Knee osteoarthritis (KOA) represents a primary driver of chronic musculoskeletal pain, physical disability, and diminished quality of life globally, imposing a heavy economic burden on healthcare systems.1 Pathophysiologically, KOA involves progressive articular cartilage breakdown, subchondral bone sclerosis, osteophyte formation, and persistent low-grade synovial inflammation, alongside a significant loss of endogenous hyaluronic acid viscoelasticity within the joint cavity.1,2 Because chronic oral nonsteroidal anti-inflammatory drugs (NSAIDs) carry well-documented gastrointestinal, renal, and cardiovascular risks, and joint replacement is reserved for end-stage destruction, there is a pressingly crucial clinical imperative for effective, joint-preserving intra-articular therapies.2,3

Intra-articular hyaluronic acid (IAHA) viscosupplementation aims to restore synovial fluid rheology, providing mechanical joint lubrication, shock absorption, and transient chondroprotective and anti-inflammatory effects.2,4 Although IAHA exhibits a favorable safety profile and offers short-term functional relief, its clinical effect is predominantly palliative, typically wearing off after 3 to 6 months without retarding cartilage degradation.2,3 Furthermore, international clinical practice guidelines remain deeply divided; whereas European societies such as ESCEO recommend IAHA for persistent symptoms, major guidelines from the American Academy of Orthopaedic Surgeons (AAOS) and the American College of Rheumatology/Arthritis Foundation (ACR/AF) recommend against routine viscosupplementation due to inconsistent trial efficacy and potential publication bias.5-7

In response to these limitations, platelet-rich plasma (PRP) has gained significant attention as an autologous orthobiologic concentrate rich in platelets, essential growth factors (including TGF-β and PDGF), and anti-inflammatory cytokines.4,8 Biologically, PRP modulates the degenerative intra-articular environment, attenuates nuclear factor-kappa B (NF-κB) pro-inflammatory signaling, and promotes chondrocyte viability and extracellular matrix synthesis.4,8,9 However, clinical adoption of PRP is constrained by substantial inter-patient biological variability, an absence of standardized preparation methods, and contradictory clinical trial findings—highlighted by the high-impact RESTORE randomized trial, which demonstrated no significant superiority of PRP over saline placebo in symptom reduction or cartilage volume preservation at 12 months.9,10

Comparative evidence and recent meta-analyses frequently indicate that PRP yields superior long-term pain reduction and functional improvement over IAHA at 6 and 12 months, particularly in younger, active patients presenting with mild-to-moderate disease (Kellgren-Lawrence grades I–III).11,12 Conversely, double-blind randomized trials with extended 5-year follow-ups demonstrate no overall clinical superiority of PRP over IAHA in functional recovery or duration of relief.13 Interpretation of the comparative body of literature is severely hampered by pervasive evidence gaps and methodological limitations, including inconsistent leukocyte concentrations (leukocyte-poor versus leukocyte-rich formulations), unstandardized HA molecular weights, non-uniform dosing schedules, short follow-up windows, and heterogeneous primary outcome measures.9,11,13

Determining the superior intra-articular injectable is of crucial clinical and economic importance to formulate standardized, evidence-based treatment algorithms that optimize patient selection and delay surgical joint replacement. An ambispective (retrospective–prospective) observational cohort design was therefore considered appropriate, as it enabled retrospective evaluation of baseline clinical and treatment characteristics from institutional records while allowing prospective follow-up of patients to assess long-term pain relief, functional recovery, treatment durability, and safety. Patients were primarily recruited and treated at Nandi Medical College and Research Institute, with follow-up assessments also obtained from patients who subsequently continued care at Hassan Institute of Medical Sciences and Bangalore Medical College & Research Institute, thereby providing a more comprehensive assessment of real-world clinical outcomes.

