Comparison of the efficacy of intra-articular polyacrylamide hydrogels versus cross-linked hyaluronic acid/chondroitin sulfate combination for the treatment of advanced-stage knee osteoarthritis

Comparison of the efficacy of intra-articular polyacrylamide hydrogels versus cross-linked hyaluronic acid/chondroitin sulfate combination for the treatment of advanced-stage knee osteoarthritis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparison of the efficacy of intra-articular polyacrylamide hydrogels versus cross-linked hyaluronic acid/chondroitin sulfate combination for the treatment of advanced-stage knee osteoarthritis Mustafa Altıntaş, Okan Ateş, Furkan Soy, Tacettin Mirzaoğlu, Mustafa Akif Sarıyıldız This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6966769/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Polyacrylamide hydrogel (PAAG) remains a novel molecule, and few human studies have validated its efficacy in knee OA, particularly in advanced stages. The aim of this study was to compare the efficacy of intra-articular polyacrylamide hydrogel (PAAG), a novel molecule, with that of the widely used cross-linked chondroitin sulfate/hyaluronic acid (HA/CS) combination in the treatment of knee osteoarthritis (OA) in a retrospective trial. Methods A total of 127 patients diagnosed with grade 3 or 4 knee OA according to the Kellgren-Lawrence scale were included. Patients’ age, education level, and body mass index (BMI) were recorded. The first group received an intra-articular injection of a cross-linked HA (60 mg)/CS (90 mg) combination, whereas the second group was administered 6 ml of PAAG. Both groups received a single injection. The outcome measures, which were assessed at baseline, 3 months, and 12 months, included knee pain severity measured by the visual analogue scale, range of motion (ROM), WOMAC scale score, and Pittsburgh Sleep Quality Index (PSQI). Results At 3 months, the PAAG group demonstrated significantly lower pain and WOMAC scores than did the HA/CS group. However, no significant differences in pain or WOMAC scores were observed between the groups at 12 months. The ROM and sleep quality scores were not significantly different at either 3 or 12 months. Within-group comparisons revealed significant reductions in pain, WOMAC, and sleep scores in both groups over time, but no significant improvement in ROM was detected in either group. Conclusion Compared with HA/CS injection, intra-articular PAAG injection significantly improved the VAS and WOMAC scores in advanced knee OA patients at 3 months. However, the outcomes for all the parameters were similar between the groups at 12 months. Figures Figure 1 Background Knee osteoarthritis (OA) is the most common joint disease worldwide and significantly reduces the quality of daily life of elderly patients [ 1 , 2 ].Patients present with progressive pain and loss of function. The incidence of knee OA in society has increased with increasing average life expectancy [ 3 – 5 ]. Current management strategies for knee OA include weight control, isometric exercises, assistive devices, and physical therapy. Pharmacological treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs), topical creams, and intra-articular injections (e.g., hyaluronic acid, platelet-rich plasma [PRP], plasma rich in growth factors [PRGF], and corticosteroids) are effective for treating Grade 1 and 2 disease. However, these treatment modalities often provide only transient benefits or may even be ineffective in patients with Grade 3 and 4 disease [ 6 – 8 ]. HA, one of the most commonly used intra-articular injections today, has not been shown to differ from other agents in terms of short-term results in analyses. However, it has been reported in the literature that its effectiveness decreases in the long term in terms of therapeutic duration [ 9 , 10 ]. With the development of regenerative therapies and new intra-articular injections, effective agents have been developed for patients with advanced arthritis. The most important of these are carboxymethyl-chitosan and polyacrylamide hydrogels (PAAGs) [ 11 ]. Polyacrylamide hydrogel (PAAG) has emerged as a promising option for patients and clinicians. Although the acrylamide monomer exhibits carcinogenic and neurotoxic properties, these adverse effects are not observed once the molecule is polymerized [ 12 , 13 ]. PAAG has been used for approximately 25 years in aesthetic procedures and intravesical injections without significant adverse effects. This molecule is biocompatible, viscoelastic, and nondegradable [ 8 , 12 , 13 ]. Because of these features, its usability in osteoarthritis has been suggested. PAAG, which has been used in other areas since 2000, was studied for intra-articular injection in horses in 2015, in rabbits and horses in 2016, and in goats in 2017, and later studies, mainly involving lame horses, revealed its effectiveness in treating knee OA [ 13 – 15 ]. The first human case series, a 2018 cohort study, included patients with grade 3‒4 knee OA [ 16 ] (72% of participants) and reported significant improvements in WOMAC scores at 13 months post-PAAG injection [ 17 ]. They reported good results with knee intraarticular PAAG injections at the 6-month follow-up in a cohort study conducted three years later [ 18 ]. The only randomized controlled trial in the literature, conducted by Bliddal et al., reported findings comparable to those obtained with intra-articular hyaluronic acid injections over a 12-month period, with PAAG not proving to be more effective than HA [ 19 ]. Although PAAG remains a novel molecule, few human studies have validated its efficacy in knee OA, particularly in advanced stages. Existing studies are limited by small sample sizes. The effectiveness of PAAG in the treatment of advanced knee OA remains controversial. Therefore, the aim of this study was to compare the efficacy of intra-articular PAAG with that of the established cross-linked HA/CS combination in the treatment of knee OA through a retrospective design. Materials and Methods Patient Characteristics The study included 127 patients who underwent intra-articular knee filling in physical, rehabilitation and orthopaedic outpatient clinics between March 2023 and April 2024. Intra-articular injections were administered to 127 patients (78 women, 49 men; age range: 55–82 years) diagnosed with grade 3 or 4 knee OA according to the Kellgren–Lawrence (KL) scale. The Kellgren and Lawrence classification system is the most commonly used and accepted OA classification, and is graded as follows: Stage 0, normal; Stage 1, minimal osteophyte presence and normal joint space, Stage 2, significant osteophyte presence and questionable narrowing of the joint space; Stage 3, moderate multiple osteophytes, definite narrowing of joint space, some sclerosis and possible deformity of bone ends; and Stage 4, large osteophytes, marked narrowing of joint space, severe sclerosis and definite deformity of bone ends. Demographic data, including age, education level, height, weight, and body mass index (BMI), were recorded. All patients underwent detailed locomotor system examinations, and the knee OA diagnosis was confirmed via clinical evaluation and radiographic imaging (X-ray). The exclusion criteria included BMI > 35, inflammatory rheumatic diseases (e.g., rheumatoid arthritis, Behçet’s disease, ankylosing spondylitis), haematologic disorders, advanced cardiac insufficiency, current chemotherapy, or intra-articular knee injections within the preceding 3 months. This study was planned as a retrospective trial. Patients were allocated to two groups accordingly. Injections were administered to the more symptomatic knee of each patient. Following sterilization of the knee with betadine, Group 1 received an intra-articular injection of 60 mg of cross-linked hyaluronic acid (HA) combined with 90 mg of chondroitin