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1. Engineering viral vectors for acoustically targeted gene delivery

   https://doi.org/10.1038/s41467-024-48974-y  

   Li, Hongyi_R; Harb, Manwal; Heath, John_E; Trippett, James_S; Shapiro, Mikhail_G; Szablowski, Jerzy_O (June 2024, Nature Communications)

   Abstract Targeted gene delivery to the brain is a critical tool for neuroscience research and has significant potential to treat human disease. However, the site-specific delivery of common gene vectors such as adeno-associated viruses (AAVs) is typically performed via invasive injections, which limit its applicable scope of research and clinical applications. Alternatively, focused ultrasound blood-brain-barrier opening (FUS-BBBO), performed noninvasively, enables the site-specific entry of AAVs into the brain from systemic circulation. However, when used in conjunction with natural AAV serotypes, this approach has limited transduction efficiency and results in substantial undesirable transduction of peripheral organs. Here, we use high throughput in vivo selection to engineer new AAV vectors specifically designed for local neuronal transduction at the site of FUS-BBBO. The resulting vectors substantially enhance ultrasound-targeted gene delivery and neuronal tropism while reducing peripheral transduction, providing a more than ten-fold improvement in targeting specificity in two tested mouse strains. In addition to enhancing the only known approach to noninvasively target gene delivery to specific brain regions, these results establish the ability of AAV vectors to be evolved for specific physical delivery mechanisms. 

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2. EFFECTS OF OSMOLARITY ON ULTRASOUND-INDUCED MEMBRANE DEPOLARIZATION IN ISOLATED CRAYFISH MOTOR AXON

   TAGEDPFEIYUAN YU, * WOLFGANG (May 2022, Ultrasound in medicine biology)

   Abstract—We have previously identified a novel non-selective membrane conductance (gUS) opened by focused ultrasound (FUS) in crayfish motor axons. In the work described here, we studied gUS properties further by comparing FUS-evoked depolarization (FUSD) in control and hypotonic saline with 75% of control osmolarity. The FUS was a train of 20 FUS bursts (2.1 MHz and 50 ms per burst) delivered at 1 kHz. The amplitude, onset latency, frequency of occurrence and duration of FUSD were compared in a 15-min time window before and after switching to hypotonic saline. Significant increases were observed for amplitude (p < 0.001) and frequency of occurrence (p < 0.01) while the onset latency exhibited a significant decrease (p < 0.001). FUSD duration did not significantly differ. These results support predictions based on our hypothesis that gUS is mediated by opening of nanopores in the lipid bilayer and that stretching of axonal membrane caused by swelling at low osmolarity should increase the probability of nanopore formation under FUS. The FUSD parameters, in addition, exhibited time-dependent trends when the window of observation was expanded to 45 min in each saline. The statistical significance of amplitude and duration differed between 15- and 45-min time windows, indicating the presence of adaptive responses of axonal membrane to osmotic manipulation. (E-mail: jenweilin@bu.edu) © 2022 Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology. 

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3. A Roadmap to Holographic Focused Ultrasound Approaches for Generating Gradient Thermal Patterns

   https://doi.org/10.1002/cnm.70055  

   Cengiz, Ceren; Eger, Zekeriya_Ender; Pewekar, Mihir; Acar, Pinar; Legon, Wynn; Shahab, Shima (June 2025, International Journal for Numerical Methods in Biomedical Engineering)

