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In the present work, we have designed a one-pot green protocol in which anti-cancer drugs (curcumin and doxorubicin) can be directly loaded on the surface of gold nanoparticles during their formation. We have further demonstrated that low-intensity pulsed ultrasound (LIPUS) can be used to effectively induce the release of anti-cancer drugs from the surface of gold nanoparticles in an ex vivo tissue model. With this protocol, gold nanoparticles can be easily loaded with different types of anticancer drugs, irrespective of their affinity towards water, and even hydrophobic molecules, like curcumin, can be attached onto the gold nanoparticles in an aqueous medium. The method is very simple and straightforward and does not require stirring or mechanical shaking. The drug molecules interact with the gold seeds formed during the reduction and growth process and modulate the final morphology into a spherical shape. A black-colored colloidal solution of gold nanowire networks is formed in the absence of these anti-cancer drug molecules in the reaction mixture. We used hyperspectral-enhanced dark field microscopy to examine the uptake of gold nanoparticles by breast cancer cells. Upon exposure to LIPUS, the release of the anti-cancer drug from the particle surface can be quantified by fluorescence measurements. This release of drug molecules along with trisodium citrate from the surface of gold nanoparticles by ultrasound resulted in their destabilization and subsequent aggregation, which could be visually observed through the change in the color of colloidal sol. Cancer cell viability was studied by MTT assay to examine the efficacy of this nanoparticle-based drug delivery system. Ultraviolet-visible spectroscopy, dynamic light scattering (DLS), and transmission electron microscope (TEM) analysis were used to characterize the nanoparticles and quantify anti-cancer drug release.

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Ultrasound is an effective tool for both diagnostic and therapeutic applications. As an imaging tool, ultrasound has mostly been used for real-time noninvasive diagnostic imaging. As ultrasound propagates through a material, a reflected radio-frequency (RF) signal is generated when encountering a mismatch in acoustic impedance. While traditionally recognized for its diagnostic imaging capabilities, the application of ultrasound has broadened to encompass therapeutic interventions, most notably in the form of Low-Intensity Pulsed Ultrasound (LIPUS). Low-Intensity Pulsed Ultrasound (LIPUS) is a form of mechanical energy transmitted transcutaneously by high-frequency acoustic pressure waves. The intensity of LIPUS (30 mW/cm2) is within the range of ultrasound intensities used for diagnostic purposes (1-50 mW/cm2) and is regarded as non-thermal, non-destructive, permeating living tissues and triggering a cascade of biochemical responses at the cellular level. The LIPUS device produces a 200 µs burst of 1.5 MHz acoustic sine waves, that repeats at a modulation frequency of 1 kHz and provides a peak pressure of 30 mW/cm2. Low-intensity pulsed ultrasound (LIPUS) forms one of the currently available non-invasive healing-enhancing devices besides electro-stimulation (pulsed electro-magnetic field, PEMF). This modality has been leveraged to enhance drug delivery, expedite injury recovery, improve muscle mobility, alleviate joint stiffness and muscle pain, and enhance bone fracture healing. Although LIPUS has been embraced within various medical disciplines, its integration into standard dental practices is still in its nascent stages, signifying an unexplored frontier with potentially transformative implications. Low-intensity pulsed ultrasound (LIPUS) has emerged as an attractive adjuvant therapy in various dental procedures, such as orthodontic treatment and maxillary sinus augmentation. Its appeal lies in its simplicity and non-invasive nature, positioning LIPUS as a promising avenue for clinical innovation. One particular area of interest is orthodontically induced inflammatory root resorption (OIIRR), an oftenunavoidable outcome of the orthodontic intervention, resulting in the permanent loss of root structure. Notably, OIIRR is the second most common form of root resorption (RR), surpassed only by root resorption related to pulpal infection. Given the high prevalence and potential long-term consequences of OIIRR, this literature review seeks to evaluate the efficacy of LIPUS as a therapeutic approach, with an emphasis on assessing its capacity to reduce the severity of OIIRR to a level of clinical significance. To conduct this systematic review, a comprehensive automated literature search was executed across multiple databases, including MEDLINE, Embase, PsycINFO, Web of Knowledge, Scopus, CINAHL, LILACS, SciELO, Cochrane, PubMed, trials registries, 3ie, and Google Scholar. Both forward and backward citation tracking was employed, encompassing studies published from database inception through January 2009 to April 2023. The review focused on randomized controlled trials (RCTs) that specifically evaluated the effects of low-intensity pulsed ultrasound therapy on orthodontically induced inflammatory root resorption (OIIRR), without restrictions of publication date. A stringent selection criterion was applied, and only studies demonstrating high levels of statistical significance were included. Ultimately, fourteen studies met the inclusion criteria and were subjected to further analysis. The overall quality of the included randomized controlled trials (RCTs) was rigorously assessed utilizing the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. This analysis revealed certain methodological limitations that posed challenges in drawing definitive conclusions from the available evidence. Despite these constraints, the review offers invaluable insights that can inform and guide future research. Specifically, it delineates recommendations for targeted populations, necessary interventions, appropriate outcome measures, suitable study designs, and essential infrastructure to facilitate further investigations. The synthesis of these insights aims to enhance the development and application of low-intensity pulsed ultrasound therapy within the field of dentistry, thereby contributing to improved patient outcomes.

