The Use of Intra-Articular Hydrogel in Knee Osteoarthritis: A Systematic Review

Abstract

Background

Knee osteoarthritis (KOA) is a prevalent cause of disability. Current intra-articular injections (hyaluronic acid [HA] and corticosteroids) fall short in maintaining long-term effects and repeated usage may result in deleterious effects on the knee. The development of hydrogels offers a potentially safe and longer-lasting alternative.

Purpose

To assess current literature and analyse the clinical outcomes of intra-articular hydrogel in patients with KOA.

Methods

A systematic search on 4 databases was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta‑Analyses. Quantitative findings were complemented by narrative synthesis. Study quality was assessed using the Cochrane Risk of Bias (RoB) 2.0 tool and Methodological Index for Non-Randomized Studies guidelines.

Results

Twelve studies comprising 1,413 patients were included. Most reported improvements in clinical outcomes above the minimal clinically important difference. Average follow-up was 11 months. Quality assessment revealed high risk of bias for randomized controlled trials (RCTs) (n = 4) and low to moderate risk of bias non-randomized studies (n = 8).

Conclusion

Intra-articular hydrogel injections for KOA represent an area of ongoing investigation. Current literature is heterogeneous and limited by methodological shortcomings. Adequately powered RCTs with standardized outcome reporting are needed to clarify their role in routine clinical practice.

Level of evidence:

Level II

Keywords

knee osteoarthritis intra-articular injections hydrogel hyaluronic acid corticosteroids

Introduction

Knee osteoarthritis (KOA) is an increasingly prevalent disease in today’s world,¹ with a rising incidence linked to ageing populations, obesity and increased physical activity demands.² This degenerative joint disease is characterized by thinning of cartilage, synovial inflammation and subchondral bone changes.³ Individuals suffering from KOA subsequently experience worsening stiffness, pain and eventually degradation of motor function.

Conventional first-line treatments for KOA include lifestyle changes (weight reduction/exercise), physiotherapy and oral/topical analgesia. Other non-surgical options also include corticosteroid and hyaluronic acid (HA) intra-articular injections.⁴ These methods aim to relieve symptoms and prolong time until surgical management is required.

Current intra-articular injection options are effective in symptom relief but have their limitations.⁵ Through systematic review and meta-analysis, Bensa et al.⁶ reported that corticosteroid injections only provide pain relief and functional improvement for up to 6 weeks after treatment. While some propose sequential injections, the repeated use of corticosteroids risk tissue atrophy and further cartilage degeneration.⁷ Similarly, on review of current literature, Migliorini et al.⁸ found that the improvements experienced after HA injections were not sustained. Moreover, the large diversity in study designs, HA products and treatment regimens hindered the authors from coming to definitive conclusions.

To improve retention time of HA viscosupplementation, researchers have delved into injectable hydrogels, which are viscoelastic, biocompatible and tissue-mimicking.⁹ These features render them favourable in acting as lubricating agents to restore synovial fluid viscosity, as scaffolds to support cartilage and tissue regeneration, or as delivery systems for drugs, growth factors, or stem cells.^10,11 In 2017, He et al. reviewed available literature and summarized the advantages of hydrogel. This was with the hope of inspiring more researchers and clinicians to adopt a hydrogel-based delivery system for the intra-articular injection treatment of knee OA.

Since then, there has been a growing number of clinical studies evaluating different hydrogel formulations. An up-to-date and focused systematic review to analyse the outcomes of these studies is warranted to guide clinical usage of these hydrogels and the direction of future papers. Hence, the aim of this review was to assess current literature and analyse the clinical outcomes of the use of intra-articular hydrogel in patients with KOA.

Methods

This review was conducted with guidance from the Methodological Expectations of Cochrane Intervention Reviews Manual (MECIR) and reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.¹²

Search Strategy

We conducted a comprehensive database search of PubMed, Embase, Web of Science and CINAHL from inception until October 4, 2025. These databases were chosen as they provided a wide range of biomedical articles from international journals.¹³

The search strategy used consisted of the following terms: (osteoarthritis OR osteoarthrosis OR osteoarthrosis deformans OR wear and tear OR degenerat* OR cartilage OR arthritis OR arthros*) AND ((hydrogel[MeSH Terms]) OR hydrogel OR patterned hydrogel* OR in situ hydrogel* OR polyethylene glycol OR polyvinyl alcohol OR natural biopolymers OR chitosan OR gelatin OR hyaluronic acid) AND (knee OR knee joint).

In addition, a snowball strategy was applied, looking at references and citations of relevant articles with similar topics. A search of grey literature (Relevant websites, Google Scholar), conference abstracts and trial registries was also conducted.

Eligibility Criteria

The inclusion and exclusion criteria were defined based on the Population, Intervention, Comparison, Outcomes and Study (PICOS) framework (Table 1).¹⁴ To provide an up-to-date review of the recent growing number of studies published following He et al.’s review, we chose to only include studies from the last 10 years in English. Hydrogels were defined as cross-linked polymeric materials forming 3-dimensional (3D) network structures. These materials may vary according to their source (synthetic or natural) and physicochemical properties (the nature of cross-linking, internal network architecture and biodegradability). Studies evaluating intra-articular knee injections containing hydrogels that met this definition were included, irrespective of specific composition or commercial brand.

Table 1.

PICOS Inclusion and Exclusion Criteria.

	Inclusion Criteria	Exclusion Criteria
Populations	Patients diagnosed with KOA >18 years old Any gender or race Any Kallgren-Lawrence Grading	Patients diagnosed with focal chondral defects rather than KOA Animal studies
Interventions	Intra-articular knee hydrogel injection	Use of hydrogel as a patch, scaffold, or implant rather than as an intra-articular injectable therapy Intra-articular corticosteroid injection alone without a hydrogel intervention
Comparison	–	–
Outcome measures	WOMAC OMERACT-OARSI responder criteria VAS Adverse outcomes	–
Study design	Randomized controlled trials Observational studies (prospective and retrospective) Case series >10 people Comparison studies with other injections (e.g. corticosteroid)	Cadaveric studies Biomechanical studies In vitro studies Case reports Case Series with <10 patients Systematic review Meta-analysis

For the purposes of this review, injectable hydrogels were classified a priori into the following categories based on polymer origin and biodegradability: (1) semi-synthetic HA-derivative hydrogels (e.g. HYMOVIS®), (2) polyacrylamide hydrogels (e.g. Arthrosamid®), (3) cross-linked HA hydrogels (e.g. Synvisc-One) and (4) composite hydrogels (Hyalflex®). This classification was adopted to account for material heterogeneity and to facilitate structured interpretation of outcomes across chemically distinct systems.

