Low intensity pulsed ultrasound in the treatment of long bone nonunions: Evaluation of cytokine expression as a tool for objectifying nonunion therapy

Moghaddam, Arash; Yildirim, Timur M.; Westhauser, Fabian; Danner, Wolfgang; Swing, Tyler; Brückner, Thomas; Biglari, Bahram

doi:10.1016/j.jor.2016.06.028

Cited by 7 publications

(6 citation statements)

References 49 publications

(71 reference statements)

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“…Low-intensity pulsed ultrasound (LIPUS) has generally been recognized that the micromechanical strains generated by high-frequency acoustic pressure waves evoke biochemical events that can regulate fracture healing [ 11 ]. Many studies have demonstrated that LIPUS stimulation produces significant multifunctional effects on bone formation and resorption [ 12 , 13 ]. It has been reported that LIPUS can stimulate fracture healing and has been used to treat bone defects in clinical therapy [ 14 , 15 ], and also accelerates bone maturation in distraction osteogenesis cases in animal models [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Low-intensity pulsed ultrasound stimulation facilitates in vitro osteogenic differentiation of human adipose-derived stem cells via up-regulation of heat shock protein (HSP)70, HSP90, and bone morphogenetic protein (BMP) signaling pathway

Zhang

Guo

et al. 2018

Bioscience Reports

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Low-intensity pulsed ultrasound (LIPUS) has positive effects on osteogenic differentiation. However, the effect of LIPUS on osteogenic differentiation of human adipose-derived stem cells (hASCs) is unclear. In the present study, we investigated whether LIPUS could promote the proliferation and osteogenic differentiation of hASCs. hASCs were isolated and osteogenically induced with LIPUS stimulation at 20 and 30 mW cm−2 for 30 min day−1. Cell proliferation and osteogenic differentiation potential of hASCs were respectively analyzed by cell counting kit-8 assay, Alizarin Red S staining, real-time polymerase chain reaction, and Western blotting. The results indicated that LIPUS stimulation did not significantly affect the proliferation of hASCs, but significantly increased their alkaline phosphatase activity on day 6 of culture and markedly promoted the formation of mineralized nodules on day 21 of culture. The mRNA expression levels of runt-related transcription factor, osteopontin, and osteocalcin were significantly up-regulated by LIPUS stimulation. LIPUS stimulation did not affect the expression of heat shock protein (HSP) 27, HSP40, bone morphogenetic protein (BMP)-6 and BMP-9, but significantly up-regulated the protein levels of HSP70, HSP90, BMP-2, and BMP-7 in the hASCs. Further studies found that LIPUS increased the mRNA levels of Smad 1 and Smad 5, elevated the phosphorylation of Smad 1/5, and suppressed the expression of BMP antagonist Noggin. These findings indicated that LIPUS stimulation enhanced osteogenic differentiation of hASCs possibly through the up-regulation of HSP70 and HSP90 expression and activation of BMP signaling pathway. Therefore, LIPUS might have the potential to promote the repair of bone defect.

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Section: Introductionmentioning

confidence: 99%

Low-intensity pulsed ultrasound stimulation facilitates in vitro osteogenic differentiation of human adipose-derived stem cells via up-regulation of heat shock protein (HSP)70, HSP90, and bone morphogenetic protein (BMP) signaling pathway

Zhang

Guo

et al. 2018

Bioscience Reports

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“…Although the therapeutic potential of LIPUS and sonoporation is well recognized, the biological grounding in our current scientific understanding of these two phenomena has remained to be critically weak. In the case of LIPUS, its stimulatory benefits are sometimes controversial [10]- [12], and a stronger knowledge of the underlying biological mechanisms is necessary to corroborate the surmised therapeutic value [13], [14]. In the case of sonoporation, its practical efficiency is deemed to be mediocre [15], [16], and the pursuit of detailed knowledge on the pertinent cellular bioeffects is seemingly essential to devise strategies for improving the overall efficiency of this membrane perforation approach [17], [18].…”

mentioning

confidence: 99%

Cellular Bioeffect Investigations on Low-Intensity Pulsed Ultrasound and Sonoporation: Platform Design and Flow Cytometry Protocol

Duan

Wan

2019

IEEE Trans. Ultrason., Ferroelect., Freq. Contr.