sulfate (CS), whereas Group 2 received 6 ml of PAAG. Both groups received a single injection. The injections used were ready and sterile and were injected by adding only a sterile needle tip. All the injections were administered by a single experienced physician. Both groups were permitted to use NSAIDs for breakthrough pain. Postinjection recommendations included cold application for 3 days and daily isometric knee exercises. For this reason, they came to the physiotherapist for weekly check-ups.This study was reviewed and approved by the Kırıkkale University Faculty of Medicine Ethics Committee (date: 27/05/2024, decision no:08/2024) and adheres to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all subjects before being included. Primary outcome measures Pain severity was measured via a 10-mm visual analogue scale (VAS) [ 20 ]. Joint swelling, the knee range of motion (ROM), the WOMAC score, and the Pittsburgh Sleep Quality Index (PSQI) [ 21 ]were assessed at baseline, 3 months, and 12 months. The purpose of the PSQI is to assess sleep disorders that occur in OA patients, especially those in advanced stages. Joint swelling was evaluated manually and via ultrasonography. The ROM was quantified via a goniometer during maximal flexion and extension. Functional status and disability Disease-related functional status and disability were assessed via the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [ 16 ]. The WOMAC comprises three subscales: pain (5 items, WOMAC-A), stiffness (2 items, WOMAC-B), and functional limitations (17 items, WOMAC-C). Each item is scored on a 5-point Likert scale (1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = extreme). Higher scores indicate greater pain, stiffness, and functional impairment. Sleep quality assessment Sleep quality was evaluated via the Pittsburgh Sleep Quality Index, which assesses sleep over the preceding month across 19 items [ 17 ]. The index includes seven components: subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medications, and daytime dysfunction. Each component is scored between 0 and 3 based on symptom frequency, yielding a total score of 0–21. Scores of six or higher indicate impaired sleep quality. The Turkish version of the PSQI was validated by Ağargün et al. Statistical analysis The calculations were carried out by using the Statistical Package for Social Sciences software version 21.0 for Windows (SPSS Inc., Chicago, IL, USA). The Kolmogorov‒Smirnov test was used to confirm that the data were normally distributed. The chi-square test was used to evaluate differences in categorical variables. Student’s t test was used to evaluate significant differences in continuous variables between the two groups. For repeated measures, ANOVA was used to analyse the effects of differences in the scores of disease-related variables at baseline, three months and twelve months. Statistical significance was based on a value of p < 0.05. Results A total of 119 patients (86 males and 33 females) were included in the study. Among the remaining 119 patients, 60 were in the HA group, and 59 were in the PAAG group. The demographic characteristics of the patients classified as having HA/CS or PAAG, as well as BMI and radiological grade, are presented in Table 1 . Among the 136 knees screened, 9 were excluded because they did not meet the inclusion criteria. Since 6 of these 9 patients had a BMI > 35, the other 3 patients were excluded due to the previously mentioned comorbid diseases. Intra-articular injections were administered to 127 knees. Eight patients were excluded during follow-up: five opted for prosthetic surgery (three from the HA/CS group, two from the PAAG group), and three were lost to follow-up. A total of 119 patients (knees) completed the study. The flowchart of the study is illustrated in Fig. 1. In the HA/CS group, 44 knees were classified as Grade 3 and 16 as Grade 4, whereas 45 Grade 3 and 14 Grade 4 knees were classified in the PAAG group. There were no statistically significant differences between the groups in terms of age, sex, BMI, or education level (p > 0.05). The demographic characteristics of both groups are shown in Table 1 . Intergroup comparisons at 3 months revealed significantly lower pain scores (p < 0.001) and WOMAC scores (p < 0.05) in the PAAG group than in the HA/CS group. However, at 12 months, although pain and WOMAC scores were lower in the PAAG group, the differences were no longer statistically significant (p = 0.071 and p = 0.142, respectively). The ROM and sleep quality scores were not significantly different at 3 or 12 months (p > 0.05; Table 1 ). Intragroup analysis (using ANOVA across baseline, 3‑month, and 12‑month data) revealed similar trends in both groups. Both groups demonstrated significant improvements in pain, WOMAC, and sleep quality scores (p < 0.001). However, no significant improvement in ROM scores was observed in either group (p 0.05) (Table 2 ). Knee replacement was performed in 4 patients in the PAAG group and 6 patients in the HA group after follow-up at an external centre due to pain relief. Discussion The findings obtained in the present study demonstrate that intra-articular PAAG, a novel therapeutic agent, provides short-term benefits in pain relief and functional improvement for advanced-stage knee OA, although its long-term efficacy aligns with that of the HA/CS combination. Intra-articular PAAG injection is a promising and frequently applied treatment option for advanced knee OA. However, the number of studies conducted to date is very limited. Preclinical studies in horses, goats, and rabbits have reported successful outcomes [ 13 – 15 , 22 ]. These studies demonstrated that intra‑articular PAAG is non‑degradable and biocompatible and that it exerts its effects by integrating into the joint capsule and synovial membrane [ 13 , 14 ]. Histopathological analyses in these models revealed synovial cell proliferation into the gel within 14 days postinjection, followed by angiogenesis and hyperplasia within the inner capsule and synovial membrane [ 14 ]. It has also been reported that macrophages phagocytose gel and transform into fibroblast‑like synovial cells, thereby establishing a barrier between inflammatory cells and the synovial membrane. This barrier is thought to suppress inflammation and limit intra‑articular effusion, suggesting that PAAG injection does not increase joint effusion [ 14 , 15 ]; this has been corroborated in equine studies showing reduced effusion over 24 months [ 13 , 23 ]. Although experimental studies in horses generally produced positive results, the average age of lame horses was typically between 2 and 4 years, indicating that these experiments were performed in a very young equine population. In contrast, PAAG is generally used in humans with advanced knee OA, who are typically over 60 years of age. Accordingly, we specifically included patients with advanced knee OA (grades 3–4) in the present study and reported that the long‑term effects of the molecule were similar to those of the HA/CS combination. The first major human study was conducted by Henriksen et al. [ 17 ]. Although their cohort included Kellgren–Lawrence grades 1–4, 72 % o participants had advanced-stage knee OA (grades 3 and 4). Each patient received a single 6 mL intra‑articular PAAG injection, and significant improvements in pain and functional scores were observed at months 7 and 13. Bliddal et al. investigated PAAG efficacy in patients with grade 2‒4 knee OA over a 12‑month follow‑up and reported significant reductions in pain and WOMAC scores [ 24 ]. A 3‑year follow‑up study conducted by the same study group confirmed sustained improvements in pain and function [ 25 ]. However, none of these studies included a control group. Similarly, in the present study, the PAAG group presented lower pain and functional scores than did the HA/CS group