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BACKGROUND: In recent years, increasing studies have shown that low-intensity pulsed ultrasound can promote the healing of acute tendon injuries, but the specific mechanism is still unclear. OBJECTIVE: To observe the effect of low-intensity pulsed ultrasound on early angiogenesis after acute tendon injury, and to detect the regulatory relationship of low-intensity pulsed ultrasound with vascular endothelial growth factor-related signaling pathways, so as to reveal its potential mechanism of action. METHODS: Animal models of acute Achilles tendon injury were established using local injection of type I collagenase for 3 days in SPF male Sprague-Dawley rats aged 8-12 weeks, and were then randomly divided into ultrasound group and control group. In the ultrasound group, low-intensity pulsed ultrasound was treated daily with a small ultrasonic probe with an effective radiation area of 1 cm2 perpendicular to the Achilles tendon. No intervention was performed in the control group. Ultrasound imaging examination was performed 2 weeks later to observe the early healing of the tendon. Hematoxylin-eosin staining and CD31 immunohistochemical staining were performed to observe the changes in the number of blood vessels in the tissues after 1 and 2 weeks of treatment. The expression of vascular endothelial growth factor-related signaling pathway molecules in Achilles tendon tissues was detected by western blot or qRT-PCR. RESULTS AND CONCLUSION: Compared with the control group, the Achilles tendon in the ultrasound group was more continuous, the echo intensity was lower and more uniform, and the tendon thickness was significantly reduced (P < 0.05). Hematoxylin-eosin staining and CD31 immunohistochemical staining results showed that after 2 weeks of treatment, the number of new vessels in the ultrasound group was significantly increased compared with the control group (P < 0.05). Western blot and qRT-PCR results showed that after 2 weeks of continuous ultrasound intervention, the protein or mRNA expressions of vascular endothelial growth factor, Yes-associated protein, angiopoietin-2 and cysteine-rich angiogenic inducer 61 in the Achilles tendon of the ultrasound group were significantly higher than those of the control group (P < 0.05). These finding indicate that low-intensity pulsed ultrasound significantly increases the number of blood vessels in the early stage of acute tendon injury and accelerate tendon healing by up-regulating vascular endothelial growth factor expression. [ABSTRACT FROM AUTHOR]

Low-intensity pulsed ultrasound (LIPUS) is a potential effective means for the prevention and treatment of disuse osteoporosis. In this paper, the effect of LIPUS exposure on the mechanical properties distribution of the osteocyte system (osteocyte body contains nucleus, osteocyte process, and primary cilia) is simulated. The results demonstrate that the mechanical micro-environment of the osteocyte is significantly improved by ultrasound exposure, and the mean von Mises stress of the osteocyte system increases linearly with the excitation sound pressure amplitude. The mechanical effect of LIPUS on osteocytes is enhanced by the stress amplification mechanism of the primary cilia and osteocyte processes. [ABSTRACT FROM AUTHOR]

This study involved the proliferation and differentiation of osteoblasts treated with low-intensity pulsed ultrasound (LIPUS) and iron (Fe3+) ions, respectively. The biological effects of LIPUS and Fe3+ ions on the proliferation and differentiation of osteoblasts were also evaluated. MC3T3-E1 cells were seeded in six-well plates with the medium, which contained different concentrations of Fe3+ (0, 100, 200, 300, 400, 500, 600 and 700 μg L-1, respectively). LIPUS treatment was directed at the bottom of the plate for 20 min at an intensity of 80 mW cm-2 every day. Viability results showed that a dose of 400 μg L-1 Fe3+ ions had the best effect at promoting osteogenic proliferation in cell culture. The results of alkaline phosphatase staining and mineralization indicated that the differentiation of osteoblasts was promoted by LIPUS and Fe3+ ions. Fluorescence staining results showed that the number of cell nuclei in the LIPUS, Fe3+ and LIPUS-Fe groups increased by 37.20%, 55.81% and 89.76%, respectively. Migration data indicated that migration and proliferation rates were increased by LIPUS and Fe3+, and the results of protein expression indicated that LIPUS and Fe3+ may increase the expression of Wnt, β-catenin, and Runx2, hence promoting normal bone regeneration and development. The combination of LIPUS (1.5 MHz, 80 mW cm-2) and Fe3+ accelerates the proliferation and differentiation of osteoblasts significantly compared with single-factor treatment (stimulated by LIPUS and Fe3+ ions, respectively). This study could establish a foundation for LIPUS-responsive biomaterials in the repair and regeneration of bone tissues. [ABSTRACT FROM AUTHOR]

Background: Low-intensity pulsed ultrasound (LIPUS) is a non-invasive therapy that accelerates fracture healing. As a new treatment method for fracture, we recently reported that the transcutaneous application of CO2 accelerated fracture healing in association with promoting angiogenesis, blood flow, and endochondral ossification. We hypothesized that transcutaneous CO2 application, combined with LIPUS, would promote bone fracture healing more than the single treatment with either of them. Methods: Femoral shaft fractures were produced in 12-week-old rats. Animals were randomly divided into four groups: the combination of CO2 and LIPUS, CO2, LIPUS, and control groups. As the transcutaneous CO2 application, the limb was sealed in a CO2-filled bag after applying hydrogel that promotes CO2 absorption. Transcutaneous CO2 application and LIPUS irradiation were performed for 20 min/day, 5 days/week. At weeks 1, 2, 3, and 4 after the fractures, we assessed the fracture healing process using radiography, histology, immunohistochemistry, real-time PCR, and biomechanical assessment. Results: The fracture healing score using radiographs in the combination group was significantly higher than that in the control group at all time points and those in both the LIPUS and CO2 groups at weeks 1, 2, and 4. The degree of bone fracture healing in the histological assessment was significantly higher in the combination group than that in the control group at weeks 2, 3, and 4. In the immunohistochemical assessment, the vascular densities of CD31- and endomucin-positive microvessels in the combination group were significantly higher than those in the control and LIPUS groups at week 2. In the gene expression assessment, significant upregulation of runt-related transcription factor 2 (Runx2) and vascular endothelial growth factor (VEGF) was detected in the combination group compared to the LIPUS and CO2 monotherapy groups. In the biomechanical assessment, the ultimate stress was significantly higher in the combination group than in the LIPUS and CO2 groups. Conclusion: The combination therapy of transcutaneous CO2 application and LIPUS had a superior effect in promoting fracture healing through the promotion of angiogenesis and osteoblast differentiation compared to monotherapy. [ABSTRACT FROM AUTHOR]

Low‐intensity pulsed ultrasound (LIPUS) and electrical stimulation (ES) are effective methods that promote neural repair. However, ES usually requires electrode implantation and a power supply, which are an inconvenience to future applications. Meanwhile, it is difficult to combine ultrasound and ES through traditional methods. Herein, a nanopatch consisting of an oriented barium titanate (BTO)‐incorporated polycaprolactone (PCL) nanofiber membrane for electricity generation and a layer of graphene oxide (GO)‐doped gelatin methacryloyl (GelMA) for neural interaction is developed. This band‐aid‐like BTO@PCL/GO@GelMA nanopatch has an excellent piezoelectric performance. In vitro, the nanopatches significantly promote axonal growth under LIPUS treatment. In a rat model of erectile dysfunction caused by peripheral nerve injury, the nanopatch is easily attached to a damaged nerve similar to a band‐aid. With the assistance of ultrasound, some mechanical energy is converted into electricity by the nanopatch, and synergistic neural stimulation of ultrasound and electricity is achieved. In this way, the nanopatch significantly promoted corpus cavernosum nerve repair, resulting in the improvement of tissue structure and erectile function as well as increased conception rate in female rats. In conclusion, the nanopatch offers a synergistic ultrasound‐ES for nerve repair easily and represents a novel strategy for peripheral nerve repair. [ABSTRACT FROM AUTHOR]

Objective: The primary objective of this clinical trial is to investigate the effect of low-intensity pulsed ultrasound (LIPUS) on patients suffering from comorbid erectile dysfunction (ED) and chronic prostatitis/chronic pelvic pain syndrome(CP/CPPS). Methods: The clinical trial was conducted in the andrology outpatient treatment room of the Department of Urology, Xiangya Hospital, Central South University from August to November 2022 A total of 60 patients who met the research criteria for comorbid ED combined with CP/CPPS were recruited and randomly assigned to three treatment groups. They were treated with LIPUS (Group A), drug therapy(Group B), and LIPUS combined with drug therapy (Group C), respectively. Each group comprised 20 patients. Statistical analysis was performed on the five-item version of International Index of Erectile Function (IIEF-5), Erection Hardness Score (EHS), National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the nine-item Patient Health Questionnaire (PHQ-9), the seven-item Generalized Anxiety Disorder Scale (GAD-7), and the incidence of adverse events to comprehensively evaluate the efficacy and safety of LIPUS. Results: The positive response rate of ED and CP/CPPS treatment in Group A is 40%(8/20) and 45%(9/20), while those in Group B is 55%(11/20) and 60%(12/20), and those in Group C is 85%(17/20) and 85%(17/20). A notable increase in IIEF-5 scores was observed across the three groups post-treatment (10.45 ± 2.50 vs. 13.65 ± 3.03, P = 0.008; 11.80 ± 3.21 vs. 16.40 ± 3.20, P = 0.011; 12.90 ± 3.92 vs. 19.40 ± 2.35, P = 0.042) with a concomitant significant decrease in NIH-CPSI scores (16.75 ± 4.53 vs. 14.65 ± 4.51, P = 0.016; 16.35 ± 4.32 vs. 12.20 ± 4.74, P = 0.007; 16.00 ± 4.40 vs. 8.15 ± 4.28, P = 0.021). Notably, the most pronounced changes were seen in the group receiving LIPUS combined with tadalafil and doxazosin. Additionally, all groups exhibited marked improvements in anxiety and depression symptoms post-treatment. No adverse events were observed during treatment. Conclusion: LIPUS can improve erectile function and CP/CPPS symptoms with good safety, and LIPUS combined with tadalafil and doxazosin is more effective during the treatment. However, its long-term efficacy remains to be seen. Trial Registration: Chinese Clinical Trial Registry; approval number: ChiCTR2200063038 (https://www.chictr.org.cn/) on August 29, 2022. [ABSTRACT FROM AUTHOR]