Study Design and Ethical Approval An ambispective (retrospective–prospective), parallel-group observational cohort study was conducted at the Department of Orthopaedics, Nandi Medical College and Research Institute, Chikkaballapura, between November 2021 and May 2025 to compare the clinical performance and safety of intra-articular hyaluronic acid (IA-HA) and autologous platelet-rich plasma (IA-PRP) in patients with primary knee osteoarthritis. Participants were recruited and treated at the Department of Orthopaedics, Nandi Medical College and Research Institute; baseline demographic, clinical, radiological, and treatment details were obtained retrospectively from hospital records, and patients were then prospectively followed according to the study protocol, while patients who subsequently continued their scheduled follow-up at other tertiary care institutions, including Hassan Institute of Medical Sciences, had their documented follow-up data incorporated into the final analysis to ensure complete outcome assessment. The study protocol was approved by the Institutional Ethics Committee of Nandi Medical College and Research Institute and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrolment. Patient Eligibility and Cohort Selection Patients with symptomatic primary knee osteoarthritis who received treatment at the Department of Orthopaedics, Nandi Medical College and Research Institute, Chikkaballapura, between November 2021 and May 2025 were identified through retrospective review of institutional medical records. Eligible patients fulfilling the predefined selection criteria were included in the study, and those available for continued evaluation were prospectively followed according to the study protocol. Patients who subsequently continued their follow-up at Hassan Institute of Medical Sciences or Bangalore Medical College and Research Institute were assessed using documented follow-up records from these institutions to ensure complete outcome evaluation. Inclusion Criteria 1. Men and women aged 40–75 years with symptomatic primary knee osteoarthritis of at least 6 months’ duration. 2. Radiographically confirmed knee osteoarthritis corresponding to Kellgren–Lawrence (KL) grades I, II, or III on weight-bearing anteroposterior and lateral radiographs. 3. Inadequate symptomatic relief following at least 3 months of conservative management, including physical therapy, activity modification, and oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs). 4. Availability of complete baseline clinical records and willingness to participate in the prospective follow-up protocol with scheduled clinical assessments. Exclusion Criteria 1. Advanced, bone-on-bone joint space loss (KL grade IV). 2. Active knee joint effusion or acute inflammatory flare requiring joint aspiration at presentation. 3. Secondary knee osteoarthritis due to post-traumatic deformity, inflammatory arthropathies, crystalline arthropathy, or previous septic arthritis. 4. Intra-articular corticosteroid, hyaluronic acid, or biological injection in the index knee within the preceding 6 months. 5. Previous high tibial osteotomy, partial or total knee arthroplasty, or concurrent mechanical symptoms from unstable meniscal tears or ligamentous instability requiring surgical intervention. 6. Baseline systemic thrombocytopenia (platelet count <150 × 10³/µL), haemoglobin <11.0 g/dL, active malignancy, systemic infection, ongoing anticoagulant therapy, or incomplete baseline records or unavailable follow-up data required for outcome assessment. Sample Size Determination Sample size calculation was based on detecting a minimum clinically important difference (MCID) of 10 to 12 points on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score at 12 months. Assuming a standard deviation of 15 points, a two-tailed significance level (α) of 0.05, and a power (1-β) of 80%, a minimum of 92 patients per treatment arm was required. To accommodate an anticipated 10% attrition rate over 12 months, 204 patients (102 per treatment arm) were selected from 220 screened individuals. Intervention Protocols Intra-Articular Hyaluronic Acid (IA-HA) Patients in the IA-HA cohort (n = 102) received a structured course of high-molecular-weight hyaluronic acid (HMW-HA). The formulation comprised bio-fermented, non-cross-linked linear HMW-HA with a molecular weight of 1.5 to 3.0 MDa, supplied in pre-filled syringes containing 30 mg / 3 mL. Under sterile conditions, three 3 mL intra-articular injections were administered at 1-week intervals via an anterolateral approach under direct musculoskeletal ultrasound guidance to confirm intra-articular placement. Intra-Articular Platelet-Rich Plasma (IA-PRP) Patients in the IA-PRP cohort (n = 