Microgel Encapsulated Nanoparticles for Intra-articular Disulfiram Delivery to Treat Osteoarthritis.

Osteoarthritis (OA) affects numerous patients worldwide, and there are no approved disease-modifying drugs. Repurposing FDA-approved small molecular drugs could be a promising alternative strategy to treat OA. Disulfiram (DSF), a clinically approved drug for treatment of alcoholism, inhibits inflammasome activation and exhibits a protective role in interleukin-1ß-induced cardiac injury. However, its efficacy in treating OA remains to be explored due to its poor water solubility and stability, which limit its use in OA treatment. Here, the anti-inflammatory effect of DSF is evaluated in vitro, and a double-layer encapsulation approach is developed for intra-articular delivery of DSF for OA treatment in vivo. DSF is loaded into poly(lactic-co-glycolic acid)-based nanoparticles and encapsulated in gelatin methacrylate microgels through a microfluidic device. Results show that DSF effectively inhibits the expression of key inflammatory cytokines in OA chondrocytes, and the double-layer encapsulation approach reduces the burst release of DSF and prolongs its retention time in the in vitro study. Sustained release of DSF from microgels mitigates cartilage inflammation and subchondral bone erosion in a monoiodoacetate-induced rat OA model. This work demonstrates the potential of repurposing FDA-approved drugs for OA treatment and provides a promising platform for intra-articular delivery of small molecules for superior therapeutic effect.

Advances in 3D Bioprinting of Biomimetic and Engineered Meniscal Grafts.

The meniscus plays a crucial role in loads distribution and protection of articular cartilage. Meniscal injury can result in cartilage degeneration, loss of mechanical stability in the knee joint and ultimately lead to arthritis. Surgical interventions provide only short-term pain relief but fail to repair or regenerate the injured meniscus. Emerging tissue engineering approaches based on 3D bioprinting provide alternatives to current surgical methods for meniscus repair. In this review, the current bioprinting techniques employed in developing engineered meniscus grafts are summarized and discuss the latest strategies for mimicking the gradient structure, composition, and viscoelastic properties of native meniscus. Recent progress is highlighted in gene-activated matrices for meniscus regeneration as well. Finally, a perspective is provided on the future development of 3D bioprinting for meniscus repair, emphasizing the potential of this technology to revolutionize meniscus regeneration and improve patient outcomes.

Fenofibrate-Loaded Biodegradable Nanoparticles for the Treatment of Experimental Diabetic Retinopathy and Neovascular Age-Related Macular Degeneration.

Fenofibrate is a peroxisome proliferator-activated receptor α (PPARα) agonist and has been shown to have therapeutic effects on diabetic retinopathy (DR). However, the effects of fenofibrate through systemic administration are not as potent as desired due to inefficient drug delivery to the retina. The present study aimed to explore the sustained therapeutic effects of fenofibrate-loaded biodegradable nanoparticles (NP) on both DR and neovascular age-related macular degeneration (AMD). Fenofibrate was successfully encapsulated into poly(lactic- co-glycolic acid) (PLGA) NP (Feno-NP), and Feno-NP were optimized by varying polymer composition to achieve high drug loading and prolonged drug release. The Feno-NP made of PLGA 34 kDa demonstrated a drug content of 6% w/w and a sustained drug release up to 60 days in vitro. Feno-NP (PLGA 34 kDa) was selected for following in vivo studies, and one single intravitreal (IVT) injection of Feno-NP into rat eyes with a 30G fine needle maintained sustained fenofibric acid drug level in the eye for more than 60 days. The efficacy of Feno-NP in DR and neovascular AMD was investigated using streptozotocin (STZ)-induced diabetic rats, laser-induced choroidal neovascularization (CNV) rats, and very low-density lipoprotein receptor knockout ( Vldlr -/-) mice. Therapeutic effects of Feno-NP were evaluated by measuring electroretinogram (ERG), retinal vascular leakage, leukostasis, CNV size, and retinal levels of vascular endothelial growth factor (VEGF) and intracellular adhesion molecule-1 (ICAM-1). In diabetic rats, Feno-NP ameliorated retinal dysfunctions, reduced retinal vascular leakage, inhibited retinal leukostasis, and downregulated the overexpression of VEGF and ICAM-1 at 8 weeks after one IVT injection. In addition, Feno-NP reduced retinal vascular leakage and CNV formation in both CNV rats and Vldlr -/- mice. Moreover, no toxicity of Feno-NP or Blank-NP to retinal structure and function was detected. Feno-NP exhibited good physiochemical characteristics and controlled drug release profile, conferring prolonged beneficial effects on DR and neovascular AMD.

Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy.

Purpose: Clinical studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate has therapeutic effects on diabetic retinopathy (DR). The purpose of this study was to identify a novel PPARα agonist and to evaluate its beneficial effects on DR. Methods: The transcriptional activity of PPARα was measured by a luciferase-based promoter assay. TUNEL was used to evaluate apoptosis in retinal precursor cells (R28). Diabetes was induced in rats by injection of streptozotocin. Retinal inflammation was examined using leukostasis assay, and retinal vascular leakage was measured using permeability assay. Retinal function was measured using electroretinogram (ERG) recording, and retinal apoptosis was quantified using the cell death ELISA. The anti-angiogenic effect was evaluated in the oxygen-induced retinopathy (OIR) model. Results: A compound, 7-chloro-8-methyl-2-phenylquinoline-4-carboxylic acid (Y-0452), with a chemical structure distinct from existing PPARα agonists, activated PPARα transcriptional activity and upregulated PPARα expression. Y-0452 significantly inhibited human retinal capillary endothelial cell migration and tube formation. The compound also protected R28 cells against apoptosis and inhibited NF-κB signaling in R28 cells exposed to palmitate. In diabetic rats, Y-0452 ameliorated leukostasis and vascular leakage in the retina. In addition, Y-0452 preserved the retinal function and reduced retinal cell death in diabetic rats. Y-0452 also alleviated retinal neovascularization in the OIR model. Conclusions: Y-0452 is a novel PPARα agonist and has therapeutic potential for DR.

Effects of avastin on expression of AQP4 in Müller cells under hypoxia.

The aim of this study was to investigate the effects of Avastin on aquaporin4 (AQP4) expression in human retinal Müller cells in vitro under hypoxia, so as to explore the mechanism of Avastin treating retinal edema. The human Müller cells were cultured using the enzymatic digestion method. Müller cells were identified under the transmission electron microscopy and by using immunofluorescence staining. By using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), the expression of AQP4 mRNA and VEGF mRNA in Müller cells cultured with 500 µmol/L CoCl(2) for 0, 3, 6, 12 and 24 h, and with 0, 100, 300, 500 and 700 µmol/L CoCl(2) for 24 h was detected. The expression of AQP4 mRNA in Müller cells cultured with 50 ng/mL exogenous vascular endothelial growth factor (VEGF) for 0, 0.5, 1, 2 and 4 h, and with 0, 25, 50 and 75 ng/mL VEGF for 24 h was detected. Amplified cDNA products of AQP4 mRNA in Müller cells cultured with 500 µmol/L CoCl(2) and 200 µg/mL Avastin for 24 h were detected. The results showed that more than 95% cells displayed positive immunofluorescence reaction. Characteristic 8-10 nm intracellular filaments could be seen in the cytoplasm under the transmission electron microscopy. In the CoCl(2) experimental groups, the expression of AQP4 mRNA and VEGF mRNA in Müller cells was increased as compared with the control group. Alteration of AQP4 mRNA and VEGF mRNA levels showed a significantly positive correlation (r (2)=0.822, P<0.05). The expression of AQP4 mRNA in Müller cells was increased by VEGF. The expression of AQP4 mRNA was significantly decreased by Avastin as compared with the control group. It is suggested that Avastin can decrease the expression of AQP4 mRNA in human Müller cells under chemical hypoxic conditions partially via VEGF path, which may be one of the mechanisms of Avastin treating retinal edema.