Table 3. Characteristics of studies included in the systematic review.
KOOS=knee and osteoarthritis outcome system, EUROQoL=European quality of life scale, KQoL=knee quality of life, LKI=Lequesne knee index, PKC=pain killer consumption, XLHA=cross linked hyaluronic acid, WBP=weight bearing pain, RCT-SR/DB/SB/OL/NB=randomized control trial simple randomization/double blind/single blind/open label/non-blinded, ESWT=extracorporeal shock wave therapy, SCT=stair climb test, KSS=knee society score, SLS=single limb stance, TUG=timed up and go, PGA=patient global assessment, PRO=patient reported outcomes, SANE=single assessment numerical evaluation, LP-PRP=leukocyte poor platelet-rich plasma, IKDC=international knee documentation committee, PGRF=PRP derived growth factor, JKOM=Japanese osteoarthritis measure, LMWHA=low molecular weight hyaluronic acid, IMWHA=intermediate molecular weight hyaluronic acid, HMWHA=high molecular weight hyaluronic acid, VAS=visual analog scale, WOMAC=western Ontario and McMaster university osteoarthritis index, HAQ=health assessment questionnaire, BM-MSC=bone marrow derived mesenchymal cells, UC-MSC=umbilical cord derived mesenchymal cells, LLLT=low level laserK therapy, PT=physical therapy, NAC=N-Acetyl Cysteine, DX=dexamethasone, TA=Triamcinolone Hexacetonide, ASA=amniotic suspension allograft
| Study Details | Patient’s Characteristics | Injection Characteristics | Outcome | ||||||||||
| Sr. | Author | Year | Study type | Number | Mean age (Yrs.) | OA grade | HA brand | Molecular weight (KDa) | No. of injections | Comparison group | Outcome measures assessed | Follow up | Conclusion |
| 1 | Henrotin et al. [32] | 2017 | RCT-DB | 66 | 65 | 2-3 | Kartilage Cross (XLHA) | NA | 1 | Saline | Reduction in Coll2-1 | 90 days | Reduction in cartilage marker was significant |
| 2 | Zhang et al. [33] | 2015 | RCT-DB | 349 | 60 | 2-3 | Durolane | 90,000 | 1 | Artz (HA)- 5 inj. (620-1200 kDa) | WOMAC, GSA | 26 wks. | Effective and non-inferior |
| 3 | Yang et al. [34] | 2018 | RCT-DB | 258 | 64 | 2-3 | HYA-JOINT plus (CCH) | NA | 1 | Hylan G-F-20 (6000 kDa) | WOMAC, SLS, TUG | 3-6 months | Improvement. CCH group superior to ADH |
| 4 | Gigis et al. [35] | 2016 | RCT-DB | 80 | 67 | 2-4 | LMW | 1,000-1,500 | 5 | HMW/3 inj. (6,000-7,000) | VAS, WOMAC | 3 mn-1 yr | Significant improvement & no difference in groups |
| 5 | Ha et al. [36] | 2017 | RCT-DB | 266 | 62 | 1-3 | XLHA (Hyruan Plus) | ≥10,000 | 1 | HMWHA (3 inj) | WBP, WOMAC | 12 wks. | Effective and non-inferior, safe |
| 6 | Petrella et al. [37] | 2015 | RCT-DB | 98 | 59 | 2-3 | Hydros(Hydro-gel beads) | NA | 1 | Hydros-TA and Synvisc-one | WOMAC | 26 wks. | Clinical improvement |
| 7 | Aguiar et al. [38] | 2019 | RCT-DB | 44 | 57 | 1-2 | Orthovisc | 1,000-2,900 | 1 | HA+DX, DX alone | WOMAC, Flx & Ext. strength | 6 months | Significant improvement |