at 12 months, but compared with the HA/CS group, no statistically significant differences were detected. The HA/CS group demonstrated comparable improvements. In a randomized controlled trial by Bliddal et al. [ 12 ], 239 patients with Grade 2‒4 knee OA were followed for 12 months (HA: n = 120; PAAG: n = 119). Although the PAAG group showed numerically better performance across all pain and WOMAC subscores, no statistically significant differences were observed between the groups [ 19 ]. These findings align with our results. The aim of the present study was to measure PAAG performance specifically in patients with advanced knee OA. All patients were grades 3–4, which may account for the diminished long‑term efficacy of PAAG. No serious adverse events occurred in our cohort, and no patient experienced increased joint effusion post‑injection. In the PAAG group, three patients reported mild pain and fullness for five days postprocedure. Overgaard et al. retrospectively reviewed 91 patients to assess adverse events; 15 patients reported transient distension, but none experienced serious side effects such as infection or ROM restriction. To date, no evidence of PAAG toxicity has been reported in the literature [ 26 , 27 ]. In the meta-analyses conducted, the greatest problem with HA, ozone therapy, and other injections is the short duration of treatment [ 28 , 29 ]. Carboxymethyl-chitosan (CM-C), a new molecule similar to PAAG, is a newly used agent in the treatment of advanced OA. Manocchio et al. reported a significant decrease in pain in the short and medium term. However, a gradual decrease in effectiveness in the 12th month compared with the 6th month was observed during the treatment period, similar to HA [ 11 ]. PAAG has been presented as a good alternative due to its longer duration of effect. In our study, although we achieved better results in the short term, the most significant difference between HA and PAAG in the one-year results was the length of the treatment duration. We have observed that PAAG treatment provides good outcomes for patients who do not require surgery or whose general condition does not allow for surgery; we aim to obtain better data through longer follow-ups to provide clearer information on reducing the need for arthroplasty in patients. The primary limitation of the present study was its retrospective design. Additionally, the sample size and follow‑up duration were relatively limited. Advanced-stage, longer-term retrospective studies are needed to provide more definitive, objective outcomes. The differences in the control groups are important limitations, since the evaluations are made by the same person. The severity of knee OA was not homogeneous among studies. Differences between Grade 3 and 4 patients undoubtedly affect the results. Conclusion Compared with HA/CS injection, intra-articular PAAG injection significantly improved the VAS and WOMAC scores of patients with advanced knee OA at 3 months. Although the long-term efficacy of PAAG is similar to that of HA, PAAG remains a valid treatment option for older patients or those with comorbidities who are not recommended for surgery. Abbreviations PAAG Polyacrylamide hydrogel HA/CS Chondroitin sulfate/hyaluronic acid OA Osteoarthritis BMI Body mass index ROM Range of motion PSQI Pittsburgh Sleep Quality Index NSAIDs Nonsteroidal anti-inflammatory drugs PRP Platelet-rich plasma WOMAC Western Ontario and McMaster Universities Osteoarthritis Index KL Kellgren-Lawrence VAS Visual analogue scale Declarations Acknowledgements No acknowledgements exist. Conflict of Interest The authors declare that they have no conflicts of interest. Consent for publication Informed consent was obtained from all the patients in this study for the article to be published. Funding The authors received no financial support for the research and/or authorship of this article. Author contributions M.A. The idea of steel design and writing, O.A. and F.S. Collecting the information of patients, T.M. and M.A.S. Patient Applications and analysis. All the authors reviewed the manuscript. Data availability Data are provided within the manuscript or supplementary information files. Ethics approval and consent to participate The study was started after the approval letter of the Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye, clinical research ethics committee, dated 22.05.2024 and numbered 2024.05.27 References Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage. 2013;21:1145–53. Hawker GA, King LK. The Burden of Osteoarthritis in Older Adults. Clin Geriatr Med. 2022;38:181–92. Migliorini F, Maffulli N, Nijboer CH, Pappalardo G, Pasurka M, Betsch M et al. Comparison of Different Molecular Weights of Intra-Articular Hyaluronic Acid Injections for Knee Osteoarthritis: A Level I Bayesian Network Meta-Analysis. Biomedicines. 2025;13. 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Tables Table 1: Comparison of demograghic and clinical variables between intragroups ( P 1 ) and intergroups ( P 2 ) Patients characteristics HA-CS Group (n = 60) Mean ± SD P 1 ANOVA PAAG Group (n = 59) Mean ± SD P 1 ANOVA P 2 Age 67.43±7.42 69.55±8.74 0.156 Gender (F/M) 42/18 44/15 0.346 BMI 30.65±3.32 31.50±4.47 0.232 Radiological grade (KL) Grade 3/4 44/16 45/14 0.262 Pain severity Baseline VAS 8.89±0.55 8.93±0.63 0.715 3 months VAS 6.88±1.47 <0.001 4.85±2.03 <0.001 <0.001 12 months VAS 7.18±1.01 6.80±1.74 0.142 ROM Baseline 116.75±11.45 114.91±12.92 0.412 3 months 118.50±11.37 0.086 115.50±12.78 0.712 0.176 12 months 117.25±11.11 114.23±13.70 0.188 WOMAC total Baseline 58.16±8.94 60.15±9.14 0.158 3 months 45.12±11.12 <0.001 40.65±9.04 <0.001 0.021 12 months 56.43±11.40 55.30±12.10 0.583 Sleep quality Baseline 34.45±4.67 35.45±7.53 0.400 3 months 27.65±4.23 <0.001 28.55±7.65 <0.001 0.427 12 months 33.25±4.15 33.31±6.89 0.950 F: Female, M: Male, KL: Kellgren-Lawrence, BMI: Body Mass index, VAS: Visual Analog Scale, ROM: Range of Motion, WOMAC: Western Ontario and Mc Master University Osteoarthritis Index, P 1 : İntragroup comparison, ANOVA, P 2 : İntergroup comparison, student t test. Table 2: Change scores of primer outcomes from baseline to 12 months Patients variables HA-CS Group (n = 60) Mean ± SD PAAG Group (n = 59) Mean ± SD P Pain severity 1.71 ± 1.06 2.13 ±1.75 0.145 ROM 1.50 ± 2.23 1.7 ± 1.23 0.565 WOMAC 1.72 ± 1.07 4.85 ± 2.45 0.075 Sleep quality 1.20 ± 0.90 2.10 ± 0.78 0.439 ROM: Range of Motion, WOMAC: Western Ontario and Mc Master University Osteoarthritis Index Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6966769","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":505160122,"identity":"835338dd-0575-41dc-898c-a99ed7b057b0","order_by":0,"name":"Mustafa Altıntaş","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIiWNgGAWjYDCCA0D8gA3CNv5TISEHFnxASEsCG4MEiF3Ac8bCGCyYQKyWD7xtFYkNIBY+LXy3j198kFBWV8cv3XxwgwSbRPr8sMMPgbbYyek2YNcieS6n2CDh3GEJyTnHkg0MeCRyN95OMwBqSTY2O4Bdi8EZnjSJxLYDEgY3cswMEiSAWmYngLQcSNyGX0sdUEv+9x8HDCTSDWenfyCghf0YUAszyBYGw4YEiQR56Rz8tkie4WEG+UVy5ow0A2OGAxKGG6RzCg4kGOD2C98Z9ocPPpTV8fNLJD8wZvxXJy8/O33zhw8VdnK4tDAw8BigORWs0gCLSjhgf4DKl2/Ap3oUjIJRMApGIgAA7nBkq/HVhwMAAAAASUVORK5CYII=","orcid":"","institution":"Diyarbakır Gazi Yaşargil Eğitim ve Araştırma Hastanesi","correspondingAuthor":true,"prefix":"","firstName":"Mustafa","middleName":"","lastName":"Altıntaş","suffix":""},{"id":505160124,"identity":"b5000797-b6e7-431f-8675-5b0c92755aa4","order_by":1,"name":"Okan Ateş","email":"","orcid":"","institution":"Diyarbakır Gazi Yaşargil Eğitim ve Araştırma Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"Okan","middleName":"","lastName":"Ateş","suffix":""},{"id":505160125,"identity":"d1dc927e-dfc4-40a0-a16a-b9db157f0428","order_by":2,"name":"Furkan Soy","email":"","orcid":"","institution":"Kırıkkale