Intra-Articular Injection of Cross-Linked Hyaluronic Acid-Dexamethasone Hydrogel Attenuates Osteoarthritis: An Experimental Study in a Rat Model of Osteoarthritis

Abstract

Cross-linked hyaluronic acid hydrogel (cHA gel) and dexamethasone (Dex) have been used to treat knee osteoarthritis (OA) in clinical practice owing to their chondroprotective and anti-inflammatory effects, respectively. The aim of the present study was to compare the treatment effects of the cHA gel pre-mixed with/without Dex in a surgery-induced osteoarthritis model in rats. Anterior cruciate ligament transection (ACLT) surgery was performed on the right knee of rats to induce OA. Male 2-month-old Sprague-Dawley rats were randomly divided into five groups (n = 10/per group): (1) ACLT + saline; (2) ACLT + cHA gel; (3) ACLT + cHA-Dex (0.2 mg/mL) gel; (4) ACLT + cHA-Dex (0.5 mg/mL) gel; (5) Sham + saline. Intra-joint injections were performed four weeks after ACLT in the right knee. All animals were euthanized at 12 weeks post-surgery. Cartilage damage and changes in the synovial membrane were assessed by micro X-ray, Indian ink articular surface staining, Safranin-O/Fast Green staining, immunohistochemistry, hematoxylin and eosin staining of the synovial membrane, and quantitative reverse transcription-polymerase chain reaction for changes in gene expression. Micro X-ray revealed that the knee joint treated with the cHA-Dex gel was wider than those treated with cHA gel alone or saline. The cHA-Dex gel group had less Indian ink staining (indicator of cartilage fibrillation) than the cHA gel or saline injection groups. Safranin-O/Fast Green staining indicated that increased proteoglycan staining and less cartilage damage were found in the cHA-Dex gel group compared with the cHA gel or saline injection groups. Quantification of histology findings from saline, cHA gel, cHA-Dex (0.2 mg/mL) gel, cHA-Dex (0.5 mg/mL) gel, and sham groups were 5.84 ± 0.29, 4.50 ± 0.87, 3.00 ± 1.00, 2.00 ± 0.48, and 0.30 ± 0.58 (p < 0.05), respectively. A strong staining of type II collagen was found in both the cHA-Dex gel groups compared with saline group or cHA alone group. Similar result was found for the mRNA level of aggrecan and opposite result for type X collagen. Hematoxylin and eosin staining in the synovial membrane showed less synovial lining cell layers and reduced inflammatory cell infiltration in cHA-Dex gel-treated animals compared with saline or cHA only groups. Altogether, cHA-Dex gel has better chondroprotective and anti-inflammatory effects in rat surgery-induced osteoarthritis than cHA alone.

Glycosaminoglycan and Proteoglycan Biotherapeutics in Articular Cartilage Protection and Repair Strategies: Novel Approaches to Visco‐supplementation in Orthobiologics

“…[391] A systematic review, which included data from six randomized controlled trials comparing the effectiveness of PRP with other intra-articular injections, exercise, or analgesia for a minimum of 6 months PRP produced statistically significant improvements in WOMAC scores for up to 12 months. [393][394][395] www.advancedsciencenews.com www.advtherap.com HA hydrogel n/a Dexamethasone Cortocosteroid [310] Adant (Suprahyal) 500-1000 Tenoxicam NSAID [311] Variofill (Adoderm, Langenfeld, Gmbh) HMWCR Diclofenac Sodium clodronate Triamcinolone acetonide Ropivacaine HCl NSAID DMOAD Cortocosteroid Anaesthetic [312] [ 313] Hydros, Hydros-TA HMW Triamcinolone acetonide Cortocosteroid [314] Cingal 1900 Triamcinolone acetonide Cortocosteroid [315] Hylan GF-20 HMWCR Triamcinolone acetonide Cortocosteroid [316] HA solution 800 Mannitol Anti-oxidant [317] Go-on matrix Ostenil Plus 1500 Mannitol Anti-oxidant [320] Happyvix 1500 Mannitol Anti-oxidant [320] Happycross 1500 Mannitol Anti-oxidant [320] Synolis V-A 2000 Sorbitol Anti-oxidant [320] HA 4AR conjugate 2200 4 aminoresorcinol Anti-oxidant [321] Ostenil 1000-2000 l-glutathione Anti-oxidant [322] Arthrum HCS 2800 CS GAG [320] Surgical Syonium 2800 CS GAG [320] HA-sCT conjugate 200 Salmon calcitonin DMOAD [323] HA ADAMTS inhibitor n/a ADAMTS inhibitor DMOAD [324] HA hydrogel 60-120 Doxycycline DMOAD [296] Hanox Hanox M-XL 1500 n/a Cortivazol Triamcinolone hexacetonide Mannitol + lidocaine clorhydrate Cortocosteroid Cortocosteroid Anti-oxidant + local anaesthetic [325] n/a, not available; HMW, high molecular weight; HMWCR, high molecular weight cross-linked. [393][394][395] www.advancedsciencenews.com www.advtherap.com HA hydrogel n/a Dexamethasone Cortocosteroid [310] Adant (Suprahyal) 500-1000 Tenoxicam NSAID [311] Variofill (Adoderm, Langenfeld, Gmbh) HMWCR Diclofenac Sodium clodronate Triamcinolone acetonide Ropivacaine HCl NSAID DMOAD Cortocosteroid Anaesthetic …”

Poly(methyl vinyl ether-co-maleic acid) Hydrogels Containing Cyclodextrins and Tween 85 for Potential Application as Hydrophobic Drug Delivery Systems

“…Additionally, the formulation should be modified to allow a more sustained drug release over a prolonged time to replace the continuous administration of DX eye drops. There are other potential applications for hydrogels for localized delivery of DX, such as the treatment of osteoarthritis (54) or the prevention of restenosis using DX eluting vascular stents (55). However, the hydrogels should be modified to allow sustained release of DX for this type of application.…”

Use of Polysaccharide Hydrogels in Drug Delivery and Tissue Engineering

“…It shows chondroprotective and anti-inflammatory effects. 4 Further, hybrid HA-PEG hydrogels are composed by using transglutaminasemediated covalent linking of HA moieties with synthetic poly (ethylene glycol) (PEG) macromer. These cytocompatible gels can serve to modulate the cellular phenotype of human mammary cancer epithelial cells as well as mouse myoblasts.…”

“…cHA-Dex gel has better chondroprotective and anti-inflammatory effects in rat surgery-induced osteoarthritis than cHA alone. 4 Tissue adhesion barriers have been developed as films, membranes, knits, sprays, and hydrogels. Adhesions cause serious complications such as postoperative pain, intestinal obstruction, and infertility.…”

“…10 Similarly, fluorescently labeled injectable hyuronon hydrogels were proved non-invasive in vivo imaging of biomaterials. 4 In addition, nanocomposite hydrogels are also developed by incorporating PEGylated gold nanorods and paclitaxel-loaded chitosan micelles. 18 This combination of photothermal-chemotherapy was found effective in tumor control.…”