Study Selection and Data Extraction

The review process was completed using Covidence software and conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, version 6.3.^13,15

Four researchers (A.T., V.V., W.Y. and D.H.M.S.) individually conducted title and abstract screening based on the inclusion and exclusion criteria. Following that, the full texts of shortlisted studies were retrieved. Investigators were blinded to each other throughout study selection and disagreements were resolved by consensus, in consultation with the senior author (H.R.). Each step of the selection process was outlined in PRISMA.

The 4 reviewers (A.T., V.V., W.Y. and D.H.M.S.) then independently extracted data from these full texts. Data extracted included study reference (author, year of publication, country of study and study design/duration/objectives), demographics of subjects (number of participants, gender and age range), details on treatment (description of treatment preparation method/dosage of injection/number of injections/time between injections), results of the study (Western Ontario and McMaster Universities Arthritis Index [WOMAC] score, Osteoarthritis Research Society International and Outcome Measures in Rheumatology [OMERACT-OARSI] responder criteria, Visual Analogue Scale [VAS] scores and other relevant scores/measurements) and adverse outcomes.

Statistical Analysis

To evaluate the outcomes of various hydrogel, data extracted was presented in tables and graphs for comparison. For studies reporting continuous outcomes as medians with ranges, means and standard deviations were estimated using established conversion methods.¹⁶ A subset analysis was performed to evaluate data based on the clinical score reported. For each clinical score, outcomes were summarized according to hydrogel subclass. Due to substantial heterogeneity in outcomes reported, pooling of data for meta-analysis was deemed inappropriate.^17,18 Hence, standardized mean differences (SMDs) were calculated to facilitate cross-study comparison. SMDs were reported descriptively to illustrate the direction and relative magnitude of treatment effects rather than to derive a pooled summary estimate.

A narrative synthesis (make use of structured narratives, summary tables or figures to aid in a descriptive summary/explanation of the primary study characteristics and findings) was undertaken to complement the quantitative analysis done.

Quality Assessment

The quality of all included studies was independently evaluated by 2 authors (W.Y. and D.H.M.S.). For randomized studies, the Cochrane Risk of Bias (ROB) 2.0 tool was utilized to assess factors such as sequence generation, allocation concealment, performance bias, detection bias, attrition bias and reporting bias.¹⁹ For non-randomized cohort studies, the Methodological Index for Non-Randomized Studies (MINORS) was applied, using an eight-item index (with a global ideal score of 16) for non-comparative studies.²⁰ Any discrepancies in scoring were resolved through discussion with the senior author (H.R.).

Results

Search Results and Population Characteristics

Eight hundred fifty articles were identified using our search strategy. After removing duplicates and screening through 449 titles and abstracts, 23 full-text studies were eventually retrieved. Of these, 12 studies were excluded. Finally, 12 studies were included in the review ( Fig. 1 ).

Figure 1.

PRISMA diagram.

Characteristics and Quality of Studies

The characteristics of all included studies are presented in Table 2 . There were 4 randomized controlled trials (RCTs), 7 prospective cohort studies and 1 retrospective cohort study, consisting of a total of 1,413 participants. Studies came from a wide variety of countries, including Italy (n = 2), Türkiye (n = 2), Denmark (n = 3), the United Kingdom (n = 1), Belgium (n = 1), Canada (n = 1), South Korea (n = 1) and Romania (n = 1). The duration of follow-up ranged from 3 to 24 months. The 2 most common hydrogels that studies reported on were injectable polyacrylamide hydrogel (iPAAG) and HYMOVIS® (a viscoelastic hydrogel containing 8 mg/ml of HA partial hexadecylamide HYADD®). Five and 4 studies reported on results of these hydrogels, respectively. Three studies each compared outcomes of hydrogel versus HA, and hydrogel versus steroid intra-articular injections.

Table 2.

Summary of Included Studies.

