Table 1.

Main characteristics of the analyzed studies.

NO.	Titles, Author, Year	Type of Study/Period	Participants	Type of Intervention	Evaluation Methods	Results
1	Babu et al., 2023 [51]	Prospective interventional cohort/March 2020–October 2022	44 participants, age-36–76 years, 73% women, 27% men. Average body mass index—25.85	HMW-IAHA The treatment involved a 90 mg dose of HMW-IAHA in 3 mL prefilled syringes.	VAS, KOOS, WORMS, Likert Scale	Over 90 days, the VAS score decreased from 8.53 to 5.97, indicating an improvement in pain levels. Additionally, the KOOS displayed both overall and specific enhancements during follow-up visits. Furthermore, the WORMS exhibited improvement, decreasing from 66.57 to 65.14 between day 0 and day 90.
2	Raeissad et al., 2021 [52]	Randomized clinical trial/December 2017–February 2019	200 participants 52 HA, 51 PRP, 49 PRGF, 48 Ozone Age 56.9 ± 6.3 Sex M/F-61/139	HA-Hyalgan (Fidia Farmaceutici S.P.A, Abano Terme, Italy) (3 doses per week), PRP—Royagen kit (made by Arya Mabna Tashkis Co., Tehran, Iran, SN: 312569) (two doses at three-week intervals), PRGF (two doses at three-week intervals), Ozone (Ozonibaric P ozone generator, by Sedecal, Madrid, Spain) (3 doses per week) IA injections were executed by a latero-median approach with the knee in extension.	VAS, WOMAC, Lequesne index	During the 2-month follow-up after the injection, lower values for WOMAC, Lequesne, and VAS scores were identified in the ozone group. At the 6-month evaluation, both the PRP and PRGF groups improved VAS and WOMAC scores compared with the HA group. When assessed at 12 months, the PRP and PRGF groups displayed significant differences compared to the HA and ozone groups.
3	Blicharski et al., 2023 [53]	Prospective randomized double-blind/January 2021–December 2021	284 participants aged ≥ 40 years, gender M/F-105/179	Hyruan ONE (LG Chem, Ltd., Seoul, South Korea), Durolane (Q-Med AB, Uppsala, Sweden)—intra-articular administration	WOMAC, Likert Scale, PGA, IGA, Kelgreen-Lawrence	The main outcome, measuring the mean change in WOMAC-Likert Pain sub-scores showed comparable improvements in both the test and comparator groups, with scores of −5.59 and −5.54, respectively, confirming the non-inferiority of the test product (difference of −0.05). The secondary outcomes, adverse events, and non-inferiority of Hyruan ONE to the comparator were consistent across both groups in European patients with mild-to-moderate knee osteoarthritis.
4	Calvet et al., 2022 [54]	Multicenter observational prospective with a single cohort	166 participants, age-63.2, sex M/F-40/126, BMI-28.6	Pronolis® HD mono 2.5% (Procare Health, Spain/KD Intra-Articular® Gel 2.5%), the subjects were followed for 24 weeks.	Womac, Likert Scale, VAS	After a single injection of high-density HA viscoelastic gel, patients experienced a significant reduction in the WOMAC score by 4.78 points at the 12-week follow-up visit. This improvement resulted in noticeable relief from pain and better management of symptoms.
5	Acharya et al., 2022 [55]	Prospective observational/November 2021–January 2022	50 participants, sexM/F-21/29, age 45–55 years-27 patients Age-55–65 years-12 patients Age > 65 years-11 patients	One intra-articular injection of 10 mL of Hylan G-F 20 (Synvisc-One® (Hylan G-F 20)/(Hylan Polymer A & B G-F 20) Patients were followed per protocol at 8, 24, and 52 weeks.	WOMAC, VAS, SF 36, Kelgreen-Lawrence	A single intra-articular injection has been proven to significantly reduce pain intensity, enhance physical functioning, and elevate overall quality of life.