| 8 | Martin et al. [39] | 2016 | RCT-DB | 60 | 69 | 2-3 | Md-knee (collagen) | 600-1200 | 5 | Supartz (HA) | LKI, VAS, PKC | 3-6 months | Significant improvement both groups |
| 9 | Goncars et al. [40] | 2017 | RCT-SR | 56 | 58 | 2-3 | BM-MSCs | 800-1,500 | 1 | GO-ON (HA -3 inj) | KOOS, KSS | 3-12 months | Significant improvement more in BM-MSCs |
| 10 | Matas et al. [41] | 2018 | RCT-DB | 26 | 55 | 2-3 | UC-MSCs 2 dose (0-6 mn) | 90,000 | 2 | UC-MSCs-1 dose, Durolane | PGA, WOMAC | 52 wks | Improvement in all group. Sustained up to 12 month in UC-MSCs-2 |
| 11 | Espinosa [42] | 2016 | RCT-NB | 30 | 60 | 2-4 | BM-MSC-LD, BM-MSC-HD Plus HA | 1,500-2,000 | 1 | Hyalone (1,500-2,000 kDa) | VAS, WOMAC, MRI, X-ray | 3-12 months | Clinical improvement. Sustained up to 12 mon in BM-HSC-HD group |
| 12 | Raeissadat et al. [43] | 2018 | RCT-DB | 141 | 60 | 2-3 | Hyalgan | 500-730 | 3 | Ozone sol. | VAS, WOMAC (Persian version) | 6 months | Clinical improvement both groups. no diff |
| 13 | Yoon et al. [44] | 2019 | RCT-DB | 30 | 65 | 2-3 | HA+PDRN (polydeoxyriboneucleotide placenetex) | 1500-2000 | 3 | HA (Hylone plus) | VAS, WOMAC, KSS | 6 months | Effective and combination can be considered for OA treatment |
| 14 | Raeissadat et al. [45] | 2020 | RCT-SB | 102 | 58 | 2-3 | PRGF (2 inj.- 3 wks. apart) | 730 | 3 | HA (Hyalgan) | VAS, WOMAC, ADL, LKI | 6-12 months | Satisfactory improvement higher in PRGF group at 12 mon. |
| 15 | Montanez et al. [46] | 2016 | RCT-DB | 53 | 61 | 1-3 | PRP | 600-1,200 | 3 | Adant (HA) | VAS, KOOS, EUROQOL | 3-6 months | Clinical improvement both groups |
| 16 | Raeissadat et al. [47] | 2017 | RCT-SB | 69 | 59 | 2-3 | PRGF | 500-730 | 2 | Hyalgan (HA-3 inj) | VAS, WOMAC, LKI | 6 months | Equally effective |
| 17 | Farr et al. [48] | 2019 | RCT-SB | 200 | 55 | 2-3 | ASA (amniotic suspension allograft) | 1,000-2,900 | 1 | Monovisc (1,000-2,900), saline | PRO, KOOS, VAS, SANE | 3-6 months | Improvement, greater in ASA group |
| 18 | Ozcamdalli et al. [50] | 2017 | RCT-SB | 20 | 55 | 2-3 | Hyalan G-F 20 | 6,000 | 1 | NAC (1 inj) | VAS, WOMAC | 6 wks. | Effective. NAC reduces cartilage degradation markers |
| 19 | Ip [54] | 2015 | RCT-DB | 70 | 75 | 3 | Hyalgan+LLLT | 500-730 | 5 | Saline+PT+ Sham light irrad | WOMAC | Mean 7 yrs. | Prolongs longevity of knee joint |
| 20 | Strand et al. [55] | 2016 | RCT-DB | 350 | 61 | 1-3 | Gel-200 | NA | 1 | Retreatment after 13 wks. | WOMAC | 26 wks. | Effective and safe |
| 21 | Paterson et al. [56] | 2016 | RCT-DB | 23 | 51 | 2-3 | PA-PRP | 6,000 | 3 | Synvisc-one | VAS, KOOS, KQoL | 12 wks. | Improvement, more significant in PRP group |
| 22 | Cole et al. [57] | 2017 | RCT-DB | 111 | 56 | 1-3 | Synvisc | 6,000 | 3 | PRP | VAS, WOMAC, IKDC | 24 wks. | Significant improvement both groups |
