Comparing the Safety and Effectiveness of Microfocused Ultrasound: Standard vs Targeted Tissue Protocol in Lifting and Tightening the Lower Face and Upper Neck.

BACKGROUND: Micro-focused ultrasound with visualization (MFU-V) delivers energy to specific soft tissue layers beneath the epidermis with the ability to lift and tighten the lower face and neck.  Objective: To determine the efficacy of microfocused ultrasound with visualization (MFU-V) using a standard treatment line protocol versus a customized treatment line protocol based on the patient's unique anatomy targeting the superficial muscular aponeurotic system and fibrous septae for lifting and tightening of the lower face and neck. METHODS: This was a single-center, prospective, randomized, investigator-blinded clinical trial. 51 subjects were randomized to receive a single treatment of MFU-V targeting the lower face and neck using either a standard or custom treatment protocol.   Results: Subjects in both standard and custom treatment groups noted a greater than one-point improvement in jawline laxity. Three-dimensional photography measurements also demonstrated lifting of the lower face and neck in both treatment groups. CONCLUSION: Custom and standard treatment MFU-V protocols produce a safe and effective treatment for tightening and lifting the lower face and neck. Custom treatment protocols aid in maximizing results for patients with variations in the anatomy of the lower face and neck.  J Drugs Dermatol. 2024;23(4):7647.     doi:10.36849/JDD.7647.

Targeted Ultrasound Nanobubbles Therapy for Prostate Cancer via Immuno-Sonodynamic Effect.

Background: Prostate cancer (PCa) poses a significant global health threaten. Immunotherapy has emerged as a novel strategy to augment the inhibition of tumor proliferation. However, the sole use of anti-PD-L1 Ab for PCa has not yielded improvements, mirroring outcomes observed in other tumor types. Methods: This study employed the thin film hydration method to develop lipid nanobubbles (NBs) encapsulating chlorin e6 (Ce6) and anti-PD-L1 Ab (Ce6@aPD-L1 NBs). Our experimental approach included cellular assays and mouse immunization, providing a comprehensive evaluation of Ce6@aPD-L1 NBs' impact. Results: The Ce6@aPD-L1 NBs effectively induced reactive oxygen species generation, leading to tumor cells death. In mice, they demonstrated a remarkable enhancement of immune responses compared to control groups. These immune responses encompassed immunogenic cell death induced by sonodynamic therapy and PD-1/PD-L1 blockade, activating dendritic cells maturation and effectively stimulating CD8+T cells. Conclusion: Ce6@aPD-L1 NBs facilitate tumor-targeted delivery, activating anti-tumor effects through direct sonodynamic therapy action and immune system reactivation in the tumor microenvironment. Ce6@aPD-L1 NBs exhibit substantial potential for achieving synergistic anti-cancer effects in PCa.

Ultrasound-augmented cancer immunotherapy.

Cancer is a growing worldwide health problem with the most broadly studied treatments, in which immunotherapy has made notable advancements in recent years. However, innumerable patients have presented a poor response to immunotherapy and simultaneously experienced immune-related adverse events, with failed therapeutic results and increased mortality rates. Consequently, it is crucial to develop alternate tactics to boost therapeutic effects without producing negative side effects. Ultrasound is considered to possess significant therapeutic potential in the antitumor field because of its inherent characteristics, including cavitation, pyrolysis, and sonoporation. Herein, this timely review presents the comprehensive and systematic research progress of ultrasound-enhanced cancer immunotherapy, focusing on the various ultrasound-related mechanisms and strategies. Moreover, this review summarizes the design and application of current sonosensitizers based on sonodynamic therapy, with an attempt to provide guidance on new directions for future cancer therapy.

Ultrasound imaging guided targeted sonodynamic therapy enhanced by magnetophoretically controlled magnetic microbubbles.