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The intermittent injection of teriparatide, a recombinant fragment of human parathyroid hormone (PTH 1-34), activates anabolic activity on bone turnover. However, the PTH administration period is limited to 2 years. Thus, sequential therapy after discontinuation of PTH is required. Low-intensity pulsed ultrasound (LIPUS) has been widely used for bone fracture healing. In this study, we examined the effects of LIPUS on bone mass after PTH withdrawal in ovariectomized (OVX) model mice. The LIPUS-non-irradiated femoral trabecular bone mineral density (BMD) in the treated after PTH withdrawal was significantly decreased. Meanwhile, the femoral BMD in the OVX + PTH-LIPUS group was remarkably higher than that of the OVX group. Additionally, mRNA expression of Runx2, Osterix, Col1a1, and ALP increased significantly following LIPUS irradiation after PTH withdrawal. These results suggest that LIPUS protected against femoral trabecular BMD loss and up-regulated the osteogenic factors following PTH withdrawal in OVX mice.

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Stress fractures are a common and significant source of pain and burden that can require long periods of rest from physical activity to allow adequate healing. Specifically in athletes or those with physically demanding occupations, the prolonged period of rest and the potential for requiring surgical intervention in the case of poor or delayed healing can have devastating impacts on these individuals' careers and socioeconomic well-being. In this population, successful healing, in addition to a quicker healing time and a sooner return to activity, are important outcomes when faced with treating stress fractures. The use of low-intensity pulsed ultrasound (LIPUS) to accelerate bone healing has been a topic of investigation, though little research has explored the use of LIPUS specifically in the physically active population. The purpose of this study was to review the existing literature on the use of LIPUS for stress fracture healing in the physically active population with the outcome of a quicker return to sport or physical duties. The PubMed and Embase databases were screened for relevant articles using defined Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Two independent researchers screened articles using PICOS criteria for inclusion in the review. Data were independently extracted regarding study and population characteristics as well as outcome measures, including time to healing of fractures and time to return to sport or physical activity. Five studies were ultimately included in the systematic review. One study investigated the use of LIPUS in pediatric athletes with spondylolysis, while four studies investigated lower extremity stress fractures in adult populations. All reported the outcomes of either rate or time to healing and ability to return to sport or activity. One study found a statistically significant improvement in the rate of bone union in the intervention group undergoing LIPUS compared to the control. Two studies found a statistically significant decrease in the time to resolution of symptoms, allowing an earlier return to sport or physical duties. Two studies found no difference in the time to healing or success rate of healing between the LIPUS group and the control group. This review of the literature suggests that the use of LIPUS for the treatment of stress fractures in the athletic or physically active population has the potential to expedite the resolution of symptoms and return to activity. Due to the heterogeneity of the existing studies, more research is needed to definitively determine the most appropriate clinical application of LIPUS and its most effective ultrasound settings. Further research should be directed toward more controlled studies specifically investigating the athletic and physically active population.

