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      Ultrasound Therapy: Experiences and Perspectives for Regenerative Medicine

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          Abstract

          Ultrasound has emerged as a novel tool for clinical applications, particularly in the context of regenerative medicine. Due to its unique physico-mechanical properties, low-intensity ultrasound (LIUS) has been approved for accelerated fracture healing and for the treatment of established non-union, but its utility has extended beyond tissue engineering to other fields, including cell regeneration. Cells and tissues respond to acoustic ultrasound by switching on genetic repair circuits, triggering a cascade of molecular signals that promote cell proliferation, adhesion, migration, differentiation, and extracellular matrix production. LIUS also induces angiogenesis and tissue regeneration and has anti-inflammatory and anti-degenerative effects. Accordingly, the potential application of ultrasound for tissue repair/regeneration has been tested in several studies as a stand-alone treatment and, more recently, as an adjunct to cell-based therapies. For example, ultrasound has been proposed to improve stem cell homing to target tissues due to its ability to create a transitional and local gradient of cytokines and chemokines. In this review, we provide an overview of the many applications of ultrasound in clinical medicine, with a focus on its value as an adjunct to cell-based interventions. Finally, we discuss the various preclinical and clinical studies that have investigated the potential of ultrasound for regenerative medicine.

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          Overview of therapeutic ultrasound applications and safety considerations.

          Applications of ultrasound in medicine for therapeutic purposes have been accepted and beneficial uses of ultrasonic biological effects for many years. Low-power ultrasound of about 1 MHz has been widely applied since the 1950s for physical therapy in conditions such as tendinitis and bursitis. In the 1980s, high-pressure-amplitude shock waves came into use for mechanically resolving kidney stones, and "lithotripsy" rapidly replaced surgery as the most frequent treatment choice. The use of ultrasonic energy for therapy continues to expand, and approved applications now include uterine fibroid ablation, cataract removal (phacoemulsification), surgical tissue cutting and hemostasis, transdermal drug delivery, and bone fracture healing, among others. Undesirable bioeffects can occur, including burns from thermal-based therapies and severe hemorrhage from mechanical-based therapies (eg, lithotripsy). In all of these therapeutic applications of ultrasound bioeffects, standardization, ultrasound dosimetry, benefits assurance, and side-effect risk minimization must be carefully considered to ensure an optimal benefit to risk ratio for the patient. Therapeutic ultrasound typically has well-defined benefits and risks and therefore presents a manageable safety problem to the clinician. However, safety information can be scattered, confusing, or subject to commercial conflicts of interest. Of paramount importance for managing this problem is the communication of practical safety information by authoritative groups, such as the American Institute of Ultrasound in Medicine, to the medical ultrasound community. In this overview, the Bioeffects Committee of the American Institute of Ultrasound in Medicine outlines the wide range of therapeutic ultrasound methods, which are in clinical use or under study, and provides general guidance for ensuring therapeutic ultrasound safety.
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            Challenges and Strategies for Improving the Regenerative Effects of Mesenchymal Stromal Cell-Based Therapies

            Cell-based therapies have the potential to revolutionize current treatments for diseases with high prevalence and related economic and social burden. Unfortunately, clinical trials have made only modest improvements in restoring normal function to degenerating tissues. This limitation is due, at least in part, to the death of transplanted cells within a few hours after transplant due to a combination of mechanical, cellular, and host factors. In particular, mechanical stress during implantation, extracellular matrix loss upon delivery, nutrient and oxygen deprivation at the recipient site, and host inflammatory response are detrimental factors limiting long-term transplanted cell survival. The beneficial effect of cell therapy for regenerative medicine ultimately depends on the number of administered cells reaching the target tissue, their viability, and their promotion of tissue regeneration. Therefore, strategies aiming at improving viable cell engraftment are crucial for regenerative medicine. Here we review the major factors that hamper successful cell engraftment and the strategies that have been studied to enhance the beneficial effects of cell therapy. Moreover, we provide a perspective on whether mesenchymal stromal cell-derived extracellular vesicle delivery, as a cell-free regenerative approach, may circumvent current cell therapy limitations.
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              Piezo type mechanosensitive ion channel component 1 functions as a regulator of the cell fate determination of mesenchymal stem cells

              The extracellular environment regulates the dynamic behaviors of cells. However, the effects of hydrostatic pressure (HP) on cell fate determination of mesenchymal stem cells (MSCs) are not clearly understood. Here, we established a cell culture chamber to control HP. Using this system, we found that the promotion of osteogenic differentiation by HP is depend on bone morphogenetic protein 2 (BMP2) expression regulated by Piezo type mechanosensitive ion channel component 1 (PIEZO1) in MSCs. The PIEZO1 was expressed and induced after HP loading in primary MSCs and MSC lines, UE7T-13 and SDP11. HP and Yoda1, an activator of PIEZO1, promoted BMP2 expression and osteoblast differentiation, whereas inhibits adipocyte differentiation. Conversely, PIEZO1 inhibition reduced osteoblast differentiation and BMP2 expression. Furthermore, Blocking of BMP2 function by noggin inhibits HP induced osteogenic maker genes expression. In addition, in an in vivo model of medaka with HP loading, HP promoted caudal fin ray development whereas inhibition of piezo1 using GsMTx4 suppressed its development. Thus, our results suggested that PIEZO1 is responsible for HP and could functions as a factor for cell fate determination of MSCs by regulating BMP2 expression.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                17 September 2020
                September 2020
                : 11
                : 9
                : 1086
                Affiliations
                [1 ]Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, 28670 Madrid, Spain; beatriz.delucas@ 123456universidadeuropea.es (B.d.L.); laura.mp.hospital@ 123456gmail.com (L.M.P.)
                [2 ]Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain; aurora.bernal@ 123456cnic.es
                Author notes
                Author information
                https://orcid.org/0000-0002-2852-0118
                https://orcid.org/0000-0002-8082-9323
                Article
                genes-11-01086
                10.3390/genes11091086
                7563547
                32957737
                06df8494-9e33-48ae-b97f-d8bfcbdcd10f
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 August 2020
                : 16 September 2020
                Categories
                Review

                ultrasound,lius,regenerative medicine,stem cells,proliferation,differentiation,migration,clinical trials

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