Novel methods and technologies that improve mesenchymal stem cells (MSCs) proliferation and differentiation properties are required to increase their clinical efficacy. Photobiomodulation (PBM) and low-intensity pulsed ultrasound (LIPUS) are two strategies that can be used to enhance the regenerative properties of dental MSCs. This study evaluated the cytocompatibility and osteo/odontogenic differentiation of dental pulp, periodontal ligament, and gingival MSCs after stimulation by either PBM or LIPUS and their combined effect. MTT assay, cell migration assay, osteo/odontogenic differentiation by AR staining and ALP activity, and expression of osteo/odontogenic markers (OPG, OC, RUNX2, DSPP, DMP1) by RT-qPCR were evaluated. Statistical analysis was performed using ANOVA, followed by Tukey's post hoc test, with a p-value of less than 0.05 considered significant. The results showed that combined stimulation by PBM and LIPUS resulted in significantly the highest viability of MSCs, the fastest migration, the most dense AR staining, the most increased ALP activity, and the most elevated levels of osteogenic and odontogenic markers. The synergetic stimulation of PBM and LIPUS can be utilized in cell-based regenerative approaches to promote the properties of dental MSCs. [ABSTRACT FROM AUTHOR]

Abstract Background Low-intensity pulsed ultrasound (LIPUS) is a non-invasive therapy that accelerates fracture healing. As a new treatment method for fracture, we recently reported that the transcutaneous application of CO2 accelerated fracture healing in association with promoting angiogenesis, blood flow, and endochondral ossification. We hypothesized that transcutaneous CO2 application, combined with LIPUS, would promote bone fracture healing more than the single treatment with either of them. Methods Femoral shaft fractures were produced in 12-week-old rats. Animals were randomly divided into four groups: the combination of CO2 and LIPUS, CO2, LIPUS, and control groups. As the transcutaneous CO2 application, the limb was sealed in a CO2-filled bag after applying hydrogel that promotes CO2 absorption. Transcutaneous CO2 application and LIPUS irradiation were performed for 20 min/day, 5 days/week. At weeks 1, 2, 3, and 4 after the fractures, we assessed the fracture healing process using radiography, histology, immunohistochemistry, real-time PCR, and biomechanical assessment. Results The fracture healing score using radiographs in the combination group was significantly higher than that in the control group at all time points and those in both the LIPUS and CO2 groups at weeks 1, 2, and 4. The degree of bone fracture healing in the histological assessment was significantly higher in the combination group than that in the control group at weeks 2, 3, and 4. In the immunohistochemical assessment, the vascular densities of CD31- and endomucin-positive microvessels in the combination group were significantly higher than those in the control and LIPUS groups at week 2. In the gene expression assessment, significant upregulation of runt-related transcription factor 2 (Runx2) and vascular endothelial growth factor (VEGF) was detected in the combination group compared to the LIPUS and CO2 monotherapy groups. In the biomechanical assessment, the ultimate stress was significantly higher in the combination group than in the LIPUS and CO2 groups. Conclusion The combination therapy of transcutaneous CO2 application and LIPUS had a superior effect in promoting fracture healing through the promotion of angiogenesis and osteoblast differentiation compared to monotherapy.

Abstract Objective The primary objective of this clinical trial is to investigate the effect of low-intensity pulsed ultrasound (LIPUS) on patients suffering from comorbid erectile dysfunction (ED) and chronic prostatitis/chronic pelvic pain syndrome(CP/CPPS). Methods The clinical trial was conducted in the andrology outpatient treatment room of the Department of Urology, Xiangya Hospital, Central South University from August to November 2022 A total of 60 patients who met the research criteria for comorbid ED combined with CP/CPPS were recruited and randomly assigned to three treatment groups. They were treated with LIPUS (Group A), drug therapy(Group B), and LIPUS combined with drug therapy (Group C), respectively. Each group comprised 20 patients. Statistical analysis was performed on the five-item version of International Index of Erectile Function (IIEF-5), Erection Hardness Score (EHS), National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the nine-item Patient Health Questionnaire (PHQ-9), the seven-item Generalized Anxiety Disorder Scale (GAD-7), and the incidence of adverse events to comprehensively evaluate the efficacy and safety of LIPUS. Results The positive response rate of ED and CP/CPPS treatment in Group A is 40%(8/20) and 45%(9/20), while those in Group B is 55%(11/20) and 60%(12/20), and those in Group C is 85%(17/20) and 85%(17/20). A notable increase in IIEF-5 scores was observed across the three groups post-treatment (10.45 ± 2.50 vs. 13.65 ± 3.03, P = 0.008; 11.80 ± 3.21 vs. 16.40 ± 3.20, P = 0.011; 12.90 ± 3.92 vs. 19.40 ± 2.35, P = 0.042) with a concomitant significant decrease in NIH-CPSI scores (16.75 ± 4.53 vs. 14.65 ± 4.51, P = 0.016; 16.35 ± 4.32 vs. 12.20 ± 4.74, P = 0.007; 16.00 ± 4.40 vs. 8.15 ± 4.28, P = 0.021). Notably, the most pronounced changes were seen in the group receiving LIPUS combined with tadalafil and doxazosin. Additionally, all groups exhibited marked improvements in anxiety and depression symptoms post-treatment. No adverse events were observed during treatment. Conclusion LIPUS can improve erectile function and CP/CPPS symptoms with good safety, and LIPUS combined with tadalafil and doxazosin is more effective during the treatment. However, its long-term efficacy remains to be seen. Trial Registration Chinese Clinical Trial Registry; approval number: ChiCTR2200063038 ( https://www.chictr.org.cn/ ) on August 29, 2022.

To determine the sensitivity of vascular endothelial cells to long durations of low-intensity pulsed ultrasound (LIPUS) compared to normal flow and identify the duration that maximizes expression of two mechanosensitive genes related to healthy endothelial function, endothelial nitric oxide synthase (eNOS) and Krüppel-like factor 2 (KLF2). Custom ultrasound exposure tanks were developed and the acoustic field was characterized. Human umbilical vein endothelial cells were seeded into culture plates and exposed to LIPUS at a frequency of 1 MHz and acoustic pressure of 217 kPa for 20 min, 1 h, 6 h, 9 h, or 24 h. As a comparator, other cells were exposed to normal flow. RT-qPCR was used to assess mRNA expression of eNOS and KLF2. Maximum eNOS and KLF2 expression occurred at 6 h and was localized to the beam path. Both genes exhibited qualitatively similar patterns of expression under LIPUS compared to normal flow. LIPUS induced a more rapid beneficial response compared to normal flow, but flow induced higher expression of both genes. eNOS expression after 6 h of LIPUS was dependent on RNA yield and culture duration prior to experiments. Endothelial cells exposed to longer durations of LIPUS than typically employed exhibited greater expression of beneficial genes. The temporal gene expression patterns resulting from LIPUS and normal flow suggest activation of similar signaling pathways. However, LIPUS also caused increased RNA yield that may be linked to proliferation, which would suggest more of a wound healing than atheroprotective phenotype. [ABSTRACT FROM AUTHOR]

Aims: Although low-intensity pulsed ultrasound (LIPUS) combined with disinfectants has been shown to effectively eliminate portions of biofilm in vitro, its efficacy in vivo remains uncertain. Our objective was to assess the antibiofilm potential and safety of LIPUS combined with 0.35% povidone-iodine (PI) in a rat debridement, antibiotics, and implant retention (DAIR) model of periprosthetic joint infection (PJI). Methods: A total of 56 male Sprague-Dawley rats were established in acute PJI models by intra-articular injection of bacteria. The rats were divided into four groups: a Control group, a 0.35% PI group, a LIPUS and saline group, and a LIPUS and 0.35% PI group. All rats underwent DAIR, except for Control, which underwent a sham procedure. General status, serum biochemical markers, weightbearing analysis, radiographs, micro-CT analysis, scanning electron microscopy of the prostheses, microbiological analysis, macroscope, and histopathology evaluation were performed 14 days after DAIR. Results: The group with LIPUS and 0.35% PI exhibited decreased levels of serum biochemical markers, improved weightbearing scores, reduced reactive bone changes, absence of viable bacteria, and decreased inflammation compared to the Control group. Despite the greater antibiofilm activity observed in the PI group compared to the LIPUS and saline group, none of the monotherapies were successful in preventing reactive bone changes or eliminating the infection. Conclusion: In the rat model of PJI treated with DAIR, LIPUS combined with 0.35% PI demonstrated stronger antibiofilm potential than monotherapy, without impairing any local soft-tissue. Cite this article: Bone Joint Res 2024;13(7):332–341.