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Postoperative neurocognitive impairment is an urgent problem with global aging accelerating. The prevention and treatment of postoperative neurocognitive impairment have been widely investigated but lack effective strategies. Low-intensity pulsed ultrasound (LIPUS), a non-invasive tool, has shown an effect on neuroprotection, but whether it could attenuate the postoperative neurocognitive impairment and the underlying mechanisms remains unknown. An experimental setup for LIPUS stimulation of the hippocampus was well established. A laparotomy model in aged mice was applied, and a Morris water maze was used to assess cognitive function. RT-qPCR and western blotting were used to detect levels of Piezo1, synapse-associated proteins in the hippocampus, respectively. Immunofluorescent staining was also used to determine the neural activation and Piezo1 expression. The results showed that LIPUS increased synapse-related proteins of the hippocampus and attenuated cognitive impairment in aged mice. Meanwhile, LIPUS suppressed the overexpression of Piezo1 in the hippocampus. We further found that LIPUS promoted Calpain1 activity and increased extracellular regulated protein kinases (Erk) phosphorylation. Our results suggested that LIPUS could improve cognitive impairment and increase hippocampal synaptogenesis through the Piezo1-mediated Calpain1/ Erk pathway. LIPUS could be used as an effective physical intervention to alleviate postoperative cognitive dysfunction in the aged population.

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BACKGROUND: Mesenchymal stem cell (MSC) transplantation therapy is highly investigated for the regenerative repair of cartilage defects. Low-intensity pulsed ultrasound (LIPUS) has the potential to promote chondrogenic differentiation of MSCs. However, its underlying mechanism remains unclear. Here, we investigated the promoting effects and mechanisms underlying LIPUS stimulation on the chondrogenic differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) and further evaluated its regenerative application value in articular cartilage defects in rats. METHODS: LIPUS was applied to stimulate cultured hUC-MSCs and C28/I2 cells in vitro. Immunofluorescence staining, qPCR analysis, and transcriptome sequencing were used to detect mature cartilage-related markers of gene and protein expression for a comprehensive evaluation of differentiation. Injured articular cartilage rat models were established for further hUC-MSC transplantation and LIPUS stimulation in vivo. Histopathology and H&E staining were used to evaluate the repair effects of the injured articular cartilage with LIPUS stimulation. RESULTS: The results showed that LIPUS stimulation with specific parameters effectively promoted the expression of mature cartilage-related genes and proteins, inhibited TNF-α gene expression in hUC-MSCs, and exhibited anti-inflammation in C28/I2 cells. In addition, the articular cartilage defects of rats were significantly repaired after hUC-MSC transplantation and LIPUS stimulation. CONCLUSIONS: Taken together, LIPUS stimulation could realize articular cartilage regeneration based on hUC-MSC transplantation due to the inhibition of the TNF signaling pathway, which is of clinical value for the relief of osteoarthritis.

