Ultrasound is a promising technology to address challenges in drug delivery, including limited drug penetration across physiological barriers and ineffective targeting. Here we provide an overview of the significant advances made in recent years in overcoming technical and pharmacological barriers using ultrasound-assisted drug delivery to the central and peripheral nervous system. We commence by exploring the fundamental principles of ultrasound physics and its interaction with tissue. The mechanisms of ultrasonic-enhanced drug delivery are examined, as well as the relevant tissue barriers. We highlight drug transport through such tissue barriers utilizing insonation alone, in combination with ultrasound contrast agents (e.g., microbubbles), and through innovative particulate drug delivery systems. Furthermore, we review advances in systems and devices for providing therapeutic ultrasound, as their practicality and accessibility are crucial for clinical application.

Introduction: Over the decades, tendon adhesion has become a major health problem threatening the rehabilitation of patients after tendon surgery. Injury of the flexor tendon leads to rupture of the synovial sheath, which causes tendon exposure and adhesion with subcutaneous tissue. Current conservative therapies can promote chronic healing of tendon adhesion but have mixed success rates. Objectives: To reduce the degree of tendon adhesion, the need for a new non-invasive and accurate treatment method is substantial. Methods: A concave spherical ultrasonic phased array was fabricated by a fast 3D printing method. We generated a set of delayed square wave pulse sequences by Field Programmable Gate Arrays (FPGA) to excite the ultrasonic array, creating an ultrasonic focal area. Then we put flexor tendon phantoms, which were constructed by chitosan hydrogel and fibrous membrane using electrospinning, into the preset focal region and injected nano drugs in them. Finally, we measured the pulling force of tendon phantoms with a tensile tester. Results: The pulling force of three experimental groups were measured by a tensile tester. Compared to the “untreated group” (0.96 N), the phantom pulling force of the “ultrasound + drug group” is 0.15 N, which is reduced by 85%. Furthermore, with the driving voltage increased from 5 V to 20 V, the pulling force can be reduced by 60%; with the duty ratio increased from 20% to 60%, the pulling force can be reduced by 50%; with treatment time increased from 1 min to 5 min, the pulling force can be reduced by 64%. Conclusion: Utilizing an ultrasonic array combined with nano drugs, our phase compensation control method can reduce the degree of tendon adhesion and hold a great implication for applications of rehabilitation treatment for postoperative patients.

Endotoxin is a deadly pyrogen, rendering it crucial to monitor with high accuracy and efficiency. However, current endotoxin detection relies on multistep processes that are labor-intensive, time-consuming, and unsustainable. Here, we report an aptamer-based biosensor for the real-time optical detection of endotoxin. The endotoxin sensor exploits the distance-dependent scattering of gold nanoparticles (AuNPs) coupled to a gold nanofilm. This is enabled by the conformational changes of an endotoxin-specific aptamer upon target binding. The sensor can be used in an ensemble mode and single-particle mode under dark-field illumination. In the ensemble mode, the sensor is coupled with a microspectrometer and exhibits high specificity, reliability (i.e., linear concentration to signal profile in logarithmic scale), and reusability for repeated endotoxin measurements. Individual endotoxins can be detected by monitoring the color of single AuNPs via a color camera, achieving single-molecule resolution. This platform can potentially advance endotoxin detection to safeguard medical, food, and pharmaceutical products.