6	Hill et al., 2023 [56]	Multicenter, randomized, double-blind, placebo-controlled clinical trial/21 December 2018–25 October 2019	93 participants, age-30–75 years FP-MD-48, placebo-45	FlexPro MD®-(combination of Euphausia superba Antarctic krill oil (321 mg, Superba®, Aker BioMarine Antarctic US LLC.; Metuchen, NJ, USA), natural astaxanthin purified from Haematococcus pluvialis (2 mg, Zanthin® Natural Astaxanthin), and a proprietary HA produced from fermentation by Streptococcus zooepidemicus (30 mg, Flexonic® sodium hyaluronate (the sodium salt of HA), Valensa International; Eustis, FL, USA) (600 mg soft capsule consisting of krill oil, natural astaxanthin, and a proprietary HA). Therapy administration: 1 capsule/day, 12 weeks.	K-VAS, K-WOMAC, KSF-36, Kelgreen-Lawrence	In the FP-MD group, there was a reduction in K-VAS score from 46.1 to 25.3 at week 12. In the placebo group, the K-VAS score started at 42.7 and reached 32.1 at week 12. Regarding the K-Womac score, individuals receiving FP-MD experienced significantly lower levels of pain, stiffness, and improved physical function.
7	Nouri et al., 2020 [57]	Randomized clinical trial/6 April 2019–16 March 2020	92 participants: HA-29 participants, PRP- 32 participants, HA + PRP-31 participants. Gender M/F-25/67 Age: HA-60.93 ± 4.54 PRP-58.22 ± 5.10 HA + PRP-60.29 ± 4.83	In the HA group-2.5 mL intra-articular (Viscor 50 mg/2.5 mL, molecular weight of 2500–3200 kDa, Nitka, Tehran, Iran) In the PRP group-5 mL autologous PRP In the HA + PRP group, 5 mL of PRP was injected and immediately after that 2.5 mL of HA.	WOMAC, Lequesne index, VAS,	Based on the study findings, all three interventions effectively improved both pain and function, demonstrating significant differences in WOMAC, VAS, and Lequesne scores at 2 and 6 months compared to the baseline. These results highlight the positive impact of the interventions and underscore their potential to bring about meaningful improvements in patient outcomes.
8	Szwedowski et al., 2022 [58]	Prospective randomized/April 2019–March 2020	75 participants: PRP-25 participants, HA-25 participants, CS-25 participants Age of PRP-40–70 years HA-40–66 years CS-46–69 years.	Subjects were randomly assigned to receive intra-articular injections in one of three treatment groups: PRP (Density Platelet Gel, IBF, Scafati, Italy), HA (Biovisc Ortho Single, 30 mg/mL, molecular weight 3.400–3.800 kDa, Atradis Medical Devices, Warsaw, Poland), or CS (Diprophos, 6.43 mg/mL betamethasone dipropionate and 2.63 mg/mL betamethasone sodium phosphate, MSD, Warsaw, Poland), determined by a computer-generated randomization system.	Kelgreen-Lawrence score, WOMAC, BMI	The first stage involved evaluating the effectiveness of injections on the WOMAC scale at 1.5 months, 3 months, and 6 months. The PRP group demonstrated a more significant reduction in pain values compared to the HA group, although both groups experienced a decrease in pain. The administration of glucocorticoids resulted in the most significant decrease at 6 weeks.
9	Sconza et al., 2024 [59]	Prospective/November 2021	83 participants, sex M/F-37/46, age-47–87 years	Patients diagnosed with symptomatic KOA were administered a single intraarticular injection of HA-SC (SINOGEL®, IBSA Farmaceutici Italia srl, Lodi, Italy), a combination of 72 mg of sodium hyaluronate and 48 mg of sodium chondroitin,	VAS, WOMAC, Likert Scale, Kelgreen-Lawrence, PtGA	A WOMAC pain score reduced from point 7 to point 4 at 6 months post-treatment was reported. At 6 months post-administration, t he WOMAC score for physical function limitation decreased significantly from 26 to 13. Following a single IA injection of SINOGEL, the VAS pain score decreased notably from 6 to 4 at the 6-month mark post-injection.
10	Perruchet et al., 2023 [60]	Cross-sectional study/October 2021–February 2022	51 participants, gender M/F-18/33, age 66 ± 12 years, mean BMI-26.1	Patients were administered a singular 2.2 mL injection of HANOX-M-XL (HAPPYCROSS®; LABRHA SAS, Lyon, France), an extended-release viscosupplement that integrates cross-linking and mannitol. This unique formulation allows for a single-injection treatment, providing convenience and potential therapeutic benefits to the patients.	Kelgreen-Lawrence Score, radiological phenotype, BMI, DE (duration of effectiveness).	A single intra-articular injection of HANOX-M provides pain relief for approximately one year for patients with KL 1 and 2.
