Comparative efficacy of polyacrylamide hydrogel versus hyaluronic acid and corticosteroids in knee osteoarthritis: A retrospective cohort study

Abstract

This study investigates whether intra-articular polyacrylamide hydrogel (iPAAG) provides superior outcomes compared to conventional injections, namely hyaluronic acid (HA) and corticosteroid, in managing knee osteoarthritis (KOA). This retrospective cohort study included primary KOA patients (Kellgren–Lawrence grade II–IV) treated between January 2023 and December 2024 with 1 of 3 intra-articular injections: iPAAG (6 mL Arthrosamid), HA (2 mL, 60 mg Artroaid), and Steroid (40 mg methylprednisolone acetate, Arhropan). Outcomes were assessed at baseline, 3, 6, and 12 months. Primary outcomes were the Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index. Clinically meaningful improvements were evaluated using minimal clinically important difference (MCID) and patient acceptable symptom state thresholds. A total of 150 patients (n = 50 per group) were included. The groups were comparable at baseline in median age (HA: 66; Steroid: 69.5; iPAAG: 69.5; P = .104), sex (female: 72%, 62%, 66%; P = .566), median body mass index (30.4, 30.6, 30.7 kg/m²; P = .716), and Kellgren–Lawrence distribution (P = .765). Baseline median VAS was 7, dropping to 3 in all groups at 3 months (P < .001). At 6 months, they rose to 4 (HA), 5 (Steroid), and 4 (iPAAG) (P < .001). By 12 months, VAS returned to baseline in HA and Steroid, while iPAAG remained slightly improved (P = .219). iPAAG outperformed Steroid at 6 months (P < .001), but not HA (P = 1.000). No significance at 12 months (P = .128). Baseline median Western Ontario and McMaster Universities Osteoarthritis Index scores were 49.5 (HA), 59.5 (Steroid), and 57 (iPAAG), improving at 3 months to 42.5, 48.5, and 45 (P < .001). At 6 months, scores were 45, 57, and 47.5 (P < .001). At 12 months, HA and Steroid returned to baseline, while iPAAG remained stable (P = .979). iPAAG was better than Steroid at 6 months (P = .008), but not HA (P = .066). Although overall differences at 12 months were significant (P = .044), pairwise comparisons were not. iPAAG showed the highest patient acceptable symptom state rates (72%, 54%, and 42% at 3, 6, and 12 months), and greatest minimal clinically important difference achievement at 3 and 6 months, though without significant intergroup differences (P > .05). iPAAG offers comparable short-term efficacy and modest advantage at 6 months. However, long-term superiority is limited. It may be a complementary option in individualized osteoarthritis management. Further prospective studies are needed to define its optimal use.

1. Introduction

Knee osteoarthritis (KOA) is a degenerative joint disorder and one of the most common causes of pain and disability in the aging population.^[1] It involves complex pathological mechanisms, including cartilage loss, synovial inflammation, and subchondral bone remodeling.^[2] As the prevalence of KOA rises globally, particularly among older adults, the demand for nonsurgical interventions that effectively relieve symptoms and delay progression has intensified.^[3,4]

Intra-articular (IA) injections are widely used for symptom management in KOA, especially in patients with inadequate response to conservative therapies.^[5,6] Corticosteroids, such as methylprednisolone acetate, offer short-term anti-inflammatory and analgesic effects, but their benefits are often transient and concerns have been raised about potential cartilage toxicity with repeated use.^[7,8] Hyaluronic acid (HA) injections aim to restore synovial fluid viscosity and modulate joint inflammation, yet evidence regarding their efficacy remains inconsistent, with meta-analyses yielding mixed conclusions.^[9,10]

Polyacrylamide hydrogel (iPAAG) has recently emerged as a novel IA injectable designed to provide sustained joint cushioning and symptom relief. Composed of a cross-linked, nonbiodegradable water-based polymer, iPAAG integrates into the synovial membrane and maintains joint space over time.^[11–13] While several preclinical studies and early-phase clinical reports have suggested promising outcomes, most of the evidence supporting iPAAG originates from animal models or uncontrolled human trials.^[14–16] Recent clinical studies have begun to explore its therapeutic value: Henriksen et al^[11] reported long-term symptomatic relief over 12 months following iPAAG injection. Similarly, Bliddal et al^[17] demonstrated that iPAAG was non-inferior to HA at both 26 and 52 weeks in a randomized controlled trial, while another open-label study by the same group showed persistent functional and analgesic benefit up to 1 year.^[16] In contrast, Issin et al^[18] found no significant difference between iPAAG and corticosteroid injection in terms of short-term clinical outcomes during a 12-week follow-up, highlighting the need for longer-term and comparative evaluations. Despite these emerging findings, comparative studies simultaneously evaluating iPAAG, HA, and corticosteroids under routine clinical settings remain scarce.

This retrospective study aims to fill that critical gap by comparing the clinical effectiveness of polyacrylamide hydrogel, HA, and corticosteroid injections in patients with KOA. By evaluating these therapies under routine care conditions, our study provides practical insight into their relative therapeutic value and supports evidence-based decision-making in the management of KOA. Accordingly, we aimed to determine whether polyacrylamide hydrogel could serve as a viable alternative to conventional IA injections by assessing its comparative effectiveness.