Abstract To detect and analyze the changes of microorganisms in expressed prostatic secretion (EPS) of patients with IIIB prostatitis before and after low-intensity pulsed ultrasound (LIPUS) treatment, and to explore the mechanism of LIPUS in the treatment of chronic prostatitis (CP). 25 patients (study power was estimated using a Dirichlet-multinomial approach and reached 96.5% at α = 0.05 using a sample size of 25) with IIIB prostatitis who were effective in LIPUS treatment were divided into two groups before and after LIPUS treatment. High throughput second-generation sequencing technique was used to detect and analyze the relative abundance of bacterial 16 s ribosomal variable regions in EPS before and after treatment. The data were analyzed by bioinformatics software and database, and differences with P

Background: Low‐intensity pulsed ultrasound (LIPUS) combined with acupoint can promote gastric motility of diabetic rats. The switch of gastric smooth muscle cell (GSMCs) phenotype was related to the diabetes‐induced gastric dysfunction, but the mechanism is not clearly elucidated. This study was aimed at exploring the underlying mechanism of LIPUS stimulation application in diabetic gastroparesis rats. Methods: In this study, Sprague–Dawley male rats were divided into three groups: control group (CON), diabetic gastroparesis group (DGP), and LIPUS‐treated group (LIPUS). LIPUS irradiation was performed bilaterally at ST36 for 20 min per day for 4 weeks. The gastric emptying rate was measured by ultrasound examination. Contraction ability of GSMCs was assessed by muscle strip experiment. The expression of related proteins or mRNAs including α‐SMA, SM22α, MHC, RhoA, Rock2, p‐MYPT1, MYPT1, p‐MLC, MLC, MALAT1, miR‐449a, and DLL1 was detected by different methods such as western blotting, RT‐qPCR, immunohistochemistry, and immunofluorescence staining, as appropriate. Key Results: (a) LIPUS stimulation at ST36 could improve the gastric motility dysfunction of diabetic rats. (b) LIPUS increased RhoA, Rock2, p‐MYPT1, and p‐MLC expression level. (c) MALAT1 and DLL1 contents were decreased, but the level of miR‐449a was increased in the LIPUS group. Conclusions & Inferences: LIPUS may affect the contractile marker expression of gastric smooth muscle through the RhoA/Rock and MALAT1/miR‐449a/DLL1 pathway to ameliorate DGP. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effects of low‐intensity pulsed ultrasound (LIPUS) on the proliferation, differentiation, and tumor necrosis factor‐α (TNF‐α)‐induced lipolysis of 3T3‐L1 cells, and to explore the feasibility of regulating the release of free fatty acids (FFA) to prevent lipotoxicity. Methods: Different intensities (30, 60, 90, and 120 mW/cm2) of LIPUS were applied to 3T3‐L1 preadipocytes for different durations (5, 10, 15, 20, 25, and 30 minutes). Appropriate parameters for subsequent experiments were selected by assessing cell viability. The effect of LIPUS on the proliferation and differentiation of 3T3‐L1 cells was evaluated by microscope observation, flow cytometry, and lipid content determination. After treated with LIPUS and TNF‐α (50 ng/mL), the degree of lipolysis was assessed by measuring the extracellular FFA content. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was used to detect the mRNA expression of relevant genes. Results: Different parameters of LIPUS significantly enhance the viability of 3T3‐L1 cells (P <.05), with 20 minutes and 30 mW/cm2 as the most suitable settings. After LIPUS treatment, 3T3‐L1 cell proliferation accelerated, apoptosis rate and G1 phase cell proportion decreased, the content of lipid droplets and TG was increased in differentiated cells, while FFA release decreased (P <.05). The expression of PCNA, PPARγ, C/EBPα, Perilipin A mRNA increased, and the expression of TNF‐α, ATGL, HSL mRNA decreased (P <.05). Conclusions: LIPUS could promote the proliferation and differentiation of 3T3‐L1 cells and inhibit TNF‐α‐induced lipolysis, indicating its potential as a therapy for mitigating lipotoxicity caused by decompensated adipocytes. [ABSTRACT FROM AUTHOR]

Ultrasound has expanded into the therapeutic field as a medical imaging and diagnostic technique. Low-intensity pulsed ultrasound (LIPUS) is a kind of therapeutic ultrasound that plays a vital role in promoting fracture healing, wound repair, immunomodulation, and reducing inflammation. Its anti-inflammatory effects are manifested by decreased pro-inflammatory cytokines and chemokines, accelerated regression of immune cell invasion, and accelerated damage repair. Although the anti-inflammatory mechanism of LIPUS is not very clear, many in vitro and in vivo studies have shown that LIPUS may play its anti-inflammatory role by activating signaling pathways such as integrin/Focal adhesion kinase (FAK)/Phosphatidylinositol 3-kinase (PI3K)/Serine threonine kinase (Akt), Vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS), or inhibiting signaling pathways such as Toll-like receptors (TLRs)/Nuclear factor kappa-B (NF-κB) and p38-Mitogen-activated protein kinase (MAPK). As a non-invasive physical therapy, the anti-inflammatory and immunomodulatory effects of LIPUS deserve further exploration. [ABSTRACT FROM AUTHOR]

Aims CD4+ T cells are activated during inflammatory dilated cardiomyopathy (iDCM) development to induce immunogenic responses that damage the myocardium. Low-intensity pulsed ultrasound (LIPUS), a novel physiotherapy for cardiovascular diseases, has recently been shown to modulate inflammatory responses. However, its efficacy in iDCM remains unknown. Here, we investigated whether LIPUS could improve the severity of iDCM by orchestrating immune responses and explored its therapeutic mechanisms. Methods and results In iDCM mice, LIPUS treatment reduced cardiac remodelling and dysfunction. Additionally, CD4+ T-cell inflammatory responses were suppressed. LIPUS increased Treg cells while decreasing Th17 cells. LIPUS mechanically stimulates endothelial cells, resulting in increased secretion of extracellular vesicles (EVs), which are taken up by CD4+ T cells and alter their differentiation and metabolic patterns. Moreover, EVs selectively loaded with microRNA (miR)-99a are responsible for the therapeutic effects of LIPUS. The hnRNPA2B1 translocation from the nucleus to the cytoplasm and binding to caveolin-1 and miR-99a confirmed the upstream mechanism of miR-99a transport. This complex is loaded into EVs and taken up by CD4+ T cells, which further suppress mTOR and TRIB2 expression to modulate cellular differentiation. Conclusion Our findings revealed that LIPUS uses an EVs-dependent molecular mechanism to protect against iDCM progression. Therefore, LIPUS is a promising new treatment option for iDCM. [ABSTRACT FROM AUTHOR]

During myocardial ischaemia‒reperfusion injury (MIRI), the accumulation of damaged mitochondria could pose serious threats to the heart. The migrasomes, newly discovered mitocytosis‐mediating organelles, selectively remove damaged mitochondria to provide mitochondrial quality control. Here, we utilised low‐intensity pulsed ultrasound (LIPUS) on MIRI mice model and demonstrated that LIPUS reduced the infarcted area and improved cardiac dysfunction. Additionally, we found that LIPUS alleviated MIRI‐induced mitochondrial dysfunction. We provided new evidence that LIPUS mechanical stimulation facilitated damaged mitochondrial excretion via migrasome‐dependent mitocytosis. Inhibition the formation of migrasomes abolished the protective effect of LIPUS on MIRI. Mechanistically, LIPUS induced the formation of migrasomes by evoking the RhoA/Myosin II/F‐actin pathway. Meanwhile, F‐actin activated YAP nuclear translocation to transcriptionally activate the mitochondrial motor protein KIF5B and Drp1, which are indispensable for LIPUS‐induced mitocytosis. These results revealed that LIPUS activates mitocytosis, a migrasome‐dependent mitochondrial quality control mechanism, to protect against MIRI, underlining LIPUS as a safe and potentially non‐invasive treatment for MIRI. [ABSTRACT FROM AUTHOR]

Purpose: We previously developed a novel therapy with low-intensity pulsed ultrasound (LIPUS) that ameliorates cognitive decline through upregulation of endothelial nitric oxide synthase (eNOS) in mouse models of Alzheimer's disease (AD). In a randomized, double-blind, placebo-controlled pilot trial, we demonstrated that whole-brain LIPUS therapy is safe and tends to suppress the cognitive decline in early AD patients. We herein report the findings of our basic experiments that we performed for the pilot trial in order to apply whole-brain LIPUS therapy to humans, as well. Methods: First, we examined the relationship between bone density/thickness and ultrasound transmittance using human temporal bone. Next, based on the results of ultrasound transmittance, we further examined mRNA expression of VEGF, FGF2, and eNOS in response to variable ultrasound frequencies, duty cycles, and sound pressures. Results: There was a significant correlation between bone thickness and transmittance (1.0 MHz, P < 0.001), while there was no significant correlation between bone density and transmittance (1.0 MHz, P = 0.421). At a frequency of 0.5 MHz, the optimum duty cycle was considered to be up to 20%. When the tissue amplitude was in the range of 0.05–0.5 MPa, VEGF, FGF2, and eNOS were significantly upregulated by LIPUS. Thus, the conditions necessary for LIPUS therapy for the human brain were identified as sound pressure just below the probe 1.3 MPa (tissue amplitude 0.15 MPa), duty cycle 5%, and frequency 0.5 MHz. Conclusion: We successfully identified the optimal treatment conditions for LIPUS therapy for patients with AD. [ABSTRACT FROM AUTHOR]