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At low-intensity levels, ultrasound can potentially generate therapeutic effects on living cells, and it can trigger sonoporation when microbubbles (MBs) are present to facilitate drug delivery. Yet, our foundational knowledge of low-intensity pulsed ultrasound (LIPUS) and sonoporation remains to be critically weak because the pertinent cellular bioeffects have not been rigorously studied. In this article, we present a populationbased experimental protocol that can effectively foster investigations on the mechanistic bioeffects of LIPUS and sonoporation over a cell population. Walkthroughs of different methodological details are presented, including the fabrication of the ultrasound exposure platform and its calibration, as well as the design of a bioassay procedure that uses fluorescent tracers and flow cytometry to isolate sonicated cells with similar characteristics. An application example is also presented to illustrate how our protocol can be used to investigate the downstream cellular bioeffects of leukemia cells. We show that, with 1-MHz LIPUS exposure (with 29.1 J/cm 2 delivered acoustic energy density), variations in viability and morphology would be found among different types of sonicated leukemia cells (HL-60, Molt-4) in the absence and presence of MBs. Taken altogether, this article provides a reference on how cellular bioeffect experiments on LIPUS and sonoporation can be planned meticulously to acquire strong observations that are critical to establish the biological foundations for therapeutic applications.

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“…Studies 63 have shown that ultrasound increases cellular migration, 64 proliferation, and localized vascularization, reducing 65 inflammation and accelerating soft tissue healing [23, 66 24,26,27,28,29,30]. The Food and Drug Administra-67 tion (FDA) has approved ultrasound treatment systems 68 for non-union fracture healing, musculoskeletal pain, 69 and soft tissue injuries as a standalone or combination 70 therapy [31,32,33,34,35].…”

mentioning

confidence: 99%

Sustained acoustic medicine treatment of discogenic chronic low back pain: A randomized, multisite, double-blind, placebo-controlled trial

Ortiz,

Motyka,

Petterson

et al. 2024

BMR

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BACKGROUND: Sustained acoustic medicine (SAM) is a noninvasive long-term treatment that provides essential mechanical and thermal stimulus to accelerate soft tissue healing, alleviate pain, and improve physical activity. SAM increases localized deep tissue temperature, blood flow, cellular proliferation, migration, and nutrition exchange, resulting in reduced inflammation and an increased rate of tissue regeneration. OBJECTIVE: To assess the efficacy of SAM treatment of discogenic back pain in the lower spinal column to reduce pain, improve quality of life, and lower pharmacotherapy use. METHODS: Sixty-five subjects with chronic low back pain were randomly assigned to SAM (N= 33) or placebo (N= 32) groups. Subjects self-applied SAM device bilaterality on the lower lumbar region for 4 hours daily for 8 weeks and completed daily pain diaries before, during, and after treatment. Subjects recorded pain reduction using a numeric rating scale (NRS), medication use, and physical activity using the Global Rating of Change (GROC) and Oswestry Disability Index (ODI). RESULTS: SAM treatment significantly reduced chronic lower back pain from baseline relative to placebo treatment (p< 0.0001). SAM treated subjects reported significantly lower back pain at 4 weeks, with the highest pain reduction (-2.58 points NRS, p< 0.0001) reported at 8 weeks. Similar trends were observed in improved physical activity (3.48 GROC, p< 0.0001, 69–88% ODI, p< 0.0001) and 22.5% (15.2 morphine milligram equivalent) reduction in the use of opioid medication from baseline to 8 weeks. CONCLUSION: Daily, home-use SAM treatment significantly improves the clinical symptoms of chronic lower back pain, improves physical mobility, and reduces daily medication use. SAM treatment is well-tolerated by patients and may be considered a safe, non-invasive treatment option for chronic discogenic, lower back pain.

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Low intensity pulsed ultrasound in the treatment of long bone nonunions: Evaluation of cytokine expression as a tool for objectifying nonunion therapy

Abstract: Our findings suggest that LIPUS does not lead to a significant increase in cytokine levels in patients with nonunions. It is likely that "successful" treatment can be attributed to spontaneous healing. Our results suggest that LIPUS is not a proper treatment for long bone nonunions.

Cited by 7 publications

References 49 publications

Low-intensity pulsed ultrasound stimulation facilitates in vitro osteogenic differentiation of human adipose-derived stem cells via up-regulation of heat shock protein (HSP)70, HSP90, and bone morphogenetic protein (BMP) signaling pathway

Low-intensity pulsed ultrasound stimulation facilitates in vitro osteogenic differentiation of human adipose-derived stem cells via up-regulation of heat shock protein (HSP)70, HSP90, and bone morphogenetic protein (BMP) signaling pathway

Cellular Bioeffect Investigations on Low-Intensity Pulsed Ultrasound and Sonoporation: Platform Design and Flow Cytometry Protocol

Sustained acoustic medicine treatment of discogenic chronic low back pain: A randomized, multisite, double-blind, placebo-controlled trial

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