University","correspondingAuthor":false,"prefix":"","firstName":"Furkan","middleName":"","lastName":"Soy","suffix":""},{"id":505160127,"identity":"46e67363-9ecb-4b57-870d-a64962595e30","order_by":3,"name":"Tacettin Mirzaoğlu","email":"","orcid":"","institution":"Memorial Dicle Hospital, Diyarbakır, Turkiye","correspondingAuthor":false,"prefix":"","firstName":"Tacettin","middleName":"","lastName":"Mirzaoğlu","suffix":""},{"id":505160128,"identity":"2132a1f1-517d-47a7-8ff4-da861e9a4057","order_by":4,"name":"Mustafa Akif Sarıyıldız","email":"","orcid":"","institution":"Memorial Dicle Hospital, Diyarbakır, Turkiye","correspondingAuthor":false,"prefix":"","firstName":"Mustafa","middleName":"Akif","lastName":"Sarıyıldız","suffix":""}],"badges":[],"createdAt":"2025-06-24 14:23:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6966769/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6966769/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90313629,"identity":"b2e56a6b-5c85-468b-8497-dc756de8d021","added_by":"auto","created_at":"2025-09-01 10:08:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26723,"visible":true,"origin":"","legend":"\u003cp\u003eFLOW CHART\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6966769/v1/a8b6df93d6488ab5c60f1b0d.png"},{"id":101852269,"identity":"aa9009f4-8ebe-4db3-8654-6663e24fa8aa","added_by":"auto","created_at":"2026-02-04 10:11:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":758771,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6966769/v1/82073b96-9086-47a8-a8f5-7e72024b526b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of the efficacy of intra-articular polyacrylamide hydrogels versus cross-linked hyaluronic acid/chondroitin sulfate combination for the treatment of advanced-stage knee osteoarthritis","fulltext":[{"header":"Background","content":"\u003cp\u003eKnee osteoarthritis (OA) is the most common joint disease worldwide and significantly reduces the quality of daily life of elderly patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].Patients present with progressive pain and loss of function. The incidence of knee OA in society has increased with increasing average life expectancy [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Current management strategies for knee OA include weight control, isometric exercises, assistive devices, and physical therapy. Pharmacological treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs), topical creams, and intra-articular injections (e.g., hyaluronic acid, platelet-rich plasma [PRP], plasma rich in growth factors [PRGF], and corticosteroids) are effective for treating Grade 1 and 2 disease. However, these treatment modalities often provide only transient benefits or may even be ineffective in patients with Grade 3 and 4 disease [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHA, one of the most commonly used intra-articular injections today, has not been shown to differ from other agents in terms of short-term results in analyses. However, it has been reported in the literature that its effectiveness decreases in the long term in terms of therapeutic duration [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. With the development of regenerative therapies and new intra-articular injections, effective agents have been developed for patients with advanced arthritis. The most important of these are carboxymethyl-chitosan and polyacrylamide hydrogels (PAAGs) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Polyacrylamide hydrogel (PAAG) has emerged as a promising option for patients and clinicians. Although the acrylamide monomer exhibits carcinogenic and neurotoxic properties, these adverse effects are not observed once the molecule is polymerized [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. PAAG has been used for approximately 25 years in aesthetic procedures and intravesical injections without significant adverse effects. This molecule is biocompatible, viscoelastic, and nondegradable [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Because of these features, its usability in osteoarthritis has been suggested. PAAG, which has been used in other areas since 2000, was studied for intra-articular injection in horses in 2015, in rabbits and horses in 2016, and in goats in 2017, and later studies, mainly involving lame horses, revealed its effectiveness in treating knee OA [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The first human case series, a 2018 cohort study, included patients with grade 3‒4 knee OA [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] (72% of participants) and reported significant improvements in WOMAC scores at 13 months post-PAAG injection [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. They reported good results with knee intraarticular PAAG injections at the 6-month follow-up in a cohort study conducted three years later [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The only randomized controlled trial in the literature, conducted by Bliddal et al., reported findings comparable to those obtained with intra-articular hyaluronic acid injections over a 12-month period, with PAAG not proving to be more effective than HA [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough PAAG remains a novel molecule, few human studies have validated its efficacy in knee OA, particularly in advanced stages. Existing studies are limited by small sample sizes. The effectiveness of PAAG in the treatment of advanced knee OA remains controversial. Therefore, the aim of this study was to compare the efficacy of intra-articular PAAG with that of the established cross-linked HA/CS combination in the treatment of knee OA through a retrospective design.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatient Characteristics\u003c/h2\u003e\u003cp\u003eThe study included 127 patients who underwent intra-articular knee filling in physical, rehabilitation and orthopaedic outpatient clinics between March 2023 and April 2024. Intra-articular injections were administered to 127 patients (78 women, 49 men; age range: 55\u0026ndash;82 years) diagnosed with grade 3 or 4 knee OA according to the Kellgren\u0026ndash;Lawrence (KL) scale. The Kellgren and Lawrence classification system is the most commonly used and accepted OA classification, and is graded as follows: Stage 0, normal; Stage 1, minimal osteophyte presence and normal joint space, Stage 2, significant osteophyte presence and questionable narrowing of the joint space; Stage 3, moderate multiple osteophytes, definite narrowing of joint space, some sclerosis and possible deformity of bone ends; and Stage 4, large osteophytes, marked narrowing of joint space, severe sclerosis and definite deformity of bone ends. Demographic data, including age, education level, height, weight, and body mass index (BMI), were recorded. All patients underwent detailed locomotor system examinations, and the knee OA diagnosis was confirmed via clinical evaluation and radiographic imaging (X-ray). The exclusion criteria included BMI\u0026thinsp;\u0026gt;\u0026thinsp;35, inflammatory rheumatic diseases (e.g., rheumatoid arthritis, Beh\u0026ccedil;et\u0026rsquo;s disease, ankylosing spondylitis), haematologic disorders, advanced cardiac insufficiency, current chemotherapy, or intra-articular knee injections within the preceding 3 months. This study was planned as a retrospective trial. Patients were allocated to two groups accordingly. Injections were administered to the more symptomatic knee of each patient. Following sterilization of the knee with betadine, Group 1 received an intra-articular injection of 60 mg of cross-linked hyaluronic acid (HA) combined with 90 mg of chondroitin sulfate (CS), whereas Group 2 received 6 ml of PAAG. Both groups received a single injection. The injections used were ready and sterile and were injected by adding only a sterile needle tip. All the injections were administered by a single experienced physician. Both groups were permitted to use NSAIDs for breakthrough pain. Postinjection recommendations included cold application for 3 days and daily isometric knee exercises. For this reason, they came to the physiotherapist for weekly check-ups.This study was reviewed and approved by the Kırıkkale University Faculty of Medicine Ethics Committee (date: 27/05/2024, decision no:08/2024) and adheres to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all subjects before being included.