The efficacy of low-intensity pulsed ultrasound on articular cartilage and clinical evaluations in patients with knee osteoarthritis

Abstract

BACKGROUND:

While a number of preclinical studies have examined the effectiveness of low-intensity pulsed ultrasound (LIPUS) as a potential treatment for knee osteoarthritis (OA), there have been few clinical studies which have indirectly confirmed cartilage regeneration by magnetic resonance imaging (MRI).

OBJECTIVE:

The aim of this clinical trial was to investigate whether LIPUS effectively increased knee cartilage thickness and improved pain and function in knee OA patients.

METHODS:

This study was a prospective, single-group, home-based self-therapy trial. We included patients ( $n=$ 20) with OA pain. Each patient used an ultrasonic stimulation device (BODITREK JOINT™) for more than 20 sessions. Outcomes were assessed by MRI, Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the 36-Item Short Form Survey (SF-36) for assessing quality of life.

RESULTS:

Nineteen subjects completed this study. There was no significant increase in the cartilage thickness measured by MRI after LIPUS treatment. LIPUS therapy significantly decreased VAS score and WOMAC score, and significantly increased SF-36 score. The subgroup analysis in patients with knee OA showed that LIPUS treatment showed better for older patients with lower Kellgren-Lawrence grades.

CONCLUSION:

Pain, function, and quality of life improved after LIPUS, but there was no significant increase in cartilage thickness through MRI.

Keywords

Ultrasonic therapy osteoarthritis arthralgia cartilage physical functional performance quality of life

1. Background

Knee osteoarthritis (OA) is one of the most common musculoskeletal complaints and is characterized by pain, disability, joint stiffness, cartilage degeneration and gradual deterioration of function. OA patients also carry a social burden in the form of reduced quality of life [1]. Symptomatic OA affects 10% of adults over the age of 60, with up to a quarter of the sufferers being severely disabled [2]. The prevalence of OA increases with age, and the condition is believed to be the result of cartilage degeneration due to an increase in the load placed on the joint [3].

Figure 1.

Experimental Design. E1: pre-treatment, on the day before treatment began, E2: within three days of the end of treatment, E3: four weeks after treatment was terminated.

Treatment is often focused on symptom relief [4] and includes lifestyle modification, physical therapy, and pharmacological interventions, such as non-steroidal anti-inflammatory drugs (NSAIDs), and hyaluronan intra-articular injections [5]. Unfortunately, many cases eventually require surgical treatment due to the progressive pain of OA [6, 7].

In preclinical studies, low-intensity pulsed ultrasound (LIPUS) has been shown to promote bone formation through chondrocyte proliferation, induces type II collagen and type X collagen proliferation, stimulates control blast proliferation and cartilage formation, and promotes chondrocyte proliferation and cartilage formation on human articular cartilage [8, 9, 10, 11]. Cartilage degeneration is an important factor in the disease state of OA [12]. Since articular cartilage is a non-vascular tissue and has low self-repair ability, cartilage regeneration may play a critical role in OA treatment [13]. While the preclinical data has been encouraging enough to attract attention to LIPUS as a potential treatment for problems with the skeletal system, pre-clinical and clinical data has not yet reached the point where LIPUS is generally recommended as a treatment [14, 15].

Many studies have examined the effects of LIPUS on pain and function in knee OA patients, and one recent meta-analysis suggested that LIPUS does provide pain relief and improve functional activity [16, 17, 18]. However, evidence of cartilage regeneration in human knee OA patients resulting from LIPUS remains lacking. A few studies have attempted to confirm the effect of LIPUS on knee cartilage regeneration by MRI, but the sample sizes were so small that they could reach no definitive conclusions [19, 20].

The clinical trial aimed to investigate the efficacy of LIPUS in knee OA patients, as measured by improvements in cartilage thickness, pain, functional activity and quality of life. We also performed an additional subgroup analysis, dividing our participants by age and Kellgren-Lawrence (K-L) grade.

2. Methods

2.1 Study design

This was a prospective, single-group, home-based self-therapy trial. This study was approved by the Institutional Review Board of Jeonbuk National University Hospital (Approval number: CUH 2018-07-034). Subjects who satisfied the inclusion criteria were allocated to a single group.

Each patient received over 20 LIPUS sessions. One session lasted 30 minutes per day, and patients received more than five sessions per week, over the course of four weeks. All patients received ultrasound stimulation over their medial and lateral knee joints, and they had their knees flexed at 90 ${}^{\circ}$ for each session to enhance energy penetration into the joint space [21].