| 23 | Lana et al. [58] | 2017 | RCT-DB | 105 | 61 | 1-3 | Euflexxa (HMW) | 2,400-3,600 | 3 | HA+PRP | VAS, WOMAC | 3-12 months | Improvement. More and sustained in HA+PRP group |
| 24 | Lee et al. [59] | 2017 | RCT-SR | 61 | 68 | 2-3 | ESWT (3 sessions) | 3,000 | 3 | HA | VAS, WOMAC, SCT | 1-3 | Significant improvement both group |
| 25 | Suppan et al. [60] | 2017 | RCT-NB | 127 | 59 | 1-3 | GO-ON (5mL) | 800-1,500 | 1 | GO-ON (HA -3 inj- 2.5ml) | WOMAC | 3 months | Good efficacy, tolerability and safety |
| 26 | Yu et al. [61] | 2018 | RCT-DB | 360 | 48 | NA | PRP | NA | 5 | HA, PRP+HA, Placebo | WOMAC, Karnofsky perfo | 52 wks. Post Trt. | Improvement significant in PRP+HA group |
| 27 | Lamo‑Espinosa et al. [62] | 2018 | RCT-NB LT | 27 | 60 | 2-4 | BM-MSCs-LD/HD +HA | 1,500-2,000 | 1 | HA alone (Hyalone) | VAS, WOMAC | 12-48 months | Safe and feasible with long term clinical improvement |
| 28 | Hangody et al. [63] | 2018 | RCT-DB | 368 | 58 | 1-3 | Cingal (HA+TA) | 1900 | 1 | Monovisc (1000-2900 kDa), saline | PGA, WOMAC | 26 WKS | Effective, immediate and LT relief with Cingal > 26 wks |
| 29 | Wang et al. [64] | 2018 | RCT-DB | 120 | 63 | 2-4 | HA+CS (betamethasone) | 600-1,500 | 1 | HMWHA | VAS, WOMAC | 6 months | Improvement, rapid in HA+CS group |
| 30 | Buendia et al. [65] | 2018 | RCT-SR | 106 | 56 | 1-2 | LP-PRP-1 | 90,000 | 1 | HA (Durolane), NSAID | VAS, WOMAC, MRI, X-RAY | 6-12 months | Improvement better in LP-PRP group at 52 wks. |
| 31 | Hermans et al. [66] | 2019 | RCT-OL | 156 | 54 | 1-3 | Hylan (G-F 20) | 6,000 | 3 | UC (usual care) | KOOS, PGA | 52 wks. | Effective |
| 32 | Maheu et al. [67] | 2019 | RCT-DB | 292 | 67 | 1-3 | Ostenil1 Plus | 1,000-,2000 | 1 | Hyalan G-F 20 | WOMAC | 6 months | Effective and non-inferior |
| 33 | Takamura et al. [68] | 2019 | RCT-SB | 311 | 61 | 1-3 | Gel-200 (XLHA) | >5,000 | 1 | Saline | VAS, WOMAC | 26 wks. | Effective and clinical improvement |
| 34 | Tavassoli et al. [69] | 2019 | RCT-SB | 95 | 63 | 1-2 | PRP-1 | 730 | 3 | PRP-2, HA-3 (Hyalgan) | VAS, WOMAC | 12 wks. | Improvement, PRP better than HA |
| 35 | Di Martino et al. [70] | 2019 | RCT-DB | 192 | 57 | 1-3 | PRP | 3,200 | 3 | Hylubrix (HA) | VAS, IKDC, EUROQoL | 24 mn & Mean 64 mn | Effective, not superior in PRP group |
| 36 | Bahrami et al. [71] | 2020 | RCT-SB | 90 | 56 | 2-3 | HMWHA (Arthromac) | NA | 1 | LMWHA (3 inj.) | VAS, WOMAC, LKI | 2-6 months | Remarkable improvement both group with no difference |
| 37 | Kesiktas et al [72] | 2020 | RCT-SR | 54 | 56 | 2-4 | Prostrolane (Peptide) | 1700-2100 | 1 | HA (Biometics), PRP | VAS, WOMAC, HAQ | 3 months | Significant improvement, better in peptide group |
| 38 | Mochizuki et al. [73] | 2020 | RCT-SB | 59 | 67 | 1-4 | Artz (LMWHA) | 620-1,200 | 5 | Suvenyl (IMMWHA ) (1500-3900) | VAS, JKOM | 6 wks. | Significant efficacy. No difference |