Ultrasound offers a noninvasive, clinically relevant means to achieve precise spatiotemporal control of cargo release from ultrasound-responsive drug delivery systems within deep tissues. This approach enables targeted delivery of therapeutic agents, enhancing efficacy while minimizing systemic toxicity. While previous studies show that release from ultrasound-responsive liposomes depends on acoustic parameters, the underlying mechanisms remain unclear. A deeper mechanistic understanding is essential to achieve precision over release and maximize therapeutic outcomes. To address this, we propose a sonoporation-based framework to describe release dynamics across varying frequencies, pressures, duty cycles, and pulse repetition frequencies for ultrasound-responsive poly(ethylene glycol)-functionalized liposomes. Using computational simulations validated by empirical results, our framework identifies a critical pressure threshold for release onset and demonstrates how the time spent above this threshold, modulated by acoustic parameters, governs release efficiency. To elucidate these effects, custom-built ultrasound transducers with different resonance frequencies were fabricated and characterized to ensure precise sample alignment, minimize acoustic distortion, and maintain a controlled focal-volume-to-sample-volume ratio across different frequencies. COMSOL simulations indicated that oscillatory acoustic pressure plays a more dominant role than acoustic radiation force, while coarse-grained molecular dynamics simulations captured pressure-dependent pore formation dynamics within the lipid bilayer. Together, our experiments and simulations highlight mechanical effects—particularly oscillatory acoustic pressure—as the primary driver of sonoporation-facilitated release. Finally, we discuss how optimizing acoustic parameters through this mechanistic framework could facilitate safe and effective clinical translation by considering tissue safety and ultrasound transducer design.

Poor stimulus-response correlation, caused by acoustic reflections from conventional culture substrates, poses a significant challenge in cellular mechanistic studies of ultrasound neuromodulation. Existing specialized setups that mitigate this interference have limited recording capabilities. In this study, we propose an anti-reflective microengineered substrate (ARMS) that can be incorporated into a standard in vitro platform. The substrate's dimensions and material composition were optimized in simulation. The optimized simulated platform exhibited an 86.3% reduction in reflection amplitude on the substrate surface compared to the conventional glass substrate. Furthermore, the ARMS reduced stimulation signal distortion to a 19.2% deviation from the expected amplitude, a substantial improvement compared to the 76.4% deviation observed with glass.

In the emerging research field of bioelectronic medicine, it has been indicated that neuromodulation of the vagus nerve (VN) has the potential to treat various conditions such as epilepsy, depression, and autoimmune diseases. In order to reduce side effects, as well as to increase the effectiveness of the delivered therapy, sub-fascicle stimulation specificity is required. In the electrical domain, increasing spatial selectivity can only be achieved using invasive and potentially damaging approaches like compressive forces or nerve penetration. To avoid these invasive methods while obtaining a high spatial selectivity, a 2-mm diameter extraneural cuff-shaped proof-of-concept design with integrated lead zirconate titanate (PZT) based ultrasound (US) transducers is proposed in this article. For the development of the proposed concept, wafer-level microfabrication techniques are employed. Moreover, acoustic measurements are performed on the device, in order to characterize the ultrasonic beam profiles of the integrated PZT-based US transducers. A focal spot size of around 200× 200 μ m is measured for the proposed cuff. Moreover, the curvature of the device leads to constructive interference of the US waves originating from multiple PZT-based US transducers, which in turn leads to an increase of 45% in focal pressure compared to the focal pressure of a single PZT-based US transducer. Integrating PZT-based US transducers in an extraneural cuff-shaped design has the potential to achieve high-precision US neuromodulation of the VN without requiring intraneural implantation.

Bulk piezoelectric ultrasound transducers on integrated circuits offer unique properties for therapeutic applications of ultrasound neuromodulation. However, current implementations of such transducers are not optimized for the high transmit efficiency required to stimulate neurons. This is mainly due to the challenge of implementing a metal layer on top of the piezoelectric film using microfabrication techniques. Here, we propose a micromachined capping structure providing an electrical connection on top of the piezoelectric film with minimal acoustic losses. The structure can potentially be used as a common ground connection in phased-array ultrasound transducers.

2D phased array ultrasonic transducers realized through the combination of bulk piezoelectric ceramics and complementary metal-oxide-semiconductor (CMOS) integrated circuits (IC) are enabling a new range of wearable ultrasound therapeutic applications. Traditional therapeutic ultrasound transducers have an air backing layer to maximize transmitted acoustic intensity. Yet, the pairing of piezoelectric transducers and silicon substrates commonly used in CMOS is still poorly understood. We integrated lead zirconate titanate (PZT) film on silicon membranes of various thicknesses to understand the im-pact of the silicon backing on the performance of bulk piezoe-lectric ultrasound transducers. The transducers with thinner sil-icon membranes exhibited higher acoustic intensity (up to 1.95 times while taking into account frequency shift), which is con-sistent with the simulation in finite element modeling. Transduc-ers with silicon substrate also demonstrated a consistent shift to a higher resonance frequency.

This paper reports on the characterization of a microfabricated wafer-scale, graphene-based, soft implant for spinal cord applications. Graphene is used because of its high transparency and good conductivity, making it suitable for optogenetic applications. Moreover it has a high mechanical strength and is potentially biocompatible. The implant consists of multi-layered chemical vapor deposited graphene, in the form of electrodes and tracks, encapsulated between 2 layers of silicone. Methods such as Raman spectroscopy, optical transmittance, and electrical measurements combined with bending tests and in-vitro experiments, using phosphate-buffered saline (PBS) solution, were employed to characterize the device. The results have shown high bendability and no critical damage of the graphene after immersing the device in PBS solution up to 7 days. To the authors' best knowledge, this is the first work that presents a soft and fully scalable optogenetics-compatible graphene-based spinal cord electrode array.