2. Material and methods

2.1. Study design

This retrospective, comparative cohort study was conducted at Bursa City Hospital, Department of Orthopedics and Traumatology, a tertiary referral center. The study protocol received approval from the institutional ethics committee (Approval No: 2025-5/1, Date: May 3, 2025), and all procedures adhered to the Declaration of Helsinki and relevant local regulatory guidelines.

2.2. Patient selection

Patients were identified through institutional electronic medical records based on a diagnosis of primary KOA, confirmed by clinical examination and radiographic assessment. Inclusion criteria comprised individuals aged >50 years with symptomatic KOA of Kellgren–Lawrence (KL) grade II, III, or IV on weight-bearing anteroposterior radiographs. Patients who received an IA injection of iPAAG, HA, or corticosteroid (methylprednisolone acetate) between January 1, 2023 and December 31, 2024, and had a minimum of 12 months of clinical follow-up were eligible for inclusion. All participants had experienced knee pain for at least 3 months that was unresponsive to conservative treatments, including oral analgesics and physical therapy. Complete clinical documentation at baseline and at follow-up visits was required for study entry.

Exclusion criteria included KL grade I osteoarthritis (OA), radiographic evidence of secondary OA (e.g., post-traumatic, inflammatory etiologies), prior knee surgery within the past year, or any IA injection (e.g., corticosteroids, HA, platelet-rich plasma, prolotherapy) within 6 months preceding the index treatment. Additional exclusions comprised systemic inflammatory arthropathies (e.g., rheumatoid arthritis, psoriatic arthritis, gout), previous septic arthritis in the affected knee, IA fractures, chronic systemic corticosteroid use, hypersensitivity to study medications, local injection site infections, or incomplete clinical follow-up.

After applying these criteria and excluding patients with incomplete records, a total of 150 patients were included in the final analysis, with 50 patients per treatment arm (Fig. 1). In the HA group, the median age was 66 years, and 72% of participants were female. The median body mass index (BMI) was 30.4 kg/m². Radiographic severity was distributed as follows: KL grade II (8%), grade III (42%), and grade IV (50%). In the Steroid group, the median age was 69.5 years, with 62% female participants. The median BMI was 30.6 kg/m². KL grades included grade II (12%), grade III (36%), and grade IV (52%). In the iPAAG group, the median age was 69.5 years, and 66% of patients were female. The median BMI was 30.7 kg/m². The KL distribution was grade II (10%), grade III (48%), and grade IV (42%).

Figure 1.

Patient selection process.

2.3. Study protocol

Prior to participation, all patients provided written informed consent, in accordance with institutional standards for invasive orthopedic procedures. As part of standard clinical workflow, baseline demographic characteristics (including age, sex, height, weight, and calculated BMI) were recorded upon admission to the outpatient clinic. Clinical assessments, including the Visual Analog Scale (VAS) for pain and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), were performed during routine evaluations and documented using standardized data collection forms. Radiographic staging of osteoarthritis was conducted using the KL classification system. Follow-up evaluations, comprising the same clinical outcome measures and radiographic reassessment, were conducted at 12th months to track treatment-related changes.

2.4. Intervention protocols

Group 1 (iPAAG) received a single IA injection of 6 mL polyacrylamide hydrogel (Arthrosamid®, Contura International A/S, Copenhagen, Denmark)). Group 2 (HA) was administered a single injection of 2 mL high molecular weight HA containing 60 mg of active substance (ArtiAid®, Maxigen Biotech Inc., Taoyuan City, Taiwan). Group 3 (Steroid) received a single IA injection of 40 mg methylprednisolone acetate (Artropan®, Koçak Farma İlaç ve Kimya Sanayi A.Ş., İstanbul, Türkiye). All injections were performed under aseptic conditions using a standardized anterolateral approach without imaging guidance. All procedures were carried out by an experienced orthopedic surgeon to ensure consistency and minimize operator-related variability. The choice of injectable was based on physician preference in alignment with patient-specific clinical features and prior treatment history, reflecting routine clinical practice without predefined allocation criteria.

2.5. Outcome measures

Clinical outcomes were evaluated at baseline and at 3, 6, and 12 months following the intervention. The primary endpoints comprised the VAS for pain intensity (scored from 0 to 10) and the WOMAC, which encompasses subdomains for pain, stiffness, and physical function. These validated patient-reported outcome measures (PROMs) were selected to comprehensively capture symptom severity and functional impairment associated with KOA. To enhance the interpretability of findings beyond conventional statistical significance, responder analyses were conducted using both the minimal clinically important difference (MCID) and patient acceptable symptom state (PASS). Thresholds for MCID and PASS were determined using distribution-based approaches, specifically the standard error of measurement (SEM) and 0.5 standard deviation (0.5 SD) methods. These approaches allowed for the identification of clinically meaningful improvements (MCID) and the symptom states patients considered satisfactory (PASS), thereby facilitating a patient-centered evaluation of therapeutic benefit over time.

2.6. Statistical analysis

The normality of continuous variables was assessed using the Shapiro–Wilk test. As the continuous data were not normally distributed, they were summarized using median values along with minimum and maximum ranges. Categorical variables were presented as frequencies and percentages.

