Environmental toxicants such as toxic metals can alter epigenetic regulatory features such as DNA methylation, histone modification, and non-coding RNA expression. Heavy metals influence gene expression by epigenetic mechanisms and by directly binding to various metal response elements in the target gene promoters. Given the role of epigenetic alterations in regulating genes, there is potential for the integration of toxic metal-induced epigenetic alterations as informative factors in the risk assessment process. Here, we focus on recent advances in understanding epigenetic changes, gene expression, and biological effects induced by toxic metals.

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For hydrogel injection applications, it is important to improve the strength and biostability of the hydrogel as well as its injectability to pass easily through the needle. Making gel microspheres is one approach to achieve these improvements. Granulization of a bulk hydrogel is a common procedure used to form microsized particles; however, the nonuniform size and shape cause an uneven force during injection, damaging the surrounding tissue and causing pain to the patients. In this study, injectable hyaluronic acid (HA)-based hybrid hydrogel microspheres were fabricated using a water-in-oil emulsion process. The injectability was significantly enhanced because of the relatively uniform size and spherical shape of the hydrogel formulates. In addition, the biostability and mechanical strength were also increased owing to the increased cross-linking density compared with that of conventionally fabricated gel microparticles. This tendency was further improved after in situ calcium phosphate precipitation. Our findings demonstrate the great potential of HA-based hydrogel microspheres for various clinical demands requiring injectable biomaterials.

In this study, we report the development of a hyaluronic acid (HA)-based composite hydrogel containing calcium fluoride (CaF2) with good biocompatibility and antibacterial properties for multifunctional wound dressing applications. CaF2 was newly selected for incorporation within HA because it can release both Ca2+ and F– ions, which are well-known ions for affecting cell proliferation and inhibiting bacterial growth, respectively. In particular, an in situ precipitation process enables easy control over the released amount of F– ions by simply adjusting the precursor solutions (calcium chloride (CaCl2) and ammonium fluoride (NH4F)) used for the CaF2 precipitation. CaF2 particles were uniformly embedded within a HA-based pure hydrogel using an in situ precipitation process. Through variation of the CaCl2 and NH4F concentrations used in the precipitation as well as the precipitation time, composite hydrogels with different ion-release profiles were obtained. By controlling the precipitation time, especially for 10 min and after 30 min, large differences in the ion-release profiles as a function of CaF2 concentration were observed. A shorter precipitation time resulted in faster release of fluoride, whereas for the 30 min and 1 h samples, sustained ion release was achieved. Colony tests and live/dead assays using Escherichia coli and Staphylococcus aureus revealed a lower density of bacteria on the CaF2 composite hydrogels than on the pure hydrogel for both strains. In addition, improved cellular responses such as cell attachment and proliferation were also observed for the CaF2 composite hydrogels compared to those for the pure hydrogel. Furthermore, the composite hydrogels exhibited excellent wound healing efficiency, as evidenced by an in vitro cell migration assay. Finally, monitoring of the wound closure changes using a full-thickness wound in a rat model revealed the accelerated wound healing capability of the CaF2 composite hydrogels compared with that of the pure hydrogel. Based on our findings, these CaF2 composite hydrogels show great potential for application as advanced hydrogel wound dressings with antibacterial properties and accelerated wound-healing capabilities.

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