102) received three intra-articular injections of leukocyte-poor platelet-rich plasma (LP-PRP) administered at 2-week intervals. LP-PRP was processed using a commercial double-spin centrifugation system (GPS III/SmartPrep system). A 35 to 40 mL sample of autologous peripheral blood was drawn into sodium citrate anticoagulant tubes. An initial low-speed spin separated red blood cells, followed by a second higher-speed spin of the plasma fraction to isolate the buffy coat and concentrate platelets while excluding leukocytes. Complete blood counts were systematically performed on both whole blood and final PRP samples. The baseline systemic platelet count was 215.4 ± 42.1 × 10³/µL, which was enriched 4.8-fold to yield a final PRP platelet concentration of 1,033.9 ± 112.5 × 10³/µL. Absolute leukocyte counts were maintained at < 0.5 × 10³/µL (0.31 ± 0.12 × 10³/µL), confirming a leukocyte-poor profile, while hematocrit was restricted to < 1.0% (0.42% ± 0.18%). Unactivated LP-PRP (4.0 to 5.0 mL) was injected intra-articularly under ultrasound guidance within 30 minutes of blood draw. Post-Injection Protocol Patients were instructed to limit joint loading for 48 hours post-injection and utilize cold therapy as needed. NSAIDs and systemic corticosteroids were prohibited for 14 days before and throughout the injection series to avoid altering platelet function and inflammatory pathways. Acetaminophen (up to 2,000 mg/day) was permitted as rescue analgesia. Outcome Measures Baseline clinical and functional characteristics were obtained retrospectively from institutional medical records at the time of enrolment and treatment. Subsequently, participants were prospectively evaluated at 1 month, 3 months, 6 months, and 12 months according to the predefined follow-up protocol. For patients who continued their scheduled follow-up at Hassan Institute of Medical Sciences or Bangalore Medical College and Research Institute, documented clinical assessments from these institutions were incorporated into the final analysis to ensure comprehensive outcome evaluation. Primary Endpoints: • Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score (0–96) and its subscales for pain (0–20), stiffness (0–8), and physical function (0–68). • Visual Analogue Scale (VAS) pain score on a 0–100 mm scale during weight-bearing activities. Secondary Endpoints: • International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Score (0–100). • Minimal Clinically Important Difference (MCID) responder rate, defined as a reduction of ≥15 mm in VAS pain score together with either a ≥12-point or ≥15% improvement in the total WOMAC score. • Twelve-month composite treatment failure rate, defined as the requirement for repeat intra-articular injection, arthroscopic intervention, or conversion to total knee arthroplasty (TKA). • Treatment-related adverse events and procedure-related complications documented throughout the follow-up period. Statistical Analysis Analyses were performed on retrospectively collected baseline variables and prospectively collected follow-up outcome data. Analyses were executed on an Intention-to-Treat (ITT) basis using SPSS (Version 27.0; IBM Corp., Armonk, NY, USA) and R (Version 4.2.1; R Foundation for Statistical Computing). Continuous variables were assessed for normality via Kolmogorov-Smirnov tests and reported as mean ± standard deviation (SD). Categorical data were presented as frequencies and percentages. Baseline demographic variables were compared between groups using independent-samples t-tests for continuous data and Chi-square (χ²) tests for categorical data. Longitudinal continuous clinical outcomes (WOMAC, VAS, IKDC) across timepoints were analyzed using Linear Mixed-Effects Models (LMM) under ITT assumptions with an unstructured covariance matrix. Fixed effects included treatment group (IA-HA vs. IA-PRP), time (baseline, 1, 3, 6, 12 months), and the Group-by-Time interaction effect (F-statistics and model-level p-values reported). Individual post-hoc pairwise comparisons were calculated with Bonferroni adjustments. Random intercepts were included for individual patients to account for within-subject correlation over time. Subgroup analyses stratified by radiographic severity (KL Grade I–II vs. KL Grade III) were evaluated by entering a Treatment Group-by-KL Grade interaction term into the mixed models. Mean differences across all tables were standardized as (IA-PRP minus IA-HA) to maintain sign consistency across outcome domains. Survival free from the 12-month composite failure endpoint (repeat injection, arthroscopy, or TKA conversion) was calculated using the Kaplan-Meier method, with differences evaluated via the log-rank test. Statistical significance was defined as p < 0.05.