Prior to treatment, the research director explained the procedures, obtained signed consent forms, and educated subjects so that they could perform self-therapy properly at home. Each patient completed a daily self-therapy checklist to track treatment and any adverse reactions throughout training. A clinical research coordinator contacted the patients by telephone once a week to monitor that the home-based self-therapy was being performed according to protocol.

Patients were assessed three times: (1) pre-treatment, on the day before treatment began, which was within 8 weeks of registration, (E1; Evaluation 1), (2) within three days of the end of treatment (E2; Evaluation 2), and (3) four weeks after treatment was terminated (E3; Evaluation 3). For E1 and E3, an MRI scan was taken on the same date that other scales were tested. Cartilage thickness on MRI images were evaluated by a radiologist who did not participate in the study (Fig. 1).

Subjective scores were measured by a single-blind physician who did not participate in treatment. All records were analyzed after the study was completed. These records were immediately verified without any modification by the investigator.

This study is registered at the Clinical Research Information Service, which is administered by the Korea Center for Disease Control and Prevention (Registration number: KCT 0005506).

2.2 Participants

Study subjects were recruited posting a notice on the bulletin board of the Jeonbuk National University Hospital and screened for potential participation by a rehabilitation physician. All participants provided written informed consent. All research procedures were conducted in accordance with the ethical standards set forth in the Declaration of Helsinki.

Participants were selected based on the following inclusion criteria: (1) patients with a diagnosis of OA according to the criteria of the American College of Rheumatology [22], and classified by Kellgren-Lawrence (K-L) scale applied to a plain radiograph [23], and (2) patients who were able to fully comprehend the purpose of this research and its associated procedures, and voluntarily consented to participate. Potential participants were excluded on the following basis: (1) patients who were unable to adequately describe their pain, (2) patients who had knee surgery in the six months prior to the study or who received cortisone injection therapy one month prior to the study (Oral analgesics taken from the time of study enrollment were maintained until the end of the study), (3) patients who had an infected knee, inflammatory arthritis, or acute injury to their knee ligament or tendon, and (4) patients with neurological disorders, including radiculopathy, polyneuropathy, or CNS disease, and (5) patients with any metabolic disease that could affect the study.

In patients with bilateral knee OA, study enrollment was limited to the one knee with the more severe condition.

2.3 Intervention

LIPUS therapy was performed using a low-intensity pulsed ultrasound device (BODITREKJOINT ${}^{\text{TM}}$ , HUVEXEL Inc., Seong-nam, South Korea). This device, which is 325 mm (width) $\times$ 270 mm (depth) $\times$ 70 mm (height) and weighs 1,150 g, transmits ultrasound to the human body. The main unit is connected to one or two round transducers (diameter 70 mm). Frequency (1 MHz–3 MHz) and intensity (0.1 $\sim$ 3 W/cm ${}^{2}$ ) can both be adjusted, and three modes (pulsed, continuous, or intermittent) are supported. In this study, the frequency was set to 1 MHz, the power output to 0.6 W/cm ${}^{2}$ , and the pulsed mode (on time: 25 ms, off time: 7 ms) was used. Only one transducer was provided to the participants.

Each patient used this equipment during each session to provide ultrasound stimulation to his or her knee joint, and applied ultrasound evenly within the entire target area for 30 minutes per session [24].

2.4 Outcomes

Articular cartilage thickness was measured by taking an MRI (Verio, Siemens AG, Erlangen, Germany) of the treated knees. A radiologist evaluated T1 weighted MRI-based 3D reconstruction coronal images. Cartilage thickness was measured between the subchondral bone and synovial fluid, which were distinguished by sharp alternations in pixel intensity. Each measurement was conducted in the thickest median part of five sites (Medial Femoral Condyle, MFC; Central Femoral Condyle, CFC; Lateral Femoral Condyle, LFC; Medial Tibial Plateau, MTP; and Lateral Tibial Plateau, LTP). Before and after treatment, the mean thickness of the five sites was also measured [25].

The knee OA pain was assessed using a visual analogue scale (VAS). The patient marked the degree of pain on a 100 mm line and measured the distance. A score of 0 indicates painlessness and a score of 10 indicates extreme pain [26]. We assessed knee pain under three different conditions; V1 asked about pain at the moment, V2 asked about pain with knee movement, and V3 asked about pain with the knee in a resting position.