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePrimary outcome measures\u003c/h3\u003e\n\u003cp\u003ePain severity was measured via a 10-mm visual analogue scale (VAS) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Joint swelling, the knee range of motion (ROM), the WOMAC score, and the Pittsburgh Sleep Quality Index (PSQI) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]were assessed at baseline, 3 months, and 12 months. The purpose of the PSQI is to assess sleep disorders that occur in OA patients, especially those in advanced stages. Joint swelling was evaluated manually and via ultrasonography. The ROM was quantified via a goniometer during maximal flexion and extension.\u003c/p\u003e\n\u003ch3\u003eFunctional status and disability\u003c/h3\u003e\n\u003cp\u003eDisease-related functional status and disability were assessed via the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The WOMAC comprises three subscales: pain (5 items, WOMAC-A), stiffness (2 items, WOMAC-B), and functional limitations (17 items, WOMAC-C). Each item is scored on a 5-point Likert scale (1\u0026thinsp;=\u0026thinsp;none, 2\u0026thinsp;=\u0026thinsp;mild, 3\u0026thinsp;=\u0026thinsp;moderate, 4\u0026thinsp;=\u0026thinsp;severe, 5\u0026thinsp;=\u0026thinsp;extreme). Higher scores indicate greater pain, stiffness, and functional impairment.\u003c/p\u003e\n\u003ch3\u003eSleep quality assessment\u003c/h3\u003e\n\u003cp\u003eSleep quality was evaluated via the Pittsburgh Sleep Quality Index, which assesses sleep over the preceding month across 19 items [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The index includes seven components: subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, use of sleep medications, and daytime dysfunction. Each component is scored between 0 and 3 based on symptom frequency, yielding a total score of 0\u0026ndash;21. Scores of six or higher indicate impaired sleep quality. The Turkish version of the PSQI was validated by Ağarg\u0026uuml;n et al.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe calculations were carried out by using the Statistical Package for Social Sciences software version 21.0 for Windows (SPSS Inc., Chicago, IL, USA). The Kolmogorov‒Smirnov test was used to confirm that the data were normally distributed. The chi-square test was used to evaluate differences in categorical variables. Student\u0026rsquo;s t test was used to evaluate significant differences in continuous variables between the two groups. For repeated measures, ANOVA was used to analyse the effects of differences in the scores of disease-related variables at baseline, three months and twelve months. Statistical significance was based on a value of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 119 patients (86 males and 33 females) were included in the study. Among the remaining 119 patients, 60 were in the HA group, and 59 were in the PAAG group. The demographic characteristics of the patients classified as having HA/CS or PAAG, as well as BMI and radiological grade, are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eAmong the 136 knees screened, 9 were excluded because they did not meet the inclusion criteria. Since 6 of these 9 patients had a BMI\u0026thinsp;\u0026gt;\u0026thinsp;35, the other 3 patients were excluded due to the previously mentioned comorbid diseases. Intra-articular injections were administered to 127 knees. Eight patients were excluded during follow-up: five opted for prosthetic surgery (three from the HA/CS group, two from the PAAG group), and three were lost to follow-up. A total of 119 patients (knees) completed the study. The flowchart of the study is illustrated in Fig. 1. In the HA/CS group, 44 knees were classified as Grade 3 and 16 as Grade 4, whereas 45 Grade 3 and 14 Grade 4 knees were classified in the PAAG group. There were no statistically significant differences between the groups in terms of age, sex, BMI, or education level (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The demographic characteristics of both groups are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eIntergroup comparisons at 3 months revealed significantly lower pain scores (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and WOMAC scores (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in the PAAG group than in the HA/CS group. However, at 12 months, although pain and WOMAC scores were lower in the PAAG group, the differences were no longer statistically significant (p\u0026thinsp;=\u0026thinsp;0.071 and p\u0026thinsp;=\u0026thinsp;0.142, respectively). The ROM and sleep quality scores were not significantly different at 3 or 12 months (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05; Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIntragroup analysis (using ANOVA across baseline, 3‑month, and 12‑month data) revealed similar trends in both groups. Both groups demonstrated significant improvements in pain, WOMAC, and sleep quality scores (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, no significant improvement in ROM scores was observed in either group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05; Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). When changes between the baseline and 12-month measurements were compared, the PAAG group showed a greater difference, but none of the parameters reached statistical significance (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Knee replacement was performed in 4 patients in the PAAG group and 6 patients in the HA group after follow-up at an external centre due to pain relief.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings obtained in the present study demonstrate that intra-articular PAAG, a novel therapeutic agent, provides short-term benefits in pain relief and functional improvement for advanced-stage knee OA, although its long-term efficacy aligns with that of the HA/CS combination.\u003c/p\u003e\u003cp\u003eIntra-articular PAAG injection is a promising and frequently applied treatment option for advanced knee OA. However, the number of studies conducted to date is very limited. Preclinical studies in horses, goats, and rabbits have reported successful outcomes [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. These studies demonstrated that intra‑articular PAAG is non‑degradable and biocompatible and that it exerts its effects by integrating into the joint capsule and synovial membrane [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Histopathological analyses in these models revealed synovial cell proliferation into the gel within 14 days postinjection, followed by angiogenesis and hyperplasia within the inner capsule and synovial membrane [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. It has also been reported that macrophages phagocytose gel and transform into fibroblast‑like synovial cells, thereby establishing a barrier between inflammatory cells and the synovial membrane. This barrier is thought to suppress inflammation and limit intra‑articular effusion, suggesting that PAAG injection does not increase joint effusion [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]; this has been corroborated in equine studies showing reduced effusion over 24 months [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Although experimental studies in horses generally produced positive results, the average age of lame horses was typically between 2 and 4 years, indicating that these experiments were performed in a very young equine population. In contrast, PAAG is generally used in humans with advanced knee OA, who are typically over 60 years of age. Accordingly, we specifically included patients with advanced knee OA (grades 3\u0026ndash;4) in the present study and reported that the long‑term effects of the molecule were similar to those of the HA/CS combination.