Research progress of focused low-intensity pulsed ultrasound in the treatment of knee osteoarthritis_West China Medical Journal

Authors：

LI Yuanchao ^1,2 , ZHAO Bingbing ¹ , YANG Changran ¹ ,  LUO Qinglu ^1,3

1. The Fifth Clinical College of Guangzhou Medical University, Guangzhou, Guangdong 510700, P. R. China;
2. Clinical Medical College of Acupuncture Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 511400, P. R. China;
3. Department of Rehabilitation, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P. R. China;

Corresponding author：

LUO Qinglu, Email: luo_qinglu@126.com

Keywords：

Ultrasound; low-intensity ultrasound; focused low-intensity pulsed ultrasound; knee osteoarthritis

DOI：

10.7507/1002-0179.202208073

Video：

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Focused low-intensity pulsed ultrasound (FLIPUS), as a non-invasive physical therapy, is widely used in orthopedics, neurosurgery, urology, rehabilitation medicine and other clinical specialties. More and more studies have found that FLIPUS can treat knee osteoarthritis (KOA) by promoting tissue regeneration, relieving pain and inhibiting inflammation, improve the common clinical symptoms of KOA, such as joint pain or stiffness, limited joint activity and decreased walking function, and improve the quality of life of patients to a certain extent. This article mainly reviews the effect and biophysical mechanism of FLIPUS in the treatment of KOA, as well as related clinical research, in order to provide a reference for clinical workers who carry out research in this field.

Citation： LI Yuanchao, ZHAO Bingbing, YANG Changran, LUO Qinglu. Research progress of focused low-intensity pulsed ultrasound in the treatment of knee osteoarthritis. West China Medical Journal, 2023, 38(1): 134-139. doi: 10.7507/1002-0179.202208073 Copy