   ABSTRACT In therapeutic focused ultrasound (FUS), such as thermal ablation and hyperthermia, effective acousto‐thermal manipulation requires precise targeting of complex geometries, sound wave propagation through irregular structures, and selective focusing at specific depths. Acoustic holographic lenses (AHLs) provide a distinctive capability to shape acoustic fields into precise, complex, and multifocal FUS‐thermal patterns. Acknowledging the under‐explored potential of AHLs in shaping ultrasound‐induced heating patterns, this study introduces a roadmap for acousto‐thermal modeling in the design of AHLs. Three primary modeling approaches are studied and contrasted using four distinct shape groups for the imposed target field. They include pressure‐based time reversal (TR) (basic (BSC‐TR) and iterative (ITER‐TR)), temperature‐based (inverse heat transfer optimization (IHTO‐TR)), and machine learning (ML)‐based (generative adversarial network (GaN) and GaN with feature (Feat‐GAN)) methods. Novel metrics, including image quality, thermal efficiency, thermal control, and computational time, are introduced, providing each method's strengths and weaknesses. The importance of evaluating target pattern complexity, thermal and pressure requirements, and computational resources is highlighted. As a further step, two case studies: (1) transcranial FUS and (2) liver hyperthermia, demonstrate the practical use of acoustic holography in therapeutic settings. This paper offers a practical reference for selecting modeling approaches based on therapeutic goals and modeling requirements. Alongside established methods like BSC‐TR and ITER‐TR, new techniques IHTO‐TR, GaN, and Feat‐GaN are introduced. BSC‐TR serves as a baseline, while ITER‐TR enables refinement based on target shape characteristics. IHTO‐TR supports thermal control, GaN offers rapid solutions under fixed conditions, and Feat‐GaN provides adaptability across varying application settings. 

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4. Tuning shape and internal structure of protein droplets via biopolymer filaments

   https://doi.org/10.1039/C9SM02462J  

   Scheff, Danielle R.; Weirich, Kimberly L.; Dasbiswas, Kinjal; Patel, Avinash; Vaikuntanathan, Suriyanarayanan; Gardel, Margaret L. (June 2020, Soft Matter)

   Macromolecules can phase separate to form liquid condensates, which are emerging as critical compartments in fields as diverse as intracellular organization and soft materials design. A myriad of macromolecules, including the protein FUS, form condensates which behave as isotropic liquids. Here, we investigate the influence of filament dopants on the material properties of protein liquids. We find that the short, biopolymer filaments of actin spontaneously partition into FUS droplets to form composite liquid droplets. As the concentration of the filament dopants increases, the coalescence time decreases, indicating that the dopants control viscosity relative to surface tension. The droplet shape is tunable and ranges from spherical to tactoid as the filament length or concentration is increased. We find that the tactoids are well described by a model of a quasi bipolar liquid crystal droplet, where nematic order from the anisotropic actin filaments competes with isotropic interfacial energy from the FUS, controlling droplet shape in a size-dependent manner. Our results demonstrate a versatile approach to construct tunable, anisotropic macromolecular liquids. 

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5. Boron nitride-based shape memory polymers for spatially targeted ultrasound actuation

   https://doi.org/10.1088/1361-665X/adeb1c  

   Xi, Jiaxin; Safranski, David_L; Mirzaeifar, Reza; Shahab, Shima (July 2025, Smart Materials and Structures)

   Abstract Focused ultrasound (FUS) presents unique advantages for noninvasive localized heating, crucial for controlled shape recovery in shape memory polymers (SMPs), especially in biomedical applications. To enhance FUS-driven actuation efficiency, we propose boron nitride (BN)-infused SMP composites (SMPCs) tailored for targeted biomedical interventions. Using tert-butyl acrylate (tBA) and di(ethylene glycol) dimethacrylate as base materials, we integrated BN fillers at varying concentrations (1, 5, and 10 wt.%). A thorough characterization was carried out, including dynamic mechanical analysis, scanning electron microscopy, uniaxial tensile testing, and swelling study. These results show that increasing the BN content improves shape recovery efficiency significantly. Specifically, the 10 wt.% BN composites outperformed plain SMP in terms of shape recovery ratio when activated with FUS, and the highest shape recovery ratio can achieve 75%. However, higher BN content decreases crosslinking density and stiffness, as shown by a lower Young’s modulus and glass transition temperature. This study demonstrates the promise of BN-infused SMPCs for advanced applications in biomedical application, where noninvasive spatiotemporal actuation of SMPs is required. 

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