11	Galluccio et al., 2022 [61]	Cohort study/2015–2022	60 patients, sex M/F-29/31, average age 61.07 ± 9.15, average value of BMI-22.075 ± 2.42	Viscosupplementation with HA (HYALUBRIX—Fidia Farmaceutici S.P.A., Abano Terme, Italy)—A complete treatment course with one weekly injection of Hyalubrix for 3 consecutive weeks, followed by a single booster injection every 3 months until the end of the 5th year of follow-up.	Kelgreen-Lawrence score, WOMAC, NRS	Over the past five years, quarterly IA injections of hyaluronic acid (HA) have proven to be a safe and efficient treatment for alleviating pain and enhancing joint function.
12	Tschopp et al., 2023 [62]	Prospective single-center placebo-controlled study/February 2016–November 2019	95 patients, sex M/F-54/41, age-54–68 years	HA (sodium hyaluronate solution, “Suplasyn 1-shot”; Viatris, Canonsburg, PA, USA), TRIAMCINOLONE (triamcinolon, “Triamcort Depot”; Zentiva, Prague, Czech Republic), PRP On day 1 of the study, patients received 1 mL of Triamcinolone (Triamcort Depot) or 6 mL of HA (Suplasyn 1-Shot), or 3 mL of the subject’s PRP.	NRS, WOMAC, TAS	After receiving glucocorticoid treatment, the group experienced a significant reduction in pain, as confirmed by both NRS and WOMAC scores one-week post-injection. However, this effect disappeared after three months. The HA-treated group had minimal changes in NRS and WOMAC scores, with the most noticeable pain reduction occurring at 15 months. The results for the group treated with PRP were inconclusive.
13	Yılmaz et al., 2024 [63]	Retrospective/February 2020–February 2022	60 participants, sex M/F-13/47, mean age 57.9 ± 4.29 years	VS with cross-linked HA (2 mL) (SO Visc Cross-Linked; Biolot Medical, Ankara, Türkiye) compared with linear HA (2 mL) (SO Visc; Biolot Medical, Ankara, Türkiye)	WOMAC, OKS	Both injections exhibited a noteworthy enhancement from the baseline in WOMAC and OKS at 3 and 6 months.
14	Colombini et al., 2023 [64]	Single arm monomeric interventional/February 2021–April 2022	38 participants gender M/F-17/21, age 26–83 years	VS with CR500 gel (a peptide mixture in a 1.5 mL monodose vial. CR500® is formulated as follows: demineralized water, glycerin 99.8% PF, Propylene glycol, PEG-40 hydrogenated castor oil, preservative, carbomer, hyaluronic Acid HMW, xanthan gum, disodium EDTA, panthenol, sodium hydroxide, SH-Polypeptide-85 and SH-Polypeptide-93). The treatment was administered during the initial visit and then repeated at home by the patients on two consecutive days per week for 4 weeks.	KOOS, LKI	The total LKI score decreased statistically from baseline to final of the research. The analysis of the KOOS pain subscale definitively demonstrated a significant improvement in the patient’s condition at two, three, and four weeks compared to baseline.
15	Ciapini et al., 2023 [65]	Prospective/January 2018–January 2020	60 participants, age 39–80 years	Subjects were randomly divided into three groups, with 20 subjects in each group (10 males and 10 females). Group A received IAHA ArthroVisc (ArthroVisc; Regen Lab, Le Mont-sur-Lausanne, Switzerland), Group B received autologous intra-articular platelet-rich plasma (PRP) (RegenKit-BCT-1; Regen Lab, Le Mont-sur-Lausanne, Switzerland), and Group C received an association of substances of plasma and HA (Cellular Matrix A-CP-HA kit; Regen Lab, Le Mont-sur-Lausanne, Switzerland). Each group underwent three intra-articular injections over the course of 2 months.	WOMAC, VAS	In Group A, the average VAS score started at 5.5 and lowered to 4.3 after 3 months, stabilizing at 4 after 6 months. The WOMAC score was 36.4 initially, decreased to 28.8 at 3 months, and increased to 31.8 at 6 months. In Group B, the mean VAS score was 6.1 before injections, decreased to 3.1 after 3 months, and remained at 3.5 after 6 months. The WOMAC score was 41.5 initially, decreased to 19.6 after 3 months, and remained unchanged in the subsequent 3 months.
