Sonodynamic Therapy: Advances and Challenges in Clinical Translation

Sonodynamic therapy (SDT) consists of the synergetic interaction between ultrasound and a chemical agent. In SDT, the cytotoxicity is triggered by ultrasonic stimuli, notably through cavitation. The unique features of SDT are relevant in the clinical context more than ever: the need for efficacy, accuracy, and safety while being noninvasive and preserving the patient's quality of life. However, despite the promising results of this technique, only a few clinical reports describe the use of SDT. The objective of this article is to provide an extensive overview of the clinical and preclinical research conducted in vivo on SDT, to identify the limitations, and to detail the developed strategies to overcome them.     

体内超声吸脂术236例临床应用体会

目的：探索体内超声吸脂术的临床效果，并与传统负压吸脂术比较。方法：在肿胀麻醉下，采用体内超声乳化吸脂方法、对236例不同部位脂肪堆积受术者，进行人体曲线美的塑造。结果：经过6～12个月随访、效果良好、易被受术者接受。结论：该术式利用超声波“空穴效应”及相关效应的吸脂原理，选择性地破碎脂肪细胞，而对周围血管、神经、淋巴管等组织无不良影响，与传统负压吸脂术比较，操作简便省力、安全、精细。     

Fragmentation process of current laser lithotriptors

Background and Objective: Flashlamp pumped dye (FPDL), Q-switched Nd:YAG, and alexandrite lasers are the most clinically used laser lithotriptors. Although calculi are fragmented by laser induced mechanical stresses for all lithotriptors, different fragment sizes and fragmentation efficiencies have been reported. In this work the effect of the pulse duration and pulse shape on the fragmentation processes is studied. Material and Methods: Fragmentation processes are characterized on model stones and on sensing target fibers. Stone fragmentation and cavitation bubble generation are observed by video flash photography. Shock wave occurrence and strength are monitored with an hydrophone. Results: For the FPDL, stone fragmentation is induced by the collapse of the large cavitation bubble formed. For the Q-switched Nd:YAG, fragmentation is already observed during the laser pulse, at the plasma onset, although further fragmentation can occur at the bubble collapse. For pulse durations corresponding to the alexandrite, an intermediate fragmentation regime is observed. Conclusion: For the first time the physical basis of the observed differences in the fragmentation efficiencies of current laser lithotriptors is described. For nanosecond durations the fragmentation processes are governed by plasma induced shock waves. On the contrary, for microsecond durations fragmentation is governed by cavitation. The high fragmentation efficiency of microsecond lasers is due to a high laser energy transfer into cavitation. © 1995 Wiley-Liss, Inc.     

低频超声增透效应

50年前人们就发现了超声的增透效应，经过40年的研究对比发现低频超声（20kHz〈f〈100kHz）更有利于促进分子的透皮传输。低频超声之所以具有较高的增透效应是因为该频段有利于空化作用的发生。发生在皮肤表面附近的惯性空化作用在低频超声增透效应中发挥主要作用。影响低频超声增透效应的既有超声因素又有非超声因素。关于超声因素的研究已比较成熟，但有关非超声因素的研究报道还很少。人们已将低频超声增透效应用于药物透皮注入．并在积极进行将低频超声增透效应用于微创透皮检测的研究。此项研究充满机遇和挑战。     

Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs

Importance of the field: Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection because of its ability to bypass the harsh gastrointestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation.

Areas covered in this review: This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications.

What the reader will gain: The reader will gain an insight into the field of LFS-mediated transdermal drug delivery, including how the use of this technology can improve on more traditional drug delivery methods.

Take home message: Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future due to its unique ability to enhance skin permeability in a controlled manner.     

根管超声冲洗的计算流体动力学分析

目的 应用计算机模型分析当超声工作尖位于根管内一定深度时冲洗液的计算流体动力学特点,以期为临床应用提供参考.方法 首先使用扫描激光振测系统扫描超声工作尖,分析其在一定功率下的振动特点.然后应用ICEM CFD 18.0软件建立根管超声冲洗模型,设置超声工作尖放置的位置为距根尖止点1 mm,通过FLUENT 18.0软件...     