The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a 24-item self-administered questionnaire commonly used to evaluate pain, physical function and stiffness in patients with knee OA. A higher score on the WOMAC reflects higher pain, stiffness and poor physical function [27].

36-Item Short Form Survey (SF-36) is also self-administered questionnaire. It consists of 36 items that survey subjective state of health. It measures health along eight multi-item dimensions, including physical functioning, physical limitations, emotional limitations, mental health, vitality, social functioning, pain, and general health perception. A higher score reflects a better state of health [28].

Safety was assessed by self-questionnaire regarding adverse reactions, including subjective awareness or symptoms.

2.5 Sample size

Yasemin et al.’s study on the use of therapeutic ultrasound for the management of patients with OA used a Sonopuls 434 US machine (Enraf Nonius, Rotterdam, The Netherlands), which is similar to our device [29]. The difference in VAS score between pre and post treatment in the therapeutic ultrasound group ( $n=$ 20) was 2.8, the standard deviation was 1.57, type 1 error was 0.05, and type 2 error was 0.2. The effect size was 1.783, and the sample size was calculated as 6 considering the drop rate of 10% using G*Power. The sample size of this study was set to 20 patients.

Figure 2.

CONSORT flow diagram, low-intensity pulsed ultrasound (LIPUS).

2.6 Statistical analysis

Statistical analysis was performed using SPSS 23.0 for Windows (SSPS Inc., Chicago, IL, USA). Data are presented as mean (SD) for continuous variables and frequency (percentage) for categorical variables. For outcome analysis, except for the cartilage thickness using the paired $t$ -test or Wilcoxon signed-rank test on difference, other outcomes (VAS, WOMAC and SF-36) were analyzed using repeated measures (RM) analysis of variance (ANOVA). Each RM-ANOVA was followed by planned multiple pairwise comparisons with Bonferroni correction to $p\leqslant$ 0.05.

3. Results

Twenty-four potential participants were recruited between April 11, 2019 and July 24, 2020. Excluding the four participants who met the exclusion criteria, 20 participants were assigned to a single group. One participant was dropped due to insufficient treatment sessions (fewer than 20), 19 participants (19 knees) completed the treatment and evaluation (including all three evaluations) (Fig. 2).

Demographic data and baseline characteristics are shown in Table 1. The mean age was 54.95 years old, and the study included seven males and twelve females. KL grade distribution was Grade I (68.4%), II (21.1%), II (10.5%).

Table 1
Baseline demographics

Variable	Mean (SD) or frequency (percentage)
Age	54.95 $\pm$ 10.46
Thirties	2 (10.5%)
Forties	4 (21.1%)
Fifties	7 (36.8%)
Sixties	5 (26.3%)
Seventies	1 (5.2%)
Sex (men/women)	7 (36.8%): 12 (63.2%)
K-L grade
I	13 (68.4%)
II	4 (21.1%)
III	2 (10.5%)

SD: standard deviation. K-L Grade, Kellgren-Lawrence grade.

Although the mean articular cartilage thickness increased slightly after treatment after treatment, it was not by a statistically significant amount (E1: 2.16 $\pm$ 0.38 mm, E3: 2.19 $\pm$ 0.39 mm, $\blacklozenge$ 0.03 $\pm$ 0.12 mm, $p=$ 0.318). Likewise, in MFC, CFC, and LTP, cartilage thickness increased slightly, but not by a statistically significant amount (MFC, $\blacklozenge$ 0.08 $\pm$ 0.24 mm, $p=$ 0.097; CFC, $\blacklozenge$ 0.06 $\pm$ 0.31 mm, $p=$ 0.405; LTP, $\blacklozenge$ 0.07 $\pm$ 0.38 mm, $p=$ 0.443). These results are presented in Table 2.

