INTRODUCCIÓN

Knee osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive cartilage loss, subchondral bone alterations, and secondary synovial inflammation. These pathological changes result in pain, functional impairment, and diminished quality of life. Leading cause of musculoskeletal disability globally, with its prevalence rising in aging populations and imposing a significant socioeconomic burden.^1-3

Intra-articular injections play a central role in the nonoperative management of knee OA.

Corticosteroids are widely used due to their rapid analgesic effect, although their benefits tend to be short-lived. Hyaluronic acid (HA) has been employed as a viscosupplementation strategy, with variable clinical results, particularly in patients with mild to moderate disease. Despite their widespread use, there is no clear consensus regarding the optimal intra-articular therapy for sustained symptom relief.⁴

Orthobiologic therapies, particularly plateletrich plasma (PRP), have emerged as promising alternatives for knee OA treatment. PRP contains a high concentration of platelets and bioactive growth factors that modulate inflammation and promote tissue repair. Recent studies and meta-analyses have demonstrated superior mid-term clinical outcomes with PRP compared with HA and corticosteroids.^5-7

PRP plasma gel represents an advancement over conventional PRP by combining a thermally induced albumin gel matrix with fresh PRP, which allows for prolonged intra-articular retention and sustained release of growth factors..^8-11

The objective of this prospective randomized clinical trial was to compare the clinical outcomes of PRP plasma gel, hyaluronic acid, and corticosteroid intraarticular injections, used alone or in combination, for the treatment of knee osteoarthritis.

MATERIALES Y MÉTODOS

This study was structured as a prospective, randomized, controlled, single-blind clinical trial. Its objective was to compare the clinical effectiveness of various intra-articular injection strategies for treating knee osteoarthritis.

Participants were randomly allocated into four parallel treatment groups and followed longitudinally.

The study was conducted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.

The study protocol was reviewed and approved by the Institutional Research Ethics Committee, in compliance with the Declaration of Helsinki and national regulations for research involving human subjects. Written informed consent was obtained from all participants prior to enrollment.

Patient recruitment was conducted between February and April 2025, and all participants were followed for 6 months after the intervention.

Eligible patients were adults aged 30 to 90 years with both a clinical and a radiographic diagnosis of knee osteoarthritis, classified as Kellgren–Lawrence grade¹² II or III, who were consecutively recruited from the outpatient clinic.

Patients were included if they reported persistent knee pain despite previous conservative treatment and were able to understand and complete all patientreported outcome measures used in the study.

Exclusion criteria comprised the presence of inflammatory rheumatic disease, use of oral, intravenous, or intra-articular corticosteroids within the 12 months preceding enrollment, hemoglobin levels below 11 g/dL, platelet counts lower than 150,000/mm³, known coagulation disorders, active infectious or inflammatory processes near the injection site, and inability to complete the scheduled follow-up assessments.

Participants were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups using a computergenerated randomization sequence. Allocation concealment was maintained through the use of sealed opaque envelopes.

To maintain participant blinding, blood samples were collected from all enrolled patients, regardless of group assignment. Only participants assigned to PRP-containing groups underwent processing and administration of the hemoderivative. During the injection procedure, a visual barrier was used to prevent participants from seeing the syringe contents, thereby ensuring single-blind conditions.

Participants were allocated to one of the following groups:

• Group A: PRP plasma gel + Hyaluronic acid + Corticosteroid
• Group B: Hyaluronic acid + Corticosteroid.
• Group C: PRP plasma gel + Corticosteroid.
• Group D: Corticosteroid alone (control group).

All injections were performed as a single intraarticular procedure.

SApproximately 20 mL of peripheral venous blood was collected from each participant using two sterile 10-mL plastic vacuum tubes without additives.