Between-group comparisons of continuous variables were performed using the Kruskal–Wallis test. When the Kruskal–Wallis test indicated a statistically significant overall difference, post hoc pairwise comparisons were conducted using the Dunn–Bonferroni method. Within-group comparisons of repeated measurements over time were conducted using the Friedman test. If the Friedman test revealed significant differences across time points, pairwise comparisons were carried out with Bonferroni correction to control for multiple testing.

For categorical variables, intergroup comparisons were performed using the chi-square test. The clinical effectiveness of interventions was further evaluated based on responder analysis using the MCID and PASS. MCID and PASS thresholds were determined using distribution-based methods, including (i) the 0.5 SD method, which reflects a moderate effect size, and (ii) the SEM approach, based on measurement precision. The proportion of patients achieving MCID and PASS was calculated accordingly.

All statistical analyses were conducted using IBM SPSS Statistics for Windows, Version 23.0 (IBM Corp., Armonk). A P-value < .05 was considered statistically significant for all tests.

3. Results

There were no significant baseline differences between groups in gender distribution (female: HA 72%, Steroid 62%, iPAAG 66%; P = .566), median age (HA 66 years, range 60–82 years; Steroid 69.5 years, 60–87 years; iPAAG 69.5 years, 60–87 years; P = .104), median BMI (HA 30.4 kg/m², range 25–47 kg/m²; Steroid 30.6, 23–48 kg/m²; iPAAG 30.7, 25–44 kg/m²; P = .716), or KL grade distribution (grade II: HA 8%, Steroid 12%, iPAAG 10%; grade III: 42%, 36%, 48%; grade IV: 50%, 52%, 42%; P = .765) (Table 1).

Table 1.

Demographic characteristics of patients by treatment group.

	HA (n = 50)	Steroid (n = 50)	PAAG (n = 50)	P-value
Gender
Female	36 (72%)	31 (62%)	33 (66%)	.566†
Male	14 (28%)	19 (38%)	17 (34%)
Age (yr)	66 (60–82)	69.5 (60–87)	69.5 (60–87)	.104*
BMI (kg/m2)	30.4 (25–47)	30.6 (23–48)	30.7 (25–44)	.716*
Kelgreen
II	4 (8%)	6 (12%)	5 (10%)	.765†
III	21 (42%)	18 (36%)	24 (48%)
IV	25 (50%)	26 (52%)	21 (42%)

Values are presented as the mean (min–max) for continuous variables and as a number (percentage) for categorical variables.

BMI = body mass index, HA = hyaluronic acid, PAAG = polyacrylamide hydrogel.

^*Kruskal–Wallis test.

^†Chi-square test with a Monte Carlo simulation.

All three groups showed marked VAS improvement at 3 months, with median scores decreasing from 7 (range: HA 5–9, Steroid 5–9, iPAAG 6–9) at baseline to 3 (range: HA 1–8, Steroid 1–7, iPAAG 1–7) (all P < .001). At 6 months, median VAS slightly increased to 4 (1–8) in HA, 5 (1–7) in Steroid, and 4 (1–9) in iPAAG (all P < .001 vs baseline). By 12 months, HA and Steroid returned to baseline values of 7 (3–8) and 7 (2–9), respectively (P = .911 and P = .786), while iPAAG remained slightly lower at 7 (2–9) (P = .219). Between 3 and 6 months, only Steroid worsened significantly (P < .001), while HA (P = .786) and iPAAG (P = .121) remained stable. From 6 to 12 months, scores worsened in all groups (P < .001, except Steroid P = .013). Between-group analysis showed iPAAG achieved a greater 3-month reduction than HA (P = .040). At 6 months, both HA (P = .001) and iPAAG (P < .001) outperformed Steroid, with no difference between HA and iPAAG (P = 1.000). At 12 months, no significant intergroup differences were found (P = .128) (Fig. 2; Table 2) (additional results are provided in Table S1, Supplemental Digital Content, https://links.lww.com/MD/Q65).

Figure 2.

Histogram of Visual Analog Scale (VAS) pain scores at baseline, 3 months, 6 months, and 12 months for patients receiving hyaluronic acid (HA, navy), corticosteroid (red), or intra-articular polyacrylamide hydrogel (iPAAG, yellow). Bars represent median values, and vertical black lines indicate minimum and maximum observed scores. Lower scores reflect less pain intensity.

Table 2.

Baseline VAS scores across treatment groups.

	HA (n = 50)	Steroid (n = 50)	PAAG (n = 50)
VAS
0 month	7 (5–9)	7 (5–9)	7 (6–9)
3 months	3 (1–8)	3 (1–7)	3 (1–7)
6 months	4 (1–8)	5 (1–7)	4 (1–9)
12 months	7 (3–8)	7 (2–9)	7 (2–9)
P-value	<.001*	<.001*	<.001*
Pairwise comparisons (P-value)†
0 month & 3 months	<.001	<.001	<.001
0 month & 6 months	<.001	<.001	<.001
0 month & 12 months	.911	.786	.219
3 months & 6 months	.786	<.001	.121
3 months & 12 months	<.001	<.001	<.001
6 months & 12 months	<.001	.013	<.001

Values are presented as the median (min–max) for continuous variables.

