Biopolymeric hydrogels have been widely used as carriers of therapeutic cells and drugs for biomedical applications. However, most conventional hydrogels cannot be injected after gelation and do not support the infiltration of cells because of the static nature of their network structure. Here, we develop unique cell-infiltratable and injectable (Ci-I) gelatin hydrogels, which are physically cross-linked by weak and highly dynamic host–guest complexations and are further reinforced by limited chemical cross-linking for enhanced stability, and then demonstrate the outstanding properties of these Ci-I gelatin hydrogels. The highly dynamic network of Ci-I hydrogels allows injection of prefabricated hydrogels with encapsulated cells and drugs, thereby simplifying administration during surgery. Furthermore, the reversible nature of the weak host–guest cross-links enables infiltration and migration of external cells into Ci-I gelatin hydrogels, thereby promoting the participation of endogenous cells in the healing process. Our findings show that Ci-I hydrogels can mediate sustained delivery of small hydrophobic molecular drugs (e.g., icaritin) to boost differentiation of stem cells while avoiding the adverse effects (e.g., in treatment of bone necrosis) associated with high drug dosage. The injection of Ci-I hydrogels encapsulating mesenchymal stem cells (MSCs) and drug (icaritin) efficiently prevented the decrease in bone mineral density (BMD) and promoted in situ bone regeneration in an animal model of steroid-associated osteonecrosis (SAON) of the hip by creating the microenvironment favoring the osteogenic differentiation of MSCs, including the recruited endogenous cells. We believe that this is the first demonstration on applying injectable hydrogels as effective carriers of therapeutic cargo for treating dysfunctions in deep and enclosed anatomical sites via a minimally invasive procedure.

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Objective: To explore the effects of Mg 2þ on the expression of osteoarthritic markers in human cartilage and synovium tissue explants. To investigate the therapeutic effect of intra-articular injection of Mg 2þ in an established rat OA (Osteoarthritis) model of anterior cruciate ligament transection with partial medial meniscectomy (ACLT þ PMM). Design: Human cartilage and synovium explants were collected from total knee replacement surgeries and incubated with MgCl 2 (20 mmol/L) in vitro. A rat OA model was established by ACLT þ PMM surgery in 450e500 g male Sprague Dawley (SD) rats. To select the optimal dose, intra-articular injections of MgCl 2 (0.05, 0.5, 5 mol/L) were performed at 4 weeks after the surgery every 3 days for 2 weeks. The effect of optimized MgCl 2 was further determined by histology, immunohistochemistry, and quantitative real-time polymerase chain reaction. Results: The expressions of osteoarthritic markers in human cartilage and synovium explants were inhibited by Mg 2þ in vitro. Immunohistochemical analysis further suggested the inhibitory effects of Mg 2þ on the expression of MMP-13 and IL-6 in the human tissue explants. Cartilage degeneration and synovitis in ACLT þ PMM rats were significantly improved by intra-articular injections of Mg 2þ (0.5 mol/ L). Immunohistochemical analysis also showed the regulatory effects of Mg 2þ on osteoarthritic markers in both cartilage and synovium in rats, consistent with in vitro results. Conclusion: Intra-articular injections of Mg 2þ at 0.5 mol/L attenuate the progression of OA in the ACLT þ PMM rat model. Such effect was at least in part explained by the promotion of cartilage matrix synthesis and the suppression of synovial inflammation.

Introduction We previously demonstrated that magnesium ions (Mg 2+ ) was a novel therapeutic alternative for osteoarthritis (OA) through promoting the hypoxia inducible factor-1α (HIF-1α)-mediated cartilage matrix synthesis. However, oxidative stress can inhibit the expression of HIF-1α, amplify the inflammation that potentially impairs the therapeutic efficacy of Mg 2+ in OA. Vitamin (VC), a potent antioxidant, may enhance the efficacy of Mg 2+ in OA treatment. This study aims to investigate the efficacy of combination of Mg 2+ and VC on alleviating joint destruction and pain in OA. Material and methods Anterior cruciate ligament transection with partial medial meniscectomy induced mice OA model were randomly received intra-articular injection of either saline, MgCl 2 (0.5 mol/L), VC (3 mg/ml) or MgCl 2 (0.5 mol/L) plus VC (3 mg/ml) at week 2 post-operation, twice weekly, for 2 weeks. Joint pain and pathological changes were assessed by gait analysis, histology, western blotting and micro-CT. Results Mg 2+ and VC showed additive effects to significantly alleviate the joint destruction and pain. The efficacy of this combined therapy could sustain for 3 months after the last injection. We demonstrated that VC enhanced the promotive effect of Mg 2+ on HIF-1α expression in cartilage. Additionally, combination of Mg 2+ and VC markedly promoted the M2 polarization of macrophages in synovium. Furthermore, combination of Mg 2+ and VC inhibited osteophyte formation and expressions of pain-related neuropeptides. Conclusions Intra-articular administration of Mg 2+ and VC additively alleviates joint destruction and pain in OA. Our current formulation may be a cost-effective alternative treatment for OA.

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