Sodium heparin (0.125 mL; 5,000 IU/mL) was added to each tube to prevent coagulation. Samples were centrifuged at 800 × g for 15 minutes using a laboratory centrifuge. After centrifugation, the lower plasma fraction enriched with platelets and the buffy coat layer (approximately 2.5–3.0 mL per tube) were carefully aspirated using sterile syringes and reserved for further processing.

The collected PRP was redistributed using a three way Luer-lock connector into two syringes at a 3:1 ratio. One syringe containing approximately 3.75 mL of PRP was subjected to controlled thermal processing in a laboratory incubator at 75 °C for 15 minutes. This process induced protein denaturation, resulting in a semi-solid albumin gel matrix. The remaining syringe containing approximately 1.25 mL of non-heated PRP was preserved for subsequent mixing.

Following thermal processing, the albumin gel was mechanically mixed with the preserved non-heated PRP using a three-way connector, maintaining a final ratio of 3 parts albumin gel to 1 part fresh PRP. The contents were transferred back and forth between syringes until a homogeneous, stable PRP plasma gel was obtained, yielding a final volume of approximately 5 mL. This final product combined the structural properties of the albumin gel with the biological activity of fresh PRP, allowing sustained intra-articular release of growth factors (Figs. 1 and 2).

TAll intra-articular injections were performed under sterile conditions by experienced orthopedic surgeons. Patients were positioned supine with the knee slightly flexed. Skin antisepsis was performed using chlorhexidine-based solutions, and sterile draping was applied. Local anesthesia was achieved with 2 mL of 2% lidocaine infiltrated into the subcutaneous and pericapsular tissues. A lateral suprapatellar approach was used in all cases.

Prior to injection, therapeutic arthrocentesis was performed to remove any joint effusion when present. The assigned injectate was then administered intra-articularly using a single needle, followed —when applicable— by hyaluronic acid and/or corticosteroid (triamcinolone hexacetonide, 20 mg/mL), according to group allocation. A sterile dressing was applied after the needle was removed. When combination therapies were used, the components were administered sequentially through the same intra-articular access. PRP plasma gel was injected first, followed by hyaluronic acid and finally corticosteroid, without prior mixing in the same syringe.

Participants were advised to avoid strenuous physical activity involving the treated knee for at least 24 hours. Cryotherapy was recommended to reduce post-procedural discomfort. Nonsteroidal anti-inflammatory drugs were discouraged during the follow-up period. Opioid analgesics were allowed as rescue medication for a maximum of five days if necessary.

No standardized rehabilitation protocol was prescribed. All patients received the same general post-procedure recommendations, including relative rest for 24 hours and gradual return to activities as tolerated.

Figure 1. Preparation of plasma gel. A) Peripheral venous blood collection into sterile vacuum tubes. Placement of tubes in the centrifuge, highlighting the importance of proper balance: tubes are positioned diametrically opposite and filled with equal volumes to ensure stability during centrifugation. B) Appearance of the centrifuged blood, showing separation of red blood cells, buffy coat, and plasma. C) Redistribution of PRP using a three-way Luer Lock connector in a 3:1 ratio. Approximately 3.75 mL of PRP is placed in one syringe, while 1.25 mL is kept in another for later use. D) The larger PRP fraction is heated in an incubator at 75 °C for 15 minutes, causing denaturation of albumin, fibrinogen, and other plasma proteins, and forming an albumin-based semisolid gel. The reserved fresh PRP (≈1.25 mL) and the albumin gel (≈3.75 mL) prepared for combination.

Clinical outcomes were assessed using validated patient-reported outcome measures: Visual Analog Scale¹³ (VAS) for pain, WOMAC,^14-16KOOS,¹⁷ Pain Catastrophizing Scale18 (PCS), PROMIS Fatigue,¹⁹ Global Rating of Change²⁰ (GROC), and Marx Activity Rating Scale.²¹ Assessments were performed at baseline and at 1, 3, and 6 months after the intervention.

All post-intervention clinical assessments were performed by independent evaluators who were not involved in patient treatment.

