The aim of this study was to investigate the effects of subconjunctivally administered mesenchymal stem cells (MSCs) on corneal wound healing in the acute stage of an alkali burn. A corneal alkali burn model was generated by placing a piece of 3-mm diameter filter paper soaked in NaOH on the right eye of 48 Sprague-Dawley female rats. 24 rats were administered a subconjunctival injection of a suspension of 2×106 MSCs in 0.1 ml phosphate-buffered saline (PBS) on day 0 and day 3 after the corneal alkali burn. The other 24 rats were administered a subconjunctival injection of an equal amount of PBS as a control. Deficiencies of the corneal epithelium and the area of corneal neovascularization (CNV) were evaluated on days 3 and 7 after the corneal alkali burn. Infiltrated CD68+ cells were detected by immunofluorescence staining. The mRNA expression levels of macrophage inflammatory protein-1 alpha (MIP-1α), tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) were analyzed using real-time polymerase chain reaction (real-time PCR). In addition, VEGF protein levels were analyzed using an enzyme-linked immunosorbent assay (ELISA). MSCs significantly enhanced the recovery of the corneal epithelium and decreased the CNV area compared with the control group. On day 7, the quantity of infiltrated CD68+ cells was significantly lower in the MSC group and the mRNA levels of MIP-1α, TNF-α, and VEGF and the protein levels of VEGF were also down-regulated. However, the expression of MCP-1 was not different between the two groups. Our results suggest that subconjunctival injection of MSCs significantly accelerates corneal wound healing, attenuates inflammation and reduces CNV in alkaline-burned corneas; these effects were found to be related to a reduction of infiltrated CD68+ cells and the down-regulation of MIP-1α, TNF-α and VEGF.

Rheumatoid arthritis (RA) is a systemic inflammatory disorder which can cause bone and cartilage damage leading to disability, yet the treatment remains unsatisfactory nowadays. Celastrol (Cel) has shown antirheumatic activity against RA. However, the frequent parenteral delivery and poor water solubility of Cel restrict its further therapeutic applications. Here, aiming at effectively overcoming the poor water solubility and short half-life of Cel to boost its beneficial effects for treating RA, we developed a polymeric micelle for Cel delivery based on a reactive oxygen species (ROS) sensitive polymer. Our results demonstrated that Cel may inhibit the repolarization of macrophages toward the proinflammatory M1 pheno-type via regulating the NF-κB and Notch1 pathways, which resulted in significantly decreased secretion of multiple pro-inflammatory cytokines to suppress the RA progression. Consequently, the Cel-loaded micelle effectively alleviated the major RA-associated symptoms including articular scores, ankle thickness, synovial inflammation, bone erosion, and cartilage degradation.

Effective osteogenesis remains a challenge in the treatment of bone defects. The emergence of artificial bone scaffolds provides an attractive solution. In this work, a new biomineralization strategy is proposed to facilitate osteogenesis through sustaining supply of nutrients including phosphorus (P), calcium (Ca), and silicon (Si). We developed black phosphorus (BP)-based, three-dimensional nanocomposite fibrous scaffolds via microfluidic technology to provide a wealth of essential ions for bone defect treatment. The fibrous scaffolds were fabricated from 3D poly ( l -lactic acid) (PLLA) nanofibers (3D NFs), BP nanosheets, and hydroxyapatite (HA)-porous SiO 2 nanoparticles. The 3D BP@HA NFs possess three advantages: i) stably connected pores allow the easy entrance of bone marrow-derived mesenchymal stem cells (BMSCs) into the interior of the 3D fibrous scaffolds for bone repair and osteogenesis; ii) plentiful nutrients in the NFs strongly improve osteogenic differentiation in the bone repair area; iii) the photothermal effect of fibrous scaffolds promotes the release of elements necessary for bone formation, thus achieving accelerated osteogenesis. Both in vitro and in vivo results demonstrated that the 3D BP@HA NFs, with the assistance of NIR laser, exhibited good performance in promoting bone regeneration. Furthermore, microfluidic technology makes it possible to obtain high-quality 3D BP@HA NFs with low costs, rapid processing, high throughput and mass production, greatly improving the prospects for clinical application. This is also the first BP-based bone scaffold platform that can self-supply Ca 2+ , which may be the blessedness for older patients with bone defects or patients with damaged bones as a result of calcium loss.

