Noninvasive release of tendons using MRI guided focused ultrasound: a hybrid therapy using long-pulse focused ultrasound followed by thermal ablation.

INTRODUCTION: Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thermal ablation is an effective noninvasive ultrasonic therapy to disrupt in vivo porcine tendon but is prone to inducing skin burns. We evaluated the safety profile of a novel hybrid protocol that minimizes thermal spread by combining long-pulse focused ultrasound followed by thermal ablation. METHODS: In-vivo Achilles tendons (hybrid N = 15, thermal ablation alone N = 21) from 15 to 20 kg Yorkshire pigs were randomly assigned to 6 treatment groups in two studies. The first (N = 21) was ablation (600, 900, or 1200 J). The second (N = 15) was hybrid: pulsed FUS (13.5 MPa peak negative pressure) followed by ablation (600, 900, or 1200 J). Measurements of ankle range of motion, tendon temperature, thermal dose (240 CEM43), and assessment of skin burn were performed in both groups. RESULTS: Rupture was comparable between the two protocols: 1/5 (20%), 5/5 (100%) and 5/5 (100%) for hybrid protocol, compared to 2/7 (29%), 6/7 (86%) and 7/7 (100%) for the ablation-only protocol with energies of 600, 900, and 1200 J, respectively. The hybrid protocol produced lower maximum temperatures, smaller areas of thermal dose, fewer thermal injuries to the skin, and fewer full-thickness skin burns. The standard deviation for the area of thermal injury was also smaller for the hybrid protocol, suggesting greater predictability. CONCLUSION: This study demonstrated a hybrid MRgFUS protocol combining long-pulse FUS followed by thermal ablation to be noninferior and safer than an ablation-only protocol for extracorporeal in-vivo tendon rupture for future clinical application for noninvasive release of contracted tendon.

Current clinical investigations of focused ultrasound blood-brain barrier disruption: A review.

The blood-brain barrier (BBB) presents a formidable challenge in delivering therapeutic agents to the central nervous system. Ultrasound-mediated BBB disruption has emerged as a promising non-invasive technique to enhance drug delivery to the brain. This manuscript reviews fundamental principles of ultrasound-based techniques and their mechanisms of action in temporarily permeabilizing the BBB. Clinical trials employing ultrasound for BBB disruption are discussed, summarizing diverse applications ranging from the treatment of neurodegenerative diseases to targeted drug delivery for brain tumors. The review also addresses safety considerations, outlining the current understanding of potential risks and mitigation strategies associated with ultrasound exposure, including real-time monitoring and assessment of treatment efficacy. Among the large number of studies, significant successes are highlighted thus providing perspective on the future direction of the field.

The value of low-intensity pulsed ultrasound in reducing ovarian injury caused by chemotherapy in mice.

BACKGROUND: Ovarian damage and follicle loss are major side effects of chemotherapy in young female patients with cancer. However, effective strategies to prevent these injuries are still lacking. The purpose of this study was to verify low-intensity pulsed ultrasound (LIPUS) can reduce ovarian injury caused by chemotherapy and to explore its underlying mechanisms in mice model. METHODS: The mice were randomly divided into the Control group, Cisplatin group, and Cisplatin + LIPUS group. The Cisplatin group and Cisplatin + LIPUS group were intraperitoneally injected with cisplatin every other day for a total of 10 injections, and the Control group was injected with saline. On the second day of each injection, the Cisplatin + LIPUS group received irradiation, whereas the other two groups received sham irradiation. We used a variety of biotechnologies to detect the differences in follicle count, granulosa cell apoptosis, fibrosis, transcriptome level, oxidative damage, and inflammation in differently treated mice. RESULT: LIPUS was able to reduce primordial follicle pool depletion induced by cisplatin and inhibit the apoptosis of granulosa cells. Transcriptomic results confirmed that LIPUS can reduce ovarian tissue injury. We demonstrated that LIPUS can relieve ovarian fibrosis by inhibiting TGF-ß1/Smads pathway. Meanwhile, it can reduce the oxidative damage and reduced the mRNA levels of proinflammatory cytokines caused by chemotherapy. CONCLUSION: LIPUS can reduce the toxic effects of chemotherapy drugs on ovaries, inhibit ovarian fibrosis, reduce the inflammatory response, and redcue the oxidative damage, reduce follicle depletion and to maintain the number of follicle pools.

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.

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.

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.

High-spatial-resolution transcranial focused ultrasound neuromodulation using frequency-modulated pattern interference radiation force.

Stimulating the brain in a precise location is crucial in ultrasound neuromodulation. However, improving the resolution proves a challenge owing to the characteristics of transcranial focused ultrasound. In this paper, we present a new neuromodulation system that overcomes the existing limitations based on an acoustic radiation force with a frequency-modulated waveform and standing waves. By using the frequency-modulated pattern interference radiation force (FM-PIRF), the axial spatial resolution can be reduced to a single wavelength level and the target location can be controlled in axial direction electronically. A linear frequency-modulated chirp waveform used in the experiment was designed based on the simulation results. The displacement of the polydimethylsiloxane (PDMS) cantilever was measured at intervals of 0.1 mm to visualize the distribution of radiation force. These results and methods experimentally show that FM-PIRF has improved spatial resolution and capability of electrical movement.

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.

Synchronized Chemotherapy/Photothermal Therapy/Sonodynamic Therapy of Human Triple-Negative and Estrogen Receptor-Positive Breast Cancer Cells Using a Doxorubicin-Gold Nanoclusters-Albumin Nanobioconjugate.