As a noninvasive technique, ultrasound stimulation is known to modulate neuronal activity both in vitro and in vivo. The latest explanation of this phenomenon is that the acoustic wave can activate the ion channels and further impact the electrophysiological properties of targeted neurons. However, the underlying mechanism of low-intensity pulsed ultrasound (LIPUS)-induced neuro-modulation effects is still unclear. Here, we characterize the excitatory effects of LIPUS on spontaneous activity and the intracellular Ca2+ homeostasis in cultured hippocampal neurons. By whole-cell patch clamp recording, we found that 15 min of 1-MHz LIPUS boosts the frequency of both spontaneous action potentials and spontaneous excitatory synaptic currents (sEPSCs) and also increases the amplitude of sEPSCs in hippocampal neurons. This phenomenon lasts for > 10 min after LIPUS exposure. Together with Ca2+ imaging, we clarified that LIPUS increases the [Ca2+]cyto level by facilitating L-type Ca2+ channels (LTCCs). In addition, due to the [Ca2+]cyto elevation by LIPUS exposure, the Ca2+-dependent CaMKII-CREB pathway can be activated within 30 min to further regulate the gene transcription and protein expression. Our work suggests that LIPUS regulates neuronal activity in a Ca2+-dependent manner via LTCCs. This may also explain the multi-activation effects of LIPUS beyond neurons. LIPUS stimulation potentiates spontaneous neuronal activity by increasing Ca2+ influx. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common disease in middle-aged and elderly people. An imbalance in calcium ion homeostasis will contribute to chondrocyte apoptosis and ultimately lead to the progression of OA. Transient receptor potential channel 4 (TRPV4) is involved in the regulation of intracellular calcium homeostasis. TRPV4 is expressed in primary cilia, which can sense mechanical stimuli from outside the cell, and its abnormal expression is closely related to the development of OA. Low-intensity pulsed ultrasound (LIPUS) can alleviate chondrocyte apoptosis while the exact mechanism is unclear. In this project, with the aim of revealing the mechanism of action of LIPUS, we proposed to use OA chondrocytes and animal models, LIPUS intervention, inhibition of primary cilia, use TRPV4 inhibitors or TRPV4 agonist, and use Immunofluorescence (IF), Immunohistochemistry (IHC), Western Blot (WB), Quantitative Real-time PCR (QP) to detect the expression of cartilage synthetic matrix and endoplasmic reticulum stress markers. The results revealed that LIPUS altered primary cilia expression, promoted synthetic matrix metabolism in articular chondrocytes and was associated with primary cilia. In addition, LIPUS exerted a active effect on OA by activating TRPV4, inducing calcium inward flow, and facilitating the entry of NF-κB into the nucleus to regulate synthetic matrix gene transcription. Inhibition of TRPV4 altered primary cilia expression in response to LIPUS stimulation, and knockdown of primary cilia similarly inhibited TRPV4 function. These results suggest that LIPUS mediates TRPV4 channels through primary cilia to regulate the process of knee osteoarthritis in mice. [ABSTRACT FROM AUTHOR]

Aim: To establish a methodology for understanding how ultrasound (US) induces drug release from nano-sized drug-delivery systems (NSDDSs) and enhances drug penetration and uptake in tumors. This aims to advance cancer treatment strategies. Materials & methods: We developed a multi-physics mathematical model to elucidate and understand the intricate mechanisms governing drug release, transport and delivery. Unique in vitro models (monolayer, multilayer, spheroid) and a tailored US exposure setup were introduced to evaluate drug penetration and uptake. Results: The results highlight the potential advantages of US-mediated NSDDSs over conventional NSDDSs and chemotherapy, notably in enhancing drug release and inducing cell death. Conclusion: Our sophisticated numerical and experimental methods aid in determining and quantifying drug penetration and uptake into solid tumors. Therapeutic ultrasound (TUS) permits targeted drug delivery by controlling the drug-release kinetics, thereby enhancing drug delivery and cell killing in tumors. Our study enabled a comprehensive understanding of the integration of TUS and nano-sized drug-delivery systems by combining experimental and theoretical analyses. We introduced a multi-scale and multi-physics mathematical and computational model for the penetration of TUS-triggered nano-sized drug-delivery systems into solid tumors. We examined three in vitro cancer cell culture methods – 2D monolayer, 3D spheroids and 3D multi-layer cells – to analyze initial cell toxicity, antiproliferative capacity and drug penetration. A customized experimental setup was developed that was suitable for TUS (i.e., LIPUS) and cell studies. The synergies between TUS, drug-release kinetics and transport characteristics were explored to increase the rate of cancer cell death. We proposed an optical sectioning technique for drug-penetration studies and utilized flow cytometry analysis for cell proliferation studies in a spheroid cancer cell model. Drug-release kinetics were determined with and without ultrasound exposure at 37°C. [ABSTRACT FROM AUTHOR]

Abstract Background Parkinson’s disease (PD) is a progressive, neurodegenerative illness marked by the loss of dopaminergic neurons, causing motor symptoms. Oral levodopa replacement therapy remains the gold standard in the treatment of PD. It is, nevertheless, a symptomatic treatment. There is currently no effective treatment for PD. Therefore, new therapies for PD are highly desirable. Low-intensity pulsed ultrasound (LIPUS) has been shown to improve behavioral functions in PD animal models. It is a new type of neuromodulation approach that combines noninvasiveness with high spatial precision. The purpose of this study is to establish a new clinical protocol for LIPUS in the treatment of movement disorders in patients with PD. Methods This protocol is a single-site, prospective, double-blind, randomized controlled trial (RCT). Forty-eight participants with clinically confirmed PD will be randomly allocated to one of two groups: LIPUS group or sham group. All of the participants continue to use pharmacological therapy as a fundamental treatment. The primary outcome is the difference between groups from baseline to 4 months in the change in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score (part III). The secondary outcomes include the rating scales such as the Mini-Mental State Examination (MMSE), and other three rating scales, and medical examinations including high-density electroencephalography (hdEEG) and functional magnetic resonance imaging (fMRI). The primary safety outcome will be assessed at 4 months, and adverse events will be recorded. Discussion This study represents the clinical investigation into the efficacy of therapeutic LIPUS in the treatment of PD for the first time. If LIPUS is determined to be effective, it could offer a practical and innovative means of expanding the accessibility of ultrasound therapy by using a wearable LIPUS device within a home setting. Trial registration Chinese Clinical Trial Registry ChiCTR2100052093. Registered on 17 October 2021.

Abstract 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-β1/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.

BACKGROUND: Gold nanoparticles are of great significance in the development of multifunctional transdermal drug delivery systems. Smaller gold nanoparticles can penetrate the dermis through the intercellular pathway, but are limited to their easy agglomeration and colloidal morphology, which makes it difficult to exert effects on low delivery efficiency. OBJECTIVE: To develop an ultrasound-optimized hydrogel delivery system by combining phase change nanodroplets with bio-adhesive hydrogel for percutaneous delivery of gold nanoparticles. METHODS: The ultrasound-responsive nanodroplets loaded with gold nanoparticles were prepared by the emulsion solvent evaporation method and loaded into the polydopamine-modified methylacryloyl gelatin hydrogel to prepare a composite hydrogel scaffold. The structure and chemical composition of the ultrasound-responsive nanogold carrier were characterized. The microstructure, porosity, permeability, rheology, in vitro hemostasis, and antibacterial properties of the composite hydrogel were characterized. The cell compatibility of the hydrogel scaffold was evaluated by live/dead staining, and the optimization effects of low-intensity pulsed ultrasound on the permeability, porosity, and mechanical properties of hydrogel were evaluated. RESULTS AND CONCLUSION: (1) Transmission electron microscopy and ultraviolet-visible spectroscopy proved the successful construction of nanogold carriers. The particle size and potential results demonstrated that the synthesized nanoscaled ultrasonic responsive carrier had good stability. (2) Live/dead cell staining proved that the prepared composite hydrogel scaffold had certain biocompatibility. (3) Scanning electron microscopy exhibited that the prepared composite hydrogel scaffold had a porous network structure, and numerous pores of about 2 μm appeared inside the macropores after the addition of nanodroplets and ultrasonic irradiation. The permeability experiment displayed that low-intensity pulsed ultrasound could optimize the porosity and permeability of hydrogel materials. The hemostatic performance of the composite hydrogel scaffold was better than that of the hemostatic sponge and polydopamine@ methylacrylylated gelatin hydrogel scaffold. Under the irradiation of low-intensity pulsed ultrasound, the composite hydrogel scaffolds had good antioxidant effects and antibacterial properties. (4) Thermal imaging results manifested that gold nanoparticles were encapsulated in ultrasound-responsive nanobubbles, and more uniform dispersion could be obtained under ultrasonic excitation. (5) The results of the mechanical property test demonstrated that the storage modulus of the hydrogel increased before and after loading gold nanoparticles-nanodroplets, which showed stronger mechanical properties. The elongation at break was 122%, and the ductility was better than that without gold nanoparticles-nanodroplets (P < 0.05). (6) These findings indicate that the composite hydrogel scaffold has good biocompatibility, antibacterial property, oxidation resistance, and hemostatic effect. [ABSTRACT FROM AUTHOR]