HA = hyaluronic acid, PAAG = polyacrylamide hydrogel, VAS = Visual Analog Scale.

^*Friedman test.

^†Wilcoxon test.

At baseline, median WOMAC Pain scores were 12 (range: HA 6–17, Steroid 6–17, iPAAG 6–17). At 3 months, scores decreased to 8 (HA 5–15, Steroid 5–16, iPAAG 5–16), indicating reduced pain in all groups (all P < .001 vs baseline). At 6 months, scores rose slightly to 9 (5–16) in HA, 10 (5–15) in Steroid, and 9 (5–16) in iPAAG (all P < .001 vs baseline). By 12 months, HA and Steroid returned to baseline values 12 (5–15) and 12 (5–17) (both P = 1.000) while iPAAG remained slightly lower at 11 (6–16) (P = .121). From 3 to 6 months, only Steroid showed a significant increase in pain scores (P = .001), whereas HA (P = .164) and iPAAG (P = 1.000) remained stable. From 6 to 12 months, pain worsened in all groups (all P < .001, except Steroid P = .001). At 6 months, iPAAG had lower pain scores than HA (P = .012) and Steroid (P = .008). At 12 months, overall differences were significant (P = .011), but only iPAAG versus HA remained statistically significant (P = .012) (Table 3) (additional results are provided in Table S2, Supplemental Digital Content, https://links.lww.com/MD/Q65).

Table 3.

WOMAC Pain score changes over time by treatment group.

	HA (n = 50)	Steroid (n = 50)	PAAG (n = 50)
WOMAC Pain
0 month	12 (6–17)	12 (6–17)	12.5 (6–17)
3 months	8 (5–15)	8 (5–16)	8 (5–16)
6 months	9 (5–16)	10 (5–15)	9 (5–16)
12 months	12 (5–15)	12 (5–17)	11 (6–16)
P-value	<.001*	<.001*	<.001*
Pairwise comparisons (P-value)†
0 month & 3 months	<.001	<.001	<.001
0 month & 6 months	<.001	<.001	<.001
0 month & 12 months	1.000	1.000	.121
3 months & 6 months	.164	.001	1.000
3 months & 12 months	<.001	<.001	<.001
6 months & 12 months	<.001	.001	<.001

Values are presented as the median (min–max) for continuous variables.

HA = hyaluronic acid, PAAG = polyacrylamide hydrogel, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

^*Friedman test.

^†Wilcoxon test.

At baseline, median WOMAC Stiffness scores were 3 (range: 1–6) in HA, 4 (0–7) in Steroid, and 4 (2–7) in iPAAG. At 3 months, scores decreased slightly to 3 (0–5) in HA, remained at 4 (1–6) in Steroid, and dropped to 3 (0–6) in iPAAG. This reduction was significant for HA (P = .013) and iPAAG (P = .003), but not for Steroid (P = .109). At 6 months, scores were 3 (1–7), 3 (1–6), and 3.5 (0–6), respectively, with no significant change from baseline in any group (P > .05). By 12 months, stiffness scores returned to or exceeded baseline in all groups: HA 3 (1–8), Steroid 3 (1–6), iPAAG 4 (0–7) with no significant differences from baseline (all P = 1.000). From 3 to 6 months and from 6 to 12 months, there were no significant changes within any group (all P > .05). Between groups, no statistically significant differences were found at any time point. The improvements observed at 3 months in HA and iPAAG were not sustained at later follow-ups (Table 4) (additional results are provided in Table S3, Supplemental Digital Content, https://links.lww.com/MD/Q65).

Table 4.

WOMAC Stiffness score changes over time by treatment group.

	HA (n = 50)	Steroid (n = 50)	PAAG (n = 50)
WOMAC Stiffness
0 month	3 (1–6)	4 (0–7)	4 (2–7)
3 months	3 (0–5)	4 (1–6)	3 (0–6)
6 months	3 (1–7)	3 (1–6)	3.5 (0–6)
12 months	3 (1–8)	3 (1–6)	4 (0–7)
P-value	<.001*	.002*	<.001*
Pairwise comparisons (P-value)†
0 month & 3 months	.013	.109	.003
0 month & 6 months	.979	.911	.051
0 month & 12 months	1.000	1.000	1.000
3 months & 6 months	.575	1.000	1.000
3 months & 12 months	.063	1.000	.121
6 months & 12 months	1.000	1.000	.847

Values are presented as the median (min–max) for continuous variables.

HA = hyaluronic acid, PAAG = polyacrylamide hydrogel, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

^*Friedman test.

^†Wilcoxon test.