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Introduction: Tissue-resident stem cells (TRSCs) have the ability to self-renew and differentiate throughout an individual's lifespan, and they utilize both mechanisms to maintain homeostasis and regenerate damaged tissues. Several studies suggest that these stem cells can serve as a potential source for cell-replacement-based therapy by promoting differentiation or expansion. In recent years, low-intensity pulsed ultrasound (LIPUS) has been demonstrated to effectively stimulate stem cell proliferation and differentiation, promote tissue regeneration, and inhibit inflammatory responses. Aims: To present a comprehensive overview of current application and mechanism of LIPUS on tissue resident stem cells. Methods: We searched PubMed, Web of Science for articles on the effects of LIPUS on tissue resident stem cells and its application. Results: The LIPUS could modulate cellular activities such as cell viability, proliferation and differentiation of tissue resident stem cells and related cells through various cellular signaling pathways. Currently, LIPUS, as the main therapeutic ultrasound, is being widely used in the treatment of preclinical and clinical diseases. Conclusion: The stem cell research is the hot topic in the biological science, while in recent years, increasing evidence has shown that TRSCs are good targets for LIPUS-regulated regenerative medicine. LIPUS may be a novel and valuable therapeutic approach for the treatment of ophthalmic diseases. How to further improve its efficiency and accuracy, as well as the biological mechanism therein, will be the focus of future research.

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Low-intensity pulsed ultrasound (LIPUS), as a safe and potent physical therapy, has been widely used. It has been demonstrated that LIPUS could induce multiple biological effects, such as relieving pain, accelerating tissue repair/regeneration, and alleviating inflammation. A number of in vitro studies have indicated that LIPUS could significantly reduce the expression of proinflammatory cytokines. This anti-inflammatory effect has also been verified in many in vivo researches. However, the molecular mechanisms underlying LIPUS against inflammation are far from fully elucidated and may differ among different tissues and cells. Here, we review the applications of LIPUS against inflammation through different signaling pathways including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/serine/threonine kinase (PI3K/Akt), and discuss the underlying mechanisms. The positive effects of LIPUS on exosomes against inflammation and related signaling pathways are also discussed. A systematic overview of recent advances will present a deeper understanding of the molecular mechanisms of LIPUS, thus boosting our ability to optimize this promising anti-inflammatory therapy.

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[Purpose] We investigated the effects of low-intensity pulsed ultrasound (LIPUS) irradiation of the infrapatellar fat pad (IFP) combined with therapeutic exercise for management of knee osteoarthritis (knee OA). [Participants and Methods] The study included 26 patients with knee OA, who were randomized into the LIPUS group (patients underwent LIPUS + therapeutic exercise) and the therapeutic exercise group (patients underwent sham LIPUS + therapeutic exercise). We measured changes in the patellar tendon-tibial angle (PTTA) and in IFP thickness, IFP gliding, and IFP echo intensity after 10 treatment sessions to determine the effects of the aforementioned interventions. We additionally recorded changes in the visual analog scale, Timed Up and Go Test, the Western Ontario and McMaster Universities Osteoarthritis Index, and Kujala scores, as well as range of motion in each group at the same end-point. [Results] Compared with patients in the therapeutic exercise group, those in the LIPUS group showed significant post-treatment improvements in PTTA, VAS, and Kujala scores, as well as in range of motion. [Conclusion] The combined use of LIPUS irradiation of the IFP and therapeutic exercise is a safe and effective modality to reduce IFP swelling, relieve pain, and improve function in patients with knee OA.

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Due to aging and long-term estrogen deficiency, postmenopausal women suffer muscle atrophy (MA), which is characterized by decreased muscle mass and muscle quality. Low-intensity pulsed ultrasound (LIPUS) is an acoustic wave inducing biological effects mainly by the mechanical stimulation and used as a non-invasive physical therapy for muscle repair. Parathyroid hormone (PTH) is an 84-amino-acid polypeptide, and its bioactive fragment [PTH (1-34)] has potential application in the treatment of MA. We speculate that the combination of physical therapy (i.e., the LIPUS) and regulatory hormone (i.e., the PTH) would be more effective in the treatment of MA. The objective of this study was to evaluate the individual and combined effects of LIPUS and PTH therapy on MA in estrogen deficiency mice. Seventy 8-week-old female C57BL/6J mice were used in this study and the MA model was induced by an intraperitoneal injection of 4-vinylcyclohexene diepoxide (VCD) for 20 consecutive days. The VCD-induced MA mice were randomly divided into MA, LIPUS, PTH and LIPUS + PTH (Combined) groups (n = 10/group). In the LIPUS group, the mice were treated by LIPUS in bilateral quadriceps muscles for 20 min, five times a week for 6 weeks. In the PTH group, the mice received subcutaneous injection of PTH (1-34) (80 ug/kg/d) five times a week, for 6 weeks. In the Combined group, the PTH was administrated 30 min before each LIPUS session. Hematoxylin-eosin (H&E) staining, serum biochemical analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to evaluate the therapeutic effects of related treatments. The results showed that the MA mice had a disordered estrus cycle, significantly decreased muscle mass and myofibers cross-sectional area (CSA). After treatments, LIPUS, PTH and Combined groups had a significantly increased CSA, compared with the MA mice without treatment. In addition, Combined group had a significantly increased mRNA expression of Pax7, MyoD and MyoG, compared with LIPUS and PTH monotherapy groups. Our findings indicated that the combination of LIPUS and PTH treatment improves muscle regeneration ability, which might have potential for treating MA in postmenopausal women.