16	Tammachote et al., 2016 [66]	Participants were recruited in a prospective, randomized, double-blind clinical trial. The treatment group was kept secret from patients and evaluators.	110 participants with knee osteoarthritis (KOA) were randomly assigned to receive either hylan G-F 20 or a triamcinolone acetonide injection.	1. Administer a single IA injection of 6 mL of hylan G-F 20 (Synvisc; Genzyme Biosurgery, Cambridge, MA, USA), a viscosupplement used to relieve joint pain. 2. Administer a single IA injection of 1 mL of 40-mg triamcinolone acetonide combined with 5 mL of 1% lidocaine hydrochloride and epinephrine for anti-inflammatory and analgesic effects.	Knee pain-100-mm VAS, WOMAC	After six months, triamcinolone acetonide exhibited equivalent improvements in knee pain, function, and range of motion compared to Hylan G-F 20. Furthermore, in contrast to Hylan G-F 20, triamcinolone acetonide exhibited superior pain control during the initial week and enhanced knee function during the subsequent week.
17	Hermans et al., 2019 [67]	RCT of subjects aged 18–65 with symptomatic KOA (Kellgren-Lawrence grade I–III)	Subjects were assigned at random to either receive standard care (control group) or standard care along with three weekly injections of high molecular weight hyaluronic acid (intervention group).	The study intervention involved three weekly injections of high-molecular-weight hyaluronic acid (Hylan G-F 20—Sanofi S. A, Paris, France), additionally to conventional care, including pain medication, physical therapy, and lifestyle recommendations.	OMERACT-OARSI criteria KOOS, NRS, Likert scale	High molecular weight hyaluronic acid (HMW-HA) injections led to a superior response to therapy and substantial improvements in pain relief, knee function, and overall assessment compared to the control group during the 52-week follow-up period. While the intervention group initially experienced temporary knee pain and swelling in the first 6 weeks, no serious adverse events were reported.
18	Bashaireh et al., 2015 [68]	Prospective, nonrandomized, unblinded, phase IV, multicenter, post-marketing study design	109 participants enrolled, with 84 completing all visits	The intervention in this study was a single intra-articular injection of 2 mL of Crespine® Gel (Biopolymer GmbH & Co. KG, Dümmer, Germany), a cross-linked hyaluronic acid product.	QoL WOMAC	The use of Crespine® Gel, a cross-linked hyaluronic acid product, unequivocally improved pain, stiffness, and physical function in subjects with KOA. The effects lasted for up to nine months following a single injection. Furthermore, the treatment demonstrated excellent tolerability, with predominantly mild and temporary local adverse events.
19	Ertürk et al., 2016 [69]	Single-blinded, randomized, prospective controlled trial	Two groups of patients were formed. One group received hyaluronic acid injections directly into the joint, while the other received a combination of hyaluronic acid injections into the joint and a single corticosteroid-lidocaine injection around the joint.	The treatment groups received either five weekly 2.5 mL injections of 900,000 Da sodium hyaluronate (10 mg/mL, Adant®, Meiji Seika Kaisha Co, Tokyo, Japan). Ethyl chloride spray (IGS AEROSOLS GMBH, D-79664 Wehr/Baden, Germany)) directly into the knee joint (IA), or a single injection of 1 mL of betamethasone dipropionate (6.43 mg) and betamethasone sodium phosphate (2.63 mg) mixed with 1 mL of 20 mg lidocaine (Diprospan®; Schering-Plough, Istanbul, Turkey) mixed in 1 ml:20 mg of lidocaine HCl without epinephrine (Jetokain simplex®; Adeka, Istanbul, Turkey) HCl into the most painful areas of the knee, in addition to the hyaluronic acid injections (periarticular lidocaine-corticosteroid injection).	VAS pain scale, WOMAC, and HSS knee scores.	Adding a periarticular lidocaine-corticosteroid injection (PALCI) to intraarticular hyaluronic acid (HA) treatment provided better pain and functional outcomes in the first 3 weeks compared to HA alone, but the differences were not significant after 6 weeks. The combined PALCI and HA treatment can offer earlier pain relief and help patients return to daily activities sooner compared to HA alone. Some minor adverse events were observed with the combined treatment, but no serious adverse events were reported.
20	Rici et al., 2017 [70]	clinical comparison study.	A total of sixty patients, comprising 32 males and 28 females aged between 40 and 70 years, were methodically assigned to two separate research study groups.	The study involved two treatment groups. Group A received three weekly injections of 1.6% hyaluronic acid directly into the joint, while Group B took Syalox (River Pharma, Orio Litta, Italy) 300 Plus (which contains 300 mg hyaluronic acid and 100 mg Boswellia serrata extract) orally for 20 days, followed by Syalox 150 (containing 150 mg hyaluronic acid) for another 20 days. Both treatments showed positive effects on individuals with early osteoarthritis. The results indicated that using both treatments together could be beneficial, especially for different age groups.	AKS, VAS	The research paper found that both hyaluronic acid (HA) injections and oral administration positively affect early osteoarthritis patients. The treatment led to significant improvements in AKSS and VAS scores. It was observed that younger patients experienced greater benefits from injections, while older patients showed improved outcomes with oral administration. These findings strongly suggest that a combined therapy approach could be highly effective. The study also highlights the potential of oral HA absorption and distribution to joints.