1.	Hu W, Chen Y, Dou C, et al. Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis. Ann Rheum Dis, 2021, 80(4): 413-422.
2.	Sharma L. Osteoarthritis of the knee. N Engl J Med, 2021, 384(1): 51-59.
3.	da Costa BR, Pereira TV, Saadat P, et al. Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis. BMJ, 2021, 375: n2321.
4.	Wu Y, Zhu S, Lv Z, et al. Effects of therapeutic ultrasound for knee osteoarthritis: a systematic review and meta-analysis. Clin Rehabil, 2019, 33(12): 1863-1875.
5.	Liang D, Chen J, Zhou W, et al. Alleviation effects and mechanisms of low-intensity focused ultrasound on pain triggered by soft tissue injury. J Ultrasound Med, 2020, 39(5): 997-1005.
6.	Fomenko A, Neudorfer C, Dallapiazza RF, et al. Low-intensity ultrasound neuromodulation: an overview of mechanisms and emerging human applications. Brain Stimul, 2018, 11(6): 1209-1217.
7.	Babakhanian M, Yang L, Nowroozi B, et al. Effects of low intensity focused ultrasound on liposomes containing channel proteins. Sci Rep, 2018, 8(1): 17250.
8.	Liu X, Hu Y, Wu L, et al. Effects of collimated and focused low-intensity pulsed ultrasound stimulation on the mandible repair in rabbits. Ann Transl Med, 2020, 8(4): 98.
9.	Xia Y, Li J, Wang D, et al. Potential application of low-intensity focused ultrasound in rapidly relieving delayed-onset muscle soreness induced by high-intensity exercise. J Ultrasound Med, 2022, 41(9): 2227-2235.
10.	Wang Y, Bai Y, Xiao X, et al. Low-intensity focused ultrasound stimulation reverses social avoidance behavior in mice experiencing social defeat stress. Cereb Cortex, 2022, 21: bhac037.
11.	Jia L, Wang Y, Chen J, et al. Efficacy of focused low-intensity pulsed ultrasound therapy for the management of knee osteoarthritis: a randomized, double blind, placebo-controlled trial. Sci Rep, 2016, 6: 35453.
12.	Tyler WJ, Tufail Y, Finsterwald M, et al. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PLoS One, 2008, 3(10): e3511.
13.	Yoo SS, Bystritsky A, Lee JH, et al. Focused ultrasound modulates region-specific brain activity. Neuroimage, 2011, 56(3): 1267-1275.
14.	Schafer ME, Spivak NM, Korb AS, et al. Design, development, and operation of a low-intensity focused ultrasound pulsation (LIFUP) system for clinical use. IEEE Trans Ultrason Ferroelectr Freq Control, 2021, 68(1): 54-64.
15.	Wasilczuk KM, Bayer KC, Somann JP, et al. Modulating the inflammatory reflex in rats using low-intensity focused ultrasound stimulation of the vagus nerve. Ultrasound Med Biol, 2019, 45(2): 481-489.
16.	Song BW, Park JH, Kim B, et al. A combinational therapy of articular cartilage defects: rapid and effective regeneration by using low-intensity focused ultrasound after adipose tissue-derived stem cell transplantation. Tissue Eng Regen Med, 2020, 17(3): 313-322.
17.	Liao B, Guan M, Tan Q, et al. Low-intensity pulsed ultrasound inhibits fibroblast-like synoviocyte proliferation and reduces synovial fibrosis by regulating Wnt/β-catenin signaling. J Orthop Translat, 2021, 30: 41-50.
18.	Jia L, Chen J, Wang Y, et al. Focused low-intensity pulsed ultrasound affects extracellular matrix degradation via decreasing chondrocyte apoptosis and inflammatory mediators in a surgically induced osteoarthritic rabbit model. Ultrasound Med Biol, 2016, 42(1): 208-219.
19.	Jia L, Li D, Wei X, et al. Efficacy and safety of focused low-intensity pulsed ultrasound versus pulsed shortwave diathermy on knee osteoarthritis: a randomized comparative trial. Sci Rep, 2022, 12(1): 12792.
20.	Wang B, Chen MX, Chen SC, et al. Low-intensity focused ultrasound alleviates chronic neuropathic pain-induced allodynia by inhibiting neuroplasticity in the anterior cingulate cortex. Neural Plast, 2022, 2022: 6472475.
21.	Haffey PR, Bansal N, Kaye E, et al. The regenerative potential of therapeutic ultrasound on neural tissue: a pragmatic review. Pain Med, 2020, 21(7): 1494-1506.
22.	Puts R, Rikeit P, Ruschke K, et al. Functional regulation of YAP mechanosensitive transcriptional coactivator by focused low-intensity pulsed ultrasound (FLIPUS) enhances proliferation of murine mesenchymal precursors. PLoS One, 2018, 13(10): e0206041.
23.	Aoyagi K, Liew JW, Farrar JT, et al. Does weight-bearing versus non-weight-bearing pain reflect different pain mechanisms in knee osteoarthritis? The Multicenter Osteoarthritis Study (MOST). Osteoarthritis Cartilage, 2022, 30(4): 545-550.