\u003c/p\u003e\u003cp\u003eThe first major human study was conducted by Henriksen et al. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Although their cohort included Kellgren\u0026ndash;Lawrence grades 1\u0026ndash;4, 72 % o participants had advanced-stage knee OA (grades 3 and 4). Each patient received a single 6 mL intra‑articular PAAG injection, and significant improvements in pain and functional scores were observed at months 7 and 13. Bliddal et al. investigated PAAG efficacy in patients with grade 2‒4 knee OA over a 12‑month follow‑up and reported significant reductions in pain and WOMAC scores [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. A 3‑year follow‑up study conducted by the same study group confirmed sustained improvements in pain and function [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. However, none of these studies included a control group. Similarly, in the present study, the PAAG group presented lower pain and functional scores than did the HA/CS group at 12 months, but compared with the HA/CS group, no statistically significant differences were detected. The HA/CS group demonstrated comparable improvements. In a randomized controlled trial by Bliddal et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], 239 patients with Grade 2‒4 knee OA were followed for 12 months (HA: n\u0026thinsp;=\u0026thinsp;120; PAAG: n\u0026thinsp;=\u0026thinsp;119). Although the PAAG group showed numerically better performance across all pain and WOMAC subscores, no statistically significant differences were observed between the groups [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These findings align with our results. The aim of the present study was to measure PAAG performance specifically in patients with advanced knee OA. All patients were grades 3\u0026ndash;4, which may account for the diminished long‑term efficacy of PAAG.\u003c/p\u003e\u003cp\u003eNo serious adverse events occurred in our cohort, and no patient experienced increased joint effusion post‑injection. In the PAAG group, three patients reported mild pain and fullness for five days postprocedure. Overgaard et al. retrospectively reviewed 91 patients to assess adverse events; 15 patients reported transient distension, but none experienced serious side effects such as infection or ROM restriction. To date, no evidence of PAAG toxicity has been reported in the literature [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn the meta-analyses conducted, the greatest problem with HA, ozone therapy, and other injections is the short duration of treatment [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Carboxymethyl-chitosan (CM-C), a new molecule similar to PAAG, is a newly used agent in the treatment of advanced OA. Manocchio et al. reported a significant decrease in pain in the short and medium term. However, a gradual decrease in effectiveness in the 12th month compared with the 6th month was observed during the treatment period, similar to HA [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. PAAG has been presented as a good alternative due to its longer duration of effect. In our study, although we achieved better results in the short term, the most significant difference between HA and PAAG in the one-year results was the length of the treatment duration. We have observed that PAAG treatment provides good outcomes for patients who do not require surgery or whose general condition does not allow for surgery; we aim to obtain better data through longer follow-ups to provide clearer information on reducing the need for arthroplasty in patients.\u003c/p\u003e\u003cp\u003eThe primary limitation of the present study was its retrospective design. Additionally, the sample size and follow‑up duration were relatively limited. Advanced-stage, longer-term retrospective studies are needed to provide more definitive, objective outcomes. The differences in the control groups are important limitations, since the evaluations are made by the same person. The severity of knee OA was not homogeneous among studies. Differences between Grade 3 and 4 patients undoubtedly affect the results.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCompared with HA/CS injection, intra-articular PAAG injection significantly improved the VAS and WOMAC scores of patients with advanced knee OA at 3 months. Although the long-term efficacy of PAAG is similar to that of HA, PAAG remains a valid treatment option for older patients or those with comorbidities who are not recommended for surgery.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePAAG Polyacrylamide hydrogel\u003c/p\u003e\n\u003cp\u003eHA/CS Chondroitin sulfate/hyaluronic acid\u003c/p\u003e\n\u003cp\u003eOA Osteoarthritis\u003c/p\u003e\n\u003cp\u003eBMI Body mass index\u003c/p\u003e\n\u003cp\u003eROM Range of motion\u003c/p\u003e\n\u003cp\u003ePSQI Pittsburgh Sleep Quality Index\u003c/p\u003e\n\u003cp\u003eNSAIDs Nonsteroidal anti-inflammatory drugs\u003c/p\u003e\n\u003cp\u003ePRP Platelet-rich plasma\u003c/p\u003e\n\u003cp\u003eWOMAC Western Ontario and McMaster Universities Osteoarthritis Index\u003c/p\u003e\n\u003cp\u003eKL Kellgren-Lawrence\u003c/p\u003e\n\u003cp\u003eVAS Visual analogue scale\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003eNo acknowledgements exist.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e The authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e Informed consent was obtained from all the patients in this study for the article to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e The authors received no financial support for the research and/or authorship of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003eM.A. The idea of steel design and writing, O.A. and F.S. Collecting the information of patients, T.M. and M.A.S. Patient Applications and analysis. All the authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e Data are provided within the manuscript or supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e The study was started after the approval letter of the Kırıkkale University Faculty of Medicine, Kırıkkale, T\u0026uuml;rkiye, clinical research ethics committee, dated 22.05.2024 and numbered 2024.05.27\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNeogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage. 2013;21:1145\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHawker GA, King LK. The Burden of Osteoarthritis in Older Adults. Clin Geriatr Med. 2022;38:181\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMigliorini F, Maffulli N, Nijboer CH, Pappalardo G, Pasurka M, Betsch M et al. Comparison of Different Molecular Weights of Intra-Articular Hyaluronic Acid Injections for Knee Osteoarthritis: A Level I Bayesian Network Meta-Analysis. Biomedicines. 2025;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSafiri S, Kolahi A-A, Smith E, Hill C, Bettampadi D, Mansournia MA, et al. Global, regional and national burden of osteoarthritis 1990\u0026ndash;2017: a systematic analysis of the Global Burden of Disease Study 2017. Ann Rheum Dis. 2020;79:819\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMigliorini F, Driessen A, Oliva F, Maffulli GD, Tingart M, Maffulli N. Better outcomes and reduced failures for arthroplasty over osteotomy for advanced compartmental knee osteoarthritis in patients older than 50 years. J Orthop Surg Res. 2020;15:545.