Table 3.

Clinical evaluation of HA-based hydrogels.

Objective	Trial/Phase	Number/Age/BMI a (kg/m2)/K-L b Grade/WOMAC c (Pain)/Sex of Participants	Treatment	Administration Route/Dose/Clinical Evaluation	Results
To assess Hydros d and Hydros d-TA e regarding their safety and initial performance in comparison with Synvisc-One f in patients with knee OA g [106]	Prospective, multicenter, randomized, double-blind feasibility trial/II	98/60 years (average)/29.0 (average)/II and III/50–90 mm (using VAS 0–100 mm)/male and female	Hydros d Hydros d-TA e Synvisc-One	i.a. h injection/6 mL of Hydros d or Hydros d-TA e, or Synvisc-One f, single dose/2, 6, 13 and 26 weeks p.i. i	Well-tolerated injections. Reduced WOMAC c A (pain) score in 26 weeks with all three formulations. Quicker pain relief with Hydros d-TA e in comparison with Hydros d Enhancement in pain relief with Hydros d-TA e in comparison with Synvisc-One f
To investigate the safety and efficiency of Gel-One® j in treating patients with symptomatic knee OA g [107] To examine the continued safety and efficacy of Gel-One® j(extension of the aforementioned clinical trial) [108]	Double-blind, multicenter, RCT k/-Multicenter extension and retreatment trial	Gel-One® j: 247, PBS l: 128/40–80 years old/28.3/I, II and III/≥40 mm (using VAS m 0–100 mm)/male and femaleContinued observation/≥ 64, second injection/≥ 196/40–80 years old/28.8/I, II and III/≥40 mm (using VAS m 0–100 mm)/male and female	Gel-One® j PBS l (control) Gel-One® j PBS l (control)	i.a. h injection/3 mL (30 mg HA n/3 mL), 3 mL PBS l, single dose/1 wk, 3, 6, 9 and 13 wks p.i. iSecond injection: i.a. h injection/3 mL (30 mg cross-linked HA n/3 mL), 3 mL PBS l, single dose/13 wks p.i. i	Significant clinical improvement with respect to pain as well as physical function as early as 3 weeks Well-tolerated treatment Pain relief over 13 weeks Continued observation: improved OA g signs/symptoms over 26 weeks Well-tolerated and safe retreatment Retreatment efficiency similar to that of initial treatment for a time period of 13 weeks The initial injection was adequately effective to eliminate the need for a second injection in a large number of patients [120]
Integrated analysis of two RCTs k aiming to investigate the safety and efficiency of a single i.a. h injection of Gel-One® j in treating knee OA g [109]	Multicenter, double-blind RCT k/- Multicenter, double-blind RCT k/-	SI-6606/01: -/60 years old (average)/~28.8 (average)/I-III/≥40 mm (using VAS m 0–100 mm)/male and female Gel/1133: -/60 years old (average)/~28.8 (average)/I-III/≥40 mm (using VAS m 0–100 mm)/male and female Pooled ITT o population: Gel-One® j: 649, PBS l: 5345	Gel-One® j PBS l (control) Gel-One® j PBS l (control)	i.a. h injection/single dose/3, 6, 9 and 13 wks p.i. ii.a. h injection/single dose/3, 6, 12, 18 and 26 wks p.i. i	Proof of the efficiency of a single i.a. h injection of Gel-One® j for the treatment of knee OA g over 26 weeks No major safety issues
To demonstrate the benefit of a single i.a. injection of Gel-One® j as treatment of knee OA g in a population similar to those of viscosupplementation-reported trials [110]	Subgroup analysis of a multicenter RCT k	Subgroup: 311 (Gel-One® j:152, PBS:159)/40–80 years old/II and III/40–80 mm (using VAS m 0–100 mm)/male and female	Gel-One® j PBS l (control)	i.a. h injection/single dose/3, 6, 12, 18 and 26 wks p.i. i	Clinically important pain improvement 26 weeks p.i. i
To compare the safety and efficiency of HYA-JOINT Plus p with Synvisc-One f in subjects with kneeOA g [111]	Prospective, double-blind RCT k/-	HYA-JOINT Plus p: 62, Synvisc-One f: 59/40–85 years old/~25 (average)/II, III//≥30 mm (using VAS m 0–100 mm)/male and female	HYA-JOINT Plus p Synvisc-One f	i.a. h injection/3 mL of HYA-JOINT Plus p (20 mg/mL), 6 mL of Synvisc-One f (8 mg/mL), single dose/1, 3 and 6 months p.i. i	Safe and efficient treatment for the time frame tested Significantly improved pain score compared with Synvisc-One f at 1, 3, and 6 months p.i. i
To examine the efficacy of hylastan SGL-80 q regarding pain reduction in patients with knee OA g, in comparison with corticosteroid injection [112]	Multicenter, double-blind, randomized, parallel group, trial/-	Hylasatan SGL-80 q (single dose): 130, hylasatan SGL-80 q (double dose): 129, methylprednisolone acetate: 132/>40 years old/-/I–III/1.5–3.5 (using Likert scale)/male and female	hylastan SGL-80 qmethylprednisolone acetate	i.a. h injection/4 mL of hylastan SGL-80 q on day 0, or 2 × 4 mL of hylastan SGL-80 q on day 0 and week 2, or 40 mg of methylprednisolone acetate on Day 0/4, 8, 12, 16, 20 and 26 weeks	Significantly reduced pain with all three treatments No safety issues Hylastan SGL-80 q was not proven to be superior to methylprednisolone acetate
To evaluate the efficacy and safety of Cingal® r in comparison with Monovisc® s for the treatment of knee OA g [113]	Prospective, randomized, multicenter, double-blind, placebo-controlled trial/-	Cingal® r:149, Monovisc® s:150, saline:69/40–75 years old/40–90/I, II or III/40–90 mm (using VAS m 0–100)/male and female	Cingal® r Monovisc® s Saline	i.a. c injection/4 mL of Cingal® r (88 mg cross-linked HA and 18 mg TH), 4 mL of Monovisc® s (88 mg cross-linked HA), 4 mL of saline, single dose/1, 3, 6, 12, 18 and 26 wks p.i. i	Significantly better performance of Cingal® r compared with Monovisc® s from 1 to 3 weeks Similar performance of Cingal® r and Monovisc® s from 6 to 26 weeks.