Author, Country	Study Design/Level of Evidence	Sample Size (M:F)/Mean Age (Years)	Average Follow-Up Period (Months)	Type of Hydrogel Used/Regime/Study Cohort	Clinical/Radiological Outcomes Reported	Adverse Effects (AEs)	Summary of Outcomes
Aykaç et al.,²¹ Türkiye	Retrospective cohort study/level III	Arthrosamid®: 50 (17:33) /median 69.5 (60-87) ArtiAid®: 50 (14:36) /median 66 (60-82) Arhropan®: 50 (19:31) /median 69.5 (60-87)	12	(1) Arthrosamid® (injectable polyacrylamide hydrogel iPAAG, containing polyacrylamide [2.5%] and non-pyrogenic water [97.5%]) (2) ArtiAid® (HA) (3) Arhropan® (methylprednisolone acetate) Single intra-articular injection. (6 ml Arthrosamid®, 2 ml ArtiAid®, 40 mg Arthropan®) Patients aged >50 years with symptomatic OA >3 months, failed conservative treatments (oral analgesia/physical therapy), KL grades 2-4.	WOMAC, VAS	No AEs reported	Significant improvement in WOMAC and VAS up to 6 months across all 3 groups, which reverted to baseline at 12 months. iPAAG had superior outcomes at 6 months and showed the highest patient acceptable symptom state rates.
Benazzo et al.,²² Italy	Prospective cohort study/level II	49 (26:23) /not reported	12	HYMOVIS® (viscoelastic hydrogel containing 8 mg/ml of hyaluronic acid partial hexadecylamide HYADD®) Total of two3 ml intra-articular injections given 1 week apart. Patients with symptomatic OA with WOMAC A first question’s score of 2-3, KL grade 2 or 3.	Clinical: WOMAC, OMERACT-OARSI responder criteria, EQ-5D questionnaire Radiological: joint space width (JSW)	76 AEs Mild/moderate – Mild intensity knee pain (n = 4) Others unrelated to investigational product: – Mild/moderate headache (14% of events) – Mild flu (12%) – Mild/moderate back pain (6%) Serious Causality with hymovis was excluded in all cases (n = 7)	Significant improvement of WOMAC and EQ-5D scores.
Bernetti et al.,²³ Italy	Prospective cohort study/level II	31 (8:23) /median 49 (25-65)	12	HYMOVIS® (elaborated above) Single 4 ml intra-articular injection. Adult regular sports players (training 2-3× a week) with knee OA arising from overuse injuries, KL grades 1-3 and VAS 40-90 mm.	Knee injury and Osteoarthritis Outcome Score (KOOS), WOMAC (A/C), VAS	Six mild-to-moderate AEs, unrelated to investigational products. Flu (n = 2), road accident (n = 2), abdominal pain (n = 1), sternoclavicular pain (n = 1). No severe AE.	Significant improvement of KOOS, VAS and WOMAC scores.
Bliddal et al.,²⁴ Denmark	Randomized controlled trial/level II	49 (18:31) /70.0 ± 8.6	12	Arthrosamid® (elaborated above) Single 6 ml intra-articular injection. Patients with symptomatic OA, KL grade 2-4, WOMAC A first question’s score ≥2.	WOMAC, patient global assessment (PGA), OMERACT-OARSI responder criteria	8 AEs Mild (n = 7) Severe (n = 1) – Cerebrovascular accident All AEs not related to treatment.	Significant improvement of WOMAC and PGA scores.
Bliddal et al.,²⁵ Denmark	Randomized controlled trial/level II	Arthrosamid®: 119 (61:58) /67.2 ± 9.5 Synvisc-One®: 120 (52:68) /66.6 ± 9.2	12	(1) Arthrosamid® (elaborated above) (2) Synvisc-One® (hylan GF 20 consisting hylan A and hylan B – a hydrogel) Single 6 ml intra-articular injection. Patients with symptomatic OA, KL grade 2-4, pain scores ≥4 on numerical rating scale when walking.	WOMAC, PGA, OMERACT-OARSI responder criteria, EQ-5D questionnaire	All AEs possibly related were mild to moderate AEs. – Arthrosamid® (n = 55) – Synvisc-One® (n = 49) Most common: joint swelling and arthralgia. Six serious AEs, all not related to treatment. Nine serious AEs not related to treatment.	No significant difference in safety or clinical outcomes between Arthrosamid® and Synvisc-One®.
Gao et al.,²⁶ UK	Prospective cohort study/level II	269 (164:104) /62.1 ± 16.93 314 knees (45 bilateral)	24	Arthrosamid® (elaborated above) Single 6 ml intra-articular injection. Patients with unilateral or bilateral knee OA, KL grades 1-4.	VAS, Oxford Knee Score (OKS), Lysholm score	Pain (n = 51) Effusion (n = 52) Swelling (n = 47) Skin infection (n = 3) Deep tissue/joint infection (n = 2), requiring surgical washout.	Significant improvement in VAS, OKS and Lysholm scores at 24 months. Patients who were older, non-diabetic, had lower KL grades, and received bilateral injections were more likely to experience clinical benefit.
Henriksen et al.,²⁷ Denmark	Prospective cohort study/ level II	84 (36:48) /68.9 ± 10.0	13	Arthrosamid® (elaborated above) Total of two3 ml intra-articular injections given 1 month apart. Patients with clinical diagnosis of OA as per American College of Rheumatology (ACR) guidelines, KL grades 1-4.	WOMAC	Not reported	Significant improvement of WOMAC scores.
Henrotin et al.,²⁸ Belgium/France	Prospective cohort study/level II	46 (15:31) /61.4 ± 9.6	12	HYMOVIS® (elaborated above) Two treatment cycles 6 months apart. Each cycle consists of a total of two3 ml intra-articular injections given at a 1-week interval. Patients with symptomatic OA >6 months, KL grade of 2 or 3.	Clinical: OMERACT-OARSI responder criteria, VAS, KOOS Radiological: Whole-Organ Magnetic Resonance Imaging Score (WORMS) Biochemical: Type II collagen-specific biomarkers (Coll2-1, Coll2-1NO2 and CTX-II).	Ninety-five AEs in 37 patients (only 1 led to patient withdrawal but not related to product) Fifteen adverse device reactions: difficulty in extension of leg, erythema, pain, swelling.	KOOS and VAS pain scores significantly improved, WORMS effusion score decreased. MRI cartilage volume and thickness increased in lateral femoral and trochlea compartments, but not in medial compartment. Safety profile favourable.
Issin et al.,²⁹ Türkiye	Prospective cohort study/level II	Noltrex: 64 (18:46) /62.3 ± 9.7 Methylprednisolone acetate: 79 (25:54) /65.7 ± 8.8	3	(1) Noltrex (polyacrylamide hydrogel) (2) Methylprednisolone acetate Single dose of intra-articular injection (2.5 ml Noltrex, 40 mg methylprednisolone acetate). Patients with symptomatic OA, failed pharmacotherapy/physiotherapy, KL grades 1-4.	WOMAC A	Not reported.	No significant difference in WOMAC scores between both groups at 3 months.
Kim et al.,³⁰ South Korea	Randomized controlled trial/level II	Hyalflex®: 107 (26:81) /63.0 ± 7.53 Synovian®: 113 (27:86) /63.9 ± 7.57	9	(1) Hyalflex® (Hyaluronic acid hydrogel cross-linked with hexamethylenediamine, HMDA-HA) (2) Synovian® (1,4-butanediol diglycidyl ether cross-linked HA, BDDE-HA) Total of two injections, with a 24-week interval in between (5 ml Hyalflex®, 3 ml Synovian®). Patients with symptomatic OA, KL grades 1-3.	VAS, WOMAC, OMERACT-OARSI responder criteria	Total 136 AEs Hyalflex®: 44 Synovian®: 32 7 serious AEs, all unrelated to study treatment Hyalflex®: n = 4 (pulmonary arteriovenous fistula, bladder neoplasm, transient ischaemic attack and hyperkeratosis) Synovian®: n = 3 (foot fracture, meniscus injury and pneumonia)	No significant difference in outcome scores between both groups.
Petrella et al.,³¹ Canada/Curacao/Belgium/The Netherlands	Randomized controlled trial/level II	Hydros: 32 (12:20) /59 ± 12 Hydros-TA: 34 (14:20) /61 ± 11 Synvisc-One: 32 (16:16) /59 ± 12	6	(1) Hydros (biosresorbable HA-based hydrogel suspended in a HA solution) (2) Hydros-TA (Hydros + 10 mg of triamcinolone acetonide) (3) Synvisc-One® (elaborated above) Single 6 ml intra-articular injection. Patients with symptomatic OA with WOMAC A pain score 50-90 mm, KL grade 2 or 3.	WOMAC, OMERACT-OARSI responder criteria	Serious Hydros (n = 3) – Colitis, broncho-pneumonia and arthralgia Hydros-TA (n = 2) – Meniscal lesion and a cyst aspiration Synvisc-One (n = 2) – Meniscal lesion and an elective surgery > All serious AEs were considered unlikely or not related to treatment 19 AEs related to study treatment: – Synvisc-One (n = 7) – Hydros (n = 9) – Hydros-TA (n = 3) Include: arthralgia and joint stiffness/swelling.	Compared between Hydros, Hydros-TA and Synvisc-One®. Reduction of WOMAC A (pain) in all three groups. Hydros-TA had a more rapid pain relief compared with Hydros alone. The percentages of strict OMERACT-OARSI responders for Hydros and Hydros-TA were numerically higher than the strict responders for Synvisc-One at 13 and 26 weeks.
Russu et al.,³² Romania	Prospective cohort study/level II	35 (10:25) /63 ± 8	6	HYMOVIS® (elaborated above) Total of two 3 ml intra-articular injections given 1 week apart. Patients with symptomatic OA >6 months, KL grade 2 or 3 and VAS >35 mm.	WOMAC, VAS	No significant AEs reported.	Significant improvement of pain (VAS and WOMAC A) and WOMAC C physical function. No difference for WOMAC B stiffness component.