24.	Barroso J, Vigotsky AD, Branco P, et al. Brain gray matter abnormalities in osteoarthritis pain: a cross-sectional evaluation. Pain, 2020, 161(9): 2167-2178.
25.	Morgan M, Thai J, Nazemian V, et al. Changes to the activity and sensitivity of nerves innervating subchondral bone contribute to pain in late-stage osteoarthritis. Pain, 2022, 163(2): 390-402.
26.	Hellman A, Maietta T, Byraju K, et al. Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury. Neuroscience, 2020, 429: 264-272.
27.	Liao YH, Chen MX, Chen SC, et al. Effects of noninvasive low-intensity focus ultrasound neuromodulation on spinal cord neurocircuits in vivo. Evid Based Complement Alternat Med, 2021, 2021: 8534466.
28.	Zhang T, Pan N, Wang Y, et al. Transcranial focused ultrasound neuromodulation: a review of the excitatory and inhibitory effects on brain activity in human and animals. Front Hum Neurosci, 2021, 15: 749162.
29.	Feng X, Niu L, Long M, et al. Transcranial ultrasound stimulation of the anterior cingulate cortex reduces neuropathic pain in mice. Evid Based Complement Alternat Med, 2021, 2021: 6510383.
30.	Hellman A, Clum A, Maietta T, et al. Effects of external low intensity focused ultrasound on inflammatory markers in neuropathic pain. Neurosci Lett, 2021, 757: 135977.
31.	Dickey TC, Tych R, Kliot M, et al. Intense focused ultrasound can reliably induce sensations in human test subjects in a manner correlated with the density of their mechanoreceptors. Ultrasound Med Biol, 2012, 38(1): 85-90.
32.	Noda K, Hirano T, Noda K, et al. Effect of low-intensity focused ultrasound on the middle ear in a mouse model of acute otitis media. Ultrasound Med Biol, 2013, 39(3): 413-423.
33.	Wang F, Wang Q, Wang L, et al. Low-intensity focused ultrasound stimulation ameliorates working memory dysfunctions in vascular dementia rats via improving neuronal environment. Front Aging Neurosci, 2022, 14: 814560.
34.	Kovacs ZI, Kim S, Jikaria N, et al. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci U S A, 2017, 114(1): E75-E84.
35.	Seok J, Woo SH, Kwon TR, et al. Role of mechanical and thermal damage in pericapsular inflammatory response to injectable silicone in a rabbit model. PLoS One, 2019, 14(5): e0216926.
36.	Ulus Y, Tander B, Akyol Y, et al. Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: a randomized double-blind controlled clinical study. Int J Rheum Dis, 2012, 15(2): 197-206.
37.	Huang MH, Lin YS, Lee CL, et al. Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis. Arch Phys Med Rehabil, 2005, 86(8): 1545-1551.
38.	Yang PF, Li D, Zhang SM, et al. Efficacy of ultrasound in the treatment of osteoarthritis of the knee. Orthop Surg, 2011, 3(3): 181-187.
39.	周崑, 周伟, 陈文直, 等. 低强度脉冲超声对美蓝渗入正常兔膝关节软骨的作用. 重庆医科大学学报, 2012, 37(2): 121-124.
40.	殷娜, 汤锋武, 符锋, 等. 低强度脉冲聚焦超声联合等速肌力训练对膝骨关节炎患者膝关节本体感觉、生活质量和炎性因子水平的影响. 现代生物医学进展, 2021, 21(22): 4275-4278, 4297.
41.	谭显春, 李智, 李欣, 等. 低强度脉冲聚焦超声治疗对膝骨关节炎患者疼痛和关节功能的改善作用及其安全性. 临床和实验医学杂志, 2020, 19(5): 541-544.
42.	Puts R, Albers J, Kadow-Romacker A, et al. Influence of donor age and stimulation intensity on osteogenic differentiation of rat mesenchymal stromal cells in response to focused low-intensity pulsed ultrasound. Ultrasound Med Biol, 2016, 42(12): 2965-2974.
43.	Liu J, Li Y, Li L, et al. Effects of acupuncture at acupoints with lower versus higher pain threshold for knee osteoarthritis: a multicenter randomized controlled trial. Chin Med, 2022, 17(1): 67.
44.	Araya-Quintanilla F, Cuyúl-Vásquez I, Gutiérrez-Espinoza H. Does acupuncture provide pain relief in patients with osteoarthritis knee? An overview of systematic reviews. J Bodyw Mov Ther, 2022, 29: 117-126.
45.	Jo NG, Ko MH, Won YH, et al. The efficacy of low-intensity pulsed ultrasound on articular cartilage and clinical evaluations in patients with knee osteoarthritis. J Back Musculoskelet Rehabil, 2022, 17: 1-9.
46.	王枰稀, 曾凡伟, 张东, 等. 低强度脉冲聚焦超声对早中期膝关节骨关节炎患者关节功能影响的研究. 川北医学院学报, 2021, 36(4): 433-436.
47.	岳恒, 甄平, 梁小弟. 低强度聚焦超声与低强度脉冲超声治疗轻度创伤性膝骨关节炎: 疼痛与功能的差异. 中国组织工程研究, 2021, 25(26): 4101-4105.
48.	柳学勇, 冉春风, 刘盼, 等. 低强度聚焦超声与普通超声治疗创伤性膝关节炎的疗效比较. 中华物理医学与康复杂志, 2011, 33(12): 927-929.
49.	陈烨, 李艳, 茅慧雯. 低强度聚焦超声波与超短波在老年性膝骨关节炎临床治疗中的对比研究. 中国伤残医学, 2018, 26(24): 11-15.