Table 2

Articular cartilage thickness

Variable (mm)	E1	E3	$\blacklozenge$	$P$ value
MFC	1.75 $\pm$ 0.89	1.83 $\pm$ 0.91	0.08 $\pm$ 0.24	0.097 ${}^{2)}$
CFC	2.73 $\pm$ 0.69	2.79 $\pm$ 0.77	0.06 $\pm$ 0.31	0.405 ${}^{1)}$
LFC	1.92 $\pm$ 0.49	1.86 $\pm$ 0.41	$-$ 0.06 $\pm$ 0.31	0.383 ${}^{1)}$
MTP	2.12 $\pm$ 1.06	2.11 $\pm$ 0.97	$-$ 0.01 $\pm$ 0.51	1.000 ${}^{2)}$
LTP	2.27 $\pm$ 0.51	2.34 $\pm$ 0.61	0.07 $\pm$ 0.38	0.443 ${}^{1)}$
Mean	2.16 $\pm$ 0.38	2.19 $\pm$ 0.39	0.03 $\pm$ 0.12	0.318 ${}^{1)}$

$\blacklozenge$ : E3–E1, 1) Paired T test, 2) Wilcoxon signed rank test on difference, E1: pre-treatment, E3: four weeks after treatment was terminated. MFC, Medial Femoral Condyle; CFC, Central Femoral Condyle; LFC, Lateral Femoral Condyle; MTP, Medial Tibial Plateau; LTP, Lateral Tibial Plateau.

The results of RM-ANOVA for VAS revealed a significant main effect in V2 ( $F=$ 9.315, $p=$ 0.001) and V3 ( $F=$ 4.628, $p=$ 0.016), but no main effect in V1 ( $F=$ 1.085, $p=$ 0.349). Planned pairwise comparisons revealed significant differences in V2 between E1 versus E2 ( $p=$ 0.025) and E1 versus E3 ( $p=$ 0.001). Although the main effect of V3 was significant, there was no significant section in the planned pairwise comparisons. These results are presented in Table 3.

Table 3

Visual analogue scale

	E1	E2	E3	$P$ value	F	$\eta^{2}$ p	E1–E2	E1–E3	E2–E3
V1	2.63 (1.57)	2.16 (1.50)	2.16 (1.12)	0.349	1.085	0.057	–	–	–
V2	4.21 (1.55)	3.16 (1.80)	2.53 (1.22)	0.001	9.315	0.341	0.025	0.001	0.525
V3	2.26 (1.59)	1.32 (1.45)	1.37 (1.21)	0.016	4.628	0.205	0.074	0.075	1.000

Data are mean (SD), significant values appear in bold, E1: pre-treatment, E2: end of treatment, E3: four weeks after treatment was terminated, V1, Pain at the current moment; V2, Pain with knee movement; V3, Pain at resting position, F, F ratio, ratio of two mean square values, $\eta^{2}$ p (partial eta squared), effect size of different variables in ANOVA models.

The results of RM-ANOVA for WOMAC revealed a significant main effect ( $F=$ 6.543, $p=$ 0.004) in total score. Planned pairwise comparisons revealed significant differences between E1 versus E2 ( $p=$ 0.040) and E1 versus E3 ( $p=$ 0.018). The results of RM-ANOVA for sub-item (pain, stiffness and physical function) revealed a significant main effect in pain ( $F=$ 5.650, $p=$ 0.007) and physical function ( $F=$ 6.300, $p=$ 0.005), but not a significant effect in stiffness ( $F=$ 1.766, $p=$ 0.185). Planned pairwise comparisons revealed significant differences between E1 versus E3 in pain ( $p=$ 0.026) and E1 versus E3 in physical function ( $p=$ 0.015). These results are presented in Table 4.

Table 4

WOMAC and SF-36

Variable	E1	E2	E3	$P$ value	$F$	$\eta^{2}$ p	E1–E2	E1–E3	E2–E3
WOMAC
Pain	7.79 (3.57)	5.68 (3.56)	5.32 (3.71)	0.007	5.650	0.239	0.095	0.026	1.000
Stiffness	1.26 (1.63)	0.37 (0.76)	0.89 (1.59)	0.185	1.766	0.089	–	–	–
Physical function	25.79 (11.96)	18.63 (12.22)	17.89 (12.26)	0.005	6.300	0.259	0.053	0.015	1.000
Total	34.84 (15.69)	24.68 (15.77)	24.11 (16.83)	0.004	6.543	0.267	0.040	0.018	1.000
SF-36	99.16 (12.21)	105.21 (16.70)	107.37 (16.68)	0.012	5.045	0.219	0.177	0.012	1.000

Data are mean (SD), significant values appear in bold, E1: pre-treatment, E2: end of treatment, E3: four weeks after treatment was terminated, WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index, SF-36, 36-Item Short Form Survey, F (F ratio), ratio of two mean square values, $\eta^{2}$ p (partial eta squared), effect size of different variables in ANOVA models.