All clinical and functional data were organized in electronic spreadsheets and analyzed using R software (Mac OS X GUI, version 1.73). Statistical significance was defined as a two-tailed p-value <0.05, at a 95% confidence level.

Categorical variables were summarized as absolute and relative frequencies and compared among groups using Pearson’s Chi-square test or Fisher’s exact test, as appropriate. Continuous variables were assessed for normality using the Shapiro–Wilk test. Normally distributed data were expressed as mean ± standard deviation and compared between groups using oneway analysis of variance (ANOVA) with Tukey post hoc tests, while non-normally distributed data were expressed as median and interquartile range and analyzed using the Kruskal–Wallis test with Dunn’s correction.

Within-group comparisons across time points were performed using paired t-tests for parametric data or Wilcoxon signed-rank tests for nonparametric data. When appropriate, mean changes (delta values) between time points were calculated to assess treatment-related effects over time, and results were graphically presented using mean values with standard deviation error bars. No formal sample size calculation or power analysis was performed.

Figure 2. PRP plasma gel combination and application. A) The albumin gel (≈3.75 mL) is mixed with the reserved fresh PRP (≈1.25 mL) using the three-way connector. Multiple passes between syringes ensure homogenization, resulting in approximately 5 mL of PRP plasma gel. B) The PRP plasma gel is transferred into a sterile syringe and injected intra-articularly under aseptic conditions, typically through a suprapatellar or anterolateral portal of the knee.

Figure 3. CONSORT flow diagram illustrating patient enrollment, randomization, allocation to treatment groups, follow-up, and final analysis in this prospective randomized clinical trial.

RESULTS

A total of 80 patients were initially enrolled and randomized; 64 completed follow-up and were included in the final analysis (Fig. 3). The overall mean age was 62.1 ± 8.9 years (range, 42–78), and 71% of participants were female. All patients had radiographic knee osteoarthritis classified as Kellgren–Lawrence grade II–III. Participant blinding was maintained throughout the trial using the predefined single-blind protocol. Final group distribution among participants with complete follow-up was Group A (PRP plasma gel + hyaluronic acid + corticosteroid), n = 14; Group B (hyaluronic acid + corticosteroid), n = 17; Group C (PRP plasma gel + corticosteroid), n = 15; and Group D (corticosteroid alone), n = 18. Outcomes were assessed longitudinally from baseline through follow-up time points as defined in the protocol. No major or minor complications, including infection, exacerbation of persistent pain, or adverse reactions, were observed during the study period.

At the 6-month follow-up, all treatment groups demonstrated a significant reduction in pain intensity compared with baseline at early time points (Fig. 4 and Table 1). At 1 and 3 months, Groups A, B, C, and D showed statistically significant decreases in VAS scores (p<0.05 for all). However, at 6 months, sustained pain reduction remained statistically significant only in Groups A (PRP plasma gel + hyaluronic acid + corticosteroid; p = 0.0037), B (hyaluronic acid + corticosteroid; p = 0.0017), and C (PRP plasma gel + corticosteroid; p = 0.0010), whereas the corticosteroid-only group (Group D) no longer demonstrated a significant difference from baseline (p = 0.1878).

Figure 4. Visual Analog Scale (VAS) pain scores at baseline, 1, 3, and 6 months following intra-articular treatment. PRP plasma gel–based groups demonstrated sustained pain reduction at 6 months, whereas the corticosteroid-only group showed loss of analgesic effect over time.

At the 6-month follow-up, Groups A, B, and C exhibited significant within-group improvements in the WOMAC pain and function domains compared with baseline (p <0.05 for all) (Fig. 5). In contrast, Group D did not show significant improvement in WOMAC pain (p = 0.115) or function (p = 0.255) at 6 months. Significant improvement in WOMAC stiffness scores was observed only in Group A (p <0.05), whereas Groups B, C, and D did not exhibit statistically significant changes in stiffness.