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OBJECTIVE: Despite advances in treatment, the management of fracture non-union remains a challenging and complex problem in orthopaedics. Low-intensity pulsed ultrasound (LIPUS) treatment has been shown to be an effective, non-invasive, affordable treatment option. This treatment was evaluated in a Scottish district hospital over a nine-year period, which included the COVID-19 pandemic. MATERIALS AND METHODS: This submission describes a case series at Dr Gray's Hospital in Scotland, 18 patients in whom fracture non-union was treated using LIPUS. RESULTS: An overall healing rate of 94% was achieved. Exogen™ (Bioventus LLC, NC, USA) proved to be most successful in oligotrophic non-union. No observed patient demographic appeared predictive of outcome. LIPUS treatment failed in one case. No significant adverse effects of LIPUS were detected. CONCLUSION: LIPUS represents a useful, cost-effective potential alternative to revision surgery. LIPUS may therefore be the preferred treatment when surgical intervention and face-to-face interactions are to be minimised, as during the COVID-19 pandemic.

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Menisci are a pair of crescent-shaped fibrocartilages and composed primarily of type I collagen. Inner region of the meniscus has similar characteristics to articular cartilage. Low-intensity pulsed ultrasound (LIPUS) has been reported to have chondroprotective effects on chondrocytes by inducing the expression of chondrocyte differentiation markers and CCN2/CTGF production. Here, we describe an experimental approach that investigates the distinct cellular behavior of human inner and outer meniscus cells in response to LIPUS stimulation. Our experimental model can analyze the relationships between LIPUS-induced CCN2 and its repairing role in the meniscus.

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Schwann cells (SCs) are the major component of myelin sheath in the peripheral nervous system, which are necessary in the development, function maintenance, and repair of peripheral nerves. This study aimed to investigate the potential mechanism of low-intensity pulsed ultrasound (LIPUS) affecting the proliferation and myelinating activity of SCs. Rat Schwann cell line RSC96 were cultured and exposed to LIPUS of different duty ratios (control, 20 %, 50 %, 80 %). Results demonstrated that LIPUS with a duty ratio of 50 % showing the maximal effect in facilitating proliferation of SCs. The expressions of Krox20 and myelin basic protein (MBP), the key molecules of SC myelination, and the potent inducer of myelination neuregulin 1 (NRG1) and its receptors ErbB2 and ErbB3 increased significantly by LIPUS. The reaction of these factors to LIPUS were both time- and duty ratio-dependent: namely LIPUS with higher duty ratios took effects when applied repeatedly over more consecutive days. These observations indicated that NRG1/ErbB signaling pathway might contribute to the effects of LIPUS on the proliferation and myelinating status of SCs, which could be one of the mechanisms in the protective role of LIPUS in nerve repair and regeneration. Our work provided novel insights for promising strategies of nerve repair therapy.