Purpose The cornea is a main barrier to drug penetration after topical application. The aim of this study was to evaluate the abilities of micelles generated from a positively charged triblock copolymer to penetrate the cornea after topical application. Methods The triblock copolymer poly(ethylene glycol)-poly(ε-caprolactone)- g -polyethyleneimine was synthesized, and the physicochemical properties of the self-assembled polymeric micelles were investigated, including hydrodynamic size, zeta potential, morphology, drug-loading content, drug-loading efficiency, and in vitro drug release. Using fluorescein diacetate as a model drug, the penetration capabilities of the polymeric micelles were monitored in vivo using a two-photon scanning fluorescence microscopy on murine corneas after topical application. Results The polymer was successfully synthesized and confirmed using nuclear magnetic resonance and Fourier transform infrared. The polymeric micelles had an average particle size of 28 nm, a zeta potential of approximately +12 mV, and a spherical morphology. The drug-loading efficiency and drug-loading content were 75.37% and 3.47%, respectively, which indicates that the polymeric micelles possess a high drug-loading capacity. The polymeric micelles also exhibited controlled-release behavior in vitro. Compared to the control, the positively charged polymeric micelles significantly penetrated through the cornea. Conclusion Positively charged micelles generated from a triblock copolymer are a promising vehicle for the topical delivery of hydrophobic agents in ocular applications.

Fungal keratitis (FK) remains a severe eye disease, and effective therapies are limited by drug shortages and critical ocular barriers. Despite the high antifungal potency and broad spectrum of econazole, its strong irritant and insolubility in water hinder its ocular application. We designed and fabricated a new drug delivery system based on a polymeric vector for the ocular antifungal application of econazole. This novel system integrates the advantages of its constituent units and exhibits superior comprehensive performance. Using the new system, drug content was significantly increased more than 600 folds. The results of in vivo and in vitro experiments demonstrated that the econazole-loaded formulation exhibited significantly enhanced corneal penetration after a single topical ocular administration, excellent antifungal activity, and good tolerance in rabbits. Drug concentrations and ocular relative bioavailability in the cornea were 59- and 29-time greater than those in the control group, respectively. Following the topical administration of one eye drop (50 μL of 0.3% w/v econazole) in fungus-infected rabbits, a high concentration of antimycotic drugs in the cornea and aqueous humor was sustained and effective for 4 h. The mechanism of corneal penetration was also explored using dual fluorescent labeling. This novel drug delivery system is a promising therapeutic approach for oculomycosis and could serve as a candidate strategy for use with various hydrophobic drugs to overcome barriers in the treatment of many other ocular diseases.

Two-dimensional (2D) nanomaterials have raised significant interest in not only energy and environmental fields but also biomedical areas. Among these materials, one type that has many interesting properties and possesses numerous exciting applications is graphene oxide (GO)-based 2D materials. However, their poor stability in aqueous solutions and weak bioactivities limit their use in biomedical applications, especially antimicrobial fields. In this study, GO was functionalized with hydrophilic polymers and used as a vector for silver nanoparticles (Ag NPs) and sulfadiazine (SD). The stability of the material in aqueous solutions was greatly improved. The antibacterial activity of the novel hybrid antibacterial system (HAS) was enhanced by over 3 times compared to that of the system lacking SD. The antibacterial performance of the HAS was due to the triple synergy: bacterial capping, puncture, and inhibition. This study provides new insights into the design and fabrication of surface-modified GO and carbon materials and their 2D hybrid multifunctional materials for advanced applications including biomedical and especially antibacterial applications, broadening the design and application scope of carbon and 2D materials.

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Biomimetic scaffolds with transparent, biocompatible, and in situ-forming properties are highly desirable for corneal tissue engineering, which can deeply fill corneal stromal defects with irregular shapes and support tissue regeneration. We here engineer a novel class of corneal scaffolds from oligoethylene glycol (OEG)-based dendronized chitosans (DCs), whose aqueous solutions show intriguing sol–gel transitions triggered by physiological temperature, resulting in highly transparent hydrogels. Gelling points of these hydrogels can be easily tuned, and furthermore, their mechanical strengths can be significantly enhanced when injected into PBS at 37 °C instead of pure water. In vitro tests indicate that these DC hydrogels exhibit excellent biocompatibility and can promote proliferation and migration of keratocyte. When applied in the rabbit eyes with corneal stromal defects, in situ formed DC hydrogels play a positive effect for new tissue regeneration. Overall, this thermo-gelling DCs possess appealing features as corneal tissue substitutes with their excellent biocompatibility and unprecedented thermoresponsiveness.