Eleven studies provided level II evidence (RCTs and prospective cohort studies) and 1 study provided level III evidence (retrospective cohort study). The 4 RCTs had an overall high ROB due to the randomization process and selection of reported results biases, which may have led to overestimation of treatment effects ( Table 3 ).

Table 3.

Risk of Bias Assessment From Randomized Controlled Trials.

	D1	D2	D3	D4	D5	Overall
Bliddal et al.²⁴
Petrella et al.³¹
Kim et al.³⁰
Bliddal et al.²⁵

D1: Risk of bias arising from the randomization process. D2: Risk of bias due to deviations from the intended interventions (effect of assignment to intervention). D3: Risk of bias due to missing outcome data. D4: Risk of bias in measurement of the outcome. D5: Risk of bias in selection of the reported result. Overall = total.

Table 4 summarizes the MINORS scores for the non-randomized cohort studies. Scores ranged from 12 to 15 (median = 13, interquartile range [IQR] = 12.5-14.5). The mean normalized methodological quality was 83.6%. The most consistently well-reported domains were “Clearly stated aim” and “Endpoints appropriate to the study aim” (100% adequacy). The weakest reporting areas were “Prospective sample size calculation” (50% adequacy) and “Loss to follow-up <5%” (62.5% adequacy). Overall, these studies demonstrate moderate-to-high methodological quality, though incomplete reporting of sample size calculations and follow-up attrition remains a limitation. This introduces potential risks of imprecision and attrition bias, which may have contributed to variability in effect estimates.

Table 4.

Methodological Index for Non-Randomized Studies (MINORS) Assessment for Cohort Studies.

Author	Clearly Stated Aim	Inclusion of Consecutive Patient	Prospective Collection of Data	EndpointsAppropriate to theAim of theStudy	UnbiasedAssessment of theStudy End-Point	Follow-UpPeriodAppropriate to theAim of theStudy	Loss to Follow-Up LessThan 5%	Prospective Calculation ofthe StudySize	Total Score
Benazzo et al.²²	2	2	2	2	2	2	2	1	15
Bernetti et al.²³	2	2	2	2	2	2	0	2	12
Henriksen et al.²⁷	2	2	1	2	1	2	2	1	13
Henrotin et al.²⁸	2	2	2	1	2	2	1	1	13
Russu et al.³²	2	1	2	2	2	2	2	1	14
Gao et al.²⁶	2	2	2	2	2	2	1	2	15
Aykaç et al.²¹	2	1	2	2	2	1	1	2	13
Issin et al.²⁹	2	2	2	2	1	1	1	1	12

Based on our quality assessment, observed outcome magnitudes should be interpreted cautiously, with consideration of the tendency for higher-risk studies to report more favourable effects. This may reflect systematic bias rather than true clinical benefit.

Study Outcomes

WOMAC

The WOMAC instrument evaluates 3 major domains: pain (WOMAC A), stiffness (WOMAC B) and activities of daily living (WOMAC C). Within each domain, there are 5, 2 and 17 items, respectively. Each item is rated on a 5-point Likert-type scale, ranging from 0 (none) to 4 (extreme). A lower score reflects a better outcome. The minimally clinically important difference (MCID) reference scores were taken to be 11 for pain, 8 for stiffness and 9 for function.³³

WOMAC A

Ten studies reported WOMAC A ( Table 5 ). Five studies reported on polyacrylamide hydrogels (4 on Arthrosamid® and 1 on Noltrex), 3 on synthetic HA-derivative hydrogels (HYMOVIS®), 1 on composite hydrogels (Hyalflex®) and 1 on cross-linked HA hydrogels (Synvisc-One). All studies reported improvement in WOMAC A scores, but 3 were below the MCID.

Table 5.