Atypical fractures are caused by the combined effects of severe suppression of bone metabolism (SSBT) due to long-term bisphosphonate therapy and chronic repetitive bone microdamage. Atypical ulnar fractures (AUFs) due to SSBT are rare, and there is no standard treatment strategy for such fractures. The relevant literature was reviewed, and the treatment strategy for AUF is discussed. A systematic review was conducted. All studies on ulnar fractures in individuals with a history of bisphosphonate use were included, and the data were extracted and analyzed from the perspective of the therapeutic strategy. Forty limbs of 35 patients were included. As for the treatment of AUF, 31 limbs were treated surgically, and conservative treatment with casting was performed for 9 limbs. The bone fusion rate was 22/40 (55.0%), and non-union was seen in all patients treated conservatively. There was a significant difference in the bone fusion rate between patients with surgical treatment and those with conservative treatment. The bone fusion rate of patients with parathyroid hormone (PTH) and surgery was 82.3% (14/17 limbs); the bone fusion rate with PTH and bone graft was 69.2% (9/13 limbs). However, there were no significant differences in the fusion rate in the groups with or without PTH, with or without bone grafting, or the combination of the two treatments. There was also no significant difference in the bone fusion rate in the groups with or without low-intensity pulsed ultrasound (LIPUS) treatment. Based on the literature review, surgery is necessary to achieve bone union, but surgery alone is not adequate to achieve bony union. Bone grafting and the administration of PTH and LIPUS may promote early bone fusion, but the present study did not show significant advantages of these additional treatments for bone union. [ABSTRACT FROM AUTHOR]

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-β1/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. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic-ischemic brain damage (HIBD) can have long-term implications on patients' physical and mental health, yet the available treatment options are limited. Recent research has shown that low-intensity pulsed ultrasound (LIPUS) holds promise for treating neurodegenerative diseases and traumatic brain injuries. Our objective was to explore the therapeutic potential of LIPUS for HIBD. Due to the lack of a suitable animal model for neonatal HIBD, we will initially simulate the therapeutic effects of LIPUS on neuronal cells under oxidative stress and neuroinflammation using cell experiments. Previous studies have investigated the biologic responses following intracranial injection of 6-hydroxydopamine (6-OHDA). In this experiment, we will focus on the biologic effects produced by LIPUS treatment on neuronal cells (specifically, SH-SY5Y cells) without the presence of other neuroglial cell assistance after stimulation with 6-OHDA. We found that (i) pulsed ultrasound exposure, specifically three-intermittent sonication at intensities ranging from 0.1 to 0.5 W/cm², did not lead to a significant decrease in viability among SH-SY5Y cells; (ii) LIPUS treatment exhibited a positive effect on cell viability, accompanied by an increase in glial cell-derived neurotrophic factor (GDNF) levels and a decrease in caspase three levels; (iii) the administration of 6-OHDA had a significant impact on cell viability, resulting in a decrease in both brain cell-derived neurotrophic factor (BDNF) and GDNF levels, while concurrently elevating caspase three and matrix metalloproteinase-9 (MMP-9) levels; and (iv) LIPUS treatment demonstrated its potential to alleviate the changes induced by 6-OHDA, particularly in the levels of BDNF, GDNF, and tyrosine hydroxylase (TH). LIPUS treatment may possess partial therapeutic capabilities for SH-SY5Y cells damaged by 6-OHDA neurotoxicity. Our findings enhance our understanding of the effects of LIPUS treatment on cell viability and its modulation of key factors involved in the pathophysiology of HIBD and show the promising potential of LIPUS as an alternative therapeutic approach for neonates with HIBD. [ABSTRACT FROM AUTHOR]

Low-intensity pulsed ultrasound (LIPUS) is a form of ultrasound that utilizes low-intensity pulsed waves. Its effect on bones that heal by intramembranous ossification has not been sufficiently investigated. In this study, we examined LIPUS and the autologous bone, to determine their effect on the healing of the critical-size bone defect (CSBD) of the rat calvaria. The bone samples underwent histological, histomorphometric and immunohistochemical analyses. Both LIPUS and autologous bone promoted osteogenesis, leading to almost complete closure of the bone defect. On day 30, the bone volume was the highest in the autologous bone group (20.35%), followed by the LIPUS group (19.12%), and the lowest value was in the control group (5.11%). The autologous bone group exhibited the highest intensities of COX-2 (167.7 ± 1.1) and Osx (177.1 ± 0.9) expression on day 30. In the LIPUS group, the highest intensity of COX-2 expression was found on day 7 (169.7 ±1.6) and day 15 (92.7 ± 2.2), while the highest Osx expression was on day 7 (131.9 ± 0.9). In conclusion, this study suggests that LIPUS could represent a viable alternative to autologous bone grafts in repairing bone defects that are ossified by intramembranous ossification. [ABSTRACT FROM AUTHOR]

The use of low‐intensity pulsed ultrasound (LIPUS) for promoting fracture healing has been Food and Drug Administration (FDA)‐approved since 1994 due to largely its non‐thermal effects of sound flow sound radiation force and so on. Numerous clinical and animal studies have shown that LIPUS can accelerate the healing of fresh fractures, nonunions, and delayed unions in pulse mode regardless of LIPUS devices or circumstantial factors. Rare clinical studies show limitations of LIPUS for treating fractures with intramedullary nail fixation or low patient compliance. The biological effect is achieved by regulating various cellular behaviors involving mesenchymal stem/stromal cells (MSCs), osteoblasts, chondrocytes, and osteoclasts and with dose dependency on LIPUS intensity and time. Specifically, LIPUS promotes the osteogenic differentiation of MSCs through the ROCK‐Cot/Tpl2‐MEK–ERK signaling. Osteoblasts, in turn, respond to the mechanical signal of LIPUS through integrin, angiotensin type 1 (AT1), and PIEZO1 mechano‐receptors, leading to the production of inflammatory factors such as COX‐2, MCP‐1, and MIP‐1β fracture repair. LIPUS also induces CCN2 expression in chondrocytes thereby coordinating bone regeneration. Finally, LIPUS suppresses osteoclast differentiation and gene expression by interfering with the ERK/c‐Fos/NFATc1 cascade. This mini‐review revisits the known effects and mechanisms of LIPUS on bone fracture healing and strengthens the need for further investigation into the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Low-intensity pulsed ultrasound (LIPUS) is a non-invasive medical therapy that has attracted recent research interest due to its therapeutic effects. However, most LIPUS driver systems currently available are large and expensive. We have proposed a LIPUS interface application-specific integrated circuit (ASIC) for use in wearable medical devices to address some of the challenges related to the size and cost of the current technologies. The proposed ASIC is a highly integrated system, incorporating a DCDC module based on a charge pump architecture, a high voltage level shifter, a half-bridge driver, a voltage-controlled oscillator, and a corresponding digital circuit module. Consequently, the functional realization of this ASIC as a LIPUS driver system requires only a few passive components. Experimental tests indicated that the chip is capable of an output of 184.2 mW or 107.2 mW with a power supply of 5 V or 3.7 V, respectively, and its power conversion efficiency is approximately 30%. This power output capacity allows the LIPUS driver system to deliver a spatial average temporal average (SATA) of 29.5 mW/cm2 or 51.6 mW/cm2 with a power supply of 3.7 V or 5 V, respectively. The total die area, including pads, is 4 mm2. The ASIC does not require inductors, improving its magnetic resonance imaging (MRI) compatibility. In summary, the proposed LIPUS interface chip presents a promising solution for the development of MRI-compatible and cost-effective wearable medical therapy devices. [ABSTRACT FROM AUTHOR]