Accurate and real-time monitoring of biomarker proteins, such as Tumor Necrosis Factor (TNF) alpha, plays a vital role in early disease diagnosis, effective treatment design, and personalized health management strategies. However, existing detection methods, including enzyme-linked immunosorbent assay (ELISA), radioimmune assays (RIA), and polymerase chain reaction (PCR), have significant drawbacks regarding sensitivity, cost, time, and labor efficiency, emphasizing the urgent need for alternative biosensing techniques. Here, we present a mass-based biosensing approach utilizing aptamers for the real-time detection of proteins, using TNF-alpha as the model analyte. The recognition process is based on the selective binding of the target molecule to the aptamer's unique three-dimensional structure. By utilizing a quartz crystal microbalance (QCM) as the transducing element, real-time detection of target binding is translated into a linear decrease in resonant frequency due to the change in mass upon target binding. The developed aptasensor enabled real-time quantification of TNF-alpha with high reliability, sensitivity, and specificity. The sensitivity of the sensor ranged from 14.5 nM to 115.6 nM, in which a linear correlation between target concentration and frequency decrease rate was found. Successful sensor regeneration demonstrated potential for continuous measurements in solution. By directly monitoring the change in mass during sensor fabrication and upon analyte binding, this platform provides key mechanistic insights in the surface functionalization process during sensor fabrication and analyte binding kinetics during sensor operation. In the future, incorporation of alternative target receptors, by simply changing the aptamer sequence, can broaden the analyte spectrum, making this platform highly versatile. We hereby demonstrate a technology that can be utilized for various biosensing platforms upon minimal modifications, including electrochemical and optical systems, for a wide range of macromolecular analytes.

Flexible and stretchable biosensors have the advantage of enhanced signal validity and patient comfort during physiological signal sensing and biomolecular analysis, crucial for disease diagnosis, treatment and health management. Their lightness, softness and excellent mechanical properties enable effective skin-device interface coupling and skin safety profiles, realizing multi-functional, intelligent real-time sensing. In this review, the basic sensing principles of biosensor systems and their applications are discussed. Moreover, the potential applications and prospective progress of these biosensors are further prospected. Flexible, wearable biosensors have the potential to realize continuous and long-term health monitoring in clinical and daily health care.

Friction materials form a critical component of piezoelectric actuators, and wear of the material affects output and service life of the actuator. This paper examines the influence of polyimide (PI) composites when used as a friction material on the performance of a legged piezoelectric bending actuator. We design and manufacture demountable shoe soles, made of a novel PI-based friction material, for an actuator. A Coulomb friction model is also established to determine the behavior resulting from contact-induced friction between the surface and the actuator. Reciprocating wear tests involving an insulation rubber pad against phosphor bronze and PI composites as friction materials yielded average friction coefficients of 0.21 and 0.28, respectively. We also found that PI composites have higher wear resistance than phosphor bronze, with a specific wear rate of 1.36 × 10-4 mm3/N m. The results of experiments and simulations indicate that the shoe soles made of PI composites reduced the actuator's driving frequency and vibrational amplitude, but they did not affect the principle of locomotion of the actuator. Furthermore, the operational stability of the actuator improved by 46.8% by using the demountable shoe soles made of PI composites, albeit at the cost of its velocity and load capacity. This work has guiding significance for the design and selection of friction materials for piezoelectric actuators.

Unresectable tumors in the gastrointestinal tract are difficult to treat, and traditional radiotherapy combined with chemotherapy can easily induce severe side-effects due to the toxicities of anticancer drugs. Effective methods to enhance the concentration of local drug release in the narrow and hollow organs of the gastrointestinal tract are unavailable. To address this shortcoming, we propose a method to thermally trigger the release of Nile Red from temperature-sensitive liposomes (TSLs) in an in vitro hydrogel phantom of the gastric mucosa through ultrasound treatment by using a small, piezoelectric, single-crystal ultrasonic transducer with a diameter of 2.2 mm. To control the rise in temperature, we establish a model for ultrasound thermal calculation according to Helmholtz's equation, the equations of heat transfer, and the Navier-Stokes equations and validate it through an in vitro experiment. The results show that the temperature reached the melting-phase transition temperature of TSL (40-42 °C) when the duty ratio of the driving voltage of the ultrasonic transducer was 60%, and the amplitude was greater than 40 V_pp and less than 60 V_pp. Furthermore, the maximum rate of release of Nile Red was 2.9 × 10⁻³ mg/min when the ultrasonic transducer was activated with a driving voltage of 60 V_pp and a duty ratio of 60%. Thus, the proposed method for temperature control can be applied to improve local drug concentration in the gastrointestinal tract and reduce the number of anticancer drugs in the body.

