Ultrasound-responsive System Research Articles

Ultrasound-Responsive Micelle-Encapsulated Mesenchymal Stem Cell-Derived EVs for the Treatment of Lower Limb Microcirculation Disease.

Lower limb microcirculatory ischemic disease is a vascular disorder primarily characterized by limb pain, gangrene, and potential amputation. It can be caused by various factors, such as hyperglycemia, atherosclerosis, and infection. Due to the extremely narrow luminal diameter in lower limb microcirculatory ischemic lesions, both surgical and medical interventions face challenges in achieving satisfactory therapeutic outcomes within the microvessels. Extracellular vesicles derived from mesenchymal stem cells (MSCs-EVs) exhibit promising potential in the treatment of microcirculation ischemic lesions due to their small size and ability to promote angiogenesis. After undergoing substantial losses during the process of EVs transportation, only a minimal fraction of EVs can effectively reach the site of microcirculatory lesions, thereby compromising the therapeutic efficacy for microcirculatory disorders. Herein, an ultrasound-responsive system utilizing 2-(dimethylamino)ethyl methacrylate-b-2-tetrahydropyranyl methacrylate (DMAEMA-b-THPMA) micelles to encapsulate MSCs-EVs has been successfully constructed, with the aim of achieving localized and targeted release of EVs at the site of microcirculatory lesions. The reversible addition-fragmentation chain transfer (RAFT) polymerization method facilitates the successful synthesis of diblock copolymers comprising monomer 2-(dimethylamino)ethyl methacrylate (DMAEMA) and monomer 2-tetrahydropyranyl methacrylate (THPMA). The DMAEMA-b-THPMA micelles exhibit a nanoscale structure, reliable biocompatibility, ultrasound responsiveness, and conspicuous protection of EVs. Furthermore, the implementation of low-energy-density ultrasound can enhance angiogenesis by upregulating the levels of the vascular endothelial growth factor (VEGF). In in vivo experiments, the ultrasound-responsive system of the DMAEMA-b-THPMA micelles and MSCs-EVs synergistically enhances therapeutic efficacy by promoting angiogenesis, improving vascular permeability, and optimizing vascular. In conclusion, this work demonstrates bioapplication of an ultrasound-responsive micellar nanosystem loaded with EVs for the treatment of lower limb microcirculatory ischemic disorders.

Ultrasound-Responsive Systems as Components for Smart Materials.

Smart materials can respond to stimuli and adapt their responses based on external cues from their environments. Such behavior requires a way to transport energy efficiently and then convert it for use in applications such as actuation, sensing, or signaling. Ultrasound can carry energy safely and with low losses through complex and opaque media. It can be localized to small regions of space and couple to systems over a wide range of time scales. However, the same characteristics that allow ultrasound to propagate efficiently through materials make it difficult to convert acoustic energy into other useful forms. Recent work across diverse fields has begun to address this challenge, demonstrating ultrasonic effects that provide control over physical and chemical systems with surprisingly high specificity. Here, we review recent progress in ultrasound–matter interactions, focusing on effects that can be incorporated as components in smart materials. These techniques build on fundamental phenomena such as cavitation, microstreaming, scattering, and acoustic radiation forces to enable capabilities such as actuation, sensing, payload delivery, and the initiation of chemical or biological processes. The diversity of emerging techniques holds great promise for a wide range of smart capabilities supported by ultrasound and poses interesting questions for further investigations.

Photothermal-Enhanced Phase-Transition Nanodroplets for Ultrasound-Mediated Diagnosis and Gene Transfection.

Gene therapy is one of the promising solutions in cancer therapeutics. Ultrasound-mediated gene delivery showed great potential as a noninvasive strategy for gene therapy. However, the efficiency of gene transfection and incorporation of multiple functions remain key challenges in the development of gene delivery systems. In this study, we developed perfluoropentane (PFP) and gold nanorods (AuNRs) loading nanodroplets for photothermal-enhanced ultrasound-mediated imaging and gene transfection. The nanodroplet theranostic system was formulated with fluorinated cationic poly(aspartamide) based polymer that encapsulated PFP, AuNRs, and plasmid DNA and was stabilized with a negatively charged poly(glutamic acid)-g-MeO-poly(ethylene glycol) (PGA-g-mPEG) coating. The nanodroplets presented good stability, biocompatibility, and DNA binding stability. Upon treatment with both near-infrared and ultrasound energy, the photothermal and ultrasound-responsive system exerted a synergistic effect, in which strong adsorption of light induced hyperthermia that promoted the phase transition of PFP and the following ultrasound irradiation, generating strong acoustic cavitation and sonoporation, thus leading to enhanced ultrasound contrast imaging and gene transfection efficiency both in vitro and in vivo.