Studies Reporting WOMAC A Pain Score.

Author	Follow-Up (Months)	Pre-Intervention	Post-Intervention	Mean Change (95% CI)	SMD (95% CI)	P Value	Above MCID?
Polyacrylamide hydrogels (Arthrosamid®, Noltrex)
Aykaç et al.^{21 a}	12	Arthrosamid®:12.5 ± 2.75ArtiAid®:12 ± 2.75Arhropan®:12 ± 2.75	Arthrosamid®:11 ± 2.50ArtiAid®:12 ± 2.50Arhropan®:12 ± 3.00	Not reported	Arthrosamid®: –0.57 (–0.97, –0.17)ArtiAid®:0.00 (–0.39, 0.39)Arhropan®:0.00 (–0.39, 0.39)	Arthrosamid®: 0.121ArtiAid®: 1.00Arhropan®:1.00	NA
Bliddal et al.²⁴	12	50.3 ± 11.8	Not reported	–17.7 (–23.1, –12.4)	–0.93 (–1.21, –0.65)	<0.0001	Yes
Bliddal et al.²⁵	12	Arthrosamid®:45.1 ± 13.4Synvisc-One®:46.5 ± 13.3	Not reported	Arthrosamid®:–17.6 (–20.9, –14.2)Synvisc-One®:–13.3 (–16.6, –10.0)	Arthrosamid®:–0.94 (–1.12, –0.76)Synvisc-One®:–0.73 (–0.91, –0.55)	Not reported	Yes
Henriksen et al.²⁷	13	44.3 ± 17.2	Not reported	–15.7 (–20.2, –11.2)	–0.88 (−1.13, −0.61)	<0.0001	Yes
Issin et al.²⁹	3	Noltrex: 12 ± 3.5Methylprednisolone acetate: 10 ± 3.6	Noltrex: 11 ± 4Methylprednisolone acetate: 9 ± 3.4	Noltrex: –1 (not reported)Methylprednisolone acetate: –1.2 (not reported)	Noltrex:–0.27 (–0.52, -0.02)Methylprednisolone acetate:–0.29 (–0.51 to –0.06)	Not reported	No
Synthetic HA-derivative hydrogels (HYMOVIS®)
Benazzo et al.²²	12	46.5 ± 7.65	17.6 ± 13.85	Not reported	–2.58 (–3.16, –2.00)	<0.001	Yes
Bernetti et al.²³	12	27.7 ± 13.8	8.040 ± 9.620	Not reported	–1.65 (−2.19, −1.11)	<0.001	Yes
Russu et al.³²	6	10 ± 3	8 ± 1	Not reported	–0.90 (−1.29, −0.50)	0.0004	No
Composite hydrogels (Hyalflex®)
Kim et al.³⁰	9	Not reported	Not reported	Hyalflex®: −3.14 (not reported)Synovian®: −3.58 (not reported)	NA	Not reported	No
Cross-linked HA hydrogels (Synvisc-One)
Petrella et al.³¹	6	Hydros: 68.1Hydros-TA: 69.4Synvisc-One: 66.4	Not reported	Hydros: –30.5 (not reported)Hydros-TA: –34.4 (not reported)Synvisc-One: –28.0 (not reported)	NA	Not reported	Yes

Studies that presented data as median with range and converted to mean and standard deviation.

WOMAC B

Eight studies reported WOMAC B ( Table 6 ). Four studies reported on polyacrylamide hydrogels (Arthrosamid®), 2 on synthetic HA-derivative hydrogels (HYMOVIS®), 1 on composite hydrogels (Hyalflex®) and 1 on cross-linked HA hydrogels (Synvisc-One). Russu et al. found no significant improvement in WOMAC B scores post treatment using HYMOVIS® after 6 months. Kim et al. observed improvement in stiffness score but below the MCID. The other 6 studies reported improvement in scores above the MCID.

Table 6.

Studies Reporting WOMAC B Stiffness Score.

Author	Follow-Up (Months)	Pre-Intervention	Post-Intervention	Mean Change (95% CI)	SMD	P Value	Above MCID?
Polyacrylamide hydrogels (Arthrosamid®)
Aykaç et al.^{21 a}	12	Arthrosamid®:4.25 ± 1.25ArtiAid®:3.25 ± 1.25Arhropan®:3.75 ± 1.75	Arthrosamid®:3.75 ± 1.75ArtiAid®:3.75 ± 1.75Arhropan®:3.25 ± 1.25	Not reported	Arthrosamid®:–0.33 (–0.61, –0.05)ArtiAid®:0.33 (0.05, 0.61)Arhropan®:–0.33 (–0.61, –0.05)	Arthrosamid®:1.00ArtiAid®:1.00Arhropan®:1.00	NA
Bliddal et al.²⁴	12	55.6 ± 17.5	Not reported	–11.0 (–17.0 to –4.9)	–0.51 (–0.79, –0.23)	0.0007	Yes
Bliddal et al.²⁵	12	Arthrosamid®:52.7 ± 20.8Synvisc-One®:51.1 ± 20.9	Not reported	Arthrosamid®:–17.5 (–21.9, –13.2)Synvisc-One®:–12.9 (–17.2, –8.6)	Arthrosamid®:–0.72 (–0.91, –0.55)Synvisc-One®:–0.54 (–0.72, –0.36)	Not reported	Yes
Henriksen et al.²⁷	13	44.9 ± 22.0	Not reported	–12.1 (–17.8, –6.4)	–0.45 (–0.67, –0.24)	<0.0001	Yes
Synthetic HA-derivative hydrogels (HYMOVIS®)
Benazzo et al.²²	12	41.1 ± 19.09	17.6 ± 16.72	Not reported	–1.31 (–1.69, –0.93)	Not reported	Yes
Russu et al.³²	6	3 ± 1	3 ± 1	Not reported	0 (–0.34, 0.34)	Not significant	No
Composite hydrogels (Hyalflex®)
Kim et al.³⁰	9	Not reported	Not reported	Hyalflex®: −1.47 (not reported)Synovian®: −1.51 (not reported)	NA	Not reported	No
Cross-linked HA hydrogels (Synvisc-One)
Petrella et al.³¹	6	Hydros: 70.5Hydros-TA: 70.3Synvisc-One: 70.1	Not reported	Hydros: –24.5 (not reported)Hydros TA: –29.8 (not reported)Synvisc-One: –25.1 (not reported)	NA	Not reported	Yes

Studies that presented data as median with range and converted to mean and standard deviation.

