The primary objective of this study is to evaluate and compare the effectiveness of ultrasound-guided combined intra-articular and peri-articular platelet-rich plasma (PRP) injections with intra-articular PRP injections alone in patients with chronic knee osteoarthritis (OA). The study specifically examines the effects of these treatment approaches on pain, physical function, activities of daily living, and structural parameters, including medial collateral ligament (MCL) thickness and distal femoral cartilage thickness.

Osteoarthritis is a degenerative joint disease characterized by progressive cartilage erosion, osteophyte formation, and subchondral sclerosis, leading to pain, stiffness, and functional disability. It is the most common form of arthritis and a leading cause of disability worldwide, affecting approximately 300 million individuals. Although the knee is the most frequently involved joint, OA is now recognized as a whole-joint disease, involving not only cartilage degeneration but also pathological changes in subchondral bone, synovium, and surrounding extra-articular structures.

Platelet-rich plasma is an autologous concentration of platelets suspended in a small volume of plasma and contains a variety of bioactive growth factors, such as transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). These factors play a crucial role in promoting cell proliferation, angiogenesis, and tissue repair. In knee OA, PRP has been shown to reduce matrix metalloproteinase (MMP) activity, particularly MMP-13, enhance endogenous hyaluronic acid production, and support chondrogenesis. Although intra-articular PRP injections are widely accepted as a safe and effective treatment and have demonstrated superiority over placebo and hyaluronic acid in long-term follow-up studies, most existing research has focused exclusively on intra-articular applications.

Knee OA is a multifactorial condition frequently associated with extra-articular pathologies, including ligament laxity, peri-articular edema, and soft tissue inflammation. Limiting treatment to the intra-articular space alone may therefore overlook these important contributors to pain and functional impairment. Emerging evidence suggests that a combined treatment approach targeting both intra-articular and peri-articular structures may provide superior outcomes in terms of pain reduction and functional improvement.

This prospective randomized controlled trial will include 42 patients aged 40-65 years with chronic knee OA classified as Kellgren-Lawrence grade 2 or 3. Participants will be randomly assigned to one of three groups: a control group receiving conservative treatment only (exercise therapy and lifestyle modifications), a group receiving conservative treatment plus ultrasound-guided intra-articular PRP injections, and a third group receiving conservative treatment plus combined ultrasound-guided intra-articular and peri-articular PRP injections targeting the MCL and pes anserinus regions.

Clinical outcomes will be assessed using validated instruments, including the Visual Analog Scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the Short Form-36 (SF-36) Quality of Life Scale. In addition, ultrasonographic measurements of MCL thickness and distal femoral cartilage thickness will be performed to evaluate structural changes. By investigating the additional value of peri-articular PRP injections, this study aims to contribute to the development of more comprehensive and effective injection protocols for the management of chronic knee osteoarthritis.

Osteoarthritis (OA) is a dynamic condition characterized by a disruption in the balance between anabolic and catabolic processes of joint matrix molecules, favoring catabolism. Although OA is primarily recognized for cartilage degeneration, its pathogenesis involves a complex inflammatory and degenerative process affecting the entire joint unit, including subchondral bone, synovium, and surrounding soft tissues. Platelet-rich plasma (PRP) has emerged as an effective and safe treatment option for knee OA, particularly for patients who are unable to tolerate oral pharmacological therapies or wish to delay surgical intervention. PRP promotes tissue healing through the release of various growth factors from platelet alpha granules, which enhance cellular proliferation, stimulate angiogenesis, and reduce the activity of inflammatory mediators.

Current literature predominantly focuses on the efficacy of intra-articular PRP applications. However, knee OA is a multifactorial disease frequently accompanied by extra-articular pathologies, such as ligament laxity, edema, and peri-articular soft tissue inflammation. An exclusive focus on the intra-articular space may therefore overlook these extra-articular contributors to pain and functional impairment. This study is based on the hypothesis that a combined treatment approach targeting both the intra-articular environment and peri-articular structures-specifically the medial collateral ligament (MCL) and pes anserinus-will result in superior clinical outcomes compared to intra-articular treatment alone.

The use of ultrasound (USG) guidance in this study ensures accurate needle placement and enables objective assessment of structural changes. While intra-articular PRP has been shown to be more effective than hyaluronic acid or saline injections at 6- to 12-month follow-ups, evidence regarding the additional benefits of peri-articular PRP injections remains limited. To our knowledge, this study will be among the few randomized controlled trials comparing combined intra-articular and peri-articular PRP application with isolated intra-articular PRP treatment. Moreover, by evaluating changes in MCL thickness and distal femoral cartilage thickness using USG, this study aims to provide objective structural data to the existing literature.

In this prospective randomized controlled trial, 42 patients will be allocated into three groups. Group 1 (control group) will receive conservative treatment consisting of exercise therapy, lifestyle modifications, and patient education. Group 2 will receive conservative treatment in addition to three sessions of USG-guided intra-articular PRP injections administered at one-week intervals. Group 3 will receive conservative treatment plus three sessions of combined USG-guided intra-articular and peri-articular PRP injections, with peri-articular injections targeting the MCL origin and insertion sites as well as the pes anserinus tendon insertion.

All PRP applications will be performed using a standardized preparation kit and a photo-activation system to maximize growth factor release. Patients will be evaluated at baseline and followed up at 1 week and 3 months post-treatment using validated outcome measures, including the Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Short Form-36 (SF-36), along with ultrasonographic assessments to evaluate pain, function, and structural regeneration.

Inclusion Criteria

• Age between 40 and 65 years.
• Patients with significant medial knee pain who have not responded to conservative treatment for at least 3 months.
• Patients diagnosed with knee osteoarthritis according to the American College of Rheumatology (ACR) criteria and with Kellgren-Lawrence grade 2 or 3 radiographic osteoarthritis.
• Intact cognitive function.
• Willingness to participate in the study and provide signed informed consent.
• Visual Analog Scale (VAS) score of 4 or higher.

Exclusion Criteria

• History of previous knee trauma or surgery.
• Physical therapy, intra-articular steroid, or hyaluronic acid injections in the knee within the last 3 months.
• Active oncological diseases.
• Local infection, sepsis, wounds, or scars in the injection area.
• Systemic infections, hepatitis, or immunosuppression.
• Bleeding diathesis or irregular International Normalized Ratio (INR) due to oral warfarin use.
• Inflammatory arthropathies.
• Uncontrolled hypertension, uncontrolled diabetes mellitus, decompensated heart failure, coronary artery disease, or asthma.
• Suspected or confirmed pregnancy.
• Use of corticosteroids or opioids.
• Anemia.
• Body mass index (BMI) greater than 35.
• Allergy to citrate.
• Use of nonsteroidal anti-inflammatory drugs (NSAIDs) within the last week that may affect platelet function analyzer-100 (PFA-100) activity.
• Physical examination findings suggestive of patellar retinaculum, meniscus, or cruciate ligament injury.
• General health impairment or lack of cooperation.
• Refusal to participate in the study.