OBJECTIVE: Novel strategies for treating triple-negative breast cancer (TNBC) are ongoing because of the lack of standard-of-care treatment. Nanoframed materials with a protein pillar are considered a valuable tool for designing multigoals of energy-absorbing/medication cargo and are a bridge to cross-conventional treatment strategies. METHODS: Nanobioconjugates of gold nanoclusters-bovine serum albumin (AuNCs-BSA) and doxorubicin-AuNCs-BSA (Dox-AuNCs-BSA) were prepared and employed as a simultaneous double photosensitizer/sonosensitizer and triple chemotherapeutic/photosensitizer/sonosensitizer, respectively. RESULTS: The highly stable AuNCs-BSA and Dox-AuNCs-BSA have ζ potentials of -29 and -18 mV, respectively, and represent valuable photothermal and sonodynamic activities for the combination of photothermal therapy and sonodynamic therapy (PTT/SDT) and synchronized chemotherapy/photothermal therapy/sonodynamic therapy (CTX/PTT/SDT) of human TNBC cells, respectively. The efficiency of photothermal conversion of AuNCs-BSA was calculated to be a promising value of 32.9%. AuNCs-BSA and Dox-AuNCs-BSA were activated on either laser light irradiation or ultrasound exposure with the highest efficiency on the combination of both types of radiation. CTX/PTT/SDT of MCF-7 and MDA-MB-231 breast cancer cell lines by Dox-AuNCs-BSA were evaluated with the MTT cell proliferation assay and found to progress synergistically. CONCLUSION: Results of the MTT assay, detection of the generation of intracellular reactive oxygen species and occurrence of apoptosis in the cells confirmed that CTX/PTT/SDT by Dox-AuNCs-BSA was attained with lower needed doses of the drug and improved tumor cell ablation, which would result in the enhancement of therapeutic efficacy and overcoming of therapeutic resistance.

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.

Analyzing Gene Expression After Administration of Low-Intensity Therapeutic Ultrasound in Human Islet Cells.

OBJECTIVES: Diabetes mellitus is a complex heterogenous metabolic disease that significantly affects the world population. Although many treatments exist, including medications such as metformin, sulfonylureas, and glucagon-like peptide-1 (GLP) receptor agonist, there is growing interest in finding alternative methods to noninvasively treat this disease. It has been previously shown that low-intensity ultrasound stimulation of pancreatic ß-cells in mice can elicit insulin secretion as a potential treatment for this disease. This is desirable as therapeutic ultrasound has the ability to induce bioeffects while selectively focusing deep within tissues, allowing for modulation of hormone secretion in the pancreas to mitigate insufficient levels of insulin. METHODS: Exactly 800 kHz ultrasound with intensity 0.5 W/cm2 was administered 5 minutes continuously, that is, 100% duty cycle, to donor pancreatic human islets, followed by 1 hour incubation and RT-qPCR to assess the effect of ultrasound stimulation on gene expression. The genes were insulin (INS), glucagon (Glu), amylin (Amy), and binding immunoglobulin protein (BiP). Nine donor pancreatic human islets were used to assess insulin and glucagon secretion, while eight samples were used for amylin and BiP. Fold change (FC) was calculated to analyze the effect of ultrasound stimulation on the gene expression of the donor islet cells. High-glucose and thapsigargin-treated islets were utilized as positive controls. Cell viability testing was done using a Trypan Blue Exclusion Test. RESULTS: Ultrasound stimulation did not cause a statistically significant upregulation in any of the tested genes (INS FC = 1.15, P-value = .5692; Glu FC = 1.60, P-value = .2231; Amy FC, P-value = .2863; BiP FC = 2.68, P-value = .3907). CONCLUSIONS: The results of this study show that the proposed ultrasound treatment parameters do not appear to significantly affect gene expression of any gene tested.

Focused ultrasound stimulation of infralimbic cortex attenuates reinstatement of methamphetamine-induced conditioned place preference in rats.

Methamphetamine (MA) use disorder poses significant challenges to both the affected individuals and society. Current non-drug therapies like transcranial direct-current stimulation and transcranial magnetic stimulation have limitations due to their invasive nature and limited reach to deeper brain areas. Transcranial focused ultrasound (FUS) is gaining attention as a noninvasive option with precise spatial targeting, able to affect deeper areas of the brain. This research focused on assessing the effectiveness of FUS in influencing the infralimbic cortex (IL) to prevent the recurrence of MA-seeking behavior, using the conditioned place preference (CPP) method in rats. The study involved twenty male Sprague-Dawley rats. Neuronal activation by FUS was first examined via electromyography (EMG). Rats received alternately with MA or saline, and confined to one of two distinctive compartments in a three compartment apparatus over a 4-day period. After CPP test, extinction, the first reinstatement, and extinction again, FUS was applied to IL prior to the second MA priming-induced reinstatement. Safety assessments were conducted through locomotor and histological function examinations. EMG data confirmed the effectiveness of FUS in activating neurons. Significant attenuation of reinstatement of MA CPP was found, along with successful targeting of the IL region, confirmed through acoustic field scanning, c-Fos immunohistochemistry, and Evans blue dye staining. No damage to brain tissue or impaired locomotor activity was observed. The results of the study indicate that applying FUS to the IL markedly reduced the recurrence of MA seeking behavior, without harming brain tissue or impairing motor skills. This suggests that FUS could be a promising method for treating MA use disorder, with the infralimbic cortex being an effective target for FUS in preventing MA relapse.

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.

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.

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.

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.

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.

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.