Patient Flow and Baseline Characteristics

Of 220 screened patients, 204 met eligibility criteria and were enrolled into the study (102 in the IA-HA group, 102 in the IA-PRP group). Over the 42-month follow-up period, 10 patients (4.9%) were lost to follow-up: 6 in the IA-HA arm (5.9% attrition) and 4 in the IA-PRP arm (3.9% attrition). Under the Linear Mixed-Effects Model ITT framework, all 204 enrolled patients contributed data to the primary longitudinal analysis.

Baseline demographic, clinical, and radiographic parameters showed no statistically significant differences between the two treatment cohorts (Table 1). The overall cohort had a mean age of 59.8 ± 8.0 years, a mean body mass index (BMI) of 26.7 ± 3.6 kg/m², and a female representation of 59.3% (n = 121). Radiographic distribution across Kellgren-Lawrence grades was equivalent across arms (KL Grade I: 22.5%, KL Grade II: 46.1%, KL Grade III: 31.4%).

Primary Outcomes: Functional and Pain Scores

Total WOMAC Score

Linear Mixed-Effects Modeling demonstrated a statistically significant overall Group-by-Time interaction effect for total WOMAC score (F = 28.42, p < 0.001), demonstrating distinct long-term functional responses between treatments (Table 2).

At 1 month post-treatment, both cohorts demonstrated early improvements from baseline without significant intergroup difference (IA-HA: 41.5 ± 8.2 vs. IA-PRP: 43.1 ± 8.8; mean difference: +1.6, 95% CI: −0.7 to 3.9, p = 0.181). By 3 months, the IA-PRP group achieved greater functional recovery (29.8 ± 7.2) compared with the IA-HA group (36.2 ± 7.9; mean difference: −6.4, 95% CI: −8.5 to −4.3, p < 0.001).

At 6 months, total WOMAC scores in the IA-PRP cohort reached 24.1 ± 6.9, whereas scores in the IA-HA group began returning toward baseline (39.4 ± 8.6; mean difference: −15.3, 95% CI: −17.5 to −13.1, p < 0.001). At 12 months, the IA-PRP group maintained clinical improvement (28.5 ± 7.6), whereas functional scores in the IA-HA cohort further deteriorated (48.7 ± 10.2; mean difference: −20.2, 95% CI: −22.6 to −17.8, p < 0.001).

VAS Pain Score

Changes in weight-bearing VAS pain scores paralleled WOMAC functional trends, demonstrating a significant overall Group-by-Time interaction effect (F = 24.15, p < 0.001). At 1 month, pain reduction was comparable between groups (42.1 ± 9.5 mm for IA-HA vs. 44.3 ± 10.1 mm for IA-PRP; mean difference: +2.2 mm, p = 0.112). IA-PRP demonstrated superior pain reduction at 6 months (26.8 ± 7.4 mm vs. 44.2 ± 9.8 mm; mean difference: −17.4 mm, p < 0.001) and 12 months (31.2 ± 8.2 mm vs. 56.3 ± 11.5 mm; mean difference: −25.1 mm, p < 0.001).

Secondary Outcomes and Composite Failure

IKDC Subjective Score and Responder Rates

IKDC scores reflected sustained gains in the IA-PRP arm at 6 months (71.4 ± 9.8 vs. 61.5 ± 11.2; mean difference: +9.9, p < 0.001) and 12 months (68.7 ± 10.5 vs. 58.4 ± 12.1; mean difference: +10.3, p < 0.001). At 6 months, 78.6% (n = 77/98) of patients in the IA-PRP cohort achieved MCID threshold criteria compared with 62.5% (n = 60/96) in the IA-HA cohort (χ² = 6.14, p = 0.013). At 12 months, MCID responder rates remained elevated in the IA-PRP group at 74.5% (n = 73/98), whereas responder rates in the IA-HA group fell to 40.6% (n = 39/96; χ² = 22.04, p < 0.001).

12-Month Composite Failure Endpoint and Survival Analysis

Kaplan-Meier survival analysis evaluated freedom from the 12-month composite failure endpoint (repeat injection series, arthroscopy, or conversion to TKA). The IA-PRP cohort demonstrated superior composite failure-free survival compared to the IA-HA cohort (log-rank χ² = 9.45, p = 0.002).

Overall 12-month composite failure occurred in 10.8% (n = 11/102) of patients in the IA-PRP group versus 27.5% (n = 28/102) in the IA-HA group (p = 0.002). In the IA-HA arm, 20 patients received repeat injections, 5 underwent arthroscopic debridement, and 3 converted to TKA. In the IA-PRP arm, 8 patients received repeat injections, 2 underwent arthroscopy, and 1 converted to TKA.