The results of RM-ANOVA for SF-36 revealed a significant main effect ( $F=$ 5.045, $p=$ 0.012). Planned pairwise comparisons revealed significant differences between E1 and E3 ( $p=$ 0.012). There was some increase in the score between E1 and E2 (E1: 99.16 $\pm$ 12.21, E2: 105.21 $\pm$ 16.70), but the difference was not significant ( $p=$ 0.117). These results are presented in Table 4.

No clinically relevant adverse effects from the treatment were observed.

4. Discussion

This study investigated the effect of low-intensity pulsed ultrasound (LIPUS) on knee cartilage thickness, pain, functional activity, and quality of life. Our results showed that patients with knee OA experienced significant pain relief after LIPUS therapy. Functional activity (measured by WOMAC) and quality of life (measured by SF-36) were significantly improved four weeks after the end of treatment. No significant difference in knee cartilage thickness before and after treatment was observed.

Previous in vitro studies have shown that LIPUS promotes micromechanical stress in the target tissue, and that LIPUS produces nitric oxide and mediates ultrasound-induced hypoxia-inducible factor-1 $\alpha$ activation and vascular endothelial growth factor-A expression in osteoblasts, prevented IL-1b suppression, and increased cell migration and cell proliferation [9, 15, 30, 31, 32]. In addition, many animal studies reported angiogenesis and callus remodeling in osteoporotic fracture healing. LIPUS affects chondrocyte extracellular matrix production via an integrin-mediated p38 MAPK signaling pathway and CCN2/CTGF, a protein involved in repairing articular cartilage, and increases articular cartilage type II collagen and encourages reproduction, promoting cartilage regeneration [33, 34, 35, 36].

Some recent studies have shown that applying LIPUS to knee OA patients alleviated their pain and swelling, and improved their mobility and motor function [9, 14, 16]. However, pre-clinical and clinical data are not yet so definitive that LIPUS has become a widely recommended treatment [15].

Information on the effect of LIPUS by age and K-L grade has also been limited. Accordingly, although our sample size was small, after our single-group analysis, we conducted an additional subgroup analysis, dividing our participants by age (aged $<$ 55 versus aged $\geqslant$ 55) and K-L grade (I versus II $+$ III) for cartilage thickness, pain, functional activity and quality of life. Demographic and baseline data for each subgroup are presented in Supplementary Table S1.

Two of the prior studies have attempted to measure the cartilage thickness in the knees of OA patients by MRI. In the first study, wherein cartilage thickness was measured at four sites (MFC, LFC, MTP and LTP) in ten patients (11 knees), no significant increase in cartilage was observed post-treatment [19]. In the other study, no significant increase in cartilage thickness at two sites (MFC and MTP) was reported in 14 LIPUS-treated patients (14 knees) [20]. We built on this work by checking the effect of LIPUS by measuring knee cartilage across a larger sample size and at a greater number of measurement sites (MFC, CFC, LFC, MTP and LTP). We found that there was no significant increase in knee cartilage thickness in each location. Mean cartilage thickness increased ( $\blacklozenge$ 0.03 $\pm$ 0.12), but not to a statistically significant degree. With respect to our subgroup analysis, while the mean cartilage thickness of the aged $<$ 55 group and K-L I group at baseline were thicker than that of the aged $\geqslant$ 55 group and the K-L II $+$ III groups, the difference was not statistically significant. Knee cartilage increased in thickness across all subgroups after treatment, but not to a statistically significant degree (Supplementary Table S2).

Knee OA is understood as a cartilage-related degenerative disease [37], triggered by a wide variety of factors, including trauma, mechanical force, inflammation, or biochemical reactions [38]. As the disease progresses, osteophyte formation, bone remodeling, ligament loosening, weakness in the muscles around the joints and synovial effusion occur and cause pain [39]. A number of studies have shown that LIPUS relieves knee OA pain [16], and the results of our study are consistent with this prior work. The pain-relief effect lasted until at least one month after treatment ceased. According to our subgroup analysis, the VAS score of the aged $\geqslant$ 55 group and the K-L I group at baseline were higher than the aged $<$ 55 group and the K-L II $+$ III groups, though the difference was not statistically significant. After treatment, the aged $\geqslant$ 55 group and K-L I group experienced more significant pain relief. Our subgroup analysis suggested that LIPUS may be more effective in relieving OA pain in older patients with a lower K-L grade (Supplementary Tables S3 and S5).