To prove the safety and efficacy of Monovisc® s in relieving joint pain inidiopathic knee OA g patients [114]	Multicenter, double-blind, randomized, placebo-controlled trial/-	Monovisc® s: 184, saline: 185/35–75 years old/20–40 kg/m2/II or III/200–400 mm (VAS m pain score 0–500 mm)/male and female	Monovisc® s Saline	i.a. h injection/4 mL of Monovisc® s, 4 mL of saline (0.9%), single dose/2, 4, 8, 12, 20 and 26 wks p.i. i	Safe and efficient treatment Clinically meaningful pain reduction in 2 weeks ≥50% improvement in WOMAC c pain by week 26
To assess thesafety and efficiency of Durolane® t in unilateral knee OA g patients [115]	Randomized, double-blind, saline-controlled trial/-	Durolane® t: 108, saline: 110/> 50 years old/20.1–41/Likert version of WOMAC c pain score: 7–17/male and female	Durolane® t Saline	i.a. c injection/3 mL of Durolane® t (20 mg/mL) or 3 mL saline, single dose/2, 4 and 6 wks p.i. i	Well-tolerated treatment No significant difference between Durolane® t and control at 6 weeks (primary analysis) Significantly higher responder rate with Durolane® t at 6 weeks compared with control for patients with no clinical effusion in the knee at baseline (post hoc subgroup analysis)
To compare Durolane® t with MPA u for the treatment of unilateralknee OA g [116]	Prospective, multicenter, randomized, active-controlled, double-blind, noninferiority trial (blinded phase)Open label extension phase	Durolane® t: 221, MPA u: 221/35–80 years old/≤40/II, III/7–17/male and female	Durolane® t MPA u	Blinded phase: i.a. h injection/3 mL of Durolane® t (20 mg/mL) or 1 mL of MPA u (40 mg/mL), single dose/2, 4, 6, 12, 18 and 26 wks p.i. iOLE v: i.a. h injection/3 mL of Durolane® t (20 mg/mL), single dose/28, 39 and 52 wks post initial i.a. h	Well-tolerated treatment and noninferior compared with MPA u at 12 weeks Benefit maintenance up to 26 weeks in contrast to MPA u Second i.a. h injection at 26 weeks resulted in long-term improvement with no risk of complications or increased sensitivity
To compare safety and effectiveness of Durolane® t and Artz w in treating knee OA g [117]	Multicenter, randomized, double-blind, noninferiority trial/-	Durolane ® t:175, Artz w:174/40–80 years old/-/II or III/7–17 (Likert pain score range 0–20)/male and female	Durolane® t Artz w	i.a. h injection/1 × 3 mL of Durolane® t (and 4 sham s.c. x injections on weeks 1, 2, 3 and 4); or 5 × 2.5 mL of Artz w on weeks 0, 1, 2, 3 and 4/0, 6, 10, 14, 18 and 26 wks	Safe, well-tolerated and efficient treatments A single dose of Durolane® t is not inferior to multiple injections of Artz w regarding pain, stiffness, function and global self-assessment, at 18 and 26 weeks
To evaluate the safety and efficiency of XLHA y in comparison with HMWHA zin treating symptomatic knee OA g [118]	Double-blind, randomized, multicenter, noninferiority trial	XLHA y (single dose): 141, HMWHA z (three doses): 146/>40 years old/<32/I-III/≥40 mm (using VAS m 0–100 mm)/male and female	XLHA y HMWHA z	i.a. h injection/XLHA y group: 2 × 2 mL of PBS l (9 mg/mL) and 3 mL of XLHA y (20 mg/mL), HMWHA z group: 3 × 2 mL of HMWHA z (10 mg/mL)/1 wk, 2, 3, 4, 9, 12 and 15 wks p.i. i	A single i.a. h injection of XLHA y was not found to be inferior to three weekly i.a. h injections of HMWHA z with respect to WBP aa reduction
To compare Conjuran® ab with Synovian® acand Hyruan Plus® ad regarding their analgesic efficiency in patients with knee OA [119]	Pilot study	Synovian® ac: 5, Hyruan Plus® ad: 5, Conjuran® ab: 5/≥40 years old/-/I- III/≥40 mm (using VAS 0–100 mm)/male and female	Synovian® acHyruan Plus® adConjuran® ab	i.a. h injection/3 i.a. h injections at 1 week interval (all three groups), 3 mL of Synovian® ac (20 mg/mL) and 2 × 3 mL of saline, 3 × 2 mL of Hyruan Plus® ad (10 mg/mL), 3 × 2 mL of Conjuran® ab (20 mg/mL)/4 wks after the last injection	Conjuran® ab reduced more effectively WBP aa in comparison with Synovian® ac and Hyruan Plus® ad