Radiographic Subgroup Analysis (KL Grade I–II vs. KL Grade III)

A statistically significant Treatment Group-by-KL Grade interaction effect was observed for 12-month total WOMAC scores (F = 12.38, p = 0.001), confirming that baseline radiographic severity influenced treatment response (Table 3).

In patients with mild-to-moderate disease (KL Grade I–II), IA-PRP produced substantial functional improvements at 12 months (24.2 ± 6.1) compared with IA-HA (45.1 ± 8.8; mean difference: −20.9, 95% CI: −23.6 to −18.2, p < 0.001). In patients with moderate-to-severe disease (KL Grade III), functional improvements were diminished in both groups, though IA-PRP retained a statistically significant advantage over IA-HA (WOMAC at 12 months: 37.8 ± 8.2 vs. 56.5 ± 10.4; mean difference: −18.7, 95% CI: −22.5 to −14.9, p < 0.001).

Safety Evaluation

No serious adverse events, deep joint infections, septic arthritis, or neurovascular complications occurred in either arm. Localized, self-limiting post-injection reactions were reported by 15.7% (n = 16/102) of patients in the IA-PRP cohort and 12.7% (n = 13/102) in the IA-HA cohort (χ² = 0.36, p = 0.548). These reactions consisted of transient joint fullness, mild erythema, or pain at the injection site, all of which resolved spontaneously within 48 to 72 hours with local cryotherapy and Acetaminophen.

Table 1. Baseline Demographic and Clinical Characteristics of Enrolled Cohort (N = 204)

Table 2. Primary and Secondary Longitudinal Clinical Outcomes Analyzed via Linear Mixed-Effects Models (ITT Population)

Note: Mean Differences are uniformly calculated as (IA-PRP minus IA-HA). For WOMAC Total and VAS Pain, negative mean differences indicate superior symptom/pain reduction in the IA-PRP group. For IKDC, positive mean differences indicate superior functional recovery in the IA-PRP group. Post-hoc pairwise p-values are Bonferroni-adjusted.

Table 3. Subgroup Analysis of 12-Month Outcome Measures Stratified by Radiographic Kellgren-Lawrence Grade

*Note: Subgroup sample sizes reflect full Intention-to-Treat (ITT) population model estimates (KL Grade I–II: n = 140; KL Grade III: n = 64). Continuous mean differences (MD) are calculated as (IA-PRP minus IA-HA); negative MDs indicate lower pain/WOMAC scores favoring IA-PRP. Odds Ratios (OR) and Hazard Ratios (HR) express relative risk in IA-PRP vs. IA-HA.

