Mode &amp; mechanism of low intensity pulsed ultrasound (LIPUS) in fracture repair

Harrison, Andrew; Lin, Sheldon S.; Pounder, Neill M.; Mikuni-Takagaki, Yuko

doi:10.1016/j.ultras.2016.03.016

Cited by 148 publications

(125 citation statements)

References 48 publications

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“…In accordance with the proposed mechanism for how LIPUS stimulation works in vivo (Harrison et al, 2016), we show that integrin-mediated cell-ECM adhesions are essential for the cellular responses to LIPUS (Fig. 4), and that vinculin has a critical role in this process (Fig.…”

Section: Mechanical Stimulation By Lipus Is Sensed By Vinculin At Fassupporting

confidence: 87%

“…Previous reports showed that the 200 ms pulses produce nano-vibrations (Argadine et al, 2005;Harrison et al, 2016) as well as acoustic pressure (Fung et al, 2014), exposing cells to rapid mechanical stimuli.…”

Section: Mechanical Stimulation By Lipus Is Sensed By Vinculin At Fasmentioning

confidence: 99%

“…LIPUS therapy consists of 20 min of daily stimulation targeted at the site of injury, with an unfocussed ultrasound transducer delivering 200 ms bursts of 1.5 MHz ultrasound pulsed at 1 kHz (Fig. S1A), to an intensity of 30 mW/cm 2 spatial averagetemporal average (SATA), with a power of 117 mW (Harrison et al, 2016). LIPUS shows particular efficacy in treating bone nonunion fractures (Nolte et al, 2001;Rutten et al, 2007;Zura et al, 2015a), and has been approved by the US FDA for treating both fresh fractures and nonunion fractures, and by NICE in the UK for treating nonunion fractures (Higgins et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…The pulse modulation of the LIPUS signal produces motion occurring at a frequency of 1 kHz, and has been shown to produce tissue movement in the nanometre range (Harrison et al, 2016); replication of this motion has been shown to generate the same phenotype in chondrocytes as stimulation with LIPUS (Argadine et al, 2005). More recently, Veronick et al (2016) showed that LIPUS stimulation induces movement of fluorescent beads encapsulated within a collagen hydrogel.…”

Section: Introductionmentioning

confidence: 99%

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Low-intensity pulsed ultrasound promotes cell motility through vinculin-controlled Rac1 GTPase activity

Atherton

Lausecker

Harrison³

et al. 2017

Journal of Cell Science

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Low-intensity pulsed ultrasound (LIPUS) is a therapy used clinically to promote healing. Using live-cell imaging we show that LIPUS stimulation, acting through integrin-mediated cell-matrix adhesions, rapidly induces Rac1 activation associated with dramatic actin cytoskeleton rearrangements. Our study demonstrates that the mechanosensitive focal adhesion (FA) protein vinculin, and both focal adhesion kinase (FAK, also known as PTK2) and Rab5 (both the Rab5a and Rab5b isoforms) have key roles in regulating these effects. Inhibiting the link of vinculin to the actin-cytoskeleton abolished LIPUS sensing. We show that this vinculin-mediated link was not only critical for Rac1 induction and actin rearrangements, but was also important for the induction of a Rab5-dependent increase in the number of early endosomes. Expression of dominant-negative Rab5, or inhibition of endocytosis with dynasore, also blocked LIPUSinduced Rac1 signalling events. Taken together, our data show that LIPUS is sensed by cell matrix adhesions through vinculin, which in turn modulates a Rab5-Rac1 pathway to control ultrasound-mediated endocytosis and cell motility. Finally, we demonstrate that a similar FAK-Rab5-Rac1 pathway acts to control cell spreading upon fibronectin.

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Section: Mechanical Stimulation By Lipus Is Sensed By Vinculin At Fassupporting

confidence: 87%

Section: Mechanical Stimulation By Lipus Is Sensed By Vinculin At Fasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Low-intensity pulsed ultrasound promotes cell motility through vinculin-controlled Rac1 GTPase activity

Atherton

Lausecker

Harrison³

et al. 2017

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…LIPUS was previously demonstrated to promote bone formation and accelerate bone maturation in cases of bone fracture (6,7), distraction osteogenesis (8) and delayed fracture union (9). LIPUS appears to act by affecting the biological mechanisms of cell proliferation, gene regulation and cell differentiation (10).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of low-intensity pulsed ultrasound sonication on the proliferation of osteosarcoma cells

et al. 2017

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Abstract. To date, there is limited data on the biological effects of low-intensity pulsed ultrasound (LIPUS) on primary malignant bone tumors. The purpose of the present study was to investigate the antitumor effects of LIPUS on osteosarcoma cells. The effects of LIPUS on cell viability, induction of apoptosis, mitochondrial membrane potential and intracellular signaling molecules in the LM8 osteosarcoma cell line were investigated. LIPUS inhibited cell viability (P=0.0022) and mitochondrial membrane potential (P=0.0019) in LM8 cells. Flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling staining revealed significantly higher numbers of apoptotic (P<0.0001) and necrotic cells (P=0.0091) compared with cells without treatment. LIPUS treatment significantly increased phosphorylated Akt (P<0.0001) and IκBα (P=0.0001) levels, and reduced phosphorylated mitogen-activated protein kinase 7 (P<0.0001) and phosphorylated checkpoint kinase 1 (P=0.0008) levels. These results suggest that LIPUS is a non-invasive adjuvant therapy that is able to inhibit cellular proliferation in osteosarcoma cells.

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Low‐intensity pulsed ultrasound inhibits VEGFA expression in chondrocytes and protects against cartilage degeneration in experimental osteoarthritis

et al. 2020

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Low‐intensity pulsed ultrasound (LIPUS), a noninvasive physical therapy, was recently demonstrated to be an effective treatment for osteoarthritis (OA). Vascular endothelium growth factor A (VEGFA) has been found to be upregulated in the articular cartilage, synovium and subchondral bone of OA patients, leading to cartilage degeneration, synovitis and osteophyte formation. However, the functions and mechanisms of LIPUS in regulating chondrocyte‐derived VEGFA expression are still unclear. In this study, we investigated whether LIPUS attenuated OA progression by (a) decreasing the percentage of VEGFA‐positive cells in mouse articular cartilage destabilised through medial meniscus surgery and (b) relieving interleukin‐1β‐induced VEGFA expression in mouse primary chondrocytes. However, this function was negated by a p38 mitogen‐activated protein kinase (p38 MAPK) inhibitor. In addition, we found that LIPUS ameliorated VEGFA‐mediated disorders in cartilage extracellular matrix metabolism and chondrocyte hypertrophy during OA development. In conclusion, our data indicate a novel effect of LIPUS in regulating the expression of osteoarthritic chondrocyte‐derived VEGFA through the suppression of p38 MAPK activity.

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Mode & mechanism of low intensity pulsed ultrasound (LIPUS) in fracture repair

Cited by 148 publications

References 48 publications

Low-intensity pulsed ultrasound promotes cell motility through vinculin-controlled Rac1 GTPase activity

Low-intensity pulsed ultrasound promotes cell motility through vinculin-controlled Rac1 GTPase activity

Inhibitory effects of low-intensity pulsed ultrasound sonication on the proliferation of osteosarcoma cells

Low‐intensity pulsed ultrasound inhibits VEGFA expression in chondrocytes and protects against cartilage degeneration in experimental osteoarthritis

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