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Injury to corpus cavernosal endothelial cells (CCECs) is an important pathological basis of diabetes mellitus-induced erectile dysfunction (DMED), while low-intensity pulsed ultrasound (LIPUS) has been shown to improve erectile function in DMED. To further understand its therapeutic mechanism of action, in this study, we first demonstrated increased apoptosis and shedding in the CCECs of DMED patients, accompanied by significant mitochondrial injury by immunohistochemistry and electron microscopy of corpus cavernosum tissue. Next, we used advanced glycation end products (AGEs) to simulate the diabetic environment in vitro and found that AGES damaged mitochondria and inhibited angiogenesis in CCECs in a dose-dependent manner, while LIPUS treatment significantly reversed its effects. Mechanistic studies based on transcriptome sequencing showed that LIPUS significantly up-regulated LC3 and PARKIN protein levels in mitochondria, promoted mitophagy, and affected mitochondrial dynamics and reactive oxygen species (ROS) production. In addition, the protective effects of LIPUS were abrogated when mitophagy was inhibited by 3-methyladenine. In summary, LIPUS exerted potent inhibitory effects on AGES-induced CCEC failure via mitophagy, providing a theoretical basis for DMED treatment that encompasses the protection of endothelial structure and function.

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AIMS: To evaluate whether low-intensity pulsed ultrasound (LIPUS) accelerates bone healing at osteotomy sites and promotes functional recovery after open-wedge high tibial osteotomy (OWHTO). METHODS: Overall, 90 patients who underwent OWHTO without bone grafting were enrolled in this nonrandomized retrospective study, and 45 patients treated with LIPUS were compared with 45 patients without LIPUS treatment in terms of bone healing and functional recovery postoperatively. Clinical evaluations, including the pain visual analogue scale (VAS) and Japanese Orthopaedic Association (JOA) score, were performed preoperatively as well as six weeks and three, six, and 12 months postoperatively. The progression rate of gap filling was evaluated using anteroposterior radiographs at six weeks and three, six, and 12 months postoperatively. RESULTS: The pain VAS and JOA scores significantly improved after OWHTO in both groups. Although the LIPUS group had better pain scores at six weeks and three months postoperatively, there were no significant differences in JOA score between the groups. The lateral hinge united at six weeks postoperatively in 34 (75.6%) knees in the control group and in 33 (73.3%) knees in the LIPUS group. The progression rates of gap filling in the LIPUS group were 8.0%, 15.0%, 27.2%, and 46.0% at six weeks and three, six, and 12 months postoperatively, respectively, whereas in the control group at the same time points they were 7.7%, 15.2%, 26.3%, and 44.0%, respectively. There were no significant differences in the progression rate of gap filling between the groups. CONCLUSION: The present study demonstrated that LIPUS did not promote bone healing and functional recovery after OWHTO with a locking plate. The routine use of LIPUS after OWHTO was not recommended from the results of our study. Cite this article: Bone Jt Open 2022;3(11):885-893.

