Integrating high-throughput phenotypic profiling and transcriptomic analyses to predict the hepatosteatosis effects induced by per- and polyfluoroalkyl substances.

Per- and polyfluoroalkyl substances (PFAS) is a large compound class (n > 12,000) that is extensively present in food, drinking water, and aquatic environments. Reduced serum triglycerides and hepatosteatosis appear to be the common phenotypes for different PFAS chemicals. However, the hepatosteatosis potential of most PFAS chemicals remains largely unknown. This study aims to investigate PFAS-induced hepatosteatosis using in vitro high-throughput phenotype profiling (HTPP) and high-throughput transcriptomic (HTTr) data. We quantified the in vitro hepatosteatosis effects and mitochondrial damage using high-content imaging, curated the transcriptomic data from the Gene Expression Omnibus (GEO) database, and then calculated the point of departure (POD) values for HTPP phenotypes or HTTr transcripts, using the Bayesian benchmark dose modeling approach. Our results indicated that PFAS compounds with fully saturated C-F bonds, sulfur- and nitrogen-containing functional groups, and a fluorinated carbon chain length greater than 8 have the potential to produce biological effects consistent with hepatosteatosis. PFAS primarily induced hepatosteatosis via disturbance in lipid transport and storage. The potency rankings of PFAS compounds are highly concordant among in vitro HTPP, HTTr, and in vivo hepatosteatosis phenotypes (ρ = 0.60-0.73). In conclusion, integrating the information from in vitro HTPP and HTTr analyses can accurately project in vivo hepatosteatosis effects induced by PFAS compounds.

Engineering pH-sensitive erodible chitosan hydrogel composite containing bacteriophage: An interplay between hydrogel and bacteriophage against Staphylococcus aureus.

Encapsulation of phages represents a key approach for improving phage stability and controlling phage delivery dosage. The hydrogel made from positively charged quaternized chitosan (QCS) and multivalent crosslinker, aldehyde-modified poly(xylitol sebacate)-co-poly(ethylene glycol) (APP) was introduced for the first time for drug (phage 44AHJD) delivery. The freeze-thawing (FT) treatment enhanced the porous structure and the stress resistance of native hydrogel with increased compression stress (stiffness) from 10 to 20 kPa. The stiffness of the phage-loaded hydrogel (FTP) was suitable for the proper release of phage particles and polymer chains, both working synergistically against bacterial growth. The FTP followed the Korsmeyer-Peppas model's anomalous diffusion of phage particles at different temperatures (30-45 °C) and pH (6.6-8.5) conditions. FTP was sensitive to pH, which released more phage particles at pH-neutral conditions, while the release under acidic and alkaline conditions was more based on gel degradation. The high biocompatibility of FTP hydrogel at its working concentration of 30 mg mL-1 was demonstrated through a hemolysis ratio of <2 %. Sixty percent of the total encapsulated phages and 6 mg mL-1 of hydrogel debris were released after 10 h of hydrogel submerge treatment, which can fight the growing bacteria and the emergence of phage-resistant bacteria.

Fabrication of versatile poly(xylitol sebacate)-co-poly(ethylene glycol) hydrogels through multifunctional crosslinkers and dynamic bonds for wound healing.

Poly(polyol sebacate) (PPS) polymer family has been recognized as promising biomaterials for biomedical applications with their characteristics of easy production, elasticity, biodegradation, and cytocompatibility. Poly(xylitol sebacate)-co-poly(ethylene glycol) (PXS-co-PEG) has been developed to fabricate PPS-based hydrogels; however, current PXS-co-PEG hydrogels presented limited properties and functions due to the limitations of the crosslinkers and crosslinking chemistry used in the hydrogel formation. Here, we fabricate a new type of PXS-co-PEG hydrogels through the use of multifunctional crosslinkers as well as dynamic bonds. In our design, polyethyleneimine-polydopamine (PEI-PDA) macromers are utilized to crosslink aldehyde-functionalized PXS-co-PEG (APP) through imine bonds and hydrogen bonds. PEI-PDA/APP hydrogels present multiple functional properties (e.g., fluorescent, elastomeric, biodegradable, self-healing, bioadhesive, antioxidant, and antibacterial behaviors). These properties of PEI-PDA/APP hydrogels can be fine-tuned by changing the PDA grafting degrees in the PEI-PDA crosslinkers. Most importantly, PEI-PDA/APP hydrogels are considered promising wound dressings to promote tissue remodeling and prevent bacterial infection in vivo. Taken together, PEI-PDA/APP hydrogels have been demonstrated as versatile biomaterials to provide multiple tailorable properties and desirable functions to expand the utility of PPS-based hydrogels for advanced biomedical applications. STATEMENT OF SIGNIFICANCE: Various strategies have been developed to fabricate poly(polyol sebacate) (PPS)-based hydrogels. However, current PPS-based hydrogels present limited properties and functions due to the limitations of the crosslinkers and crosslinking chemistry used in the hydrogel formation. This work describes that co-engineering crosslinkers and interfacial crosslinking is a promising approach to synthesizing a new type of poly(xylitol sebacate)-co-poly(ethylene glycol) (PXS-co-PEG) hydrogels as multifunctional hydrogels to expand the utility of PPS-based hydrogels for advanced biomedical applications. The fabricated hydrogels present multiple functional properties (e.g., fluorescent, biodegradable, elastomeric, self-healing, bioadhesive, antioxidative, and antibacterial), and these properties can be fine-tuned by the defined crosslinkers. The fabricated hydrogels are also used as promising wound dressing biomaterials to exhibit promoted tissue remodeling and prevent bacterial infection in vivo.

Ultrasonic interfacial crosslinking of TiO2-based nanocomposite hydrogels through thiol-norbornene reactions for sonodynamic antibacterial treatment.

Nanocomposite (NC) hydrogels used for sonodynamic therapy (SDT) face challenges such as lacking interfacial interactions between the polymers and nanomaterials as well as presenting uneven dispersion of nanomaterials in the hydrogel network, reducing their mechanical properties and treatment efficiency. Here, we demonstrate a promising approach of co-engineering nanomaterials and interfacial crosslinking to expand the materials construction and biomedical applications of NC hydrogels in SDT. In this work, mesoporous silica-coated titanium dioxide nanoparticles with thiolated surface functionalization (TiO2@MS-SH) are utilized as crosslinkers to react with norbornene-functionalized dextran (Nor-Dex) through ultrasound-triggered thiol-norbornene reactions, forming TiO2@MS-SH/Nor-Dex NC hydrogels. The TiO2@MS-SH nanoparticles act not only as multivalent crosslinkers to improve the mechanical properties of hydrogels under ultrasound irradiation but also as reactive oxygen species (ROS) generators to allow the use of TiO2@MS-SH/Nor-Dex NC hydrogels in SDT applications. Particularly, the TiO2@MS-SH/Nor-Dex NC hydrogels present tailorable microstructures, properties, and sonodynamic killing of bacteria through the modulation of the ultrasound frequency. Taken together, a versatile TiO2-based NC hydrogel platform prepared under ultrasonic interfacial crosslinking reactions is developed for advancing the applications in SDT.