We also attempted to confirm whether LIPUS improved functional outcomes in knee OA patients. Significant functional improvement was reported. According to some studies, treatment with LIPUS can lead directly to functional improvements [40]. One recent clinical study reported functional improvement (WOMAC scale and Time Up and Go test) after 12 LIPUS sessions over 24 weeks [41]. A different clinical study also reported functional improvements (WOMAC scale) after ten sessions [42].

Our results were consistent with these previous studies. Our subgroup analysis revealed that the total WOMAC score of the aged $\geqslant$ 55 group and the K-L I group at baseline was higher than that of the aged $<$ 55 group and the K-L II $+$ III groups, though the difference was not statistically significant. After treatment, the aged $\geqslant$ 55 group and the K-L I group showed significant functional improvement. In terms of function, LIPUS therapy was more effective in older patients with a lower K-L grade (Supplementary Tables S4 and S5).

Patients with knee OA experience a significant decrease in quality of life (QOL), as they gradually lose their physical abilities as their pain and impaired joint function escalate [43]. QOL was assessed with SF-36, a commonly used health survey tool [44]. Significant improvements in QOL were reported after treatment with LIPUS. Previous studies have reported that a group treated with LIPUS and NSAID experienced a great improvement in QOL than a group treated only with NSAIDs [45]. The results of our study were consistent with this result. Based on our subgroup analysis, the SF-36 score of the aged $\geqslant$ 55 group and the K-L II $+$ III groups at baseline were lower than the aged $<$ 55 group and the K-L I group, though the difference was not statistically significant. After treatment, the aged $<$ 55 group and the K-L I group experienced greater improvement in their quality of life, suggesting that the effects of LIPUS were more positive in younger patients with a lower K-L grade (Supplementary Tables S4 and S5).

Our study also explored how the effects of LIPUS vary across populations by age and OA severity. Based on our subgroup analysis, the K-L I group experienced a more significant improvement in pain, WOMAC, and SF-36 than the K-L II $+$ II groups. Older participants experienced a greater reduction in pain and improvement in WOMAC, while younger participants experienced a more improved SF-36. In particular, in terms of pain, planned pairwise comparisons revealed significant differences only between E1 and E3 of the older patients group. This may have been influenced by the higher baseline (E1) pain score of the older group, although not a significant difference. In general, the activity of the elderly is less than that of the young, so the longer-term effect (between E1 and E3) may be more pronounced in the older group. There was no significant difference in the MRI-measured cartilage thickness after treatment across all subgroups.

There was no significant difference between the two groups at the baseline between the subgroups that the elderly group had more significant improvement, but it may have been influenced by the tendency for the elderly group to have a higher pain scale and the general lack of physical activity in the elderly group. will be.

This study has several limitations. First, the effectiveness of LIPUS could not be compared with other conservative or combination treatments, and above all, this study had no control group. Second, while more evidence concerning the possible effectiveness of LIPUS could have been found if joint fluid analysis for TNF- $\alpha$ , IL-1 and IL-6 had been carried out, this could not be performed as it would have been an invasive procedure. Third, this study was a single-center study and had small sample sizes in subgroup analysis. Fourth, the long-term effect of LIPUS (i.e., the effect after three months) could not be evaluated. We are planning further research as a complement to the present study.

5. Conclusion

We found that the pain, function, and quality of life improved after LIPUS in the patients with knee OA, but there was no significant increase in cartilage thickness through MRI.

Funding

This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, Republic of Korea, the Ministry of Food and Drug Safety) (Project Number: KMDF_ PR_20200901_0166) and by grants from the Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea.

Data availability

The data used to support the findings of this study are included in the article.

Supplementary data

The supplementary files are available to download from https://dx-doi-org.web.bisu.edu.cn/10.3233/BMR-210357.

Footnotes

Acknowledgments

The authors thank all members of the Department of Physical Medicine & Rehabilitation, and Translational Research and Clinical Trials Center for Medical Devices, Jeonbuk National University Hospital, and Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, Korea. This paper was proofread by the Writing Center at Jeonbuk National University in November 2020. The authors declare no conflicts of interest.

Conflict of interest

The authors declare no conflict of interest.

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The efficacy of low-intensity pulsed ultrasound on articular cartilage and clinical evaluations in patients with knee osteoarthritis

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Background

2.1 Study design

2.2 Participants

2.3 Intervention

2.4 Outcomes

2.5 Sample size

3. Results

Table 1 Baseline demographics

5. Conclusion

Funding

Data availability

Supplementary data

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Baseline demographics