Acoustic tweezers are gaining increasing attention as a noncontact method that is capable of handling microparticles and nanoparticles in a controllable manner. By designing the acoustic field, objects, such as cells, bacteria, exosomes, and even worms, could be precisely and flexibly manipulated by the acoustic radiation force. With the advantages of non-invasiveness, label-free operation, and low power consumption, acoustic tweezers have been proven to be crucially important for a diverse range of applications, particularly in the biomedical domain. In this paper, we review the historical development and the current state of the theory of the acoustic radiation force. Furthermore, we introduce recent advancements in acoustic tweezers based on the standing wave, travelling wave, single beam, and arbitrary wave fields; its mechanism and potential applications are also presented. Finally, some perspectives referring to the future development of acoustic tweezers are discussed.

Background: Extracellular vesicles, including exosomes, are secreted by a variety of cell types in the central nervous system. Exosomes play a role in removing intracellular materials from the endosomal system. Alzheimer's disease (AD) is caused by an overproduction or reduced amyloid-beta (Aβ) peptide clearance. Increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway. Therapeutic ultrasound stimulation demonstrated its potential for promoting Aβ degradation efficiency in clinical trials. However, the underlying mechanism of ultrasound stimulation is still unclear.

Sonoporation is a targeted drug delivery technique that employs cavitation microbubbles to generate transient pores in the cell membrane, allowing foreign substances to enter cells by passing through the pores. Due to the broad size distribution of microbubbles, cavitation events appear to be a random process, making it difficult to achieve controllable and efficient sonoporation. In this work a technique is reported using a microfluidic device that enables in parallel modulation of membrane permeability by an oscillating microbubble array. Multirectangular channels of uniform size are created at the sidewall to generate an array of monodispersed microbubbles, which oscillate with almost the same amplitude and resonant frequency, ensuring homogeneous sonoporation with high efficacy. Stable harmonic and high harmonic signals emitted by individual oscillating microbubbles are detected by a laser Doppler vibrometer, which indicates stable cavitation occurred. Under the influence of the acoustic radiation forces induced by the oscillating microbubble, single cells can be trapped at an oscillating microbubble surface. The sonoporation of single cells is directly influenced by the individual oscillating microbubble. The parallel sonoporation of multiple cells is achieved with an efficiency of 96.6 ± 1.74% at an acoustic pressure as low as 41.7 kPa.

Objective: Low-frequency low-intensity pulsed ultrasound (LIPUS) has emerged as a non-invasive neuromodulation tool. The aim of this study is to examine whether LIPUS stimulation of the motor cortex can improve parkinsonian motor deficit in a mouse model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Methods: Acute Parkinson's disease (PD) mouse model is built by injection of MPTP (20 mg/kg) every 4 h in a total of four doses in one day. Mice are randomized into control, MPTP, sham-LIPUS+MPTP, and LIPUS+MPTP group. For LIPUS+MPTP group, 7 days of LIPUS (800 kHz, 10% duty cycle, 100-Hz pulse repetition frequency, 40 min/day) is delivered to the motor cortex. An open field test (OFT) is conducted on day 4 and a pole test on day 5, respectively. Striatal total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-PX) are measured on day 8. The safety of LIPUS is verified using Hematoxylin and esosin (HE) staining and Nissl staining. Results: LIPUS treatment improves rearing number in the OFT on day 4 (n = 8, p = 0.037) and locomotor activity in the pole test on day 5 (n = 8, p = 0.007) compared with the sham-LIPUS+MPTP group. Moreover, LIPUS increases T-SOD (n = 7, p = 0.006) and GSH-PX (n = 7, p = 0.030) compared with the sham-LIPUS+MPTP group. In addition, HE and Nissl staining shows no brain tissue injury induced by LIPUS. Conclusion: These findings demonstrate that LIPUS may have neuromodulation effects in PD mice. Significance: LIPUS may provide a novel neuromodulation tool for PD treatment.

Ultrasound neuro-modulation has gained increasing attention as a non-invasive method. In this paper, we present an ultrasound neuro-modulation chip, capable of initiating reversal behaviour and activating neurons of C. elegans under the stimulation of a single-shot, short-pulsed ultrasound. About 85.29% ± 6.17% of worms respond to the ultrasound stimulation exhibiting reversal behaviour. Furthermore, the worms can adapt to the ultrasound stimulation with a lower acoustic pulse duration of stimulation. In vivo calcium imaging shows that the activity of ASH, a polymodal sensory neuron in C. elegans, can be directly evoked by the ultrasound stimulation. On the other hand, AFD, a thermal sensitive neuron, cannot be activated by the ultrasound stimulation using the same parameter and the temperature elevation during the stimulation process is relatively small. Consistent with the calcium imaging results, the tax-4 mutants, which are insensitive to temperature increase, do not show a significant difference in avoidance probability compared to the wild type. Therefore, the mechanical effects induced by ultrasound are the main reason for neural and behavioural modulation of C. elegans. With the advantages of confined acoustic energy on the surface, compatible with standard calcium imaging, this neuro-modulation chip could be a powerful tool for revealing the molecular mechanisms of ultrasound neuro-modulation.

Objective: Neuroinflammation contributes to the development and progression of Parkinson's disease (PD). The aim of this study was to examine whether ultrasound (US) stimulation of the subthalamic nucleus (STN) could suppress the neuroinflammation in a chronic PD mouse model induced by 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Methods: A chronic PD mouse model was built by injections of 20mg/kg MPTP and 250 mg/kg probenecid at 3.5-day intervals for 5 weeks. Mice were randomized into control+sham, MPTP+sham and MPTP+STN+US group. For MPTP+STN+US group, ultrasound wave (3.8 MHz, 50% duty cycle, 1 kHz pulse repetition frequency, 30 min/day) was delivered to the STN the day after MPTP and probenecid injection (the early stage of PD progression). The rotarod test and pole test were performed to evaluate the behavioral changes after ultrasound treatment. Then, the activity of microglia and astrocyte were measured to evaluate the inflammation level in the brain. Results: Ultrasound stimulation improved the latency to falls in the rotarod test (p = 0.033) and decreased the climbing time in the pole test (p = 0.016) compared with MPTP+sham group. Moreover, ultrasound stimulation reduced the chronic inflammation response as shown in microglia (p = 0.007) and astrocyte (p = 0.032) activation. In addition, HE, Nissl and Tunel staining showed that no brain tissue injury was induced by US. Conclusion: These findings demonstrated that ultrasound stimulation could suppress neuroinflammation in PD mice. Significance: Transcranial ultrasound neuromodulation offers a novel approach for Parkinson's disease intervention, potentially through its anti-neuroinflammation functions.