At 6 months, KOOS subscale analysis indicated a consistent trend favoring Group A across pain, symptoms, activities of daily living, sport/ recreation function, and knee-related quality of life.

Nevertheless, after adjustment for baseline values using ANCOVA, no statistically significant differences between groups were identified at the 6-month time point (Type III ANCOVA, p >0.05 for all domains).

Significant reductions in PCS scores from baseline to 6 months were observed in Group A (Δ = −13.42; p = 0.0043), Group B (Δ = −13.47; p = 0.0040), and Group C (Δ = −13.50; p = 0.0202), indicating meaningful improvement in pain-related catastrophizing.

Group D showed a smaller non-significant reduction (Δ = −8.38; p = 0.0843). Adjusted between-group comparisons at 6 months were not statistically significant (ANCOVA p = 0.760).

PROMIS Fatigue scores improved over time in all treatment, but only Group A demonstrated a statistically significant within-group improvement at 6 months (Δ = −16.83; p = 0.0395). No statistically significant between-group differences were detected after adjustment for baseline values (ANCOVA p = 0.2944).

At the 6-month evaluation, patient-perceived improvement assessed by the GROC scale showed significant within-group improvement across all treatment arms. The greatest magnitude of perceived improvement was observed in Group A (Δ = +5.14; p = 0.0135) and Group C (Δ = +4.67; p = 0.0132).

Adjusted between-group comparisons did not reveal statistically significant differences at 6 months (ANCOVA p = 0.953).

MARX activity scores demonstrated a nonsignificant upward trend from baseline to 6 months in all groups: Group A (Δ = +1.33; p = 0.1661), Group B (Δ = +0.71; p = 0.3061), Group C (Δ = +0.58; p = 0.3934), and Group D (Δ = +1.44; p = 0.1216). No statistically significant differences within-group or between-groups were identified at the 6-month follow-up (ANCOVA p = 0.733).

DISCUSSION

The primary finding of this study was that intraarticular strategies incorporating PRP plasma gel were associated with more sustained clinical improvement over time compared with corticosteroid alone. However, no statistically significant differences between groups were observed after adjustment.

Although all treatment arms demonstrated early pain relief, only the PRP-containing groups maintained improvements over time, whereas the corticosteroidonly group showed loss of efficacy at mid-term followup. Despite the absence of statistically significant differences between groups after adjustment, the observed sustained improvements in pain and function may be clinically meaningful, particularly in the context of chronic conditions such as knee osteoarthritis, where long-term symptom control is a key therapeutic goal.

Figure 5. WOMAC subscale scores (pain, stiffness, and function) from baseline to 6-month follow-up. Significant improvements in pain and function were observed in PRP plasma gel–containing groups, with stiffness improvement occurring exclusively in the combined PRP plasma gel, hyaluronic acid, and corticosteroid group.

This temporal pattern is consistent with previous literature. Corticosteroids are known to provide rapid analgesia with limited durability, a finding repeatedly reported in clinical trials and systematic reviews. In contrast, biologically active therapies such as PRP have demonstrated superior mid-term outcomes when compared with corticosteroids and hyaluronic acid, particularly for pain and function. Meta-analyses by Belk et al.²² and Khalid et al.²³ have shown that PRP results in greater improvements in WOMAC and VAS scores at follow-ups beyond 3 months, supporting the sustained analgesic effect observed in the present study

Functional outcomes assessed by WOMAC further support these findings. At 6 months, patients who received with PRP plasma gel —with or without hyaluronic acid— demonstrated significant improvements in pain and function, whereas corticosteroid alone failed to produce meaningful functional gains. Notably, improvement in WOMAC stiffness was observed only in the group that received the combined PRP plasma gel, hyaluronic acid, and corticosteroid injection, suggesting a potential synergistic effect.²³ Similar benefits of combined PRP and hyaluronic acid therapies have been reported in recent systematic reviews, including the metaanalysis by Karasavvidis et al.,²⁴ which demonstrated superior functional outcomes compared with hyaluronic acid alone.