1. Hu W, Chen Y, Dou C, et al. Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis. Ann Rheum Dis, 2021, 80(4): 413-422.
2. Sharma L. Osteoarthritis of the knee. N Engl J Med, 2021, 384(1): 51-59.
3. da Costa BR, Pereira TV, Saadat P, et al. Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis. BMJ, 2021, 375: n2321.
4. Wu Y, Zhu S, Lv Z, et al. Effects of therapeutic ultrasound for knee osteoarthritis: a systematic review and meta-analysis. Clin Rehabil, 2019, 33(12): 1863-1875.
5. Liang D, Chen J, Zhou W, et al. Alleviation effects and mechanisms of low-intensity focused ultrasound on pain triggered by soft tissue injury. J Ultrasound Med, 2020, 39(5): 997-1005.
6. Fomenko A, Neudorfer C, Dallapiazza RF, et al. Low-intensity ultrasound neuromodulation: an overview of mechanisms and emerging human applications. Brain Stimul, 2018, 11(6): 1209-1217.
7. Babakhanian M, Yang L, Nowroozi B, et al. Effects of low intensity focused ultrasound on liposomes containing channel proteins. Sci Rep, 2018, 8(1): 17250.
8. Liu X, Hu Y, Wu L, et al. Effects of collimated and focused low-intensity pulsed ultrasound stimulation on the mandible repair in rabbits. Ann Transl Med, 2020, 8(4): 98.
9. Xia Y, Li J, Wang D, et al. Potential application of low-intensity focused ultrasound in rapidly relieving delayed-onset muscle soreness induced by high-intensity exercise. J Ultrasound Med, 2022, 41(9): 2227-2235.
10. Wang Y, Bai Y, Xiao X, et al. Low-intensity focused ultrasound stimulation reverses social avoidance behavior in mice experiencing social defeat stress. Cereb Cortex, 2022, 21: bhac037.
11. Jia L, Wang Y, Chen J, et al. Efficacy of focused low-intensity pulsed ultrasound therapy for the management of knee osteoarthritis: a randomized, double blind, placebo-controlled trial. Sci Rep, 2016, 6: 35453.
12. Tyler WJ, Tufail Y, Finsterwald M, et al. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PLoS One, 2008, 3(10): e3511.
13. Yoo SS, Bystritsky A, Lee JH, et al. Focused ultrasound modulates region-specific brain activity. Neuroimage, 2011, 56(3): 1267-1275.
14. Schafer ME, Spivak NM, Korb AS, et al. Design, development, and operation of a low-intensity focused ultrasound pulsation (LIFUP) system for clinical use. IEEE Trans Ultrason Ferroelectr Freq Control, 2021, 68(1): 54-64.
15. Wasilczuk KM, Bayer KC, Somann JP, et al. Modulating the inflammatory reflex in rats using low-intensity focused ultrasound stimulation of the vagus nerve. Ultrasound Med Biol, 2019, 45(2): 481-489.
16. Song BW, Park JH, Kim B, et al. A combinational therapy of articular cartilage defects: rapid and effective regeneration by using low-intensity focused ultrasound after adipose tissue-derived stem cell transplantation. Tissue Eng Regen Med, 2020, 17(3): 313-322.
17. Liao B, Guan M, Tan Q, et al. Low-intensity pulsed ultrasound inhibits fibroblast-like synoviocyte proliferation and reduces synovial fibrosis by regulating Wnt/β-catenin signaling. J Orthop Translat, 2021, 30: 41-50.
