, pressure and molar yields of free radicals, hence weakening the cavitation intensity and cavitation- associated physico-chemical effects. Moreover, the influences of the interactions between bubbles were further assessed quantitatively under various parameters, such as the ultrasound amplitude P_A and frequency f, the distance between bubbles d₀, the initial radius of the large bubble R₂₀, as well as the liquid properties (e.g., surface tension σ and viscosity μ). It was found that the suppression effect can be amplified when subjected to ultrasound with an increased P_A and/or a decreased f, probably due to a stronger cavitation intensity under this condition. Additionally, the suppression effect is also enhanced with a decrease in d₀, σ and μ, but with R₂₀ increasing. This study can contribute to deepening knowledge about acoustic cavitation and the resultant physical and/or chemical effects, potentially further facilitating the ultrasound-assisted various applications involving acoustic cavitation.

The cavitation dynamics of an air-vapor mixture bubble with ultrasonic excitation can be greatly affected by the equation of state (EOS) for the interior gases. To simulate the cavitation dynamics, the Gilmore-Akulichev equation was coupled with the Peng-Robinson (PR) EOS or the Van der Waals (vdW) EOS. In this study, the thermodynamic properties of air and water vapor predicted by the PR and vdW EOS were first compared, and the results showed that the PR EOS gives a more accurate estimation of the gases within the bubble due to the less deviation from the experimental values. Moreover, the acoustic cavitation characteristics predicted by the Gilmore-PR model were compared to the Gilmore-vdW model, including the bubble collapse strength, the temperature, pressure and number of water molecules within the bubble. The results indicated that a stronger bubble collapse was predicted by the Gilmore-PR model rather than the Gilmore-vdW model, with higher temperature and pressure, as well as more water molecules within the collapsing bubble. More importantly, it was found that the differences between both models increase at higher ultrasound amplitudes or lower ultrasound frequencies while decreasing as the initial bubble radius and the liquid parameters (e.g., surface tension, viscosity and temperature of the surrounding liquid) increase. This study might offer important insights into the effects of the EOS for interior gases on the cavitation bubble dynamics and the resultant acoustic cavitation-associated effects, contributing to further optimization of its applications in sonochemistry and biomedicine.

A high incidence of restenosis has been reported at the site of inflammation following angioplasty and stent implantation. The anti-proliferative drug paclitaxel (PTX) could help to reduce inflammation and restenosis; however, it has poor water solubility and serious adverse side effects at high doses. Given the presence of metabolic acidosis at the site of inflammation, we hypothesized that nanoparticles that are responsive to low pH could precisely release the loaded drug at the target site. We successfully constructed pH-responsive poly(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles loaded with PTX and NaHCO₃ as a pH-sensitive therapeutic agent (PTX-NaHCO₃-PLGA NPs). The NPs exhibited remarkable pH sensitivity and a good safety profile both in vitro in rat vascular smooth muscle cells and in vivo in Sprague Dawley rats after tail vein injection. In the rat model, the PTX-NaHCO₃-PLGA NPs treatment group showed suppressed intimal proliferation following balloon-induced carotid artery injury compared with that of the saline-treated control. Overall, these results demonstrate that our newly developed pH-responsive nanodrug delivery platform has the potential to effectively inhibit restenosis.

The cavitation dynamics of a two-bubble system in viscoelastic media excited by dual-frequency ultrasound is studied numerically with a focus on the effects of inter-bubble interactions. Compared to the isolated bubble cases, the enhancement or suppression effects can be exerted on the amplitude and nonlinearity of the bubble oscillations to different degrees. Moreover, the interaction effects are found to be highly sensitive to multiple paramount parameters related to the two-bubble system, the dual-frequency ultrasound and the medium viscoelasticity. Specifically, the larger bubble of a two-bubble system shows a stronger effect on the smaller one, and this effect becomes more pronounced when the larger bubble undergoes harmonic and/or subharmonic resonances as well as the two bubbles get closer (e.g., d₀ < 100 μm). For the influences of the dual-frequency excitation, the results show that the bubbles can achieve enhanced harmonic and/or subharmonic oscillations as the frequency combinations with small frequency differences (e.g., Δf < 0.2 MHz) close to the corresponding resonance frequencies of bubbles, and the interaction effects are consequently intensified. Similarly, the bubble oscillations and the interaction effects can also be enhanced as the acoustic pressure amplitude of each frequency component is equal and the pressure amplitude p_A increases. Above a pressure threshold (p_A = 215 kPa), a larger bubble undergoes period 2 (P2) oscillations, which can force a smaller bubble to change its oscillation pattern from period 1 (P1) into P2 oscillations. In addition, it is found that the medium viscosity dampens the bubble oscillations while the medium elasticity affects the bubble resonances, accordingly exhibiting stronger interaction effects at smaller viscosities (e.g., μ < 4 mPa·s) or certain elasticities (approximately G = 70-120 kPa, G = 160-200 kPa and G = 640-780 kPa) at which the bubble resonances occur. The study can contribute to a better understanding of the complex dynamic behaviors of interacting cavitation bubbles in viscoelastic tissues for high efficient cavitation-mediated biomedical applications using dual-frequency ultrasound.