At baseline, median WOMAC Physical Function scores were 34 (range: 15–55) in HA, 43.5 (17–56) in Steroid, and 39.5 (15–58) in iPAAG, indicating worse baseline function in the Steroid group. At 3 months, scores decreased to 31.5 (15–49) in HA, 37 (15–54) in Steroid, and 34 (15–55) in iPAAG (all P < .001 vs baseline). At 6 months, scores were 32.5 (15–50), 42.5 (15–55), and 35 (17–55), respectively (HA P = .012, Steroid P < .001, iPAAG P < .001 vs baseline). By 12 months, values returned close to baseline [HA 34.5 (18–55), Steroid 46 (24–55), iPAAG 43 (18–55)] with no significant within-group differences (P = 1.000 for HA and iPAAG, P = .346 for Steroid). From 3 to 6 months, deterioration was significant in Steroid (P = .003) and iPAAG (P = .017), but not HA (P = .488). From 3 to 12 months, all groups worsened significantly (all P < .001). From 6 to 12 months, deterioration persisted (HA P = .002, Steroid and iPAAG P < .001). Baseline differences between groups were significant (P = .001), with Steroid performing worse than HA (P = .001) and iPAAG (P = .042). At 3 months, the overall group difference was significant (P = .047), but no pairwise comparisons reached significance (all P > .05). At 6 and 12 months, no significant between-group differences were observed (Table 5) (additional results are provided in Table S4, Supplemental Digital Content, https://links.lww.com/MD/Q65).

Table 5.

WOMAC Physical Function score changes over time by treatment group.

	HA (n = 50)	Steroid (n = 50)	PAAG (n = 50)
WOMAC Physical Function
0 month	34 (15–55)	43.5 (17–56)	39.5 (15–58)
3 months	31.5 (15–49)	37 (15–54)	34 (15–55)
6 months	32.5 (15–50)	42.5 (15–55)	35 (17–55)
12 months	34.5 (18–55)	46 (24–55)	43 (18–55)
P-value	<.001*	<.001*	<.001*
Pairwise Comparisons (P-value)†
0 month & 3 months	<.001	<.001	<.001
0 month & 6 months	.012	<.001	<.001
0 month & 12 months	1.000	.346	1.000
3 months & 6 months	.488	.003	.017
3 months & 12 months	<.001	<.001	<.001
6 months & 12 months	.002	<.001	<.001

Values are presented as the median (min–max) for continuous variables.

HA = hyaluronic acid, PAAG = polyacrylamide hydrogel, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

^*Friedman test.

^†Wilcoxon test.

At baseline, median WOMAC Total scores were 49.5 (range: 23–79) in HA, 59.5 (25–78) in Steroid, and 57 (25–81) in iPAAG, with significantly higher scores in the Steroid group compared to HA (P = .014). At 3 months, scores decreased to 42.5 (6–61) in HA, 48.5 (22–74) in Steroid, and 45 (20–75) in iPAAG (all P < .001 vs baseline). At 6 months, scores were 45 (22–67), 57 (22–74), and 47.5 (22–73), respectively (all P < .001 vs baseline). By 12 months, values returned close to baseline [HA 49 (26–77), Steroid 62 (32–77), iPAAG 57 (26–77)] with no significant within-group differences (P = 1.000 for HA and Steroid, P = .979 for iPAAG). From 3 to 6 months, a small but significant increase in total scores (worsening) was observed in HA (P = .032) and Steroid (P = .001), while iPAAG remained stable (P = .063). From 6 to 12 months, all groups worsened significantly (all P < .001). But none of the pairwise comparisons reached statistical significance (Fig. 3; Table 6) (additional results are provided in Table S5, Supplemental Digital Content, https://links.lww.com/MD/Q65).

Figure 3.

Histogram of WOMAC Total scores at baseline, 3 months, 6 months, and 12 months for patients receiving hyaluronic acid (HA, navy), corticosteroid (red), or intra-articular polyacrylamide hydrogel (iPAAG, yellow). Bars represent median values, and vertical black lines indicate minimum and maximum observed scores. Lower scores reflect better joint function. WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

Table 6.

WOMAC Total score changes over time by treatment group.

	HA (n = 50)	Steroid (n = 50)	PAAG (n = 50)
WOMAC Total
0 month	49.5 (23–79)	59.5 (25–78)	57 (25–81)
3 months	42.5 (6–61)	48.5 (22–74)	45 (20–75)
6 months	45 (22–67)	57 (22–74)	47.5 (22–73)
12 months	49 (26–77)	62 (32–77)	57 (26–77)
P-value	<.001*	<.001*	<.001*
Pairwise Comparisons (P-value)†
0 month & 3 months	<.001	<.001	<.001
0 month & 6 months	<.001	<.001	<.001
0 month & 12 months	1.000	1.000	.979
3 months & 6 months	.032	.001	.063
3 months & 12 months	<.001	<.001	<.001
6 months & 12 months	<.001	<.001	<.001

Values are presented as the median (min–max) for continuous variables.

HA = hyaluronic acid, PAAG = polyacrylamide hydrogel, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

^*Friedman test.

^†Wilcoxon test.

PASS thresholds were calculated using both SEM and 0.5 SD methods, yielding cutoffs of ≤3.30 and ≤3.48 for VAS, and ≤46.06 and ≤48.43 for WOMAC Total. At 3 months, VAS PASS was achieved by 58.0% (HA), 68.0% (iPAAG), and 70.0% (Steroid). WOMAC PASS was highest in iPAAG (72.0% and 62.0%), intermediate in HA (56.0% and 54.0%), and lowest in Steroid (36.0% for both). At 6 months, VAS PASS dropped to 42.0% (HA), 40.0% (iPAAG), and 10.0% (Steroid). WOMAC PASS remained highest in iPAAG (54.0%), followed by HA (42.0%), and lowest in Steroid (26.0%). At 12 months, all PASS rates further declined; iPAAG retained the highest values (VAS: 12.0%; WOMAC: 42.0%), while Steroid had the lowest (VAS: 8.0%; WOMAC: 18.0%) (Table 7).