Key Findings & Clinical Interpretation This ambispective parallel-group observational study demonstrates that intra-articular leukocyte-poor platelet-rich plasma (IA-PRP) provides superior, sustained symptomatic and functional improvement over 12 months compared with intra-articular high-molecular-weight hyaluronic acid (IA-HA) in patients with primary knee osteoarthritis. Analysis of longitudinal trajectories reveals that both interventions produce substantial, equivalent clinical benefits during the early post-injection period. At 1 month post-treatment, total WOMAC scores and weight-bearing VAS pain scores improved markedly in both cohorts, showing no statistically significant intergroup differences. However, the therapeutic responses diverged beyond this early window. While the clinical benefit of non-cross-linked linear HMW-HA decayed progressively between 3 and 12 months, returning toward baseline levels by 1 year, the LP-PRP cohort maintained robust functional recovery and pain attenuation. By 6 months, mean WOMAC and VAS scores were markedly lower in the LP-PRP arm, an advantage that persisted through the 12-month endpoint. At 12 months, the mean differences favoring LP-PRP reached −20.2 points on the total WOMAC index (95% CI: −22.6 to −17.8; p < 0.001) and −25.1 mm on the weight-bearing VAS pain scale (95% CI: −28.0 to −22.2; p < 0.001). When evaluated against established minimal clinically important difference (MCID) thresholds—typically defined as a 10 to 12 point reduction for total WOMAC and a 15 mm reduction for VAS pain—the 12-month mean differences between groups comfortably exceeded these cutoffs.14,15 Consequently, the observed superiority of LP-PRP represents a clinically meaningful divergence in patient-reported outcomes rather than an artifact of statistical modeling. This sustained therapeutic effect was further demonstrated by the 12-month composite failure rates: only 10.8% of LP-PRP recipients required reintervention, surgical referral, or arthroplasty conversion, compared to 27.5% of IA-HA recipients (p = 0.002). Pathophysiological & Biological Rationale The contrasting clinical durability observed between IA-HA and LP-PRP stems directly from their distinct biochemical and biomechanical mechanisms within the osteoarthritic joint cavity. Hyaluronic acid viscosupplementation acts primarily through rheological restoration.16 In native, healthy articular environments, endogenous high-molecular-weight hyaluronan provides boundary lubrication and shock absorption during shear stress.16 In knee osteoarthritis, enzymatic degradation and oxidative stress reduce both the concentration and molecular mass of native hyaluronan, increasing articular friction.2,16 Exogenous HMW-HA (1.5–3.0 MDa) temporarily replenishes joint fluid viscoelasticity and engages cell-surface CD44 receptors to transiently suppress inflammatory cascades.2,16 However, linear non-cross-linked HA remains susceptible to rapid depolymerization by endogenous hyaluronidases and joint clearance, explaining why its mechanical and palliative actions dissipate within 3 to 6 months.2,17 Conversely, autologous LP-PRP functions as a bioactive signaling pool rather than a simple joint lubricant.18,19 Alpha-granules contained within concentrated platelets release a complex milieu of growth factors, including transforming growth factor-beta 1 (TGF-β1), platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF).18,19 Upon intra-articular administration, these factors bind specific transmembrane receptors on synoviocytes, subchondral bone cells, and articular chondrocytes.18,19 This binding inhibits nuclear factor-kappa B (NF-κB) signaling, downregulates interleukin-1 beta (IL-1β)-induced inflammatory cascades, and suppresses matrix metalloproteinase (MMP-3, MMP-13) activity.18,19 Furthermore, TGF-β1 and PDGF stimulate chondrocyte proliferation, upregulate proteoglycan and type II collagen synthesis, and alter the intra-articular environment from catabolic destruction toward anabolic homeostasis.18,19 The strict restriction of absolute leukocyte counts (< 0.5 × 10³/µL; mean 0.31 × 10³/µL) in the LP-PRP formulation represents a critical procedural factor.9,20,21 Leukocyte-rich PRP formulations contain elevated concentrations of neutrophils and monocytes, which release catabolic matrix metalloproteinases, reactive oxygen species, and pro-inflammatory cytokines (IL-1β, IL-6, TNF-α).20,21 These mediators can provoke acute post-injection pain flares, synovial inflammation, and accelerated chondrocyte apoptosis.20,21 By eliminating the cellular leukocyte fraction while enriching platelets 4.8-fold (1,033.9 × 10³/µL), the LP-PRP protocol delivered an anabolic signaling payload without inducing secondary synovial irritation.9,20 Impact of Radiographic Severity (KL Grade Interaction) Statistical evaluation confirmed a significant Treatment Group-by-KL Grade interaction effect for 12-month total WOMAC scores (F = 12.38, p = 0.001) and VAS pain scores (F = 9.84, p = 0.002). This demonstrates that baseline radiographic structural degeneration influences the magnitude and durability of response to intra-articular injectable therapies.22 In patients with early-to-moderate disease (KL Grade I–II), joint space narrowing is mild to moderate, and a viable population of responsive chondrocytes remains present within the articular cartilage matrix.11,22 In this subgroup, LP-PRP