Gelatin hydrogels with eicosapentaenoic acid can prevent osteoarthritis progression in vivo in a mouse model

Abstract

Eicosapentanoic acid (EPA) is an antioxidant and omega‐3 polyunsaturated fatty acid that reduces inflammatory cytokine production. Gelatin hydrogel can be used as a carrier of a physiologically active substance that release it gradually for an average of ~3 weeks. Therefore, this study aimed to clarify the effect of EPA‐incorporating gelatin hydrogels on osteoarthritis (OA) progression in vivo. Ten‐week‐old male C57BL/6J mice were randomly divided into six groups (n = 6): Sham, destabilization of the medial meniscus (DMM), Corn: DMM + 2 µL corn oil, EPA injection alone (EPA‐I): DMM + 2 µL corn oil + 125 μg/μL EPA, Gel: DMM + gelatin hydrogels, and EPA‐G: DMM + 125 μg/μL EPA‐incorporating gelatin hydrogels. The mice were euthanized at 8 weeks after DMM or Sham surgery, and subjected to histological evaluation. Matrix‐metalloproteinases‐3 (MMP‐3), MMP‐13, interleukin‐1β (IL‐1β), p‐IKK α/β, CD86, and CD163 protein expression in the synovial cartilage was detected by immunohistochemical staining. F4/80 expression was also assessed using the F4/80 score of macrophage. Histological score was significantly lower in EPA‐G than in EPA‐I. MMP‐3‐, MMP‐13‐, IL‐1β‐, and p‐IKK α/β‐positive cell ratio was significantly lower in EPA‐G than in EPA‐I. However, CD86‐ and CD163‐positive cell ratio was not significantly different between EPA‐I and EPA‐G. The average‐sum F4/80 score of macrophage in EPA‐G was significantly lower than that in EPA‐I. EPA‐incorporating gelatin hydrogels were shown to prevent OA progression in vivo more effectively than EPA injection alone. Our results suggested that intra‐articular administration of controlled‐release EPA can be a new therapeutic approach for treating OA.

Susceptibility of cyclin-dependent kinase inhibitor 1-deficient mice to rheumatoid arthritis arising from interleukin-1β-induced inflammation

“…First, the cultured RA synoviocytes were treated with or without 10-ng/ml recombinant human IL-1β (R&D Systems, Minneapolis, Minnesota, USA) for 5, 10, 15, 30, 60 min, and 24 h; stimulation time for IL-1β was determined as previously reported 41 . The synoviocytes were washed with Tris-buffered saline with Tween-20 (TBST) and lysed in a buffer containing 25-mM Tris, 1% Nonidet P-40, 150 mM NaCl, 1.5 mM ethylene glycol tetraacetic acid, and a protease/phosphatase inhibitor mix (Roche Diagnostics, Basel, Switzerland).…”

Drug Delivery Systems for the Treatment of Knee Osteoarthritis: A Systematic Review of In Vivo Studies

“…Summarizing the in vivo effects of hydrogels, two studies reported a more favorable histological structure [64,71], and five studies showed an improvement in the OARSI score compared to control [61,62,[68][69][70]. Concerning the level of inflammatory mediators, six studies [61][62][63]66,70,71] observed a decrease in IL-1β, IL-6, IL-17, TNF-α, ADAMTS-5, and MMP3 expression levels. The abovementioned results were observed in an average follow up time of 8.4 weeks (range 2-24 weeks).…”

“…Indeed, PLA is prepared starting from L-lactide monomers that are subject to ringopening polymerization to form L-lactic acid oligomers (LAo). This polymer is then mixed with a gelatin solution and is ready to be loaded with drugs, as described by three studies [61][62][63]. Instead, one study employed a HA-based gel [64] and another one a combination of HA and dextran [65].…”

Hydrogels for Treatment of Different Degrees of Osteoarthritis

“…This mixed hydrogel has the properties of lubricity, slow degradation, and continuous drug release and has a therapeutic effect on OA. Tsubosaka et al (2020) reported that the EPA-containing gelatin hydrogels could reduce the level of intra-articular inflammation more effectively than a single injection of eicosapentaenoic acid (EPA) in an OA mouse model, established by the surgery of destabilization of the medial meniscus (DMM). This indicates that the intra-articular injection of EPA with the hydrogel as a carrier may be a novel treatment for osteoarthritis.…”