Sonodynamic therapy (SDT) utilizes ultrasonic excitation of a sensitizer to generate reactive oxygen species (ROS) to destroy tumor. Two dimensional (2D) black phosphorus (BP) is an emerging sonosensitizer that can promote ROS production to be used in SDT but it alone lacks active targeting effect and showed low therapy efficiency. In this study, a stable dispersion of integrated micro-nanoplatform consisting of BP nanosheets loaded and Fe3O4 nanoparticles (NPs) connected microbubbles was introduced for ultrasound imaging guided and magnetic field directed precision SDT of breast cancer. The targeted ultrasound imaging at 18 MHz and efficient SDT effects at 1 MHz were demonstrated both in-vitro and in-vivo on the breast cancer. The magnetic microbubbles targeted deliver BP nanosheets to the tumor site under magnetic navigation and increased the uptake of BP nanosheets by inducing cavitation effect for increased cell membrane permeability via ultrasound targeted microbubble destruction (UTMD). The mechanism of SDT by magnetic black phosphorus microbubbles was proposed to be originated from the ROS triggered mitochondria mediated apoptosis by up-regulating the pro-apoptotic proteins while down-regulating the anti-apoptotic proteins. In conclusion, the ultrasound theranostic was realized via the magnetic black phosphorus microbubbles, which could realize targeting and catalytic sonodynamic therapy.

Quality assurance for focused ultrasound-induced blood-brain barrier opening procedure using passive acoustic detection.

BACKGROUND: Focused ultrasound (FUS) combined with microbubbles is a promising technique for noninvasive, reversible, and spatially targeted blood-brain barrier opening, with clinical trials currently ongoing. Despite the fast development of this technology, there is a lack of established quality assurance (QA) strategies to ensure procedure consistency and safety. To address this challenge, this study presents the development and clinical evaluation of a passive acoustic detection-based QA protocol for FUS-induced blood-brain barrier opening (FUS-BBBO) procedure. METHODS: Ten glioma patients were recruited to a clinical trial for evaluating a neuronavigation-guided FUS device. An acoustic sensor was incorporated at the center of the FUS device to passively capture acoustic signals for accomplishing three QA functions: FUS device QA to ensure the device functions consistently, acoustic coupling QA to detect air bubbles trapped in the acoustic coupling gel and water bladder of the transducer, and FUS procedure QA to evaluate the consistency of the treatment procedure. FINDINGS: The FUS device passed the device QA in 9/10 patient studies. 4/9 cases failed acoustic coupling QA on the first try. The acoustic coupling procedure was repeatedly performed until it passed QA in 3/4 cases. One case failed acoustic coupling QA due to time constraints. Realtime passive cavitation monitoring was performed for FUS procedure QA, which captured variations in FUS-induced microbubble cavitation dynamics among patients. INTERPRETATION: This study demonstrated that the proposed passive acoustic detection could be integrated with a clinical FUS system for the QA of the FUS-BBBO procedure. FUNDING: National Institutes of Health R01CA276174, R01MH116981, UG3MH126861, R01EB027223, R01EB030102, and R01NS128461.

Vectorized facial skin tightening: A study on the Thermal Thread Technique™ utilizing high-intensity, high-frequency, parallel ultrasound beam.

BACKGROUND: Facial skin tightening with wrinkle/fine line reduction is a highly demanded procedure in the aesthetic field. Although there are studies focused on the types of energy sources, the total amount of thermal energy, and the affected depth, there have been no reports examining the relationship between the shape of thermal energy and the directivity of skin tightening. We have developed a specific method to apply thermal energy to the dermis in continuous parallel lines, resembling a thread, perpendicular to the Relaxed Skin Tension Lines (RSTL) for vectorized collagen contraction using synchronous ultrasound parallel beam technology. OBJECTIVE: To evaluate the safety, tightening capability, and directivity of the Thermal Thread Technique™ utilizing a high-intensity, high-frequency, parallel ultrasound beam. MATERIALS AND METHODS: A total of 34 cases, both males and females aged between 30 and 70 years with Fitzpatrick skin types 2-4, exhibiting mild to moderate skin laxity, participated. All subjects received one treatment using the Thermal Thread Technique™ utilizing high-intensity, high-frequency parallel ultrasound beam to cover the full face and submental area. 3D clinical images were captured before, 8 weeks, and 24 weeks after the treatment. A quantitative image analysis of captured 3D images was performed to objectively measure the direction and distance of contraction. RESULTS: The average contraction distance from baseline (0 mm) to 8 weeks and 24 weeks posttreatment were 1.91 ± 0.61 mm (p < 0.001) and 1.96 ± 0.67 mm (p < 0.001) respectively. Regarding the contraction direction at 24 weeks posttreatment, the angle formed between the contraction direction and the base axis, which is perpendicular to the RSTL, was + 9.85° ± 32.94°. Out of 34 cases, 28 met the criteria with the angle within ±22.5° of the base axis (p < 0.001). The average pain score on a 0-5 scale (0 being no pain, and 5 being maximum pain) was 2.63 ± 0.78. No side effects were reported during the treatment or observation period. CONCLUSION: The Thermal Thread Technique™ utilizing a high-intensity, high-frequency, parallel ultrasound beam was proven to be clinically safe and effective for vectorized facial skin tightening.