Modern advanced minimally invasive surgery has been implemented for most of the significant gastrointestinal diseases. However, patients with coagulopathy or unresectable tumors cannot be cured by current treatment methods. Moreover, other existing medical devices for targeted drug release are too large to be applied in gastric endoscope because the diameter of the biopsy channel is smaller than 3 mm. To address it, in this work, we developed a piezoelectric single crystal ultrasonic transducer (the diameter was only 2.2 mm and the mass was 0.076 g) to produce acoustic waves, which could promote the drug release in the designed position of the digestive tract through an endoscope. It exhibited the electromechanical coupling coefficient of 0.36 and the center frequency of 6.9 MHz with the -6-dB bandwidth of 23%. In in vitro sonophoresis experiment, the gastric mucosa permeability to Bovine Serum Albumin increased about 5.6 times when the ultrasonic transducer was activated at 40 \text{V} {{\text {pp}}} and 60% duty ratio, proving that employment of this transducer could facilitate drug penetration in the gastric mucosa. Meanwhile, the permeability could be adjusted by tuning the duty ratio of the ultrasonic transducer. The corresponding sonophoresis mechanism was related to the acoustic streaming and the thermal effect produced by the transducer. In addition, the measured maximum power density was 128 mW/cm2 and the mechanical index of the ultrasonic transducer was 0.02. The results held a great implication for applications of the transducer for targeted drug release in the gastrointestinal tract.

Micro actuators have been used to realize the arrival of digestive tract lesions for the local targeted application of drugs in endoscopes. However, there still exists a key safety issue that casts a shadow over the practical and safe implementation of actuators in the human body, namely an overheated environment caused by actuators' operation. Herein, with the aim of solving the temperature rising problem of a piezoelectric micro actuator operating in an endoscopic biopsy channel (OLYMPUS, Tokyo, Japan), a thermal finite element method (FEM) based on COMSOL Multiphysics software is proposed. The temperature distribution and its rising curves are obtained by the FEM method. Both the simulated and experimental maximum temperatures are larger than the safety value (e.g., 42 °C for human tissues) when the driving voltage of the actuator is 200 V_pp, which proves that the overheating problem really exists in the actuator. Furthermore, the results show that the calculated temperature rising curves correspond to the experimental results, proving the effectiveness of this FEM method. Therefore, we introduce a temperature control method through optimizing the duty ratio of the actuator. In comparison with a 100% duty ratio operation condition, it is found that a 60% duty ratio with a driving voltage of 200 V_pp can more effectively prevent the temperature rising issue in the first 3 min, as revealed by the corresponding temperatures of 44.4 and 41.4 °C, respectively. When the duty ratio is adjusted to 30% or less, the temperature rise of the actuator can be significantly reduced to only 36.6 °C, which is close to the initial temperature (36.4 °C). Meanwhile, the speed of the actuator can be well-maintained at a certain level, demonstrating its great applicability for safe operation in the human body.

Low frequency sonophoresis (LFS) is currently being attempted as a transdermal drug delivery method in clinical areas. However, it lacks both an effective control method and the equipment to satisfy the varying drug dosage requirements of individual patients. Herein, a novel method aimed at controlling permeability is proposed and developed, using a pressure control strategy which is based on an accurate, adjustable and non-invasive ultrasound transdermal drug delivery system in in vitro LFS. The system mainly consists of a lead screw linear ultrasonic motor and an ultrasonic transducer, in which the former offers pressure and the latter provides ultrasound wave in the liquid. The ultrasound can enhance non-invasive permeation and the pressure from the motor can control the permeability. The calculated and experimental results demonstrate that the maximum pressure on artificial skin is under the area with the maximum vibration amplitude of the ultrasonic transducer, and the total pressure consists of acoustic pressure from the transducer and approximate static pressure from the motor. Changing the static pressure from the ultrasonic motor can effectively control the non-invasive permeability, by adjusting the duty ratio or the amplitude of the motor's driving voltage. In addition, the permeability control of calcein by thrust control is realized in 15 min, indicating the suitability of this method for application in accurate medical technology. The obtained results reveal that the issue of difficult permeability control can be addressed, using this control method in in vitro LFS to open up a route to the design of accurate drug delivery technology for individual patients.