WOMAC C

Nine studies reported WOMAC C ( Table 7 ). Four studies reported on polyacrylamide hydrogels (Arthrosamid®), 3 on synthetic HA-derivative hydrogels (HYMOVIS®), 1 on composite hydrogels (Hyalflex®) and 1 on cross-linked HA hydrogels (Synvisc-One). Russu et al. observed a significant improvement in WOMAC C score but below the MCID. The rest of the studies reported improvement above the MCID.

Table 7.

Studies Reporting WOMAC C Activities of Daily Living Score.

Author	Follow-Up (Months)	Pre-Intervention	Post-Intervention	Mean Change (95% CI)	SMD	P Value	Above MCID?
Polyacrylamide hydrogels (Arthrosamid®)
Aykaç et al.^{21 a}	12	Arthrosamid®:39.5 ± 10.75ArtiAid®:34.75 ± 10.0Arhropan®:44.0 ± 9.75	Arthrosamid®:44.0 ± 9.25ArtiAid®:35.5 ± 9.25Arhropan®:46.25 ± 7.75	Not reported	Arthrosamid®:0.45 (0.16, 0.74) ArtiAid®:0.08 (–0.20, 0.36)Arhropan®:0.26 (–0.02, 0.54)	Arthrosamid®:1.00ArtiAid®:1.00Arhropan®:0.346	NA
Bliddal et al.²⁴	12	46.6 ± 16.1	Not reported	–14.9 (–19.1, –10.6)	–0.98 (–1.26, -0.70)	<0.0001	Yes
Bliddal et al.²⁵	12	Arthrosamid®:44.4 ± 15.1Synvisc-One®:43.5 ± 16.2	Not reported	Arthrosamid®:–17.5 (–20.9, –14.1)Synvisc-One®:-15.2 (-18.6, -11.8)	Arthrosamid®:–0.93 (–1.11, –0.75) Synvisc-One®:–0.80 (–0.98, -0.62)	Not reported	Yes
Henriksen et al.²⁷	13	42.2 ± 20.7	Not reported	–9.4 (–14, –4.9)	–0.44 (–0.66, –0.23)	<0.0001	Yes
Synthetic HA-derivative hydrogels (HYMOVIS®)
Benazzo et al.²²	12	40.4 ± 12.63	17.9 ± 12.51	Not reported	–1.79 (–2.24, –1.34)	Not reported	Yes
Bernetti et al.²³	12	23.6 ± 15.9	5.05 ± 10.0	Not reported	–1.40 (–1.89, –0.91)	<0.001	Yes
Russu et al.³²	6	30 ± 8	25 ± 5	Not reported	–0.75 (–1.12, -0.38)	0.0025	No
Composite hydrogels (Hyalflex®)
Kim et al.³⁰	9	Not reported	Not reported	Hyalflex®: −11.25 (not reported)Synovian®: −11.90 (not reported)	NA	Not reported	Yes
Cross-linked HA hydrogels (Synvisc-One)
Petrella et al.³¹	6	Hydros: 66.2Hydros-TA: 65.1Synvisc-One: 63.5	Not reported	Hydros: –27.3 (not reported)Hydros TA: –30.0 (not reported)Synvisc-One: –24.3 (not reported)	NA	Not reported	Yes

Studies that presented data as median with range and converted to mean and standard deviation.

OMERACT-OARSI Responder Criteria

The OMERACT-OARSI responder criteria define a response in osteoarthritis clinical trials by combining both relative and absolute changes in pain, function and patient’s global assessment.³⁴ To classify patients as respondents to the therapy, the WOMAC scores are utilized. Patients are classified as responders if they have improvement in pain or function > 50% and absolute change > 20. Otherwise, patients with improvement in at least 2 of the 3 following are also considered as responders: (1) Function ≥ 20% and absolute change ≥ 10; (2) global assessment ≥ 20% and absolute change ≥ 10 and (3) pain ≥ 20% and absolute change ≥ 10.³⁵

Six studies used the OMERACT-OARSI responder criteria (Table 8). All studies reported > 50% of their study population as responders, with the highest being reported by Benazzo et al. (87.8%).

Table 8.

Studies Reporting OMERACT-OARSI Responder Criteria.

Author	Follow-Up (Months)	Total Score Non-Responder %	Total Score Responder/%
Benazzo et al.²²	12	12.2	87.8
Bliddal et al.²⁴	12	38.8	62.2
Bliddal et al.²⁵	12	Arthrosamid®: 44.3Synvisc-One®: 43.1	Arthrosamid®: 55.7Synvisc-One®: 56.9
Henrotin et al.²⁸	12	29.3	70.7
Kim et al.³⁰	9	Hyalflex®: 25.4Synovian®: 27.5	Hyalflex®: 74.6Synovian®: 72.5
Petrella et al.³¹	6	Hydros: 31Hydros-TA: 35Synvisc-One: 41	Hydros: 69Hydros-TA: 65Synvisc-One: 59

VAS Scores

VAS is a substantial and accepted instrument in calculating the severity of chronic pain.³⁶ The score consists of a scale that extends from 0 to 100 mm, where 0 suggests that the patient feels no pain, while 100 mm on the scale indicates the worst possible pain.³⁷ Based on previous studies, the MCID was set at 8.4.³⁸ For those studies reporting VAS score on a scale of 0 to 10, MCID was set at 1.4.⁶

Six studies reported VAS scores (Table 9). Gao et al. used a scale of 0 to 10 while the other studies made use of the 0 to 100 mm scale. All studies reported an improvement of VAS above the MCID.

Table 9.

Studies Reporting VAS Score.