18. Jia L, Chen J, Wang Y, et al. Focused low-intensity pulsed ultrasound affects extracellular matrix degradation via decreasing chondrocyte apoptosis and inflammatory mediators in a surgically induced osteoarthritic rabbit model. Ultrasound Med Biol, 2016, 42(1): 208-219.
19. Jia L, Li D, Wei X, et al. Efficacy and safety of focused low-intensity pulsed ultrasound versus pulsed shortwave diathermy on knee osteoarthritis: a randomized comparative trial. Sci Rep, 2022, 12(1): 12792.
20. Wang B, Chen MX, Chen SC, et al. Low-intensity focused ultrasound alleviates chronic neuropathic pain-induced allodynia by inhibiting neuroplasticity in the anterior cingulate cortex. Neural Plast, 2022, 2022: 6472475.
21. Haffey PR, Bansal N, Kaye E, et al. The regenerative potential of therapeutic ultrasound on neural tissue: a pragmatic review. Pain Med, 2020, 21(7): 1494-1506.
22. Puts R, Rikeit P, Ruschke K, et al. Functional regulation of YAP mechanosensitive transcriptional coactivator by focused low-intensity pulsed ultrasound (FLIPUS) enhances proliferation of murine mesenchymal precursors. PLoS One, 2018, 13(10): e0206041.
23. Aoyagi K, Liew JW, Farrar JT, et al. Does weight-bearing versus non-weight-bearing pain reflect different pain mechanisms in knee osteoarthritis? The Multicenter Osteoarthritis Study (MOST). Osteoarthritis Cartilage, 2022, 30(4): 545-550.
24. Barroso J, Vigotsky AD, Branco P, et al. Brain gray matter abnormalities in osteoarthritis pain: a cross-sectional evaluation. Pain, 2020, 161(9): 2167-2178.
25. Morgan M, Thai J, Nazemian V, et al. Changes to the activity and sensitivity of nerves innervating subchondral bone contribute to pain in late-stage osteoarthritis. Pain, 2022, 163(2): 390-402.
26. Hellman A, Maietta T, Byraju K, et al. Effects of external low intensity focused ultrasound on electrophysiological changes in vivo in a rodent model of common peroneal nerve injury. Neuroscience, 2020, 429: 264-272.
27. Liao YH, Chen MX, Chen SC, et al. Effects of noninvasive low-intensity focus ultrasound neuromodulation on spinal cord neurocircuits in vivo. Evid Based Complement Alternat Med, 2021, 2021: 8534466.
28. Zhang T, Pan N, Wang Y, et al. Transcranial focused ultrasound neuromodulation: a review of the excitatory and inhibitory effects on brain activity in human and animals. Front Hum Neurosci, 2021, 15: 749162.
29. Feng X, Niu L, Long M, et al. Transcranial ultrasound stimulation of the anterior cingulate cortex reduces neuropathic pain in mice. Evid Based Complement Alternat Med, 2021, 2021: 6510383.
30. Hellman A, Clum A, Maietta T, et al. Effects of external low intensity focused ultrasound on inflammatory markers in neuropathic pain. Neurosci Lett, 2021, 757: 135977.
31. Dickey TC, Tych R, Kliot M, et al. Intense focused ultrasound can reliably induce sensations in human test subjects in a manner correlated with the density of their mechanoreceptors. Ultrasound Med Biol, 2012, 38(1): 85-90.