To examine the safety and efficiency of YYD302 ae for knee OA g [121]	Randomized, double-blind, active-controlled, multicenter trial/III	190/≥40 years old/≤32/I- III/≥40 mm (using VAS m 0–100 mm)/male and female	YYD302 aeSynovian® ac	i.a. h injection/2 mL of YYD302 ae, 3 mL of Synovian® ac, single dose/2, 4 and 12 wks after the i.a. h injection
To examine the safety and efficiency of Cartistem® af with respect to the regeneration of articular cartilage [103]	Open-label, single-arm, single-center trial/I/II	7/51–77 years old/-/III (ICRS ag grade of defect: 4)/40–60 mm (using VAS m 0–100 mm)/male and female	Cartistem® af	Transplantation, closure of wound and application of a splint/0.5 mL of Cartistem® af per cm2 of defect (0.5 × 107 cells per ml), low-dose: 2.3–2.5 mL of Cartistem® af, high dose: 3.3–4.0 mL of Cartistem® af/24 weeks (short term), 7 years (long term)	Efficient medicinal product for regeneration of robust cartilage The 7-year follow up revealed stable, improved clinical outcome and absence of significance adverse effects
To investigate the ability of Cartistem® af to reliably restore cartilage in patients with large cartilage lesions and to examine the long-term maintenance of the potential clinical improvements [105]	Randomized controlled trial/III	Cartistem® af: 57, microfracture: 57/55.9 years old (average)/~ 26 (average)/II, III (ICRS ag grade 4)/-/male or female	Cartistem® afmicrofracture	Surgical implantation, closure of wound and application of a splint/-/48 weeks, 36, 48 and 60 months	Improvement of ICRS ag grade at 48 weeks No significant improvement of VAS m pain, IKDC ah and WOMAC c scores compared with microfracture at 48 weeks Significantly better clinical results in comparison with microfracture 36 and 60 months postsurgical intervention. Improved grade of cartilage in elderly patients with full-thickness cartilage lesions as well as improved cartilage function and pain 60 months post operation compared with microfracture
To evaluate the safety and efficiency of Cartistem® af, in treating articular cartilage lesions in the knee due to trauma, ageing, or degenerative diseases [104]	Open label trial/I/IIa	12/>18 years old/≤35/ICRS ag grade 3 or 4/20–60 mm (using VAS m 0–100 mm)/male and female	Cartistem® af	Surgical implantation/0.5 mL of the medicinal product per cm2 of cartilage lesion/12 months

^a Body mass index, ^b Kellgren–Lawrence, ^c Western Ontario and McMaster Universities Osteoarthritis Index, ^d hyaluronan-based hydrogel suspended in hyaluronan solution, ^e triamcinolone acetonide, ^f hylan-based viscosupplement, ^g osteoarthritis, ^h intra-articular, ⁱ postinjection, ^j viscoelastic hydrogel for intra-articular use based on hyaluronic acid (HA) derivative, ^k randomized controlled trial, ^l phosphate buffered saline, ^m Visual Analog Scale, ⁿ hyaluronic acid, ^o intention-to-treat, ^p novel cross-linked hyaluronan, ^q soft gel-80, ^r cross-linked sodium hyaluronate containing triamcinolone hexacetonide, ^s cross-linked sodium hyaluronate viscosupplement, ^t transparent gel (viscosupplement) based on nonanimal stabilized hyaluronic acid (NASHA), ^u methylprednisolone acetate, ^v open-label extension phase, ^w noncross-linked animal-derived HA, ^x subcutaneous, ^y cross-linked hyaluronate, ^z linear high molecular weight hyaluronate, ^aa weight-bearing pain, ^ab polynucleotide sodium, ^ac 1,4-butanediol diglycidyl ether-cross-linked sodium hyaluronate, ^ad sodium hyaluronate, ^ae intra-articular hyaluronic acid, ^af medicinal product comprising culture-expanded allogeneic human umbilical-cord-blood-derived mesenchymal stem cells (hUCB-MSCs) and hyaluronic acid (HA) hydrogel, ^ag International Cartilage Repair Society, ^ah International Knee Documentation Committee.