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMigliorini F, Maffulli N, Pipino G, Jeyaraman M, Ramasubramanian S, Jeyaraman N. Intra-articular injections of hyaluronic acid versus plasma rich in growth factors (PRGF) for knee osteoarthritis: a meta-analysis of randomised controlled trials: A meta-analysis. Orthopadie (Heidelberg Germany). 2025;54:218\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHawker GA, Mian S, Bednis K, Stanaitis I. Osteoarthritis year 2010 in review: non-pharmacologic therapy. Osteoarthritis Cartilage. 2011;19:366\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaheu E, Rannou F, Reginster J-Y. Efficacy and safety of hyaluronic acid in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin Arthritis Rheum. 2016;45:S28\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMigliorini F, Sch\u0026auml;fer L, Pilone M, Bell A, Simeone F, Maffulli N. Similar efficacy of intra-articular hyaluronic acid injections and other biologically active injections in patients with early stages knee osteoarthritis: a level I meta-analysis. Arch Orthop Trauma Surg. 2024;145:68.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFu LL, Maffulli N, Chan KM. Intra-articular hyaluronic acid following knee immobilisation for 6 weeks in rabbits. Clin Rheumatol. 2001;20:98\u0026ndash;103.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eManocchio N, Pirri C, Ljoka C, Sorbino A, Piacentini N, Monello C et al. Long-Term Efficacy of Carboxymethyl-Chitosan in Advanced Knee Osteoarthritis: A Twelve-Month Follow-Up Study on Non-Responders to Hyaluronic Acid. Biomedicines. 2025;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBliddal H, Beier J, Hartkopp A, Conaghan PG, Henriksen M. Effectiveness and safety of polyacrylamide hydrogel injection for knee osteoarthritis: results from a 12-month follow up of an open-label study. J Orthop Surg Res. 2024;19:274.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTnibar A, Schougaard H, Camitz L, Rasmussen J, Koene M, Jahn W, et al. An international multi-centre prospective study on the efficacy of an intraarticular polyacrylamide hydrogel in horses with osteoarthritis: a 24 months follow-up. Acta Vet Scand. 2015;57:20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChristensen L, Camitz L, Illigen KE, Hansen M, Sarvaa R, Conaghan PG. Synovial incorporation of polyacrylamide hydrogel after injection into normal and osteoarthritic animal joints. Osteoarthritis Cartilage. 2016;24:1999\u0026ndash;2002.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eda Silva Xavier AA, da Rosa PP, de Brum Mackmill L, Roll VFB. An assessment of the effectiveness of hyaluronic acid and polyacrylamide hydrogel in horses with osteoarthritis: Systematic review and network meta-analysis. Res Vet Sci. 2021;134:42\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKELLGREN JH, LAWRENCE JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16:494\u0026ndash;502.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHenriksen M, Overgaard A, Hartkopp A, Bliddal H. Intra-articular 2.5% polyacrylamide hydrogel for the treatment of knee osteoarthritis: an observational proof-of-concept cohort study. Clin Exp Rheumatol. 2018;36:1082\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePolyacrylamide Hydrogel Injection for Knee Osteoarthritis. A 6 Months Prospective Study. J Orthop Res Ther. 2021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBliddal H, Beier J, Hartkopp A, Conaghan PG, Henriksen M. Polyacrylamide gel versus hyaluronic acid for the treatment of knee osteoarthritis: a randomised controlled study. Clin Exp Rheumatol. 2024;42:1729\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKelly AM. Does the clinically significant difference in visual analog scale pain scores vary with gender, age, or cause of pain? Acad Emerg Med. 1998;5:1086\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSmyth C. The Pittsburgh Sleep Quality Index (PSQI). J Gerontol Nurs. 1999;25:10\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ede Souza AF, Paretsis NF, De Zoppa. AL do V. What is the Evidence of Hyaluronic Acid and Polyacrylamide Hydrogel in Intra-articular Therapy in Equines? Systematic Literature Review. J Equine Vet Sci. 2020;86:102909.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTnibar A. Intra-articular 2.5% polyacrylamide hydrogel, a new concept in the medication of equine osteoarthritis: A review. J Equine Vet Sci. 2022;119:104143.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988;15:1833\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHenriksen M, Beier J, Hartkopp A, Conaghan PG, Bliddal H. 3 Year results from a prospective study of polyacrylamide hydrogel for knee osteoarthritis. Osteoarthritis Cartilage. 2023;31:682\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcCollister DD, Hake CL, Sadek SE, Rowe VK. Toxicologic investigations of polyacrylamides. Toxicol Appl Pharmacol. 1965;7:639\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNegredo E, Puig J, Ornelas A, Echeverr\u0026iacute;a P, Bonjoch A, Estany C, et al. Ten-Year Safety with Polyacrylamide Gel Used to Correct Facial Lipoatrophy in HIV-Infected Patients. AIDS Res Hum Retroviruses. 2015;31:817\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMigliorini F, Maffulli N, Sch\u0026auml;fer L, Kubach J, Betsch M, Pasurka M. Less Pain with Intra-Articular Hyaluronic Acid Injections for Knee Osteoarthritis Compared to Placebo: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Pharmaceuticals (Basel). 2024;17.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMigliorini F, Giorgino R, Mazzoleni MG, Sch\u0026auml;fer L, Bertini FA, Maffulli N. Intra-articular injections of ozone versus hyaluronic acid for knee osteoarthritis: a level I meta-analysis. Eur J Orthop Surg Traumatol. 2024;35:20.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Comparison of demograghic and clinical variables between intragroups (\u003cem\u003eP \u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e) and intergroups (\u003cem\u003eP \u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"671\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatients characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHA-CS Group (n = 60)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP \u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003eANOVA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePAAG Group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 59)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP \u003csup\u003e1\u0026nbsp;\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003cem\u003eANOVA\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP \u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e67.43\u0026plusmn;7.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e69.55\u0026plusmn;8.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.156\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eGender (F/M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e42/18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e44/15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.346\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e30.65\u0026plusmn;3.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e31.50\u0026plusmn;4.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.232\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003eRadiological grade (KL)\u003c/p\u003e\n \u003cp\u003eGrade 3/4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 44/16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e45/14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.262\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePain severity\u003c/em\u003e\u003c/strong\u003e\u0026nbsp; \u0026nbsp; Baseline\u003csup\u003e\u0026nbsp;VAS\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e8.89\u0026plusmn;0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e8.93\u0026plusmn;0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.715\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;3 months \u003csup\u003eVAS\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e6.88\u0026plusmn;1.