Author, year	Follow-Up (Months)	Pre-Intervention	Post-Intervention	Mean Change (95% CI)	SMD	P Value	Above MCID?
Polyacrylamide hydrogels (Arthrosamid®)
Aykaç et al.²¹	12	Arthrosamid®:7.25 ± 0.75ArtiAid®:7.0 ± 1.0Arhropan®:7.0 ± 1.0	Arthrosamid®:6.25 ± 1.75ArtiAid®:6.25 ± 1.25Arhropan®:6.25 ± 1.75	Not reported	Arthrosamid®:–0.74 (–1.05, –0.43)ArtiAid®:–0.66 (–0.97, –0.35)Arhropan®:–0.53 (–0.83, –0.23)	Arthrosamid®:0.219ArtiAid®:0.911Arhropan®:0.786	NA
Gao et al.^{26 a}	24	6.64 ± 1.87	Not reported	–5.06 (not reported)	NA	Not reported	Yes
Semi-synthetic HA-derivative hydrogels (HYMOVIS®)
Henrotin et al.²⁸	12	Not reported	Not reported	–29.8 (not reported)	NA	<0.001	Yes
Bernetti et al.²³	12	68.7 ± 11.5	14.4 ± 15.4	Not reported	–3.99 (–5.05, –2.93)	<0.001	Yes
Russu et al.³²	6	74.2 ± 11.7	57.3 ± 12.1	Not reported	–1.42 (–1.89, –0.95)	<0.0001	Yes
Composite hydrogels (Hyalflex®)
Kim et al.³⁰	9	Not reported	Not reported	Hyalflex®:–32.2 (not reported)Synovian®:–30.0 (not reported)	NA	Hyalflex®:<0.0001Synovian®: <0.0001	Yes

VAS reported as a 0 to 10 scale.

Discussion

The main finding of this review is that intra-articular injection of hydrogel for the treatment of KOA represents an area of ongoing investigation. While the included studies generally report an improvement of clinical outcomes, the authors recommend interpreting this with caution given the large heterogeneity and lack of quality of current literature. Adequately powered RCTs with standardized outcome reporting are needed prior to coming to definite conclusions on the role of hydrogels in clinical practice, or any superiority over current options such as HA and corticosteroids.

Hydrogels can be characterized into synthetic polymers (e.g. polyacrylamide, polyethylene glycol and polyvinyl alcohol) or natural biopolymers (e.g. chitosan, gelatin and HA derivatives).^9,10 They have varying 3D structures, porosities, elasticities and mechanical strength that can be cross-linked in a physical or chemical manner to form insoluble network structures. They maintain a high moisture content, with water as their predominant dispersion medium, through a cross-linked network which can be used to form a microenvironment similar to that of extracellular matrices in the knee. These properties allow them to serve as lubricating agents to restore synovial fluid viscosity, as scaffolds to support cartilage and tissue regeneration, or as delivery systems for medications and bioactive substances (growth factors, mesenchymal stem cells and plasma-rich platelet [PRP]). Theoretically, they would be able to remain in the joint for longer periods of time and allow for the slow release of substances that they deliver.

In our review, there were generally 4 types of hydrogels: semi-synthetic HA-derivative hydrogels (HYMOVIS®), polyacrylamide hydrogels (Arthrosamid®, Noltrex), cross-linked HA hydrogels (Synvisc-One) and composite hydrogels (Hyalflex®). Among the injectable hydrogels, larger SMDs were observed in studies evaluating semi-synthetic HA-derivative hydrogels for pain (WOMAC A: –2.58 to –0.90; VAS: –3.99 to –1.42) and functional improvement (WOMAC B: –1.31; WOMAC C: –1.79 to –0.75) at up to 1-year follow-up. One possible explanation is the combination of enhanced viscoelasticity and bioactive properties, which may improve lubrication while modulating inflammation. However, this mechanism remains speculative. Polyacrylamide hydrogels provided moderate improvements (WOMAC A: –0.94 to –0.57; WOMAC B: –0.72 to –0.33; WOMAC C: –0.98 to –0.44; VAS: –0.74). This could possibly reflect sustained mechanical support but minimal bioactivity. However, since they are theoretically known to be non-degradable with longer-lasting structural support, the authors postulate that this could explain for the delayed improvement in outcomes.²⁴ There were few studies reporting on the other 2 types of hydrogels. Cross-linked HA hydrogels have some bioactivity but are biodegradable although cross-linking aims to prolong residence in the joint. The mechanical characteristics of composite hydrogels are highly variable depending on the formulation, with synergy between mechanics and bioactivity dependent on formulation. These findings indicate that formulations integrating both viscoelastic mechanical support and bioactive modulation may achieve the greatest clinical benefit. In addition, a limited number of studies reported magnetic resonance imaging or biochemical outcomes. However, these data were exploratory, heterogeneous and not powered to assess structural modification. Thus, they should not be interpreted as evidence of disease-modifying activity.

However, caution is warranted when interpreting these findings. The included studies were not designed for direct comparison, and differences in baseline characteristics, follow-up duration, outcome measures and ROB limit meaningful cross-study inference. Larger effect sizes were frequently reported in smaller or methodologically limited studies, which may overestimate treatment effects. Hence, SMD magnitude should not be interpreted as evidence of relative superiority between hydrogel formulations. Instead, the observed differences should be interpreted as hypothesis-generating, providing direction for future adequately powered head-to-head trials rather than indicating a clinical ranking between hydrogel subclasses.

Safety reporting of hydrogel use was variable and often incomplete in the included studies. Adverse events were reported in 10 of 12 studies, with limited standardized or long-term surveillance. While most adverse events (including all serious events) were reported as unrelated to treatment, serious complications have nevertheless been documented. Gao et al.²⁶ reported 2 cases requiring surgical washout for deep joint infection. Treatment-related events were generally described as mild to moderate and consisted mainly of transient local reactions such as joint swelling, arthralgia, stiffness and superficial skin infection. However, the predominance of short follow-up durations, small sample sizes and inconsistent adverse event reporting substantially limits the ability of existing studies to detect rare or delayed complications. This limitation is particularly important for non-biodegradable polyacrylamide-based hydrogels, for which long-term safety, durability and potential delayed complications remain insufficiently characterized.

