| BackgroundOsteoarthritis(OA) results from an imbalance between breakdown and repair of the tissues in the synovial joint organ and occurs as a result of multiple risk factors including trauma, overuse, and genetic predisposition.Knees is most commonly affected. Clinical practice guidelines for OA recommend self-management programs, including body-strengthening, low-impact aerobic exercises, neuromuscular education, weight loss, nonsteroidal anti-inflammatory drugs (NSAIDs) and tramadol for most patients who suffer less severe OA. Surgery is reserved for patients whose symptoms have not responded to other treatments. Guideline recommendations are imperfect, often expensive, and invasive if surgery is involved, and NSAIDs side effects present other issues. Therefore, innovative and cost-effective approaches to prevent development and progression of OA are urgently needed.Ultrasound (US) treatment has been used as a non-invasive modality for management of OA over the past 60 years,but clinical efficacy for this is controversial. In order to give full play to ultrasound characteristics and effect, whether lower frequency and intensity pulse focused ultrasound(FLIPUS) is more effective on KOA is needed to elucidate. We investigated the mechanism, safety and effects of FLIPUS on knee osteoarthritis by experimental animals and a randomized controlled trial.Objective1. To investigate the safety and effect of FLIPUS in the treatment of osteoarthritis of the knee.2.To assess changes in osteophytic, chondral, and subchondral structures in a surgically-induced osteoarthritis rabbit model in order to correlate MRI findings with the macroscopic progress of OA and to define the timepoint for disease status in this OA model.3.To study mechanical effect of FLIPUS on cartilage matrix micro-environment by measuring expression of type II collagen (COL II) and proteoglycan (PGs).4. To study mechanical effect of FLIPUS on chondrocyte proliferation and apoptosis.5. To study mechanical effect of FLIPUS on synovia microenviron-ment by measuring knee effusion volume, PGE2 and NO in the synovial fluid.Materials and methods1. A total of 100 subjects with bilateral knee OA (grade I-III) were randomized sequentially into 2 groups (groups A and groups B). Group A received FLIPUS+Diclofenac Sodium Sustained Release Tablets; group B received sham FLIPUS+Diclofenac Sodium Sustained Release Tablets. The therapeutic effects of the interventions were evaluated by changes in VAS, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, Lequesne’s index after the third,sixth and tenth times of treatment, knee range of motion, ambulation speed and quality of life after tenth times of treatment and at follow up 4weeks and 12weeks later.2. The OA model was constructed by surgery in thirty rabbits with ten normal rabbits serving as controls (baseline). High-resolution three-dimensional MRI using a 1.5-T coil was performed at baseline, two, four, and eight weeks postsurgery. MRIs of cartilage lesions, subchondral bone lesions, and osteophyte formations were independently assessed by two blinded radiologists. Ten rabbits were sacrificed at baseline, two, four, and eight weeks post-surgery, and macroscopic evaluation was independently performed by two blinded orthopedic surgeons.3. OA model New Zealand White (NZW) rabbits (N=30) and 30 normal rabbits were randomized into three groups (2-,4-, and 8-week groups; N=10 each). A knee from each rabbit was randomly selected to receive FLIPUS and the other knee received a sham treatment as a control. Another 30 normal rabbits were blank controls. The efficacy of FLIPUS treatment was measured via type II collagen and proteoglycan expression and measuring PGE2 and NO. Also, we calculated the ratio of chondrocyte anti-proliferating cell nuclear antigen and apoptosis as well as measured joint effusion volume via MRI evaluation.Results1. Patients in group A exhibited increased ambulation speed, quality of life and significantly reduced pain and disability after treatment and at followup compared to group B.2. The signal intensities and morphologies of chondral and subchondral structures by MRI accurately reflected the degree of OA. MRI and macroscopic grading showed that the scores and grades of cartilagenous and subchondral bone defects progressively increased over time,and cartilagenous lesions remained higher in the medial compartment (p<0.05). This result indicates that the animal model can duplicate the characteristics of OA in humans.3. COL II losses in the ECM were significantly decreased after FLIPUS (0.13±0.02,0.06±0.01, and 0.03±0.01) compared to controls (0.07±0.01, 0.03±0.01, and 0.01±0.01; p<0.05) at 2,4, and 8 weeks after the intervention, but these significantly increased compared to blanks (p<0.01). PGs loss in the ECM was significantly decreased after FLIPUS (0.11±0.004,0.06±0.01, and 0.03±0.01) compared to controls (0.06±0.01, 0.04±0.01, and 0.01±0.003) at 2,4, and 8 weeks after the intervention (p <0.05), but this significantly increased compared to blanks (p<0.01). COLII and PGs were both lost after FLIPUS and in controls, but the losses were slighter after FLIPUS treatment.4. The ratio of chondrocyte proliferation after FLIPUS (21.10±1.52%) was significantly greater than those of controls and blanks (4.20±1.93% and 0.31±0.20%) at 2 weeks after the intervention (p<0.01). However, no significant changes were seen after FLIPUS treatment (14.50±7.56% and 9.95±4.47%) and in controls (11.44±5.79% and 9.30±5.08%) at 4 and 8 weeks after the intervention (p>0.05).Ratios of apoptotic chondrocytes after FLIPUS (27.82±5.25% and 41.40±6.89% and 45.54±5.16%) were significantly less than in controls (41.74±3.43%,49.76±7.05%, and 56.83±5.32%) at 2,4, and 8 week after the intervention (p<0.01), but significantly higher ratios of apoptotic chondrocytes were observed compared to blanks (p<0.01).5. knee effusion volumes were significantly decreased after FLIPUS (0.76±0.46 ml,0.68±0.42 ml, and 0.86±0.43 ml; p<0.05) compared to control (1.15±0.70 ml,1.34±0.55 ml, and 1.70±0.68 ml); however, effusion volumes increased compared with no treatment (p<0.01) at 2,4, and 8 weeks after the intervention. Despite variations in data of knee effusion volumes after FLIPUS over time, the difference was not statistically significant (p>0.05). Data show that FLIPUS decreased knee effusion volumes, and maintained these volumes at a relatively low level over time.Conclusions1. FLIPUS therapy is a safe and effective treatment modality for pain relief and that it improves function in patients with knee OA.2. Serial observations revealed that MRI can accurately detect the progression of cartilage lesions and subchondral bone edema over an eight-week period but may not be accurate in detecting osteophyte sizes. This result provide a basis for early or later stages of KOA identification in animal models by non-invasive method.3. FLIPUS improved the chondrocyte survival microenvironment by reducing inflammatory mediators, decreasing knee effusion, and collagen and proteoglycan loss. |
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