Table 7.

PASS achievement rates VAS and WOMAC at different time points.

Time	Group	VAS (0.5 SD) (%)	VAS (SEM) (%)	WOMAC (0.5 SD) (%)	WOMAC (SEM) (%)
3 months	HA	58.0	58.0	56.0	54.0
	PAAG	68.0	68.0	72.0	62.0
	Steroid	70.0	70.0	36.0	36.0
6 months	HA	42.0	42.0	42.0	40.0
	PAAG	40.0	40.0	54.0	54.0
	Steroid	10.0	10.0	26.0	26.0
12 months	HA	6.0	6.0	28.0	26.0
	PAAG	12.0	12.0	42.0	34.0
	Steroid	8.0	8.0	18.0	16.0

PASS thresholds were determined using distribution-based methods: SEM (25th percentile + SEM) and 0.5 SD (25th percentile + 0.5 × SD), yielding cutoffs of ≤3.30 and ≤3.48 for VAS, and ≤46.06 and ≤48.43 for WOMAC Total.

HA = hyaluronic acid, PAAG = polyacrylamide hydrogel, SD = standard deviation, SEM = standard error of measurement, VAS = Visual Analog Scale, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

MCID thresholds were set at ≥0.30 (SEM) and ≥0.48 (0.5 SD) for VAS, and ≥4.06 (SEM) and ≥6.43 (0.5 SD) for WOMAC Total. At 3 months, VAS MCID achievement was high across all groups (HA: 98.0%; iPAAG: 96.0%; Steroid: 96.0%). At 6 months, the rates remained high in HA (94.0%), iPAAG (84.0%), and Steroid (80.0%). By 12 months, MCID achievement dropped in all groups: VAS: HA (84.0%), iPAAG (78.0%), and Steroid (70.0%). For WOMAC Total, 3-month MCID rates ranged from 62.0% to 86.0%; at 6 months, rates decreased most in Steroid (30.0%–50.0%), followed by HA (36.0%–54.0%) and iPAAG (40.0%–64.0%). By 12 months, WOMAC MCID rates ranged from 26.0% to 54.0%, with iPAAG again showing the highest retention (Table 8).

Table 8.

MCID achievement rates: VAS and WOMAC at different time points.

Time	Group	VAS (0.5 SD) (%)	VAS (SEM) (%)	WOMAC (0.5 SD) (%)	WOMAC (SEM) (%)
3 months	HA	96.0	96.0	62.0	74.0
	PAAG	96.0	96.0	70.0	82.0
	Steroid	98.0	98.0	76.0	86.0
6 months	HA	94.0	94.0	36.0	54.0
	PAAG	84.0	84.0	40.0	64.0
	Steroid	80.0	80.0	30.0	50.0
12 months	HA	84.0	84.0	28.0	46.0
	PAAG	78.0	78.0	34.0	54.0
	Steroid	70.0	70.0	26.0	44.0

MCID thresholds were determined using distribution-based methods: SEM (≥SEM) and 0.5 SD (≥0.5 × SD), yielding cutoffs of ≥0.30 and ≥0.48 for VAS, and ≥4.06 and ≥6.43 for WOMAC Total, respectively.

HA = hyaluronic acid, PAAG = polyacrylamide hydrogel, SD = standard deviation, SEM = standard error of measurement, VAS = Visual Analog Scale, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.

4. Discussion

This study demonstrated that IA injections of polyacrylamide hydrogel (iPAAG), steroid (Steroid), and HA significantly improved pain and function at 3 months, as confirmed by VAS, WOMAC scores, MCID, and PASS achievement rates, validating the short-term efficacy of all treatments. By 6 months, iPAAG exhibited a comparatively favorable profile, maintaining significant improvements versus baseline and generally outperforming Steroid and HA, particularly regarding WOMAC Pain, Physical Function, and Total scores, along with MCID and PASS rates. However, statistical significance between iPAAG and HA was inconsistent, indicating that mid-term superiority, although suggestive, was not uniformly confirmed across all outcomes. At the 12-month follow-up, therapeutic effects declined across all treatments, with Steroid and HA outcomes returning towards baseline and iPAAG maintaining only marginally better but statistically insignificant benefits. Similarly, MCID and PASS responder rates decreased uniformly. Collectively, these results highlight the limited durability of IA therapies for KOA, suggesting that while iPAAG may provide beneficial mid-term relief and modestly delay symptomatic progression, it does not offer clear long-term superiority over traditional injectables.

These findings partially align with, yet also challenge, the existing literature regarding IA therapies for KOA, while the short-term efficacy of corticosteroid and HA injections is already well-established.^[19,20] Our observed mid-term advantages with iPAAG prompt closer examination in the context of recent hydrogel-based therapy research.