produced marked improvements in 12-month WOMAC total scores (24.2 ± 6.1) compared with IA-HA (45.1 ± 8.8; mean difference: −20.9, p < 0.001). The 12-month MCID responder rate reached 82.9% in the LP-PRP arm versus 47.1% in the IA-HA arm (OR = 5.42, p < 0.001). Furthermore, the 12-month composite failure rate among KL Grade I–II patients receiving LP-PRP was 5.7%, compared to 20.0% for IA-HA (HR = 0.26, p = 0.011). These data confirm that orthobiologic therapies yield their highest efficacy when administered before extensive structural degradation occurs.11,22 In patients with moderate-to-severe disease presenting with severe joint space narrowing and subchondral sclerosis (KL Grade III), overall clinical efficacy was diminished in both treatment cohorts. Extensive cartilage loss, subchondral remodeling, and cellular senescence limit the regenerative responsiveness of the remaining joint tissue. Nevertheless, LP-PRP retained a statistically significant advantage over IA-HA at 12 months in KL Grade III patients (WOMAC total score: 37.8 ± 8.2 vs. 56.5 ± 10.4; mean difference: −18.7, p < 0.001). The 12-month MCID responder rate in KL Grade III knees remained higher with LP-PRP (56.3%) than with IA-HA (18.8%; OR = 5.57, p = 0.002). Correspondingly, 12-month composite failure in KL Grade III patients occurred in 21.9% of LP-PRP recipients versus 43.8% of IA-HA recipients (HR = 0.42, p = 0.057). While LP-PRP does not reverse severe joint space loss, it provides superior, clinically relevant symptom control compared to viscosupplementation in moderate-to-severe joint degeneration. Safety Profile & Methodological Strengths Both intra-articular modalities demonstrated favorable safety profiles. Adverse events were limited to localized, self-limiting post-injection reactions, occurring in 15.7% of LP-PRP recipients and 12.7% of IA-HA recipients (χ² = 0.36, p = 0.548). Localized reactions consisted of transient joint fullness, mild injection site erythema, and post-procedural discomfort, all of which resolved spontaneously within 48 to 72 hours following temporary rest, local cryotherapy, and Acetaminophen. No cases of septic arthritis, deep joint infection, pseudo-septic flare, or neurovascular injury were observed. The safety and consistency of clinical responses observed in this trial can be attributed to key methodological choices. First, direct musculoskeletal ultrasound guidance was used for all 612 intra-articular injection procedures across both cohorts.23 Ultrasound verification eliminates extra-articular misinjection—which occurs in up to 20% of unguided, palpation-based anterolateral knee injections—thereby ensuring full delivery of the active agent into the joint space and minimizing fat pad or soft tissue irritation.23 Second, the study protocol standardized the biological composition of the LP-PRP product using a commercial double-spin system. Every prepared batch underwent hematological validation to confirm a 4.8-fold platelet enrichment, an absolute leukocyte count below 0.5 × 10³/µL, and a hematocrit under 1.0%. Third, the analytical framework utilized Linear Mixed-Effects Models under Intention-to-Treat assumptions. By utilizing random patient intercepts and unstructured covariance matrices, the mixed-effects model incorporated data from all 204 enrolled patients, preventing the attrition bias and loss of statistical power common to complete-case per-protocol analyses. Limitations & Future Directions Several limitations of this study warrant consideration. First, the study design was an ambispective observational cohort rather than a double-blind, sham-controlled randomized trial. Although baseline demographic, clinical, and radiographic characteristics were well-balanced between arms, unmeasured confounding variables and patient treatment awareness cannot be entirely excluded. Second, the follow-up duration was limited to 12 months. While 12 months is sufficient to characterize the primary duration of effect for injectable therapies, extended multi-year monitoring is necessary to determine whether LP-PRP alters long-term arthroplasty conversion rates over 3 to 5 years.13 Third, clinical efficacy was evaluated using patient-reported outcome measures (WOMAC, VAS, IKDC) without objective structural endpoints, such as quantitative MRI cartilage volume mapping, T2-relaxation time analysis, or biochemical synovial biomarker profiling (e.g., CTX-II, COMP, IL-1β).10 Future investigations should combine standardized LP-PRP dosing protocols with multi-center randomized designs, serial quantitative magnetic resonance imaging, and biomarker tracking to determine whether biological symptom relief correlates with structural cartilage preservation.

Leukocyte-poor platelet-rich plasma demonstrated superior and more durable improvements in pain, function, and treatment success than high-molecular-weight hyaluronic acid over 12 months in primary knee osteoarthritis. Benefits were clinically meaningful, particularly in early disease, with comparable safety profiles, supporting LP-PRP as an effective long-term intra-articular therapeutic option.

Author Contributions

The first author conducted the primary study. The second, third, and corresponding author independently supervised the study to minimize bias, assisted with data collection and interpretation, and prepared the manuscript.

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