32. Noda K, Hirano T, Noda K, et al. Effect of low-intensity focused ultrasound on the middle ear in a mouse model of acute otitis media. Ultrasound Med Biol, 2013, 39(3): 413-423.
33. Wang F, Wang Q, Wang L, et al. Low-intensity focused ultrasound stimulation ameliorates working memory dysfunctions in vascular dementia rats via improving neuronal environment. Front Aging Neurosci, 2022, 14: 814560.
34. Kovacs ZI, Kim S, Jikaria N, et al. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci U S A, 2017, 114(1): E75-E84.
35. Seok J, Woo SH, Kwon TR, et al. Role of mechanical and thermal damage in pericapsular inflammatory response to injectable silicone in a rabbit model. PLoS One, 2019, 14(5): e0216926.
36. Ulus Y, Tander B, Akyol Y, et al. Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: a randomized double-blind controlled clinical study. Int J Rheum Dis, 2012, 15(2): 197-206.
37. Huang MH, Lin YS, Lee CL, et al. Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis. Arch Phys Med Rehabil, 2005, 86(8): 1545-1551.
38. Yang PF, Li D, Zhang SM, et al. Efficacy of ultrasound in the treatment of osteoarthritis of the knee. Orthop Surg, 2011, 3(3): 181-187.
39. 周崑, 周伟, 陈文直, 等. 低强度脉冲超声对美蓝渗入正常兔膝关节软骨的作用. 重庆医科大学学报, 2012, 37(2): 121-124.
40. 殷娜, 汤锋武, 符锋, 等. 低强度脉冲聚焦超声联合等速肌力训练对膝骨关节炎患者膝关节本体感觉、生活质量和炎性因子水平的影响. 现代生物医学进展, 2021, 21(22): 4275-4278, 4297.
41. 谭显春, 李智, 李欣, 等. 低强度脉冲聚焦超声治疗对膝骨关节炎患者疼痛和关节功能的改善作用及其安全性. 临床和实验医学杂志, 2020, 19(5): 541-544.
42. Puts R, Albers J, Kadow-Romacker A, et al. Influence of donor age and stimulation intensity on osteogenic differentiation of rat mesenchymal stromal cells in response to focused low-intensity pulsed ultrasound. Ultrasound Med Biol, 2016, 42(12): 2965-2974.
43. Liu J, Li Y, Li L, et al. Effects of acupuncture at acupoints with lower versus higher pain threshold for knee osteoarthritis: a multicenter randomized controlled trial. Chin Med, 2022, 17(1): 67.
44. Araya-Quintanilla F, Cuyúl-Vásquez I, Gutiérrez-Espinoza H. Does acupuncture provide pain relief in patients with osteoarthritis knee? An overview of systematic reviews. J Bodyw Mov Ther, 2022, 29: 117-126.
45. Jo NG, Ko MH, Won YH, et al. The efficacy of low-intensity pulsed ultrasound on articular cartilage and clinical evaluations in patients with knee osteoarthritis. J Back Musculoskelet Rehabil, 2022, 17: 1-9.
46. 王枰稀, 曾凡伟, 张东, 等. 低强度脉冲聚焦超声对早中期膝关节骨关节炎患者关节功能影响的研究. 川北医学院学报, 2021, 36(4): 433-436.
47. 岳恒, 甄平, 梁小弟. 低强度聚焦超声与低强度脉冲超声治疗轻度创伤性膝骨关节炎: 疼痛与功能的差异. 中国组织工程研究, 2021, 25(26): 4101-4105.
48. 柳学勇, 冉春风, 刘盼, 等. 低强度聚焦超声与普通超声治疗创伤性膝关节炎的疗效比较. 中华物理医学与康复杂志, 2011, 33(12): 927-929.
49. 陈烨, 李艳, 茅慧雯. 低强度聚焦超声波与超短波在老年性膝骨关节炎临床治疗中的对比研究. 中国伤残医学, 2018, 26(24): 11-15.

West China Medical Journal

Research progress of focused low-intensity pulsed ultrasound in the treatment of knee osteoarthritis

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