Low-intensity pulsed ultrasound (LIPUS) has been gradually used to treat Achilles tendinopathy. However, there are limited non-invasive and efficient instruments for monitoring LIPUS efficacy in Achilles tendinopathy. The purpose of this study was to assess the therapeutic effectiveness of LIPUS after Achilles tendinopathy by 2-D ultrasound and real-time shear wave elastography (SWE). Ninety New Zealand white rabbits were divided into control, sham and LIPUS groups after tendinopathy modeling. On days 1, 4, 7, 14 and 28, the Achilles tendon thickness and SWE Young's modulus on the long axis were measured. The tissues of the Achilles tendon were then evaluated histologically. The mean SWE values increased while the average thickness and histologic scores decreased, especially in the LIPUS group (9.5% and 80.7% on day 28, respectively). The SWE values in the LIPUS group were significantly lower than those in the control group on day 1 (121.0 kPa vs. 177.6 kPa) and peaked on day 7 (173.7 kPa, p < 0.001). By day 28, the SWE value had approached that of the control (191.2 kPa vs. 192.4 kPa), and had been significantly higher than that in the sham group since day 7. SWE values and histologic scores were correlated (r = –0.792, p < 0.01). The average thickness decreased in the three groups but did not differ significantly. Two-dimensional ultrasound is beneficial to the diagnosis of Achilles tendinopathy. SWE could quantify changes in Achilles tendon stiffness non-invasively during LIPUS treatment, enabling the study of early Achilles tendon healing after LIPUS treatment. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy is booming around the world. However, strategies to activate the immune system and alleviate the immunosuppression still need to be refined. Here, we demonstrate for the first time that low-intensity pulsed ultrasound (LIPUS, spatial average time average intensity (Isata) is 200 mW/cm2, frequency is 0.3 MHz, repetition frequency is 1 kHz, and duty cycle is 20%) triggers the immune system and further reverses the immunosuppressive state in the mouse models of breast cancer by irradiating the spleen of mice. LIPUS inhibited tumor growth and extended survival in mice with 4 T-1 tumors. Further studies had previously shown that LIPUS enhanced the activation of CD4+ and CD8+ T cells in the spleen and led to significant changes in cytokines, as well as induced upregulation of mRNA levels involved in multiple immune regulatory pathways in the spleen. In addition, LIPUS promoted tumor-infiltrating lymphocyte accumulation and CD8+ T cell activation and improved the dynamics of cytokines/chemokines in the tumor microenvironment, resulting in a reversal of the immunosuppressive state of the tumor microenvironment. These results suggest a novel approach to activate the immune response by irradiating the spleen with LIPUS. [ABSTRACT FROM AUTHOR]

Abstract During myocardial ischaemia‒reperfusion injury (MIRI), the accumulation of damaged mitochondria could pose serious threats to the heart. The migrasomes, newly discovered mitocytosis‐mediating organelles, selectively remove damaged mitochondria to provide mitochondrial quality control. Here, we utilised low‐intensity pulsed ultrasound (LIPUS) on MIRI mice model and demonstrated that LIPUS reduced the infarcted area and improved cardiac dysfunction. Additionally, we found that LIPUS alleviated MIRI‐induced mitochondrial dysfunction. We provided new evidence that LIPUS mechanical stimulation facilitated damaged mitochondrial excretion via migrasome‐dependent mitocytosis. Inhibition the formation of migrasomes abolished the protective effect of LIPUS on MIRI. Mechanistically, LIPUS induced the formation of migrasomes by evoking the RhoA/Myosin II/F‐actin pathway. Meanwhile, F‐actin activated YAP nuclear translocation to transcriptionally activate the mitochondrial motor protein KIF5B and Drp1, which are indispensable for LIPUS‐induced mitocytosis. These results revealed that LIPUS activates mitocytosis, a migrasome‐dependent mitochondrial quality control mechanism, to protect against MIRI, underlining LIPUS as a safe and potentially non‐invasive treatment for MIRI.

Abstract Background The low-level laser therapy (LLLT) and low-intensity pulsed ultrasound (LIPUS) have been recently applied to control pain during orthodontic treatment. Objective To evaluate and compare the effectiveness of LLLT and LIPUS in reducing pain induced by orthodontic separation. Study design A single-blinded randomized controlled trial. Methods One hundred and fifty patients were randomly assigned into three groups; LLLT group, LIPUS group, and control group. After 5 min from the separators’ placement, the first dose of the laser or the ultrasound was applied, the second dose was applied after 24 h, and the third dose was applied after 48 h on both maxillary and mandibular first molars. The exposure of laser was for 20 s at each point (maxillary and mandibular first molars), with an 810-nm aluminum-gallium-arsenide (AlGaAs) diode laser on continuous mode. The output power set at 150 mW, the energy density of 4 J/cm2, and a laser spot diameter of 7 mm were applied. Whereas the frequency of ultrasonic toothbrush was 1.6 MHz; and average output intensity was 0.2 W/cm2. The application was for 20 min (5 min on each first molar). The control group received the separators without another intervention. A Visual Analog Scale (VAS 100 mm) was used to assess pain intensity at several time intervals during the first four days after the separators’ placement. Results A total of 145 patients were assessed. There was a significant difference in pain perception among the three groups after 5 min (P = .002). The maximum pain level was reached after 24 h. However, the laser group and the ultrasound group showed a statistically significant decrease in pain scores compared to the control group at all the assessment time points (P .05). Conclusions The LLLT and the LIPUS effectively reduce the separation pain when applied in multiple doses without differences between them. Trial registration This trial was registered with the German Clinical Trials Register (DRKS). ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID= DRKS00029991). Date of registration: 26/08/2022.

Objectives: The aim of this study was to investigate the effects of low-intensity pulsed ultrasound (LIPUS) in a post-traumatic osteoarthritis (OA) rat model and in vitro. Methods: Thirty-eight male, four-month-old Sprague Dawley rats were randomly assigned to Sham, Sham ​+ ​US, OA, and OA ​+ ​US. Sham surgery was performed to serve as a negative control, and anterior cruciate ligament transection was used to induce OA. Three days after the surgical procedures, Sham ​+ ​US and OA ​+ ​US animals received daily LIPUS treatment, while the rest of the groups received sham ultrasound (US) signals. Behavioral pain tests were performed at baseline and every week thereafter. After 31 days, the tissues were collected, and histological analyses were performed on knees and innervated dorsal root ganglia (DRG) neurons traced by retrograde labeling. Furthermore, to assess the activation of osteoclasts by LIPUS treatment, RAW264.7 ​cells were differentiated into osteoclasts and treated with LIPUS. Results: Joint degradation in cartilage and bone microarchitecture were mitigated in OA ​+ ​US compared to OA. OA ​+ ​US showed improvements in behavioral pain tests. A significant increase of large soma-sized DRG neurons was located in OA compared to Sham. In addition, a greater percentage of large soma-sized innervated neurons were calcitonin gene-related peptide-positive. Daily LIPUS treatment suppressed osteoclastogenesis in vitro, which was confirmed via histological analyses and mRNA expression. Finally, lower expression of netrin-1, a sensory innervation-related protein, was found in the LIPUS treated cells. Conclusion: Our findings demonstrate that early intervention using LIPUS treatment has protective effects from the progression of knee OA, including reduced tissue degradation, mitigated pain characteristics, improved subchondral bone microarchitecture, and less sensory innervation. Furthermore, daily LIPUS treatment has a suppressive effect on osteoclastogenesis, which may be linked to the suppression of sensory innervation in OA. The translational potential of this article: This study presents a new potential for early intervention in treating OA symptoms through the use of LIPUS, which involves the suppression of osteoclastogenesis and the alteration of DRG profiles. This intervention aims to delay joint degradation and reduce pain.

AbstractLow-intensity pulsed ultrasound (LIPUS) is a kind of therapeutic ultrasound. It can help improve bone fracture repair and soft tissue healing. Our previous study found that LIPUS treatment could halt the chronic kidney disease (CKD) progression in mice; unexpectedly, we observed the improvement of CKD-reduced muscle weights by LIPUS treatment. Here, we further tested the protective potential of LIPUS on CKD-associated muscle wasting/sarcopenia using the CKD mouse models. Mouse models of both unilateral renal ischemia/reperfusion injury (IRI) with nephrectomy and adenine administration were used to induce CKD. LIPUS with condition of 3 MHz, 100 mW/cm2, 20 min/day was applied to the kidney of CKD mice. LIPUS treatment significantly reversed the increased serum BUN/creatinine levels in CKD mice. LIPUS effectively prevented the decrease in grip strength, muscle weight (soleus, tibialis anterior, and gastrocnemius muscles), cross-section areas of muscle fibres, and muscular phosphorylated Akt protein expression by immunohistochemistry, and the increase in muscular atrogenes Atrogin1 and MuRF1 protein expression by immunohistochemistry in CKD mice. These results indicated that LIPUS could help improve weak muscle strength, muscle mass loss, muscle atrophy-related protein expression, and Akt inactivation. LIPUS application may be an alternative non-invasive therapeutic intervention on the management of CKD-associated muscle wasting.