A cancer cell nanotherapy method based on GHz film bulk acoustic resonator and nanoscale CaO2.

Sonodynamic therapy (SDT) is an emerging cancer treatment method in recent years. However, the ultrasound signal utilized for SDT is usually located at a low-frequency spectrum (<2 MHz), and in the field of SDT research, few studies have focused on the exploration and development of ultrasound frequency. Studies have shown that the GHz-level ultrasound can increase cell membrane permeability and have a negligible effect on cell vitality. Herein, we reported the study of a GHz thin film bulk acoustic resonator as an ultrasound source for synergistic treatment with nanoscale calcium peroxide (CaO2). It was discovered that this ultrasound source ultimately achieved an efficient therapeutic outcome on mouse breast cancer cell line 4T1. Such GHz-level ultrasound application in SDT is of high significance to broaden the cognition and application scope of SDT.

The impact of ischemic vascular stenosis on LIPU hyperthermia efficacy investigated Based on in vivo rabbit limb ischemia model.

Ischemic diseases due to arterial stenosis or occlusion are common and can have serious consequences if untreated. Therapeutic ultrasound like high-intensity focused ultrasound (HIFU) ablates tissues while low-intensity pulsed ultrasound (LIPU) promotes healing at relatively low temperatures. However, blood vessel cooling effect and reduced flow in ischemia impact temperature distribution and ultrasonic treatment efficacy. This work established a rabbit limb ischemia model by ligating the femoral artery, measuring vascular changes and temperature rise during LIPU exposures. Results showed the artery diameter was narrowed by 46.2% and the downstream velocity was reduced by 51.3% after ligation. Finite element simulations verified that the reduced flow velocity impaired heat dissipation, enhancing LIPU-induced heating. Simulation results also suggested the temperature rise was almost related linearly to vessel diameter but decayed exponentially with the increasing flow velocity. Findings indicate that the proposed model could be used as an effectively tool to model the heating effects in ischemic tissues during LIPU treatment. This research on relating varied ischemic flow to LIPU-induced thermal effects is significant for developing safe and efficacious clinical ultrasound hyperthermia treatment protocols for the patients with ischemic diseases.

Safety Review of Therapeutic Ultrasound for Spinal Cord Neuromodulation and Blood-Spinal Cord Barrier Opening.

New focused ultrasound spinal cord applications have emerged, particularly those improving therapeutic agent delivery to the spinal cord via blood-spinal cord barrier opening and the neuromodulation of spinal cord tracts. One hurdle in the development of these applications is safety. It may be possible to use safety trends from seminal and subsequent works in focused ultrasound to guide the development of safety guidelines for spinal cord applications. We collated data from decades of pre-clinical studies and illustrate a clear relationship between damage, time-averaged spatial peak intensity and exposure duration. This relationship suggests a thermal mechanism underlies ultrasound-induced spinal cord damage. We developed minimum and mean thresholds for damage from these pre-clinical studies. When these thresholds were plotted against the parameters used in recent pre-clinical ultrasonic spinal cord neuromodulation studies, the majority of the neuromodulation studies were near or above the minimum threshold. This suggests that a thermal neuromodulatory effect may exist for ultrasonic spinal cord neuromodulation, and that the thermal dose must be carefully controlled to avoid damage to the spinal cord. By contrast, the intensity-exposure duration threshold had no predictive value when applied to blood-spinal cord barrier opening studies that employed injected contrast agents. Most blood-spinal cord barrier opening studies observed slight to severe damage, except for small animal studies that employed an active feedback control method to limit pressures based on measured bubble oscillation behavior. The development of new focused ultrasound spinal cord applications perhaps reflects the recent success in the development of focused ultrasound brain applications, and recent work has begun on the translation of these technologies from brain to spinal cord. However, a great deal of work remains to be done, particularly with respect to developing and accepting safety standards for these applications.