Notably, our findings resonate with the prospective observational study by Bliddal et al,^[16] involving patients across the OA severity spectrum. They demonstrated sustained WOMAC improvements following a single iPAAG injection, with 62.2% of participants meeting the OMERACT-OARSI responder criteria at 52 weeks. However, a crucial distinction arises from patient severity distribution; unlike our study, Bliddal et al’s^[16] cohort did not stratify outcomes by radiographic severity, potentially explaining their more favorable long-term outcomes compared to our nearly 50% severe OA (KL grade IV) population.

Further supporting this context, a randomized controlled trial by the same group^[17] compared iPAAG directly to HA, demonstrating non-inferiority at 26 weeks, although statistical significance in superiority was absent by 52 weeks. This aligns closely with our results. Importantly, the trial also documented a slightly higher rate of mild-to-moderate adverse events with iPAAG, highlighting considerations critical to real-world clinical practice.

Complementing this evidence, Henriksen et al^[11] offered additional insights into iPAAG’s mid-term effectiveness through their observational study predominantly involving mild-to-moderate OA (KL grades II–III). They reported clinically meaningful improvements sustained through 13 months, with 62% achieving minimal clinically important improvement. The marked responsiveness noted in their less severely affected population contrasts with our study’s greater proportion of advanced cases, providing context for differences in long-term outcomes.

Additionally, Issin et al^[18] reported comparable short-term outcomes between iPAAG and methylprednisolone acetate injections at 12 weeks, paralleling our 3-month findings. Nevertheless, their study limitations (such as the inclusion of mostly mild-to-moderate OA, lack of long-term follow-up, and absence of detailed radiographic or joint-effusion data) restrict deeper interpretations regarding long-term efficacy and treatment responsiveness.

Adding further perspective, albeit indirectly, de Clifford et al^[21] demonstrated superior short-to-mid-term outcomes with PAAG injections compared to HA and corticosteroids in racehorses. Though encouraging, these animal-model findings require cautious extrapolation due to interspecies anatomical and biomechanical variations.

However, significant methodological variations across these studies (including differences in design, OA severity, duration of follow-up, and choice of outcome measures) complicate direct cross-study comparisons. The current study addresses these gaps through its 3-arm comparative design, inclusion of significant proportions of severe OA cases, comprehensive 12-month follow-up, and robust evaluation using validated measures such as WOMAC, MCID, and PASS.

Nevertheless, despite promising mid-term results for iPAAG across selected patient populations,^[11,16–18] current literature remains limited and inconsistent regarding definitive long-term superiority. Such variability underscores that treatment responses likely depend heavily on factors such as disease severity, joint structural integrity, and patient-specific characteristics. Additionally, the relatively high cost of iPAAG compared to HA and corticosteroids remains an important consideration, particularly given the absence of sustained clinical superiority at 1 year. Consequently, cautious interpretation and individualized patient selection remain essential when integrating iPAAG into the therapeutic landscape for KOA.

The therapeutic effects of IA injections for KOA arise from distinct mechanisms specific to each agent: structural integration for polyacrylamide hydrogel (iPAAG), viscoelastic supplementation for HA, and anti-inflammatory modulation for corticosteroids.

The primary therapeutic action of iPAAG is its biomechanical integration into the joint environment rather than direct pharmacological activity.^[12,22,23] Animal studies by Christensen et al^[13] demonstrated that PAAG integrates into the synovial membrane, forming a stable, elastic layer without inflammatory or structural disruption. This integration likely reduces friction, enhances joint biomechanics, and provides mechanical cushioning, thus alleviating pain primarily in the short-to-mid-term period. McClure et al^[24] further confirmed the biocompatibility of PAAG through repeated injections in equine models, reporting no inflammatory reactions or cartilage damage. Whitaker et al^[25] similarly observed no cytotoxic or inflammatory response when combining PAAG with corticosteroids in equine joints, highlighting potential versatility. Supporting in vitro evidence by Nasircilar et al^[26] confirmed PAAG’s safety profile, indicating no cytotoxic effects on human mesenchymal stem cells or osteoblasts. Systematic reviews by de Souza et al^[27] and da Silva Xavier et al^[28] reinforced these findings, noting improved joint consistency and reduced effusion in equine models. Collectively, these studies underscore PAAG’s viscoelastic, non-pharmacological mechanism of redistributing mechanical load and improving synovial homeostasis. However, this structural support may not be sufficient to overcome advanced cartilage degeneration seen in severe OA cases, explaining the diminished efficacy at 12 months observed clinically.

Conversely, HA acts primarily through visco-supplementation, enhancing synovial fluid properties.^[29] It also exerts secondary anti-inflammatory and chondroprotective effects via CD44 receptor binding, cytokine modulation, and matrix metalloproteinase inhibition.^[30,31] These combined actions improve lubrication, reduce inflammation, and potentially slow cartilage degeneration, particularly in less advanced OA stages. However, HA’s limited IA half-life,^[6,32] likely contributes to the reduction in therapeutic benefit observed at 12 months in our study, despite retaining moderate benefits up to 6 months.