Although KOOS outcomes did not reach statistical significance after adjustment for between-group differences, the consistent trend favoring the combined PRP plasma gel strategy across all subdomains suggests a clinically relevant effect that may not have been fully captured due to sample size limitations. Previous studies evaluating PRP in knee osteoarthritis have similarly reported clinically meaningful improvements without consistent statistical separation across all KOOS subscales, particularly in heterogeneous patient populations.^22,23

Psychosocial and patient-centered outcomes provide additional evidence supporting the effectiveness of sustained biologic modulation.

Significant reductions in pain catastrophizing were observed only in groups receiving PRP and/or hyaluronic acid, which is consistent with evidence that longer-lasting symptom control improves pain perception and coping strategies.^18,22 Furthermore, only the combined PRP plasma gel group exhibited significant improvement in PROMIS Fatigue scores, suggesting broader functional and quality-of-life benefits beyond pain relief.¹⁹ These results align with previous reports suggesting that biologic intraarticular therapies may modulate inflammatory mediators and synovial biomarkers associated with systemic fatigue and symptom burden.^25,26

The sustained performance of PRP plasma gel can be attributed to its unique structural characteristics.

Unlike conventional liquid PRP, plasma gel contains a thermally induced albumin matrix combined with fresh PRP, which enables prolonged intra-articular retention and gradual release of growth factors such as PDGF, TGF-β, and VEGF.^8-11 Experimental and translational studies, including those by Godoi et al.¹¹ and Nakamura et al.,⁸ have shown that plasma-based gels serve as effective biological carriers, facilitating controlled release and prolonged bioactivity, which may explain the sustained clinical effects observed in this trial.

Although corticosteroids have been rshown to inhibit specific growth factors, their inclusion in this study was informed by both clinical and methodological considerations. Clinically, corticosteroids provide rapid analgesic and anti-inflammatory effects, which may contribute to early symptom relief while the biological effects of PRP plasma gel take time to emerge, reflecting a pragmatic real-world strategy.

In addition, corticosteroids were administered at a low dose, as lower doses have been associated with reduced deleterious effects on mesenchymal cells.

Methodologically, the use of corticosteroids across all treatment groups allowed for a more controlled comparison, helping to isolate the additional effects of PRP plasma gel and hyaluronic acid beyond the known effects of corticosteroids. This design aimed to reduce confounding and better clarify the contribution of each therapeutic component.

From both clinical and economic perspectives, the comparison between PRP plasma gel plus corticosteroid and hyaluronic acid plus corticosteroid is particularly relevant. Although both strategies demonstrated comparable clinical improvements, PRP plasma gel represents an autologous therapy that can be prepared with standard laboratory equipment, potentially at lower cost than commercially available hyaluronic acid formulations. In resourcelimited healthcare systems, this distinction may have significant implications for accessibility and cost-effectiveness, without compromising clinical outcomes.²⁷

Further research directly comparing PRP plasma gel with conventional PRP formulations is necessary to clarify the potential benefits of this modified biological approach.

This study has limitations, such as a modest sample size, lack of a formal sample size calculation, unequal group sizes following attrition, and a 6-month followup. Additionally, imaging or biochemical markers were not assessed, which could have provided additional mechanistic insights. However, the study’s strengths include its prospective randomized design, the use of multiple validated outcome measures, and direct comparison of clinically relevant intra-articular interventions.

CONCLUSION

The combination of PRP plasma gel, hyaluronic acid, and corticosteroid resulted in more consistent and sustained clinical improvement at 6 months compared to corticosteroid alone. However, no statistically significant differences between groups were observed after adjustment. PRP plasma gel alone showed clinical outcomes comparable to those of hyaluronic acid.

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