Background: The low-level laser therapy (LLLT) and low-intensity pulsed ultrasound (LIPUS) have been recently applied to control pain during orthodontic treatment. Objective: To evaluate and compare the effectiveness of LLLT and LIPUS in reducing pain induced by orthodontic separation. Study design: A single-blinded randomized controlled trial. Methods: One hundred and fifty patients were randomly assigned into three groups; LLLT group, LIPUS group, and control group. After 5 min from the separators' placement, the first dose of the laser or the ultrasound was applied, the second dose was applied after 24 h, and the third dose was applied after 48 h on both maxillary and mandibular first molars. The exposure of laser was for 20 s at each point (maxillary and mandibular first molars), with an 810-nm aluminum-gallium-arsenide (AlGaAs) diode laser on continuous mode. The output power set at 150 mW, the energy density of 4 J/cm2, and a laser spot diameter of 7 mm were applied. Whereas the frequency of ultrasonic toothbrush was 1.6 MHz; and average output intensity was 0.2 W/cm2. The application was for 20 min (5 min on each first molar). The control group received the separators without another intervention. A Visual Analog Scale (VAS 100 mm) was used to assess pain intensity at several time intervals during the first four days after the separators' placement. Results: A total of 145 patients were assessed. There was a significant difference in pain perception among the three groups after 5 min (P =.002). The maximum pain level was reached after 24 h. However, the laser group and the ultrasound group showed a statistically significant decrease in pain scores compared to the control group at all the assessment time points (P <.001). Whereas there was no difference between the laser group and the ultrasound group in reducing the pain scores (P >.05). Conclusions: The LLLT and the LIPUS effectively reduce the separation pain when applied in multiple doses without differences between them. Trial registration: This trial was registered with the German Clinical Trials Register (DRKS). (https://www.drks.de/drks%5fweb/navigate.do?navigationId=trial.HTML&TRIAL%5fID= DRKS00029991). Date of registration: 26/08/2022. [ABSTRACT FROM AUTHOR]

Simple Summary: Advancements in understanding the blood–brain barrier (BBB) and blood–tumor barrier (BTB) structures emphasize the need to explore functional differences influencing drug distribution to the central nervous system (CNS). Various methods for overcoming the BBB/BTB have been proposed. Osmotic BBB disruption with intra-arterial administration effectively obtains local, clinically relevant concentrations in large brain areas, with an acceptable safety profile in experienced hands. Convection-enhanced delivery allows for homogenous and safe drug delivery to the tumor but demands further technical refinement and clinical evaluation. Emerging therapies like high-intensity focused and low-intensity pulsed ultrasound show great promise in delivering large therapeutic agents to small brain areas. While laser interstitial thermal therapy is effective in ablating local brain tumors, its impact on disrupting the BBB remains inadequately understood. Similarly, tumor-treating fields aid chemotherapy in inducing cycle arrest, but the proof of their ability to disrupt the BBB/BTB has been so far limited to preclinical studies. The blood–brain barrier (BBB) poses a significant challenge to drug delivery for brain tumors, with most chemotherapeutics having limited permeability into non-malignant brain tissue and only restricted access to primary and metastatic brain cancers. Consequently, due to the drug's inability to effectively penetrate the BBB, outcomes following brain chemotherapy continue to be suboptimal. Several methods to open the BBB and obtain higher drug concentrations in tumors have been proposed, with the selection of the optimal method depending on the size of the targeted tumor volume, the chosen therapeutic agent, and individual patient characteristics. Herein, we aim to comprehensively describe osmotic disruption with intra-arterial drug administration, intrathecal/intraventricular administration, laser interstitial thermal therapy, convection-enhanced delivery, and ultrasound methods, including high-intensity focused and low-intensity ultrasound as well as tumor-treating fields. We explain the scientific concept behind each method, preclinical/clinical research, advantages and disadvantages, indications, and potential avenues for improvement. Given that each method has its limitations, it is unlikely that the future of BBB disruption will rely on a single method but rather on a synergistic effect of a combined approach. Disruption of the BBB with osmotic infusion or high-intensity focused ultrasound, followed by the intra-arterial delivery of drugs, is a promising approach. Real-time monitoring of drug delivery will be necessary for optimal results. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitors (ICIs) have transformed traditional cancer treatments. Specifically, ICI-related myocarditis is an immune-related adverse event (irAE) with high mortality. ICIs activate CD4+ T-lymphocyte reprogramming, causing an imbalance between Th17 and Treg cell differentiation, ultimately leading to myocardial inflammatory damage. Low-intensity pulsed ultrasound (LIPUS) can limit inflammatory responses, with positive therapeutic effects across various cardiovascular inflammatory diseases; however, its role in the pathogenesis of ICI-related myocarditis and CD4+ T-cell dysfunction remains unclear. Accordingly, this study investigated whether LIPUS can alleviate ICI-related myocarditis inflammatory damage and, if so, aimed to elucidate the beneficial effects of LIPUS and its underlying molecular mechanisms. Methods: An in vivo model of ICI-related myocarditis was obtained by intraperitonially injecting male A/J mice with an InVivoPlus anti-mouse PD-1 inhibitor. LIPUS treatment was performed via an ultrasound-guided application to the heart via the chest wall. The echocardiographic parameters were observed and cardiac function was assessed using an in vivo imaging system. The expression of core components of the HIPPO pathway was analyzed via western blotting. Results: LIPUS treatment reduced cardiac immune responses and inflammatory cardiac injury. Further, LIPUS treatment alleviated the inflammatory response in mice with ICI-related myocarditis. Mechanistically, in the HIPPO pathway, the activation of Mst1–TAZ axis improved autoimmune inflammation by altering the interaction between the transcription factors FOXP3 and RORγt and regulating the differentiation of Treg and Th17 cells. Conclusion: LIPUS therapy was shown to reduce ICI-related myocarditis inflammatory damage and improve cardiac function, representing an exciting finding for irAEs treatment. [ABSTRACT FROM AUTHOR]

Stem cells have self-renewal, replication, and multidirectional differentiation potential, while progenitor cells are undifferentiated, pluripotent or specialized stem cells. Stem/progenitor cells secrete various factors, such as cytokines, exosomes, non-coding RNAs, and proteins, and have a wide range of applications in regenerative medicine. However, therapies based on stem cells and their secreted exosomes present limitations, such as insufficient source materials, mature differentiation, and low transplantation success rates, and methods addressing these problems are urgently required. Ultrasound is gaining increasing attention as an emerging technology. Low-intensity pulsed ultrasound (LIPUS) has mechanical, thermal, and cavitation effects and produces vibrational stimuli that can lead to a series of biochemical changes in organs, tissues, and cells, such as the release of extracellular bodies, cytokines, and other signals. These changes can alter the cellular microenvironment and affect biological behaviors, such as cell differentiation and proliferation. Here, we discuss the effects of LIPUS on the biological functions of stem/progenitor cells, exosomes, and non-coding RNAs, alterations involved in related pathways, various emerging applications, and future perspectives. We review the roles and mechanisms of LIPUS in stem/progenitor cells and exosomes with the aim of providing a deeper understanding of LIPUS and promoting research and development in this field. [ABSTRACT FROM AUTHOR]

Introduction: Low-intensity pulsed ultrasound (LIPUS) is a recognized tool for promoting nerve regeneration and repair; however, the intracellular mechanisms of LIPUS stimulation remain underexplored. Method: The present study delves into the effects of varying LIPUS parameters, namely duty cycle, spatial average-temporal average (SATA) intensity, and ultrasound amplitude, on the therapeutic efficacy using SK-N-SH cells cultured in serum-starved conditions. Four distinct LIPUS settings were employed: (A) 50 mW/cm², 40%, (B) 25 mW/cm², 10%, (C) 50 mW/cm², 20%, and (D) 25 mW/cm², 10%. Results: Immunochemistry analysis exhibited neurite outgrowth promotion in all LIPUS-treated groups except for Group D. Further, LIPUS treatment was found to successfully promote brain-derived neurotrophic factor (BDNF) expression and enhance the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, protein kinase B (Akt), and mammalian target of rapamycin (mTOR) signaling pathways, as evidenced by western blot analysis. Discussion: The study suggests that the parameter combination of LIPUS determines the therapeutic efficacy of LIPUS. Future investigations should aim to optimize these parameters for different cell types and settings and delve deeper into the cellular response mechanism to LIPUS treatment. Such advancements may aid in tailoring LIPUS treatment strategies to specific therapeutic needs. [ABSTRACT FROM AUTHOR]

The aim of the work described here was to investigate the efficacy and potential mechanisms of low-intensity pulsed ultrasound (LIPUS) for the treatment of arthrogenic contracture induced by immobilization in rabbits. The left knee joint of rabbits was immobilized for 6 wk to establish the model of extending knee joint contracture. The rabbits were divided into a control group (C), a group immobilized for 6 wk (IM-6w), a group remobilized for 1 wk (RM-1w), a group subjected to LIPUS intervention for 1 wk (LIPUS-1w), a group remobilized for 2 wk (RM-2w) and a group subjected to LIPUS intervention for 2 wk (LIPUS-2w). The degrees of arthrogenic contracture and joint capsule fibrosis were assessed, as were the levels of reactive oxygen species (ROS) and the activation status of the TGF-β1/Smad signaling pathway in the joint capsule. After immobilization for 6 wk, the degrees of arthrogenic contracture and joint capsule fibrosis increased. The ROS level increased, as evidenced by an increase in malondialdehyde content and a decrease in superoxide dismutase content. In addition, the TGF-β1/Smad signaling pathway was significantly activated. The degrees of knee joint contracture increased in the first week after remobilization and decreased in the second week. Furthermore, joint capsule fibrosis continued to develop during the 2 wk of remobilization, and the ROS level increased, while the TGF-β1/Smad signaling pathway was significantly activated. LIPUS effectively reduced the level of ROS in the joint capsule, which further inhibited activation of the TGF-β1/Smad signaling pathway, thereby improving joint capsule fibrosis and reducing arthrogenic contracture. The high ROS levels and overactivation of the TGF-β1/Smad signaling pathway may be reasons why immobilization induces knee joint capsule fibrosis. LIPUS can alleviate the degree of knee joint capsule fibrosis induced by immobilization by inhibiting the production of ROS and the activation of the TGF-β1/Smad signaling pathway. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is distinguished by pathological alterations in the synovial membrane, articular cartilage, and subchondral bone, resulting in physical symptoms such as pain, deformity, and impaired mobility. Numerous research studies have validated the effectiveness of low-intensity pulsed ultrasound (LIPUS) in OA treatment. The periodic mechanical waves generated by LIPUS can mitigate cellular ischemia and hypoxia, induce vibration and collision, produce notable thermal and non-thermal effects, alter cellular metabolism, expedite tissue repair, improve nutrient delivery, and accelerate the healing process of damaged tissues. The efficacy and specific mechanism of LIPUS is currently under investigation. This review provides an overview of LIPUS’s potential role in the treatment of OA, considering various perspectives such as the synovial membrane, cartilage, subchondral bone, and tissue engineering. It aims to facilitate interdisciplinary scientific research and further exploration of LIPUS as a complementary technique to existing methods or surgery. Ongoing research is focused on determining the optimal dosage, frequency, timing, and treatment strategy of LIPUS for OA. Additional research is required to clarify the precise mechanism of action and potential impacts on cellular, animal, and human systems prior to its integration into therapeutic applications.