Roles of Textural and Surface Properties of Nanoparticles in Ultrasound-Responsive Systems.

Acoustic inertial cavitation (IC) is a crucial phenomenon for many ultrasound (US)-related applications. This study aimed to investigate the roles of textural and surface properties of NPs in IC generation by combining typical IC detection methods with various types of silica model NPs. Acoustic passive cavitation detection, optical high-speed photography, and US imaging have been used to quantify IC activities (referred to as the IC dose, ICD) and describe the physical characteristics of IC activities from NPs. The results showed that the ICDs from NPs were positively correlated to their surface hydrophobicity and that their external surface hydrophobicity plays a much more crucial role than do the textural properties. The high-speed photography revealed that the sizes of IC-generated bubbles from superhydrophobic NPs ranged from 20-40 μm at 4-6 MPa and collapsed in several microseconds. Bubble clouds monitored with US imaging showed that IC from NPs was consistent with the surface hydrophobicity. The simulation results based on the crevice model of cavitation nuclei correlated well with the experimental results. This study has demonstrated that the surface property, instead of the textural property, of NPs dominated the IC generation, and surface nanobubbles adsorbed on the NP surface have been proposed to be cavitation nuclei.

Polymer-Grafted Mesoporous Silica Nanoparticles as Ultrasound-Responsive Drug Carriers.

A new ultrasound-responsive system based on mesoporous silica nanoparticles was developed for biomedical applications, grafting a copolymer on their surface that acts as gatekeeper of the pores. The nanoparticles can be loaded with a cargo at low temperature (4 °C), taking advantage of the open conformation that the polymer presents under these conditions. Then, at 37 °C the copolymer collapses closing the pore entrances and allowing the nanoparticles to carry the drugs at physiological temperature without premature release, which is of great importance when dealing with cytotoxic drugs in cancer treatments. Upon ultrasound irradiation, the sensitive polymer changes its hydrophobicity and, therefore, its conformation toward coil-like opening the gates and releasing the cargo. These hybrid nanoparticles have been shown to be noncytotoxic and can be internalized into LNCaP cells retaining their ultrasound-responsive capability in the cytoplasm of the cells. Moreover, doxorubicin-loaded hybrid MSNs were incubated with LNCaP cells to show their capacity to induce cell death only when the nanoparticles had been exposed to ultrasound. This work demonstrates that our hybrid-MSNs can be triggered by remote stimuli, which is of capital importance for future applications in drug delivery and cancer therapy.

Acceleration of permeability barrier recovery by exposure of skin to 10-30 kHz sound

Previous reports show that ultrasound can influence human brain electrical activity and systemic hormone levels in various parts of the body, other than the ear, so there may be an unknown ultrasound-responsive system in humans. In the present study, we examined the effects of sound on skin permeability barrier homeostasis. We broke the skin barrier of hairless mice by tape stripping, and then exposed the skin to sound for 1 h to evaluate the effect on barrier recovery rate. Exposure of skin to sound at frequencies of 10, 20 and 30 kHz for 1 h accelerated barrier recovery, and 20 kHz sound induced the fastest recovery. Application of 5 kHz sound had no effect on barrier recovery rate. Significant acceleration was observed even when the sound source was located 3 cm away from the skin surface. The recovery rate depended on the sound pressure. An electron-microscopic study indicated that lamellar body secretion between stratum corneum and stratum granulosum was increased by exposure to sound at 20 kHz. These results suggest that epidermal keratinocytes might be influenced by ultrasound in a manner that results in modulation of epidermal permeability barrier homeostasis.

Ultrasonic synthesis of enzyme coated microbubbles

Gas-filled polymer coated microbubbles are intrinsically ultrasound responsive systems and when tailored with targeting features are promising candidates for smart drug delivery. We have ultrasonically synthesised stable, versatile, biodegradable and biocompatible microbubbles using the enzyme, lysozyme. The synthesis of lysozyme microbubbles has been achieved by sonicating an aqueous solution containing denatured lysozyme. The microbubbbles have been characterised using a number of imaging techniques such as, SEM, AFM and light microscopy. We have observed that the experimental parameters such as, length of sonication, DTT concentration and denaturisation time deeply affect the yield and the size of the microbubbles. We have also investigated the secondary structure and the enzymatic activity of lysozyme coated microbubbles. The lysozyme microbubbles have retained their enzymatic antimicrobial activities.