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Premature ovarian insufficiency (POI) can cause multiple sequelae and is currently incurable. Mesenchymal stem cell (MSC) transplantation might provide an effective treatment method for POI. However, the clinical application of systemic MSC transplantation is limited by the low efficiency of cell homing to target tissue in vivo, including systemic MSC transplantation for POI treatment. Thus, exploration of methods to promote MSC homing is necessary. This study was to investigate the effects of low-intensity pulsed ultrasound (LIPUS) on the migration and homing of transplanted human amnion-derived MSCs (hAD-MSCs) to ovaries in rats with chemotherapy-induced POI. For LIPUS treatment, hAD-MSCs were exposed to LIPUS or sham irradiation. Chemokine receptor expressions in hAD-MSCs were detected by polymerase chain reaction (PCR), Western blot, and immunofluorescence assays. hAD-MSC migration was detected by wound healing and transwell migration assays. Cyclophosphamide-induced POI rat models were established to evaluate the effects of LIPUS on the homing of systemically transplanted hAD-MSCs to chemotherapy-induced POI ovaries in vivo. We found that hAD-MSCs expressed chemokine receptors. The LIPUS promoted the expression of chemokine receptors, especially CXCR4, in hAD-MSCs. SDF-1 induced hAD-MSC migration. The LIPUS promoted hAD-MSC migration induced by SDF-1 through SDF-1/CXCR4 axis. SDF-1 levels significantly increased in ovaries induced by chemotherapy in POI rats. Pretreating hAD-MSCs with LIPUS increased the number of hAD-MSCs homing to ovaries in rats with chemotherapy-induced POI to some extent. However, the difference was not significant. Both hAD-MSC and LIPUS-pretreated hAD-MSC transplantation reduced ovarian injuries and improved ovarian function in rats with chemotherapy-induced POI. CXCR4 antagonist significantly reduced the number of hAD-MSCs- and LIPUS-pretreated hAD-MSCs homing to POI ovaries, and further reduced their efficacy in POI treatment. According to these findings, pretreating MSCs with LIPUS before transplantation might provide a novel, convenient, and safe technique to explore for improving the homing of systemically transplanted MSCs to target tissue.

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Menisci are fibrocartilaginous structures in the knee joint with an inadequate regenerative capacity, which causes low healing potential and further leads to osteoarthritis. Recently, three-dimensional (3D) printing techniques and ultrasound treatment have gained plenty of attention for meniscus tissue engineering. The present study investigates the effectiveness of low-intensity pulsed ultrasound stimulations (LIPUS) on the proliferation, viability, morphology, and gene expression of the chondrocytes seeded on 3D printed polyurethane scaffolds dip-coated with gellan gum, hyaluronic acid, and glucosamine. LIPUS stimulation was performed at 100, 200, and 300 mW/cm2 intensities for 20 min/day. A faster gap closure (78.08 ± 2.56%) in the migration scratch assay was observed in the 200 mW/cm2 group after 24 h. Also, inverted microscopic and scanning electron microscopic images showed no cell morphology changes during LIPUS exposure at different intensities. The 3D cultured chondrocytes under LIPUS treatment revealed a promotion in cell proliferation rate and viability as the intensity doses increased. Additionally, LIPUS could stimulate chondrocytes to overexpress the aggrecan and collagen II genes and improve their chondrogenic phenotype. This study recommends that the combination of LIPUS treatment and 3D hybrid scaffolds can be considered as a valuable treatment for meniscus regeneration based on our in vitro data.

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Background Fracture non-union can lead to significant patient morbidity with poor quality of life. Due to the cost, complexity, and potential risks of revision surgery, there has been an increased popularity in the use of low-intensity pulsed ultrasound therapy (LIPUS), which accelerates and promotes bone consolidation. There is an ongoing debate regarding the use and efficacy of LIPUS in delayed union and non-union. This study aims to assess the success rate of LIPUS therapy in patients treated for delayed and non-union fractures, explicitly focusing on the impact of patient co-morbidities and fracture characteristics. Method A retrospective observational study was performed of all consecutive patients who received LIPUS therapy in a single institution from January 2016 to September 2022. Of 127 identified patients, only 99 patients met our inclusion criteria. Data collection entailed reviewing the clinical notes to assess patients' sex, age, co-morbidities, initial treatment method, time to initiate LIPUS, whether a CT was performed to diagnose non-union, time to union and whether revision surgery was needed. Two independent senior orthopedic doctors reviewed the patients' radiographs, measured the interfragmentary bone gap of all fractures, and assessed whether the radiographic union was achieved. Results The mean age of the included patients was 52.5 (SD±16.9) years with a male-to-female ratio of 1:1.6. At initial presentation, 65 (out of 99) patients were treated surgically, whereas the rest were managed conservatively. 80.8% of patients developed atrophic non-union. All 99 included patients were fitted with LIPUS once delayed/ non-union was diagnosed; the average time to fitting was 5.1 (SD±3.9) months. Of these, 61.6% of patients were successfully treated with LIPUS with a clinical and radiological union at an average of 4.3 (SD±1.9) months. The rest of the patients needed further surgical intervention due to ongoing non-union. The interfragmentary bone gap was the only statistically significant factor influencing the success of LIPUS therapy (p=0.003). In contrast, no statistically significant association was identified between the outcome of LIPUS therapy and the patient's age, sex, diabetes, and smoking status. Conclusion This study demonstrated a 61.6% progression to union rate of patients treated with LIPUS therapy for delayed union and non-union. The interfragmentary bone gap was identified as the only statistically significant factor influencing the success of LIPUS therapy. In the current climate post-lockdown and with ongoing Covid 19 outbreaks impacting elective waiting lists negatively, there is increased value and demand for non-surgical treatment options. LIPUS therapy represents an important complementary non-surgical and low-risk treatment pathway for delayed union and non-union.