Cathepsin B Responsive Peptide-Purpurin Conjugates Assembly-Initiated in Situ Self-Aggregation for Cancer Sonotheranostics.

Sonodynamic therapy (SDT) was hampered by the sonosensitizers with low bioavailability, tumor accumulation, and therapeutic efficiency. In situ responsive sonosensitizer self-assembly strategy may provide a promising route for cancer sonotheranositics. Herein, an intelligent sonotheranostic peptide-purpurin conjugate (P18-P) is developed that can self-assemble into supramolecular structures via self-aggregation triggered by rich enzyme cathepsin B (CTSB). After intravenous injection, the versatile probe could achieve deep tissue penetration because of the penetration sequence of P18-P. More importantly, CTSB-triggered self-assembly strongly prolonged retention time, amplified photoacoustic imaging signal for sensitive CTSB detection, and boosted reactive oxygen species for advanced SDT, evoking specific CTSB responsive sonotheranostics. This peptide-purpurin conjugate may serve as an efficient sonotheranostic platform for the early diagnosis of CTSB activity and effective cancer therapy.

Oxygen-Vacancy-Engineered W18 O49-x Nanobrush with a Suitable Band Structure for Highly Efficient Sonodynamic Therapy.

With the rapid development of external minimally invasive or noninvasive therapeutic modalities, ultrasound-based sonodynamic therapy (SDT) is a new alternative for treating deep tumors. However, inadequate sonosensitizer efficiency and poor biosecurity limit clinical applications. In this study, we prepared an oxygen-vacancy-engineered W18 O49-x nanobrush with a band gap of 2.79 eV for highly efficient SDT using a simple solvothermal method. The suitable band structures of the W18 O49-x nanobrush endows it with the potential to simultaneously produce singlet oxygen (1 O2 ), superoxide anions (⋅O2 - ), and hydroxyl radicals (⋅OH) under ultrasound irradiation. Additionally, abundant oxygen vacancies that serve as further charge traps that inhibit electron-hole recombination are incidentally introduced through one-step thermal reduction. Collectively, the in vitro and in vivo results demonstrate that the oxygen-vacancy-engineered W18 O49-x nanobrush delivers highly efficient reactive oxygen species (ROS) for SDT in a very biosafe manner. Overall, this study provides a new avenue for discovering and designing inorganic nanosonosensitizers with enhanced therapeutic efficiencies for use in SDT.

One Stone, Three Birds: Design and Synthesis of "All-in-One" Nanoscale Mn-Porphyrin Coordination Polymers for Magnetic Resonance Imaging-Guided Synergistic Photodynamic-Sonodynamic Therapy.

Multifunctional nanomaterials with potential applications in both bioimaging and photodynamic-sonodynamic therapy have great advantages in cancer theranostic, but the design and preparation of "all-in-one" type of multifunctional nanomaterials with single component remains challenging. Herein the "all-in-one" type of Mn-PpIX (Protoporphyrin IX) coordination polymers (MnPPs) was reported as efficient nano-photo/sonosensitizers. The MnPPs had an average size of âˆ¼ 110 nm. Upon light/US (ultrasound) irradiation for 5 min, 61.8 % (light) and 32.4 % (US) of DPBF (1.3-diphenyl isobenzofuran) was found to be oxidized by MnPPs, which showed effective ROS (reactive oxygen species) generation for photodynamic/sonodynamic therapy (PDT/SDT). In addition, MnPPs revealed excellent biosafety and could be engulfed by cells to produce intracellular ROS under light/US excitation for efficient killing tumor cells. When MnPPs was injected into mice, the tumor could be monitored via MRI (magnetic resonance imaging). In addition, tumor growth could be significantly inhibited by the synergistic PDT-SDT. Therefore, the present study not only represents MnPPs as an "all-in-one" type of multifunctional nanomaterials for MRI-guided PDT-SDT therapy, but also provides some insights for designing other PpIX-related molecules with the similar structure for bioapplication.