Effects of In-Process Ultrasonic Vibration on Weld Formation and Grain Size of Wire and Arc Additive Manufactured Parts

Wire and arc additive manufacturing (WAAM) is a competitive technique, which enables the fabrication of medium and large metallic components. However, due to the presence of coarse columnar grains in the additively manufactured parts, the resultant mechanical properties will be reduced, which limits the application of WAAM processes in the engineering fields. Grain refinement and improved mechanical properties can be achieved by introducing ultrasonic vibration. Herein, we applied ultrasonic vibration to the WAAM process and investigated the effects of wire feed speed, welding speed, and ultrasonic amplitude on the weld formation and grain size during ultrasonic vibration. Finally, a regression model between the average grain size and wire feed speed, welding speed, and ultrasonic amplitude was established. The results showed that due to the difference in heat input and cladding amount, wire feed speed, welding speed, and ultrasonic amplitude have a significant influence on the weld width and reinforcement. Excessive ultrasonic amplitude could cause the weld to crack during spreading. The average grain size increased with increasing wire feed speed and decreasing welding speed. With increasing ultrasonic amplitude, the average grain size exhibited a trend of decreasing first and then increasing. This would be helpful to manufacture parts of the required grain size in ultrasonic vibration-assisted WAAM fields.     

A Misinterpreted Case of Aorta Prosthesis Endocarditis: Remember The Phenomenon of Microbubbles

A 17‐year‐old male with a history of newly implanted mechanical valve at the aortic position, presented with fever, rigors, and painful cutaneous abscesses on his lower extremities and was suspected for infective endocarditis. Transthoracic echocardiography (TTE) showed a vegetation‐like structure following the movement of the mechanical heart valve (MHV), which eventually proved to be a product of degassing microbubbles (MB).     

Bubble dynamics in boiling histotripsy

Boiling histotripsy is a non-invasive, cavitation-based ultrasonic technique which uses a number of millisecond pulses to mechanically fractionate tissue. Though a number of studies have demonstrated the efficacy of boiling histotripsy for fractionation of solid tumours, treatment monitoring by cavitation measurement is not well studied because of the limited understanding of the dynamics of bubbles induced by boiling histotripsy. The main objectives of this work are to (a) extract qualitative and quantitative features of bubbles excited by shockwaves and (b) distinguish between the different types of cavitation activity for either a thermally or a mechanically induced lesion in the liver. A numerical bubble model based on the Gilmore equation accounting for heat and mass transfer (gas and water vapour) was developed to investigate the dynamics of a single bubble in tissue exposed to different High Intensity Focused Ultrasound fields as a function of temperature variation in the fluid. Furthermore, ex vivo liver experiments were performed with a passive cavitation detection system to obtain acoustic emissions. The numerical simulations showed that the asymmetry in a shockwave and water vapour transport are the key parameters which lead the bubble to undergo rectified growth at a boiling temperature of 100°C. The onset of rectified radial bubble motion manifested itself as (a) an increase in the radiated pressure and (b) the sudden appearance of higher order multiple harmonics in the corresponding spectrogram. Examining the frequency spectra produced by the thermal ablation and the boiling histotripsy exposures, it was observed that higher order multiple harmonics as well as higher levels of broadband emissions occurred during the boiling histotripsy insonation. These unique features in the emitted acoustic signals were consistent with the experimental measurements. These features can, therefore, be used to monitor (a) the different types of acoustic cavitation activity for either a thermal ablation or a mechanical fractionation process and (b) the onset of the formation of a boiling bubble at the focus in the course of HIFU exposure.     

Generation of Reactive Oxygen Species in Heterogeneously Sonoporated Cells by Microbubbles with Single-Pulse Ultrasound

To develop and realize sonoporation-based macromolecule delivery, it is important to understand the underlying cellular bioeffects involved. It is known that an appropriate level of reactive oxygen species (ROS) is necessary to maintain normal physiologic function, but excessive ROS triggers adverse downstream bioeffects. However, it is still unclear whether a relationship exists between intracellular ROS levels and sonoporation. Using a customized platform for 1.5-MHz ultrasound exposure (13.33 µs duration and 0.70?MPa peak negative pressure) and imaging the dynamics of sonoporation and intracellular ROS at the single-cell level, we quantified the exogenous molecular uptake and the concentration of intracellular ROS indicator to evaluate the extent of sonoporation and ROS change, respectively. Our results revealed that the intracellular ROS level was correlated with the degree of the sonoporation. (i) Within ~120?s of the onset of ultrasound, during which membrane perforation and complete membrane resealing occurred, intracellular ROS rapidly decreased because of extracellular diffusion of dichlorofluorescein through the perforated membrane and positively correlated with the degree of the sonoporation. (ii) In the following 270?s (120–390?s post-exposure), ROS generation in reversibly sonoporated cells gradually increased and was positively correlated with the degree of the sonoporation. (iii) The ROS level in irreversibly sonoporated cells reduced to depletion during this time interval. It is possible that ROS generation in reversibly sonoporated cells can impact their long-term fate. These results thus provide new insight into the biological response to sonoporation.