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OBJECTIVES: Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by angiotensin II (AngII). Low-intensity pulsed ultrasound (LIPUS) has been reported to ameliorate cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechano-transduction and its downstream pathways. In this study, we aimed to investigate whether LIPUS could exert a protective effect by ameliorating AngII-induced cardiac hypertrophy and fibrosis and if so, to further elucidate the underlying molecular mechanisms. METHODS: We used AngII to mimic animal and cell culture models of cardiac hypertrophy and fibrosis. LIPUS irradiation was applied in vivo for 20 min every 2 d from one week before mini-pump implantation to four weeks after mini-pump implantation, and in vitro for 20 min on each of two occasions 6 h apart. Cardiac hypertrophy and fibrosis levels were then evaluated by echocardiographic, histopathological, and molecular biological methods. RESULTS: Our results showed that LIPUS could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-induced release of inflammatory cytokines, but the protective effects on cardiac hypertrophy were limited in vitro. Given that LIPUS increased the expression of caveolin-1 in response to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vivo and in vitro. LIPUS-induced downregulation of inflammation was reversed and the anti-fibrotic effects of LIPUS were absent. CONCLUSIONS: These results indicated that LIPUS could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeutic apparatus in clinical practice.

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Vascular events can trigger a pathological phenotypic switch in vascular smooth muscle cells (VSMCs), decreasing and disrupting the plasticity and diversity of vascular networks. The development of novel therapeutic approaches is necessary to prevent these changes. We aimed to investigate the effects and associated mechanisms of low-intensity pulsed ultrasound (LIPUS) irradiation on the angiotensin II (AngII)-induced phenotypic switch in VSMCs. In vivo, AngII was infused subcutaneously for 4 weeks to stimulate vascular remodeling in mice, and LIPUS irradiation was applied for 20 min every 2 days for 4 weeks. In vitro, cultured rat aortic VSMCs (RAVSMCs) were pretreated once with LIPUS irradiation for 20 min before 48-h AngII stimulation. Our results showed that LIPUS irradiation prevents AngII-induced vascular remodeling of the whole wall artery without discriminating between adventitia and media in vivo and RAVSMC phenotypic switching in vitro. LIPUS irradiation downregulated miR-17-5p expression and upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. The PPAR-γ activator rosiglitazone could mimic the favorable effects of LIPUS irradiation on AngII-treated RAVSMCs. In contrast, GW9662 could impede the LIPUS-mediated downregulation of RAVSMC proliferation and inflammation under AngII stimulation conditions in vivo and in vitro. Also, the miR-17-5p agomir has the same effects as GW9662 in vitro. Besides, the inhibitory effects of GW9662 against the anti-remodeling effects of LIPUS irradiation in AngII-induced RAVSMCs could be blocked by pretreatment with the miR-17-5p antagomir. Overall, LIPUS irradiation prevents AngII-induced RAVSMCs phenotypic switching through hampering miR-17-5p and enhancing PPAR-γ, suggesting a new approach for the treatment of vascular disorders.

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