Evaluation of the cytotoxic and immunomodulatory effects of sonodynamic therapy in human pancreatic cancer spheroids.

Sonodynamic therapy (SDT) exploits the energy generated by ultrasound (US) to activate sound-sensitive drugs (sonosensitizers), leading to the generation of reactive oxygen species (ROS) and cancer cell death. Two-dimensional (2D) and three-dimensional (3D) cultures of human pancreatic cancer BxPC-3 cells were chosen as the models with which to investigate the therapeutic effects of the US-activated sonosensitizer IR-780 as pancreatic cancer is still one of the most lethal types of cancer. The effects of SDT, including ROS production, cancer cell death and immunogenic cell death (ICD), were extensively investigated. When subjected to US, IR-780 triggered significant ROS production and caused cancer cell death after 24 h (p ≤ 0.01). Additionally, the activation of dendritic cells (DCs) led to an effective immune response against the cancer cells undergoing SDT-induced death. BxPC-3 spheroids were developed and studied extensively to validate the findings observed in 2D BxPC-3 cell cultures. An analysis of the pancreatic cancer spheroid section revealed significant SDT-induced cancer cell death after 48 h after the treatment (p ≤ 0.01), with this being accompanied by the presence of SDT-induced damage-associated molecular patterns (DAMPs), such as calreticulin (CRT) and high mobility group box 1 (HMGB1). In conclusion, the data obtained demonstrates the anticancer efficacy of SDT and its immunomodulatory potential via action as an ICD-inducer.

Low-Intensity Pulsed Ultrasound Promotes the Repair of Achilles Tendinopathy by Downregulating the JAK/STAT Signaling Pathway in Rabbits.

Tendinopathy is a complex tendon injury or pathology outcome, potentially leading to permanent impairment. Low-intensity pulsed ultrasound (LIPUS) is emerging as a treatment modality for tendon disorders. However, the optimal treatment duration and its effect on tendons remain unclear. This study aims to investigate the efficacy of LIPUS in treating injured tendons, delineate the appropriate treatment duration, and elucidate the underlying treatment mechanisms through animal experiments. Ninety-six three-month-old New Zealand white rabbits were divided into normal control (NC) and model groups. The model group received Prostaglandin E2 (PGE2) injections to induce Achilles tendinopathy. They were then divided into model control (MC) and LIPUS treatment (LT) groups. LT received LIPUS intervention with a 1-MHz frequency, a pulse repetition frequency (PRF) of 1 kHz, and spatial average temporal average sound intensity ( [Formula: see text]) of 100 mW/cm2. MC underwent a sham ultrasound, and NC received no treatment. Assessments on 1, 4, 7, 14, and 28 days after LT included shear wave elastography (SWE), mechanical testing, histologic evaluation, ribonucleic acid sequencing (RNA-seq), polymerase chain reaction (PCR), and western blot (WB) analysis. SWE results showed that the shear modulus in the LT group was significantly higher than that in the MC group after LT for seven days. Histological results demonstrated improved tendon tissue alignment and fibroblast distribution after LT. Molecular analyses suggested that LIPUS may downregulate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway and regulate inflammatory and matrix-related factors. We concluded that LT enhanced injured tendon elasticity and accelerated Achilles tendon healing. The study highlighted the JAK/STAT signaling pathway as a potential therapeutic target for LT of Achilles tendinopathy, guiding future research.

An Ultrasound Array of Emitter-Receiver Stacks for Microbubble-Based Therapy.