In contrast, corticosteroids rapidly alleviate symptoms primarily through potent anti-inflammatory actions, inhibiting and downstream pro-inflammatory mediators such as prostaglandins and cytokines.^[33] Despite effective short-term relief, repeated steroid use may induce chondrotoxicity and accelerate joint tissue degeneration,^[34] possibly explaining the sharp decline in effectiveness observed at 6 and 12 months in our Steroid group.

In summary, each IA agent exerts its effects via a distinct mechanism. These mechanistic differences may help explain the observed divergence in treatment response, particularly when considering the underlying structural and inflammatory burden. Consequently, aligning the therapeutic approach with the patient’s disease stage and joint pathology is essential for optimizing long-term outcomes.

One of the key strengths of this study lies in its robust 3-arm comparative design, enabling direct evaluation of iPAAG, HA, and Steroid under consistent clinical conditions. This approach provides meaningful comparative data and minimizes confounding related to treatment selection. Another notable strength is the inclusion of a substantial proportion of patients with advanced OA (KL grade IV), a population often underrepresented in prior iPAAG research. Including a broad spectrum of disease severity enhances generalizability and offers insight into therapeutic performance in more challenging clinical scenarios.

The 12-month follow-up period further contributes to the literature, given that many previous studies assessing iPAAG have limited follow-up to 12 to 26 weeks. This extended observation allows a better understanding of therapeutic durability and temporal response patterns. Additionally, the study incorporated validated PROMs, including WOMAC, VAS, MCID, and PASS, which provide nuanced, patient-centered evaluations of treatment effectiveness beyond group-level mean changes. The multidimensional assessment of pain, stiffness, function, and overall satisfaction, combined with appropriate statistical analyses and follow-up consistency, strengthens the clinical relevance and methodological rigor of the findings.

Nonetheless, several limitations should be acknowledged. First, the retrospective design introduces risks of selection bias and limits control over confounders. Although standardized criteria were used, the absence of randomization and blinding reduces internal validity. Second, the lack of imaging follow-up, such as magnetic resonance imaging or ultrasound, precluded assessment of structural changes in cartilage or synovial tissue, limiting mechanistic interpretation (particularly for iPAAG, which exerts biomechanical rather than pharmacologic effects). Third, although the follow-up extended to 12 months, this may still be inadequate to fully capture the long-term behavior of iPAAG, which is hypothesized to integrate progressively into the synovium. Fourth, the inclusion of a high proportion of severe OA cases may have limited responsiveness to HA and steroids, complicating comparisons with milder cohorts in prior studies. Fifth, while MCID and PASS thresholds were derived from established literature, their interpretation may vary depending on patient expectations and baseline severity. Lastly, as a single-center study, the findings may not be fully generalizable to broader populations.

Future research should aim to better define iPAAG’s long-term role in KOA by conducting large-scale, randomized controlled trials stratified by disease severity. Given the varying treatment responses observed in moderate versus advanced OA, dedicated subgroup analyses are needed to optimize patient selection. Moreover, incorporating synovial effusion status and inflammatory markers could help predict response, especially for mechanical agents like iPAAG. Advanced imaging methods such as ultrasonography and magnetic resonance imaging should be utilized to monitor structural joint changes and enhance stratification accuracy.

Additional investigations should also address the need for and timing of repeat iPAAG injections, as some patients may experience diminishing benefit by 12 months. Trials exploring scheduled reinjections could clarify whether sustained outcomes can be achieved safely. Furthermore, human histopathologic studies confirming synovial integration would strengthen the mechanistic rationale for iPAAG and help differentiate it from purely lubricative agents. Finally, future trials comparing iPAAG as monotherapy versus in combination or sequence with other injectables (e.g., corticosteroids or HA) may uncover synergistic strategies. Long-term studies with both clinical and imaging endpoints will be essential to establish iPAAG’s position in the evolving treatment landscape of KOA.

5. Conclusion

This study demonstrates that iPAAG, HA, and corticosteroid injections provide comparable symptomatic relief in KOA over 12 months. Although iPAAG showed a trend toward longer-lasting benefit, this was not consistently superior to conventional options. Given its higher cost, iPAAG may be considered a viable alternative in selected patients unresponsive to standard treatments, but its routine use requires further evidence of long-term and cost-effective benefit.

Acknowledgments

We would like to acknowledge Ph.Dr Gökhan Ocakoğlu for his outstanding statistical analysis.

Author contributions

Conceptualization: Bilal Aykaç, Mustafa Dinç, Hünkar Çağdaş Bayrak.

Data curation: Bilal Aykaç.

Formal analysis: Bilal Aykaç, Özgür Oktay Nar, Recep Karasu.

Investigation: Bilal Aykaç, Mustafa Dinç, Recep Karasu, Hünkar Çağdaş Bayrak.

Methodology: Bilal Aykaç, Hünkar Çağdaş Bayrak.

Resources: Bilal Aykaç, Özgür Oktay Nar, Hünkar Çağdaş Bayrak.

Software: Bilal Aykaç, Mustafa Dinç, Recep Karasu, Hünkar Çağdaş Bayrak.

Supervision: Bilal Aykaç, Mustafa Dinç, Recep Karasu.

Validation: Bilal Aykaç, Mustafa Dinç, Özgür Oktay Nar, Recep Karasu.

Writing – original draft: Bilal Aykaç, Mustafa Dinç.