BackgroundLow-intensity pulsed ultrasound (LIPUS) can accelerate tooth movement and preserve tooth and bone integrity during orthodontic treatment. However, the mechanisms by which LIPUS affects tissue remodeling during orthodontic tooth movement (OTM) remain unclear. Periodontal ligament cells (PDLCs) are pivotal in maintaining periodontal tissue equilibrium when subjected to mechanical stimuli. One notable mechano-sensitive ion channel, Piezo1, can modulate cellular function in response to mechanical cues. This study aimed to elucidate the involvement of Piezo1 in the osteogenic response of force-treated PDLCs when stimulated by LIPUS.MethodAfter establishing rat OTM models, LIPUS was used to stimulate rats locally. OTM distance and alveolar bone density were assessed using micro-computed tomography, and histological analyses included hematoxylin and eosin staining, tartrate-resistant acid phosphatase staining and immunohistochemical staining. GsMTx4 and Yoda1 were respectively utilized for Piezo1 functional inhibition and activation experiments in rats. We isolated human PDLCs (hPDLCs) in vitro and evaluated the effects of LIPUS on the osteogenic differentiation of force-treated hPDLCs using real-time quantitative PCR, Western blot, alkaline phosphatase and alizarin red staining. Small interfering RNA and Yoda1 were employed to validate the role of Piezo1 in this process.ResultsLIPUS promoted osteoclast differentiation and accelerated OTM in rats. Furthermore, LIPUS alleviated alveolar bone resorption under pressure and enhanced osteogenesis of force-treated PDLCs both in vivo and in vitro by downregulating Piezo1 expression. Subsequent administration of GsMTx4 in rats and siPIEZO1 transfection in hPDLCs attenuated the inhibitory effect on osteogenic differentiation under pressure, whereas LIPUS efficacy was partially mitigated. Yoda1 treatment inhibited osteogenic differentiation of hPDLCs, resulting in reduced expression of Collagen Ⅰα1 and osteocalcin in the periodontal ligament. However, LIPUS administration was able to counteract these effects.ConclusionThis research unveils that LIPUS promotes the osteogenesis of force-treated PDLCs via downregulating Piezo1.

Abstract Background Intracerebral hemorrhage (ICH) is a condition associated with high morbidity and mortality, and glia-mediated inflammation is a major contributor to neurological deficits. However, there is currently no proven effective treatment for clinical ICH. Recently, low-intensity pulsed ultrasound (LIPUS), a non-invasive method, has shown potential for neuroprotection in neurodegenerative diseases. This study aimed to investigate the neuroprotective effects and potential mechanisms of LIPUS on glia-mediated inflammation in ICH. Methods This study used 289 mice to investigate the effects of LIPUS on ICH. ICH was induced by injecting bacterial collagenase (type VII-S; 0.0375 U) into the striatum of the mice. LIPUS was applied noninvasively for 3 days, including a 2-h-delayed intervention to mimic clinical usage. The study evaluated neurological function, histology, brain water content, hemoglobin content, MRI, and protein expression of neurotrophic factors, inflammatory molecules, and apoptosis. In vitro studies investigated glia-mediated inflammation by adding thrombin (10 U/mL) or conditioned media to primary and cell line cultures. The PI3K inhibitor LY294002 was used to confirm the effects of PI3K/Akt signaling after LIPUS treatment. Results LIPUS treatment improved neurological deficits and reduced tissue loss, edema, and neurodegeneration after ICH. The protective effects of LIPUS resulted from decreased glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling, which reduced cytokine expression and attenuated microglial activation-induced neuronal damage in vitro. Conclusions LIPUS treatment improved neurological outcomes and reduced glia-mediated inflammation by inhibiting PI3K/Akt-NF-κB signaling after ICH. LIPUS may provide a non-invasive potential management strategy for ICH.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have emerged as a new mode of intercellular crosstalk and are responsible for many of the therapeutic effects of MSCs. To promote the application of MSC-EVs, recent studies have focused on the manipulation of MSCs to improve the production of EVs and EV-mediated activities. The current paper details an optimization method using non-invasive low-intensity pulsed ultrasound (LIPUS) as the stimulation for improving oral MSC-EV production and effectiveness. Stem cells from apical papilla (SCAP), a type of oral mesenchymal stem cell, displayed intensity-dependent pro-osteogenic and anti-inflammatory responses to LIPUS without significant cytotoxicity or apoptosis. The stimuli increased the secretion of EVs by promoting the expression of neutral sphingomyelinases in SCAP. In addition, EVs from LIPUS-induced SCAP exhibited stronger efficacy in promoting the osteogenic differentiation and anti-inflammation of periodontal ligament cells in vitro and alleviating oral inflammatory bone loss in vivo. In addition, LIPUS stimulation affected the physical characteristics and miRNA cargo of SCAP-EVs. Further investigations indicated that miR-935 is an important mediator of the pro-osteogenic and anti-inflammatory capabilities of LIPUS-induced SCAP-EVs. Taken together, these findings demonstrate that LIPUS is a simple and effective physical method to optimize SCAP-EV production and efficacy.

Abstract Background To investigate the effect of low-intensity pulsed ultrasound (LIPUS) combined with lipid microbubbles on the proliferation and bone regeneration of bone marrow mesenchymal stem cells (BMSCs) in poly (lactic-glycolic acid copolymer) (PLGA)/α-tricalcium phosphate (TCP) 3D-printed scaffolds. Methods BMSCs were irradiated with different LIPUS parameters and microbubble concentrations, and the best acoustic excitation parameters were selected. The expression of type I collagen and the activity of alkaline phosphatase were detected. Alizarin red staining was used to evaluate the calcium salt production during osteogenic differentiation. Results BMSCs proliferation was the most significant under the condition of 0.5% (v/v) lipid microbubble concentration, 2.0 MHz frequency, 0.3 W/cm2 sound intensity and 20% duty cycle. After 14 days, the type I collagen expression and alkaline phosphatase activity in the scaffold increased significantly compared to those in the control group, and alizarin red staining showed more calcium salt production during osteogenic differentiation. After 21 days, scanning electron microscopy experiments showed that osteogenesis was obvious in the PLGA/TCP scaffolds. Conclusion LIPUS combined with lipid microbubbles on PLGA/TCP scaffolds can promote BMSCs growth and bone differentiation, which is expected to provide a new and effective method for the treatment of bone regeneration in tissue engineering.

Objective: The objective of this study is to assess the impact of low-intensity pulsed ultrasound (LIPUS) therapy on the peri-implant osteogenesis in a Type II diabetes mellitus (T2DM) rat model.Methods: A total of twenty male Sprague-Dawley (SD) rats were randomly allocated into four groups: Control group, T2DM group, Control-LIPUS group, and T2DM-LIPUS group. Implants were placed at the rats’ bilateral maxillary first molar sites. The LIPUS treatment was carried out on the rats in Control-LIPUS group and T2DM-LIPUS group, immediately after the placement of the implants, over three consecutive weeks. Three weeks after implantation, the rats’ maxillae were extracted for micro-CT, removal torque value (RTV), and histologic analysis.Results: Micro-CT analysis showed that T2DM rats experienced more bone loss around implant cervical margins compared with the non-T2DM rats, while the LIPUS treated T2DM rats showed similar bone heights to the non-T2DM rats. Bone-implant contact ratio (BIC) were lower in T2DM rats but significantly improved in the LIPUS treated T2DM rats. Bone formation parameters including bone volume fraction (BV/TV), trabecular thickness (Tb.Th), bone mineral density (BMD) and RTV were all positively influenced by LIPUS treatment. Histological staining further confirmed LIPUS’s positive effects on peri-implant new bone formation in T2DM rats.Conclusion: As an effective and safe treatment in promoting osteogenesis, LIPUS has a great potential for T2DM patients to attain improved peri-implant osteogenesis. To confirm its clinical efficacy and to explore the underlying mechanism, further prospective cohort studies or randomized controlled trials are needed in the future.