Dexamethasone-loaded thermo-sensitive hydrogel attenuates osteoarthritis by protecting cartilage and providing effective pain relief

Abstract

Background: We utilized the destabilization of medial meniscus (DMM)-induced mice to illustrate the osteoarthritis (OA) suppressing and pain-relieving effects of a novel prolonged-release intra-articular (IA)dexamethasone-loaded thermo-sensitive hydrogel (DLTH).Methods: The effects of temperature and pH on DLTH formation and in vitro DLTH release profile were assessed. C57BL/6J mice were randomly divided into three groups: Ctrl group Model group and DLTH group. The DLTH group received joint injections of 10 μL DLTH (1 mg/kg) into the right knee once a week from week 2 to week 11. We performed micro-computed tomography (Micro-CT) and histological analyses of safranin O-fast green, hematoxylin and eosin, and tartrate-resistant acid phosphatase in knee joints. We also carried out immunohistochemical (IHC) staining for matrix metalloproteinase-9 (MMP-9), MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs-5 in cartilage and Ki-67 in synovia. Pain behavioral testing was carried out in all mice. The serum content of prostaglandin E2 (PGE2) and real-time polymerase chain reaction (PCR) of inflammatory cytokines and pain-related factors in dorsal root ganglia (DRGs) were evaluated. Results: It took 20 minutes to form DLTH at pH 7.0 and 37 ℃. The cumulative release profiles of dexamethasone (Dex) from DLTH at 37 ℃ revealed a rapid release in the first 24 h and a sustained slow release for 7 days. In vivo study illustrated that DLTH attenuated OA bone destruction and ameliorated synovitis and progression of OA in DMM-induced mice. The chondroprotective effects of DLTH were mediated by decreased expressions of MMP-9, MMP-13, and ADAMTS-5. The results showed that IA-DLTH exerted pain-relieving effects in OA mice. Upregulation of nociceptive response time (NRT) and downregulations of serum PGE2, inflammatory factors, and pain-related mediators in DRGs of mice in the DLTH group were recorded. Conclusions: Data presented in this study elucidated that DLTH exhibited a long and lasting Dex release and it is a potential sustainable drug delivery system (DDS) to treat OA locally. IA-DLTH injection exerted chondroprotective and pain-relieving effects in DMM-induced arthritis. The involvement of MMP-9, MMP-13, ADAMTS-5, and inflammatory and pain-related factors, may account for the suppression of OA progression and pain.

Thermosensitive Hydrogels and Advances in Their Application in Disease Therapy

“…With chitosan-glycerin-borax as the carrier, Wang et al [107] used medial meniscus (DMM) instability in mice to illustrate the effect of a new intra-articular (IA)-loaded dexamethasone temperature-sensitive hydrogel (DLTH) on the inhibition and pain relief of osteoarthritis (OA). This in situ DLTH formed at 37 • C in the articular cavity.…”

Advanced injectable hydrogels for cartilage tissue engineering

“…It can reduce the loss of collagen and proteoglycan in ECM, maintain ECM synthesis, and maintain the viability of chondrocytes. In addition, it is a key reagent for inducing chondrogenesis of MSCs in vitro ( García-Fernández et al, 2020 ; Wang et al, 2021e ; García-Couce et al, 2022 ). GlcN is a naturally occurring amino monosaccharide, widely used to reduce joint pain and repair cartilage ( Suo et al, 2020 ; Zhang et al, 2021c ).…”

Knee Osteoarthritis Therapy: Recent Advances in Intra-Articular Drug Delivery Systems

“…Chondrogenic factors, 53 chondroitin sulfate nanoparticles, 54 and oligonucleotides 55 , 56 have been commonly loaded into hydrogel delivery systems for therapeutic studies. Some traditional medicines (such as celecoxib, 57 meloxicam, 58 dexamethasone, 59 and triamcinolone 60 loaded in hydrogel delivery systems not only provided improved long-term drug release, but also enhanced anti-inflammatory effect than the original formulations (See Table 2 for details).…”

“… [ 58 ] Chitosan Dexamethasone Slow release Thermal response In vivo Mice The cumulative release profiles of dexamethasone from hydrogels at 37 °C revealed a rapid release in the first 24 h and a sustained slow release for 7 days; In vivo studies showed that the drug-loaded hydrogels exerted a cartilage protective effect by reducing the expression of MMP-9, MMP-13, and ADAMTS-5, attenuated bone destruction in DMM-induced OA in mice, and improved synovitis and OA progression progress. [ 59 ] GEL-MAN Triamcinolone Slow release In vivo Mice In vitro, hydrogels can be continuously released for 24h under H 2 O 2 environment; In vivo experiments showed that the hydrogels group had a higher OARSI score, less inflammatory response, and less cartilage matrix degradation than triamcinolone acetonide alone. [ 60 ] Polyglucosamine/glucosamine carbonate ADMSCs Trestle In vivo Human Patients The initial WOMAC score of 58.6 ± 11.0 in the study group was reduced by 88% at 6 months (7.1 ± 9.2) and 95% at 24 months (2.9 ± 5.9); Separate biopsies performed at 12 months post-op in the study group also revealed type 2 collagen and hyaline-like cartilage in the regenerated tissue.…”