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Abstract
To provide a vehicle for sustained release of cartilage-protective agent for the potential application of osteoarthritis (OA) treatment, we developed a kartogenin (KGN)-incorporated thermogel for intra-articular injection. We fabricated a poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA–PEG–PLGA) thermogel as a KGN carrier for IA injection. OA chondrocytes were cultured in thermogel with or with no KGN to investigate the effect of KGN thermogel on cartilage matrix. The in vivo effect of KGN thermogel on OA was examined in a rabbit OA model. The KGN thermogel showed a sustained in vitro release of KGN for 3 weeks. OA chondrocytes proliferated well both in thermogel and KGN thermogel. In addition, OA chondrocytes produced higher amount of [type 2 collagen (COL-2) and glycosaminoglycan (GAG)], as well as lower level of matrix metalloproteinase 13 (MMP-13) in KGN thermogel that those in thermogel with no addition of KGN. The gene analysis supported that KGN thermogel enhanced expression of hyaline-cartilage specific genes Col 2 and AGC, and inhibited the expression of MMP-13. Compared with intra-articular injection of saline or thermogel containing no KGN, KGN thermogel can enhance cartilage regeneration and inhibit joint inflammation of arthritic knees in a rabbit ACLT-induced OA model at 3 weeks after the injection. Therefore, the KGN-incorporated PLGA–PEG–PLGA thermogel may provide a novel treatment modality for OA treatment with IA injection.
Highlights
Osteoarthritis (OA) is a common degenerative joint pathology affecting 151 million people worldwide
After culture in growth medium for 72 h, CCK assay showed that OA chondrocytes proliferated in both PLGA-PEGPLGA thermogel and KGN thermogel showed an increased proliferation during 7 days of in vitro culture (Figure 2A)
The number of OA chondrocytes in thermogel and KGN thermogel on Day 7 did not differ significantly, compared to that on Day 1 (p > 0.05)
Summary
Osteoarthritis (OA) is a common degenerative joint pathology affecting 151 million people worldwide. Direct intra-articular injections of drugs are commonly used to improve the joint bioavailability while minimizing systemic complications. Kartogenin (KGN), has been reported to promote collagen synthesis (Johnson, 2012). Intra-articular injection of KGN has been reported to enhance cartilage regeneration (Kang et al, 2014; Mohan et al, 2016; Fan et al, 2018). KGN cannot provide long-term therapeutic effects due to fast clearance and short retention of KGN in joints, posing a disadvantage in its clinical application. In order to improve residence time of treatment agents in joints, researchers have employed hydrogels for drug delivery and drug control release (Seliktar, 2012)
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