Most therapeutic ultrasound devices place emitters and receivers in separate locations, so that the long therapeutic pulses (>1 ms) can be emitted while receivers monitor the procedure. However, with such placement, emitters and receivers are competing for the same space, producing a trade-off between emission efficiency and reception sensitivity. Taking advantage of recent studies demonstrating that short-pulse ultrasound can be used therapeutically, we aimed to develop a device that overcomes such trade-offs. The array was composed of emitter-receiver stacks, which enabled both emission and reception from the same location. Each element was made of a lead zirconate titanate (PZT)-polyvinylidene fluoride (PVDF) stack. The PZT (frequency: 500 kHz, diameter: 16 mm) was used for emission and the PVDF (thickness: 28 µm, diameter: 16 mm) for broadband reception. 32 elements were assembled in a 3D-printed dome-shaped frame (focal length: 150 mm; [Formula: see text]-number: 1) and was tested in free-field and through an ex-vivo human skull. In free-field, the array had a 4.5 × 4.5 × 32 mm focus and produced a peak-negative pressure (PNP) of 2.12 MPa at its geometric center. The electronic steering range was ±15 mm laterally and larger than ±15 mm axially. Through the skull, the array produced a PNP of 0.63 MPa. The PVDF elements were able to localize broadband microbubble emissions across the skull. We built the first multi-element array for short-pulse and microbubble-based therapeutic applications. Stacked arrays overcome traditional trade-offs between the transmission and reception quality and have the potential to create a step change in treatment safety and efficacy.

Glucosylated Hybrid TiO2 /Polymer Nanomaterials for Actively Targeted Sonodynamic Therapy of Cancer.

Sonodynamic therapy (SDT) is an anti-cancer therapeutic strategy based on the generation of reactive oxygen species (ROS) upon local ultrasound (US) irradiation of sono-responsive molecules or nanomaterials that accumulate in the tumor. In this work, the sonodynamic efficiency of sono-responsive hybrid nanomaterials composed of amorphous titanium dioxide and an amphiphilic poly(ethylene oxide)-b-poly(propylene oxide) block copolymer is synthesized, fully characterized, and investigated both in vitro and in vivo. The modular and versatile synthetic pathway enables the control of the nanoparticle size between 30 and 300 nm (dynamic light scattering) and glucosylation of the surface for active targeting of tumors overexpressing glucose transporters. Studies on 2D and 3D rhabdomyosarcoma cell cultures reveal a statistically significant increase in the sonodynamic efficiency of glucosylated hybrid nanoparticles with respect to unmodified ones. Using a xenograft rhabdomyosarcoma murine model, it is demonstrated that by tuning the nanoparticle size and surface features, the tumor accumulation is increased by ten times compared to main off-target clearance organs such as the liver. Finally, the SDT of rhabdomyosarcoma-bearing mice is investigated with 50-nm glucosylated nanoparticles. Findings evidence a dramatic prolongation of the animal survival and tumor volumes 100 times smaller than those treated only with ultrasound or nanoparticles.

Exploring Different Ultrasonic Parameters and Treatment Conditions to Optimize In Vitro Sonodynamic Therapeutic Effects in Cancer Cells.

The effects of ultrasonic parameters and treatment conditions on the in vitro cellular experiments of sonodynamic therapy (SDT) have not been fully studied. Exploring the factors that affect the efficacy of SDT can provide a reference for screening effective sonosensitizers in vitro. The aim of this work is to investigate the factors that affected the SDT effects in cancer cells. Cancer cells in culture plates were exposed to ultrasound and sonosensitizers. The intracellular drug concentration was measured by using flow cytometry and the cell viability was determined by MTT assay. The SDT effects of cancer cells treated with different ultrasonic parameters under the same sonosensitizer concentration were different. The ultrasonic parameters, intracellular drug concentration, drug treatment time, cell amount, and cell status could affect the sonodynamic therapeutic effects. It is necessary to select appropriate ultrasound conditions and optimize the cellular status to make the results of the in vitro cellular experiments more reliable.

[Effectiveness of low-intensity pulsed ultrasound in patients after osteotomy: A systematic review]. / Efectividad del ultrasonido pulsado de baja intensidad en pacientes tras osteotomía: una revisión sistemática.

The use of low intensity pulsed ultrasound (LIPUS) therapy for bone healing and fracture treatment is increasingly considered as a therapeutic alternative with moderate economic cost and none or minimal adverse effects (e.g., low reaction to the conductive gel). However, there is some controversy regarding its scientific evidence. The present review seeks to shed some light on this controversy and to cover an area of study not occupied by previous or current work on ultrasound therapy. It is necessary to know the real impact of the treatment with low intensity pulsed ultrasound in patients with osteotomy, as well as its applicability as a post-surgery protocol to improve the recovery and rehabilitation processes and, at the end of the day, to reduce the time of disability.