Even with the development of hydrogels, HA and corticosteroid injections are still widely used. HA injections aim to restore synovial fluid viscosity and aid with lubrication. However, unmodified HA is easily degraded by endogenous hyaluronidases in the joint within days.³⁹ This results in the need for multiple repeat injections which increase the risk of infection and damage the synovium. Glucocorticosteroid injections work by tackling the inflammatory pathophysiology of KOA. They are advantageous in having an immediate effect, but similarly, are unable to maintain lasting symptom relief. Moreover, repeated injections risk chondrotoxicity, damage cartilage and accelerate joint tissue degeneration.^7,40

Despite the benefits that hydrogels theoretically have over current options (HA and corticosteroid), the outcomes are still not evidently reflected in current literature. Amongst the included studies that compared between hydrogel and other injectables (n = 5), results varied across the board. Studies either supported the hypothesis of hydrogel being superior to HA or glucocorticosteroids (n = 2), or that there was no difference in outcomes (n = 3). None of the studies observed that HA or glucocorticosteroids was superior to hydrogel. The small number of comparative studies highlight the paucity in literature in comparing the clinical outcomes of hydrogels to HA and corticosteroids.

Moreover, a key challenge in interpreting the current literature is the disconnect between the proposed mechanistic advantages of injectable hydrogels and the methodological limitations of the available clinical studies. While improvements in clinical outcomes were reported across studies evaluating hydrogel injections, these findings should be interpreted with caution given the predominance of non-comparative designs and the moderate to high risk of systematic bias. Similarly, the limited number and quality of comparative studies assessing hydrogels against established intra-articular therapies (HA and corticosteroids), preclude reliable conclusions regarding clinical superiority or a distinct therapeutic advantage. Overall, the current evidence base remains insufficient to support definitive claims regarding differentiated efficacy of injectable hydrogels in KOA.

In 2024, the European Society for Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA) ORthoBIologics InitiaTive (ORBIT) consensus made recommendations for nonoperative management of KOA.⁴¹ The use of PRP was recommended over intra-articular HA and corticosteroid in mild to moderate KOA.⁴¹ Current literature shows that PRP, as compared with corticosteroids, can provide anti-inflammation properties while avoiding cartilage degeneration.⁴¹ Based on study results, PRP is superior to HA in maintaining longer-term clinical outcomes.^41,42 The ESSKA-ORBit consensus also acknowledged cell-based therapy as a possible second-line orthobiologic injectable option.⁴¹

In our review, Petrella et al. found that a combination of steroid with HA-based hydrogel resulted in more rapid pain relief than hydrogel alone. This suggests the potential benefits of hydrogel as a delivery system for drugs or bioactive substances. While hydrogels are not currently included in the ESSKA ORBIT consensus, their potential to enhance the clinical application of PRP highlights an area warranting further investigation. Jain et al.⁴³ previously carried out in-vitro experiments, but the idea has not been developed to trial in live organisms. A combined product could possibly harness the benefits from both PRP and hydrogel, maintaining pain relief and functional improvement in the long run while encouraging cartilage regeneration. Randomized controlled trials with larger population sizes and longer follow-up are needed to compare longer-term efficacy against current available options. Furthermore, the diversity and inconsistency of guidelines for intra-articular preparations (illustrated by differing recommendations for HA) underscore the need for high-quality comparative studies to define the role of novel therapies and support future standardization of recommendations.⁴⁴

There are several limitations that the authors acknowledge. First, current literature on this topic is limited resulting in a small number of papers included (n = 12). Second, as reported above, included RCTs (n = 4) were of poor quality due to randomization process and selection of reported results biases. This may have led to overestimation of treatment effects. Next, studies were heterogeneous and the significant methodological variations (differences in design, inclusion criteria, treatment regiment, hydrogel variation, follow-up duration, choice of outcome measures and format of data presented) complicated direct cross-study comparisons. Accordingly, our findings should not be interpreted as evidence of a uniform “hydrogel class effect,” but rather as an overview of outcomes associated with diverse injectable hydrogel-based systems. Finally, the heterogeneity across studies also precluded meaningful statistical pooling. As such, SMDs were used descriptively to contextualize effect sizes rather than to infer a summary treatment effect.

Despite the heterogeneity and lack of high-quality papers, the authors believe that research on hydrogel intra-articular injections for KOA is a crucial and upcoming treatment option. Since the scoping review in 2017 by He et al., 10 of 12 of our included studies were published. These papers came from all around the world, signifying the extensive reach of this topic. During our literature review, we also noted many pre-clinical trials in progress. To realize the potential of this treatment, larger, more long-term comparative studies are needed to investigate if hydrogel injections are truly able to increase and maintain the duration of therapeutic effects. Control groups are essential to reduce the placebo effect. Studies should also compare against HA and corticosteroid injections to investigate if hydrogels are truly superior. Standardized treatment regimes, especially for studies using the same product would be essential. Sub-group analysis of outcomes could be performed based on patient factors (age, gender, body mass index and OA severity based on KL grade) to better customize treatment regimes.²⁶ Future studies should also incorporate standardized and comprehensive adverse event reporting, with sufficient follow-up duration to adequately assess both short- and long-term safety outcomes. Finally, future studies could also look into the cost analysis of treatment.

Conclusion

In conclusion, intra-articular hydrogel injections for KOA represent an area of active investigation. However, the current literature is heterogeneous and limited by methodological shortcomings. Adequately powered RCTs with standardized outcome reporting are needed before the role of hydrogels in routine clinical practice, or any potential superiority over established intra-articular therapies can be reliably established.

Footnotes

ORCID iDs

Ashton Kai Shun Tan

Hamid Rahmatullah Bin Abd Razak

Ethical Considerations

This systematic review used published data only and did not require ethical approval. It was conducted in accordance with the PRISMA guidelines.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ashton Kai Shun Tan, Vijay Vengkat Samynathan C, Muhammad Sulaiman DH and Au Wei Yung. The first draft of the manuscript was written by Ashton Kai Shun Tan and Vijay Vengkat Samynathan C. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

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