21	Tang et al., 2015 [71]	Observational, comparative clinical trial	The study included 23 subjects with KOA and 14 age-matching control subjects without knee osteoarthritis from an outpatient clinic	Bilateral intra-articular knee joint injections with hyaluronic acid (HA) were administered to the knee OA group using a 1% HA solution (ARTZ). The injections were administered at 2.5 mL per joint/weekly for 5 consecutive weeks.	Muscle co-contraction and motor response of quadriceps, hamstrings, tibialis anterior, and medial gastrocnemius	The paper’s research shows that injecting hyaluronic acid into the knee joint can change muscle activation patterns. In a study involving 23 knee osteoarthritis patients and 14 control subjects, the injections improved muscle activation, reduced co-contraction, and enhanced motor activity. These improvements lasted for up to six months after treatment, demonstrating the effectiveness of hyaluronic acid in altering muscle activation patterns in knee osteoarthritis patients.
22	Lisi et al., 2018 [72]	Phase-2 randomized controlled trial.	The study comprised 156 participants, with 77 in the intervention group and 79 in the control group. All participants exhibited symptomatic KOA and were aged between 18 and 65	In the intervention group, patients underwent a series of three autologous PRP alongside calcium gluconate injections, whereas the control group received three hyaluronic acid injections (20 mg/2 mL; Hyalgan; Fidia, Abano Terme, Italy).	MRI scans and functional scales like WOMAC, Lysholm, Tegner, AKSS, Lequesne, and VAS for pain	The MRI scans showed improvement in twenty-eight patients in the intervention group and twenty-two in the control group six months after treatment. It is evident that activated platelet-rich plasma effectively reduced joint damage and improved pain, function, and quality of life for at least one year. The treatment group consistently exhibited superior improvements in symptoms and functional scales compared to the control group, and these improvements were statistically significant across various scales.
23	Di Martino et al., 2019 [73]	Randomized Controlled Trial-5 years follow-up	The population sample size for the study was 192 patients who were enrolled in RTC comparing PRP and HA administrating for KOA	One group of 85 participants received three weekly intra-articular injections of leukocyte-rich PRP, while the other group of 82 participants received three weekly intra-articular injections of high-molecular-weight HA (Hyalubrix 30 mg/2 mL, molecular weight > 1500 kDa, Fidia Farmaceutici S.P.A., Abano Terme, Italy).	International Knee Documentation Committee (IKDC) subjective score, EuroQol VAS, Tegner score.	Both PRP and HA therapies demonstrated effectiveness in improving knee function and symptoms. At the final assessment, PRP exhibited higher values compared to baseline; however, It did not demonstrate a significantly better clinical improvement compared to HA. The PRP group exhibited a notably lower rate of reintervention at 24 months.

KOOS—Knee Injury and Osteoarthritis Outcomes Score, VAS—Visual analog Scale, K-VAS—Korean Visual analog Scale, WORMS—Whole Organ Magnetic Resonance Imaging, OKS—Oxford Knee Score, WOMAC—The Western Ontario and McMaster Universities Arthritis Index, K-WOMAC—Korean Western Ontario and McMaster Universities Arthritis Index, KSF-36—Korean Medical Outcome Study 36-Item Short Form, PGA—Patient Global Assessment, IGA—Investigator Global Assessment, HAQ—Health Assessment Questionnaire, SF 36—Short Form 36 Health Survey, ROS—Reactive Oxigen Species, MW—Molecular Weight, LMW—Law Molecular Weight, HMW—Height Molecular Weight, BMI—Body Mass Index, PAGA—Patient Global Assessment of disease activity, NRS—Numeric Rating Pain Scale, IAHA—Intraarticular Hyaluronic Acid, HMW-IAHA—High Molecular Weight-Intraarticular Hyaluronic Acid, PRP—Platelet Rich Plasma, PRGF—Plasma Rich in Growth Factor, VS—Viscosupplementation, HA-SC—Hyaluronic Acid Sinogel, TAS—Tegner Activity Scale, LKI—Lequesne Knee Index.