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e4.85\u0026plusmn;2.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 12 months \u003csup\u003eVAS\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e7.18\u0026plusmn;1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e6.80\u0026plusmn;1.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.142\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eROM\u003c/em\u003e\u003c/strong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Baseline\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e116.75\u0026plusmn;11.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e114.91\u0026plusmn;12.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.412\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e118.50\u0026plusmn;11.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e0.086\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e115.50\u0026plusmn;12.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e0.712\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e117.25\u0026plusmn;11.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e114.23\u0026plusmn;13.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.188\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eWOMAC total \u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eBaseline\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e58.16\u0026plusmn;8.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e60.15\u0026plusmn;9.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.158\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e45.12\u0026plusmn;11.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e40.65\u0026plusmn;9.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e56.43\u0026plusmn;11.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e55.30\u0026plusmn;12.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.583\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSleep quality\u003c/em\u003e\u003c/strong\u003e\u0026nbsp; \u0026nbsp; Baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e34.45\u0026plusmn;4.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e35.45\u0026plusmn;7.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.400\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e27.65\u0026plusmn;4.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e28.55\u0026plusmn;7.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.427\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;12 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 103px;\"\u003e\n \u003cp\u003e33.25\u0026plusmn;4.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e33.31\u0026plusmn;6.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.950\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eF: Female, M: Male, KL: Kellgren-Lawrence, BMI: Body Mass index, VAS: Visual Analog Scale, ROM: Range of Motion, WOMAC: Western Ontario and Mc Master University Osteoarthritis Index, \u0026nbsp;P\u003csup\u003e1\u003c/sup\u003e: İntragroup comparison, ANOVA, P\u003csup\u003e2\u003c/sup\u003e: İntergroup comparison, student t test.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Change scores of primer outcomes from baseline to 12 months\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatients variables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHA-CS Group (n = 60)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePAAG Group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 59)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003ePain severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.71 \u0026plusmn; \u0026nbsp; \u0026nbsp; 1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e2.13 \u0026nbsp; \u0026nbsp; \u0026plusmn;1.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eROM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.50 \u0026plusmn; \u0026nbsp; \u0026nbsp; 2.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1.7 \u0026nbsp; \u0026nbsp; \u0026plusmn; \u0026nbsp;1.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e0.565\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eWOMAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.72 \u0026nbsp;\u0026plusmn; 1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e4.85 \u0026nbsp; \u0026nbsp; \u0026plusmn; \u0026nbsp;2.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e0.075\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003eSleep quality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e1.20 \u0026plusmn; \u0026nbsp; \u0026nbsp; 0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e2.10 \u0026plusmn; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e0.439\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eROM: Range of Motion, WOMAC: Western Ontario and Mc Master University Osteoarthritis Index\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6966769/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6966769/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePolyacrylamide hydrogel (PAAG) remains a novel molecule, and few human studies have validated its efficacy in knee OA, particularly in advanced stages. The aim of this study was to compare the efficacy of intra-articular polyacrylamide hydrogel (PAAG), a novel molecule, with that of the widely used cross-linked chondroitin sulfate/hyaluronic acid (HA/CS) combination in the treatment of knee osteoarthritis (OA) in a retrospective trial.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA total of 127 patients diagnosed with grade 3 or 4 knee OA according to the Kellgren-Lawrence scale were included. Patients\u0026rsquo; age, education level, and body mass index (BMI) were recorded. The first group received an intra-articular injection of a cross-linked HA (60 mg)/CS (90 mg) combination, whereas the second group was administered 6 ml of PAAG. Both groups received a single injection. The outcome measures, which were assessed at baseline, 3 months, and 12 months, included knee pain severity measured by the visual analogue scale, range of motion (ROM), WOMAC scale score, and Pittsburgh Sleep Quality Index (PSQI).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAt 3 months, the PAAG group demonstrated significantly lower pain and WOMAC scores than did the HA/CS group. However, no significant differences in pain or WOMAC scores were observed between the groups at 12 months. The ROM and sleep quality scores were not significantly different at either 3 or 12 months. Within-group comparisons revealed significant reductions in pain, WOMAC, and sleep scores in both groups over time, but no significant improvement in ROM was detected in either group.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eCompared with HA/CS injection, intra-articular PAAG injection significantly improved the VAS and WOMAC scores in advanced knee OA patients at 3 months. However, the outcomes for all the parameters were similar between the groups at 12 months.\u003c/p\u003e","manuscriptTitle":"Comparison of the efficacy of intra-articular polyacrylamide hydrogels versus cross-linked hyaluronic acid/chondroitin sulfate combination for the treatment of advanced-stage knee osteoarthritis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 10:08:07","doi":"10.21203/rs.3.rs-6966769/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b3cffeff-095e-4ed4-b583-45d1bf7afb13","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-04T10:10:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-01 10:08:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6966769","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6966769","identity":"rs-6966769","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}